Phase I study of phosphonacetyl-l-aspartate, 5-fluorouracil,and leucovorin in patients with advanced cancer

Low-dose phosphonacetyl-l-aspartate (PALA) may potentiate both 5-fluorouracil (5-FU) incorporation into RNA and thymidylate synthase inhibition by 5-fluorodeoxyuridylate (5-FdUMP). The gastrointestinal toxicity of 5-FU is not increased by PALA administration. Exogenous leucovorin, on the other hand, which enhances thymidylate synthase inhibition, appears to increase the clinical toxicity of 5-FU in a dose-dependent manner. As a result, the clinical use of high-dose leucovorin requires a marked dose reduction of 5-FU. Extracellular leucovorin levels of 1 M suffice to maximize the enhancement of thymidylate synthase inhibition in several models. We conducted a trial to add leucovorin to the PALA/5-FU regimen. We chose a leucovorin dose that was predicted to yield end-infusion total reduced folate concentrations of 1 M. The major endpoint was to determine the maximum tolerated dose of 5-FU in this combination. The regimen consisted of 250 mg/m² PALA given on day 1 and, 24 h later, escalating 5-FU doses ranging from 1,850 to 2,600 mg/m² admixed with 50 mg/m² leucovorin and given by 24-h infusion. Courses were repeated weekly. A total of 24 patients with a median performance status of 1 were entered at three dose levels. Diarrhea was dose-limiting; 6/13 patients had grade II or worse diarrhea at 2,600 mg/m². Dose modification resulted in a mean dose intensity of 2,300 mg/m² at both the 2,600- and 2,300-mg/m² dose levels. The 2,300-mg/m² dose is suitable for phase II testing of this regimen. Three patients (two with breast cancer and 1 with sarcoma) had a partial remission. We measured steady-state concentrations (C_ss) of 5-FU in 23 patients. The mean C_ss increased with dose from 0.738 to 1.03 g/ml. Total body clearance did not vary with dose in this range. Patients with grade II or worse diarrhea had a higher mean C_ss (1.10±0.19) than those with grade O or I toxicity (0.835±0.25,P<0.02). Total bioactive folates (bound and free) were measured using a biological assay. Pretreatment values ranged from 2 to 52 nM and were not predictive of toxicity. End-infusion (23-h) values were somewhat lower than predicted and ranged from 400 to 950 nM. The risk of diarrhea was positively correlated with end-infusion total folate values. In a logistic regression analysis, total folate values obtained at 23 h were a more powerful predictor of diarrhea than were 5-FU C_ss values. These results confirm the contribution of leucovorin to the toxicity of the 5-FU/leucovorin combination and suggest that interpatient differences in folate pharmacology may contribute to the therapeutic index of the 5-FU/leucovorin combination.Supported in part by NCI CA06927, NCI CA38053, and an appropriation from the Commonwealth of Pennsylvania     

A phase I, dose-finding study of irinotecan (CPT-11) short i.v. infusion combined with fixed dose of 5-fluorouracil (5-FU) protracted i.v. infusion in adult patients with advanced solid tumours

Purpose Irinotecan (CPT-11) and 5-fluorouracil (5-FU) are effective cytotoxic agents in the treatment of solid tumours. Continuous i.v. infusion (CI) of 5-FU is significantly more active and better tolerated than bolus i.v. 5-FU. This phase I pharmacokinetic and clinical study evaluated escalating CPT-11 doses administered every 3 weeks combined with a fixed dose of 5-FU CI over 14 days to find the maximum tolerated dose (MTD) of this combined chemotherapy.Patients and methods Patients with solid tumours showing failure with previous standard treatment or for whom no established curative therapy existed received CPT-11 i.v. over 90 min (six dose levels were evaluated: 150, 175, 200, 250, 300 and 350 mg/m²) plus a fixed dose of 5-FU CI 250 mg/m² per day over 14 days. If the MTD was not reached at CPT-11 level 6, then 5-FU was increased to 300 mg/m². In step 2, 5-FU was administered as a true protracted infusion at the recommended dose found during step 1. In step 3, the recommended dose of CPT-11 was divided and administered in a weekly schedule for 4 weeks combined with a fixed dose of 5-FU CI 250 mg/m², and then followed by 2–5 weeks rest.Results Neutropenia and diarrhoea were the main toxicities, leading to early termination of infusion in three of six patients in level 7. Therefore, CPT-11 350 mg/m² + 5-FU 250 mg/m² CI over 14 days was identified as the recommended dose. In step 2, CPT-11 dose had to be reduced to 300 mg/m² due to toxicity. The weekly schedule of CPT-11 75 mg/m² + 5-FU 250 mg/m² CI was feasible with only one patient experiencing severe diarrhoea. No interactions were found in the kinetics parameters of CPT-11 or 5-FU for the different dose levels studied.Conclusion CPT-11 300 mg/m² + 5-FU 250 mg/m² protracted infusion is the recommended dose for phase II trials, neutropenia and diarrhoea being the dose-limiting toxicities.     

5-fluorouracil,leucovorin, hydroxyurea,and escalating doses of continuous-infusion cisplatin with concomitant radiotherapy: a clinical and pharmacologic study

Summary Cisplatin (CDDP), 5-fluorouracil (5-FU), and hydroxyurea (HU) have individually demonstrated activity against several solid tumors, act synergistically with each other in vitro, and may act as radiation sensitizers. Therefore, we designed a phase I study to determine the maximally tolerated dose of cisplatin as given in addition to our previously described combination of 5-FU, HU, and concomitant radiotherapy (XRT). Patients exhibiting advanced solid tumors requiring palliative XRT were eligible. The regimen consisted of 1 g HU given p.o.b.i.d. on days 1–5,600 mg/m² 5-FU given i.v. daily by continuous infusion (c.i.) on days 1–5, escalating doses of cisplatin starting at 10 mg/m² daily given by c.i. on days 1–5, and involved-field XRT carried out on days 1–5. The cycle was repeated every 14 days until the target XRT dose had been reached. In all, 19 patients were entered at the first dose level, and cumulative grade 3–4 myelosuppression was seen in 16 subjects. As no dose escalation was feasible, the chemotherapy was subsequently altered by using the above regimen for cycles 1, 3, 5, and 7 and substituting the less myelosuppressive regimen of 1 g HU given p.o.b.i.d. on days 1–5, 400 mg/m² 5-FU given i.v. daily by c.i., and 100 mg leucovorin given p.o. 4 h on days 1–5 for cycles 2, 4, and 6. On this alternating program, 28 patients were treated with escalating doses of CDDP. The dose-limiting toxicity was again myelosuppression, which was prohibitive at a CDDP dose of 20 mg/m² daily. In the final phase of the protocol, 30 subjects were treated with the above alternating-cycle regimen at a CDDP dose of 20 mg/m² daily and a decreased HU dose of 500 mg p.o.b.i.d. in an attempt to circumvent the myelosuppression associated with this dose of CDDP. Although severe acute toxicity (cycles 1 and 2) was observed less frequently, cumulative toxicity (all cycles) remained pronounced. The other major toxicity encountered was mucositis, which was particularly pronounced in patients receiving radiation to the head and neck and following leucovorin-containing cycles. Plasma concentrations of free platinum did not correlate with the CDDP dose, possibly due to the narrow range of doses given. Pharmacodynamic modeling demonstrated that the CDDP dose and the HU dose were associated with leukopenia. Antitumor activity was demonstrated in a number of solid tumors, particularly non-small-cell lung cancer and head and neck cancer. Due to the high incidence of severe cumulative toxicity, we recommend further use of this regimen only as part of a curative treatment strategy for patients presenting with locoregionally advanced solid tumors.Supported in part by an American Cancer Society Clinical Oncology Cancer Development Award (to M. J. R.) and by National Cancer Institute grant CA-14599-17     

Sequential chemotherapy with cisplatin, leucovorin, and 5-fluorouracil followed by docetaxel in previously untreated patients with metastatic gastric cancer: a phase II study

Background

The combination of docetaxel, cisplatin, and 5-fluorouracil (5-FU) has demonstrated a survival advantage over cisplatin and 5-FU, but with substantial hematological toxicity. We aimed to evaluate the efficacy and toxicity of a sequential regimen with cisplatin, leucovorin, and 5-FU (PLF) followed by docetaxel in metastatic gastric cancer patients.

Methods

Treatment consisted of 4 cycles of biweekly PLF (cisplatin 50?mg/m² as a 30-min infusion on day 1, leucovorin 200?mg/m² in a 2-h infusion, and 5-FU 2,800?mg/m² in a 48-h continuous infusion starting on day 1) followed, in cases of response or stable disease, by 3 cycles of docetaxel (75?mg/m², every 3?weeks).

Results

Thirty-four patients were enrolled, with an average age of 64?years (range 34–69). The main cumulative grade 3–4 toxicities were: neutropenia (38.2%), febrile neutropenia (11.8%), and fatigue (14.7%). After the planned 7 cycles of treatment, the overall response rate was 38.2% (95% confidence interval [CI] 21.9–54.6), with 3 complete and 10 partial responses. Median progression-free survival and overall survival were 4.8 and 10.6?months, respectively.

Conclusions

For patients with metastatic gastric cancer, the sequential administration of cisplatin, leucovorin, 5-FU, and docetaxel may be an effective palliative option and offers a far more favorable toxicity profile than the simultaneous use of docetaxel, cisplatin, and 5-FU.     

Phase I trial of combined chemotherapy with docetaxel, cisplatin, and 5-fluorouracil for patients with locally advanced squamous cell carcinoma of the head and neck

Background This phase I study was designed to determine the maximum tolerated dose (MTD) and toxicities of combination chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (5-FU) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).Methods Patients received two cycles of chemotherapy repeated every 4 weeks. Starting doses (dose level 0) were: docetaxel 60mg/m², cisplatin 60mg/m², and 5-day continuous infusion 5-FU 600mg/m² per day. At least three patients were examined at each dose level before advancing to the next level.Results Nineteen male patients (median age, 59.5 years) were enrolled. Eighteen patients had previously untreated stage III or IV SCCHN and 1 had local relapse, rT4. In the 19 patients, the regimen was well tolerated, with neutropenia as the most common toxicity (grade 3; n = 11; grade 4; n = 1). Dose-limiting toxicity (DLT) was observed at the fifth dose level (docetaxel 70mg/m², cisplatin 70mg/m², 5-FU 750mg/m² per day), when 1 patient developed grade 2 renal toxicity during the first course; another 2 patients had persistent neutropenia. These doses were thus deemed the MTD for the regimen. In the 18 assessable patients, the overall clinical response rate was 94% (17/18 patients) and primary-site complete response (CR) occurred in 4 (22%) patients.Conclusion The MTD of this regimen was docetaxel 70mg/m² on day 1, cisplatin 70mg/m² on day 4, and 5-FU 750mg/m² per day for 5 days. The regimen was safe and generally well-tolerated and demonstrated good efficacy in patients with locally advanced SCCHN.     

A phase I study of 5-fluorouracil, leucovorin and levamisole

 Purpose: The activity of 5-fluorouracil (5-FU) against colon cancer is enhanced by leucovorin and the combination of 5-FU and levamisole has activity in the adjuvant treatment of colonic malignancies. The combination of 5-FU with both leucovorin and levamisole may provide additional benefit in the treatment of colon cancer. Methods: A phase I study to assess qualitative and quantitative toxicities of this three-drug combination and to determine a dose for further phase II testing was undertaken. The role of levamisole as an immunomodulator was also assessed. Results: A group of 38 patients with incurable etastatic malignancies received 119 cycles of treatment at eight dose levels. 5-FU (375 mg/m² per day) and leucovorin (200 mg/m² per day) were administered intravenously (days 1–5). Levamisole was administered orally (days 1–3 and 15–17) at doses from 30 to 470 mg/m² per day. Patients received both 5FU/leucovorin and 5-FU/leucovorin/levamisole in random order for their initial two cycles. All subsequent treatments were with the three-drug combination. Toxicities included nausea, vomiting, stomatitis, thrombocytopenia and granulocytopenia. Diarrhea was the dose-limiting toxicity at 470 mg/m² per day levamisole. The addition of levamisole resulted in more toxicity than 5-FU and leucovorin alone. No clinical responses were seen with this regimen. The addition of levamisole resulted in more immunomodulation than 5-FU and leucovorin alone as evidenced by release of neopterin from monocytes. Conclusion: With this schedule and dose of 5-FU and leucovorin, the maximum tolerated dose of levamisole was 354 mg/m². However, given the lack of response and the absence of dose-dependent immunomodulation, this may not be the appropriate dose for further phase 11 studies. Received: 20 October 1995 / Accepted: 16 June 1996     

Biweekly docetaxel, cisplatin, and 5-fluorouracil (DCF) chemotherapy for advanced esophageal squamous cell carcinoma: a phase I dose-escalation study

Background and purpose

The optimal chemotherapeutic protocol for the treatment of esophageal cancer has not yet been established. A dose-escalation study of docetaxel combined with cisplatin and 5-fluorouracil (5-FU) was performed to determine the optimal dose in patients with advanced esophageal squamous cell carcinoma.

Patients and method

We studied a total of 18 patients who had previously untreated thoracic esophageal squamous cell carcinoma with T4 tumors and/or metastasis. The patients received an infusion of docetaxel at different dose levels (levels 1, 2, 3: 30, 35, 40 mg/m², respectively) and an infusion of cisplatin (40 mg/m²) on days 1 and 15 plus a continuous infusion of 5-FU (400 mg/m²/day) on days 1–5 and 15–19.

Results

Dose-limiting toxicities (DLT) included febrile neutropenia and leukopenia. DLT occurred in 2 of 6 patients at level 1, 2 and in 3 of 6 patients at level 3. The response rate was 88.9%, including a complete response rate of 33.3%.

Conclusions

To minimize toxicity and maximize dose intensity, we elected to investigate a biweekly regimen. The maximum tolerated dose was level 3, and the recommended dose was determined to be docetaxel 35 mg/m² with cisplatin 40 mg/m² plus 5-FU 400 mg/m², administered biweekly. This regimen was tolerable and highly active. A phase II study has been started.     

Phase I study of gefitinib, irinotecan, 5-fluorouracil and leucovorin in patients with metastatic colorectal cancer

Purpose To determine the maximum tolerated doses (MTD), toxicities, efficacy, and pharmacokinetics (PK) of gefitinib combined with irinotecan, 5-fluorouracil (5-FU) and leucovorin (IFL) in patients with previously untreated advanced colorectal cancer. Experimental Design Starting doses were gefitinib 250 mg/day orally without interruption, irinotecan 100 mg/m² as a 90 min intravenous (i.v.) infusion, 5-FU 400 mg/m² bolus i.v. and leucovorin 20 mg/m² i.v. on days 1 and 8 of a 21-day cycle. Dose escalations involved increasing gefitinib to 500 mg then increasing irinotecan to 125 mg/m² and 5-FU to 500 mg/m². Results Twenty-four patients received therapy. The starting doses proved to be the MTD, as attempts to increase the dose of either gefitinib or the chemotherapeutic agents resulted in dose-limiting toxicities. Gastrointestinal effects and bone marrow suppression were the principal toxicities; however, only 1/17 (6%) patients treated with the MTD had severe (grades 3–4) diarrhea and severe neutropenia occurred in only two (12%) patients. Partial responses occurred in 10/17 patients receiving the MTD and another five had stable disease. Median progression-free and overall survivals were 12.2 and 26.6 months, respectively. In ten patients treated with the MTD, the steady-state PK of gefitinib was not affected by IFL nor did gefitinib appear to influence the PK of either irinotecan or 5-FU. Conclusions Gefitinib can be safely combined with an intermittent weekly schedule of IFL. Evidence of promising activity should encourage further clinical evaluation of epidermal growth factor receptor tyrosine kinase inhibitors, such as gefitinib, combined with multiagent chemotherapy for metastatic colorectal cancer.     

A phase I study of recombinant human interferon alpha-2b combined with 5-fluorouracil and cisplatin in patients with advanced cancer

To determine the maximum tolerated dose (MTD) of escalating doses of interferon--2b (IFN, Intron A) with 5-fluorouracil (5-FU) and cisplatin (DDP) in patients with advanced cancer, 15 patients were accrued between May 1990 and July 1991. Primary sites were unknown (3), colorectal (3), head and neck (2), lung (2), gynecologic (1), gallbladder (1), sarcoma (1), anal canal (1) and pancreas (1). IFN was given s.c. on days 1–5 and then three times weekly with DDP (75 mg/m², day 1) and 5-FU [750 mg/m², days 1–5, continuous infusion (CI) on a 28-day cycle. The first two patients treated at level I (3×10⁶ U/m² s.c.) experienced possible neurotoxic deaths [massive cerebrovascular accident (CVA) and metabolic encephalopathy], and patient 3 had a grade 4 toxicity of performance status decline. Analysis of these events led us to exclude the enrollment of patients on i.v. morphine and of those with prior exposure to DDP. This resulted in grade 3 toxicity in terms of nausea, vomiting, fatigue and leukopenia but in no further CNS event. All patients were evaluable for toxicity but only ten were evaluable for response. Only two partial responses were seen, one in a patient with an unknown primary tumour and one in a patient with head and neck cancer. The combination of IFN is possible with 5-FU and DDP. The recommended dose of IFN is 2×10⁶ U/m² s.c. in patients with no prior exposure to DDP or i.v. morphine, given together with 5-FU (750 mg/m², days 1–5, CI) and DDP (75 mg/m², day 1) on a 28-day cycle.Supported in part by a grant from Schering Canada Inc.     

Epirubicin, cisplatin and oral UFT with leucovorin (''ECU''): a phase I-II study in patients with advanced upper gastrointestinal tract cancer.

Background: ECF (epirubicin, cisplatin, protracted venous fluorouracil) is superior to FAMTX in gastroesophageal cancer, but protracted fluorouracil adds to its morbidity and cost. In this dose-escalation pilot study, fluorouracil was replaced by oral UFT and leucovorin.Patients and methods: Thirty unpretreated patients with advanced upper gastrointestinal cancers received epirubicin 50 mg/m² and cisplatin 60 mg/m² i.v. on day 1, and leucovorin 45 mg p.o. on days 1, 8 and 15, of a 21-day cycle for up to 8 cycles. UFT was taken 12-hourly throughout, at escalating doses in four cohorts ranging from 150–325 mg/m² per day.Results: The maximum tolerable dose of UFT, recommended for further study, was 200 mg/m² per day. At higher doses, more than two-thirds patients required dose reductions, although mostly for persistent mild (CTC grade 2) nausea, diarrhoea or fatigue, rather than for severe acute toxicity. Myelotoxicity was mild. Twenty patients, including 15 with gastroesophageal cancer, had assessable disease. Among these there were nine WHO objective responses, all in gastroesophageal patients, including two radiological complete responses.Conclusions: ECU is well tolerated at the defined dose, with activity comparable to ECF in gastroesophageal cancer. UFT and other oral 5FU dosing strategies make promising components of combination chemotherapy, deserving further, randomised evaluation.     

Biochemical modulation of 5-fluorouracil with brequinar: results of a phase I study

Biochemical modulation can increase the efficacy of 5-fluorouracil (5-FU). Pizzorno et al. have previously shown that brequinar, a de novo pyrimidine synthesis inhibitor, enhances the antitumor effect of 5-FU in vivo [Cancer Res 52: 1660–1665, 1992]. On the basis of their data, we conducted a phase I study of brequinar in combination with 5-FU in patients with refractory solid tumors. The initial dose (100 mg/m²) of brequinar was raised in 100-mg/m² increments in cohorts of three assessable patients. The initial dose of 5-FU was 500 mg/m², but escalation was allowed in patients who showed no significant toxic reaction. Brequinar was administered over 1 h and 5-FU over 2 h starting 18–20 h after the initiation of infusion of brequinar. Treatments were repeated weekly. Responses were evaluated after 4 weeks (one course) and then every 8 weeks thereafter. Pharmacokinetics of brequinar and determination of plasma uridine levels were performed in at least three patients at each dose level. Of the 25 patients registered in the study, 21 were assessable for toxicity studies. The dose of brequinar was escalated up to 600 mg/m². In addition, the dose of 5-FU was increased to 600 mg/m² as a result of a lack of a significant toxic reaction in the first nine patients. No objective responses were observed. One patient developed grade 3 stomatitis, and one developed grade 3 esophagitis at the 400 and 600 mg/m² dose of brequinar, respectively. Brequinar produced a dosedependent decrease in plasma uridine levels at doses up to 500 mg/m². No additional decrease in plasma uridine occurred with higher doses of brequinar, thus suggesting a plateau effect. This observation prompted us to terminate the study before reaching the maximum tolerated dose of brequinar. Our data indicate that brequinar in doses400 mg/m² results in significant biochemical modulation. The lack of toxicity seen at these doses of brequinar suggests that the initial dose of the effector agent 5-FU should be increased in future studies.Abbreviations 5-FU 5-Fluorouracil - PALA N-(phosphonacetyl)-l-aspartic acid - UXP total uridine nucleotide - AGC absolute granulocyte count - MTD maximum tolerated dose - ECOG Eastern Cooperative Oncology Group     

Phase I study of 5-fluorouracil and leucovorin by a 14-day circadian infusion in metastatic adenocarcinoma patients

Initial experimental and clinical studies have indicated that 5-fluorouracil (5-FU) toxicity can be reduced by delivering 5-FU at around 4 a.m. More recent data have suggested that the toxicity might be reduced even more with delivery at around 9–10 p.m. The current study determined the maximum tolerated dose (MTD) for 5-FU and leucovorin (LV) delivered as a continuous circadian infusion over 14 days every 28 days, with the peak of the infusion occurring at around 3–4 a.m. The peak drug delivery was shifted to 9–10 p.m. in all patients developing toxicity of grade II (Eastern Cooperative Oncology Group) to determine if this timing further reduced toxicity and enabled increased dose intensity. A total of 14 patients with metastatic adenocarcinoma received an admixture of 5-FU and LV via a programmable portable infusion pump, with 62.5% of the 24-h dose being given over 7 h around the infusion peak. The starting dose level of 5-FU (200 mg/m² daily) and LV (5 mg/m² daily) was that established as the highest tolerable dose rate in a previously reported phase I study using a 14-day flat infusion of 5-FU and LV. The LV dose was first escalated to 20 mg/m² daily, followed by escalations of the 5-FU dose. A total of 51 courses were evaluable for toxicity. The dose-limiting toxicity was oral mucositis and hand-foot syndrome. More dose intensity could be delivered using a circadian infusion peaking at around 3–4 a.m. than was possible with a flat infusion of these drugs. Toxicity was redouced even further with peak drug delivery at around 9–10 p. m. The recommended dose for phase II studies using this schedule is 250 mg/m² 5-FU daily and 20 mg/m² LV daily with the peak of the infusion occurring at 9–10 p.m. This is a 300% and 25% higher dose for LV and 5-FU, respectively, than was found to be safe for a flat infusion.This work was supported in part by a grant from Lederle Laboratories Division, Cyanamid Canada Inc. This paper was presented in part in abstract form (abstract 528) at the 6th European Conference on Clinical Oncology and Cancer Nursing, October 27–31, 1991, Florence, Italy     

Efficacy and toxicity of concurrent chemoradiotherapy in patients with advanced oropharyngeal squamous cell carcinoma

Purpose

The aim of this study was to evaluate the feasibility and toxicity of concurrent chemoradiotherapy (CCRT) with docetaxel, cisplatin (CDDP) and 5-fluorouracil (5-FU) (TPF regimen) or with CDDP, 5-FU, methotrexate and leucovorin (PFML regimen) in previously untreated patients with advanced oropharyngeal squamous cell carcinoma (SCC).

Methods

Fifty-six eligible patients with stage III or IV oropharyngeal SCC were treated with CCRT. Forty-four patients were men and 12 were women, and the average age of the patients was 58.8?years (range, 37?C72?years). In the TPF group, patients received CCRT with the TPF regimen [docetaxel (50?mg/m², day 1), CDDP (60?mg/m², day 4) and a continuous 5-FU infusion (600?mg/m²/day, days 1?C5)]. In the PFML group, patients received CCRT with the PFML regimen [CDDP (60?mg/m², day 4), a continuous 5-FU infusion (600?mg/m²/day, days 1?C5), methotrexate (30?mg/m², day 1) and leucovorin (10?mg/m²/day, days 1?C5)]. The total radiation dose was between 66.6 and 70.2?Gy.

Results

The overall 5-year survival rate was 64.6% in all patients, 68.6% in the resectable group and 47.4% in the unresectable group. The 5-year disease-specific survival rate was 72.2% in all patients, 78.1% in the resectable group and 47.7% in the unresectable group. Regarding clinical stage, the 5-year disease-specific survival rates were 91% in stage III, 72% in stage IVa and 44% in stage IVb.

Conclusion

CCRT with TPF or PFML regimen for advanced oropharyngeal SCC is tolerable and effective, especially in patients with resectable disease.     

Phase I dose-escalating study of 24-h continuous infusion of 5-fluorouracil in combination with weekly docetaxel and cisplatin in patients with advanced gastric cancer

Purpose

To determine the maximum-tolerated dose (MTD) of a 24-h continuous infusion of 5-fluorouracil (5-FU) when administered in combination with a fixed weekly dose of docetaxel and cisplatin in patients with advanced gastric cancer.

Methods

Patients with advanced gastric adenocarcinoma (n = 21) received a weekly regimen of docetaxel, cisplatin and 5-FU (DCF) for 3 consecutive weeks every 4 weeks. The doses of docetaxel and cisplatin were fixed at 33.3 and 30 mg/m², respectively. The dose of 5-FU was increased from a starting dose of 1,000 mg/m² to the MTD.

Results

A total of 53 cycles of chemotherapy were administered (median = 3 cycles/patient). The MTD of 5-FU was 1,750 mg/m². All 21 patients were assessed for toxicity and 19 patients (90%) were evaluated for response. Both grade 3–4 hematologic and non-hematologic toxicities occurred in less than 10% of patients and there were no treatment-related deaths. Among the 19 patients, we observed 1 complete and 4 partial responses for an overall response rate of 26% (95% CI: 6–46%). This rate increased to 39% (95% CI: 12–66%) in 13 chemotherapy-naïve patients.

Conclusions

A consecutive weekly DCF regimen at 4-week intervals appears feasible for advanced gastric cancer with a favorable toxicity profile. The recommended doses are 33.3 mg/m² of docetaxel, 30 mg/m² of cisplatin and 1,500 mg/m² of a 24-h continuous intravenous infusion of 5-FU. The response of this weekly regimen in our study was favorable and deserved further investigation in a phase II trial.     

A phase I study of paclitaxel, cisplatin, and fluorouracil (TCF) for advanced gastric cancer

Purpose

A phase I study of TCF therapy, which consists of paclitaxel (TXL: Taxol^®) + cisplatin (CDDP) + 5-fluorouracil (5-FU), in advanced gastric cancer patients was performed to determine the recommended dose (RD) for a phase II study by checking the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of 5-FU above the fixed dose of TXL and CDDP.

Methods

The doses of TXL and CDDP were fixed at 80 and 25 mg/m², respectively, while that of 5-FU was increased by 100 mg/m² in each cohort from 300 mg/m² (level 1) to a maximum of 600 mg/m² (level 4). One cycle consisted of administration of these agents once per week for 3 weeks, every 4 weeks.

Results

A total of twelve eligible patients were included in this study. At level 1, two of three cases showed grade 3 leukopenia. At level 2, one of three cases showed grade 4 neutropenia (recovered within 3 days), and another one case showed grade 3 neutropenia. At level 3, one of three cases showed grade 3 neutropenia, and at level 4, one of three cases showed grade 4 neutropenia (recovered within 3 days), with grade 3 neutropenia in the other two cases. Even at the highest dose administered, none of the patients showed DLT. Moreover, no non-hematological toxicity judged to be DLT was observed through all levels. Six of the twelve patients had measurable disease, and the overall response rate was 83%.

Conclusions

Although the MTD level was not determined, based on the observed efficacy and the results of other clinical trials, the recommended doses of TXL, CDDP, and 5-FU for the TCF regimen were set as 80, 25, and 600 mg/m², respectively, and a phase II study to investigate the clinical effectiveness and safety of this regimen has now begun.     

Randomized controlled phase II comparison study of concurrent chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil versus CCRT with cisplatin, 5-fluorouracil, methotrexate and leucovorin in patients with locally advanced squamous cell carcinoma of the head and neck

We compared concurrent chemoradiotherapy (CCRT) with docetaxel, cisplatin (CDDP), and 5-fluorouracil (5-FU) (TPF) with CCRT with CDDP, 5-FU, methotrexate and leucovorin (PFML) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) in terms of safety and efficacy on survival. A total of 100 patients were enrolled. The TPF group received CCRT with the TPF regimen [docetaxel (50 mg/m²: day 1), CDDP (60 mg/m²: day 4), and continuous 5-FU infusion (600 mg/m²/day: days 1–5)]. In the PFML group, patients received CCRT with the PFML regimen [CDDP (60 mg/m²: day 4)], continuous 5-FU infusion (600 mg/m²/day: days 1–5), methotrexate (30 mg/m²: day 1) and leucovorin (20 mg/m²/day: days 1–5)]. Both groups received 2 cycles of chemotherapy during definitive radiotherapy. The total radiation dose was between 66.6 and 70.2 Gray. The overall response rates after CCRT were 98 with 90% of a pathologically complete response (pCR) in the TPF group and 94 with 77% in the PFML group. For grade 3/4 adverse events, mucositis was more frequent in the PMFL group, and the TPF group showed a higher incidence of hematological toxicity. CCRT with TPF or PMFL for advanced SCCHN was tolerable and produced excellent survival rates.     

Combination chemotherapy of cisplatin and 5-fluorouracil for advanced colorectal adenocarcinoma

Summary A total of 24 patients with advanced colorectal adenocarcinoma were entered into a phase I–II study of 5-fluorouracil (5-FU) and cisplatin, 21 of whom had previously received 5-FU. The starting dose of cisplatin was 20 mg/m² diluted in 1000 cc normal saline, given over 20 h daily for 5 days, together with 600 mg/m² 5-FU diluted in 1000cc fluid, given simultaneously over 20 h daily for 5 days. This regiment was given every 4 weeks. The dose-limiting toxicity was renal and cumulative. All 24 patients were evaluable for toxicity. Of 12 patients on the abovementioned starting dose, 8 underwent a cisplatin dose reduction to 15 mg/m² due to a progressive decrease in creatinine clearance following the second or third course of treatment. Of 12 patients who started cisplatin at 15 mg/m² and 5-FU at 600 mg/m², 11 were maintained at this dose. A WBC nadir count of<2000/mm³ was seen in four patients. Thrombocytopenia occurred in three patients who received 15 mg/m² cisplatin and 600 mg/m² 5-FU. In all, 21 of the 24 patients had objectively measurable disease and were also evaluable for response as follows: 1 complete response, 2 partial responses, 1 case of stable disease, and 17 patients with progressive disease.     

Cisplatin, fluorouracil, and high-dose leucovorin for recurrent or metastatic head and neck cancer

We added high-dose oral leucovorin to the combination of cisplatin and fluorouracil (5-FU) to assess the efficacy of this regimen in the treatment of patients with head and neck cancer. Cisplatin, 100 mg/m2, was followed by a 5-FU continuous infusion at 600 mg/m2/d for five days. Leucovorin, 50 mg/m2, was administered at the start of cisplatin and every six hours throughout the duration of the 5-FU infusion. The dose of 5-FU was escalated to 800 mg/m2 and 1,000 mg/m2 according to observed toxicity. In a second phase of the study, the dose of leucovorin was escalated to 50 mg/m2 every four hours. A total of 25 patients were registered: 23 had recurrent disease after extensive prior treatment; and two had newly diagnosed metastatic disease. The maximally tolerated dose of 5-FU was 800 mg/m2/d with leucovorin administered every six hours. Toxicities at that level included mild to moderate myelosuppression and dose-limiting mucositis in the previously irradiated field. Identical toxicities were observed when administering 800 mg/m2/d of 5-FU with leucovorin every four hours. Eighteen patients were evaluated for response: one had a pathologic complete response; nine had a partial response (including four who received prior cisplatin and 5-FU as induction chemotherapy); and eight patients failed to respond. The mean peak and trough plasma leucovorin concentrations were 2.61 (+/- 1.07) mumol/L and 2.46 (+/- 0.95) mumol/L with administration of the drug every six hours, and 2.75 (+/- 2.15) mumol/L and 2.52 (+/- 1.48) mumol/L with administration every four hours. We conclude that the combination of cisplatin, 5-FU, and leucovorin has activity in the treatment of recurrent head and neck cancer. The maximally tolerated dose of 5-FU in this study was 800 mg/m2/d, with mucositis in previously irradiated sites being dose-limiting. Plasma leucovorin concentrations exceeding 1 mumol/L are achieved following oral administration of this drug.     

Phase I Study of Oxaliplatin in Combination with Gemcitabine, Irinotecan, and 5-Fluorouracil/Leucovorin (G-FLIE) in Patients with Metastatic Solid Tumors Including Adenocarcinoma of the Pancreas

Purpose

The aims of this study were to establish the maximum tolerated dose (MTD) of oxaliplatin in combination with fixed doses of gemcitabine, irinotecan, and 5-fluorouracil/leucovorin (G-FLIE) in solid tumors, including advanced pancreatic cancer, and to evaluate the toxicity of the regimen.

Methods

Patients with metastatic solid tumors were treated with a regimen consisting of gemcitabine (500 mg/m² by fixed-dose-rate infusion), irinotecan (120 mg/m²), leucovorin 300 mg, bolus/infusion 5-fluorouracil (400 and 1,500 mg/m2, respectively), and oxaliplatin at doses from 50 to 85 mg/m² according to the escalation schema. Treatment was repeated every 14 days.

Results

The study enrolled 25 patients with a median age of 64 years and median Karnofsky performance score of 80. Patients had metastatic adenocarcinomas of pancreas (n?=?9), as well as gastroesointestinal, hepatobiliary, or unknown primary tumors. With only one dose limiting toxicity (neutropenia and constipation), the MTD of oxaliplatin was not reached up to the pre-specified maximum level of 85 mg/m². Other toxicities predictably included cytopenias, fatigue, sensory neuropathy, nausea/vomiting, diarrhea, and constipation. Four partial responses and ten disease stabilizations were observed. The overall median time to disease progression was 17 weeks (2–110 weeks) with median overall survival of 31.5 weeks (7–139 weeks).

Conclusions

G-FLIE is a tolerable multi-agent chemotherapy regimen with the oxaliplatin dose up to 85 mg/m². The combination of full-dose oxaliplatin with gemcitabine, irinotecan, and 5-fluorouracil is feasible with attenuated doses of the drugs, but further optimization is necessary before assessment of efficacy.     

Phase I/II study of irinotecan, 5-fluorouracil,and <Emphasis Type="Italic">l</Emphasis>-leucovorin combination therapy (modified Saltz regimen) in patients with metastatic colorectal cancer

Background A combination of irinotecan 125mg/m², 5-fluorouracil (5-FU) 500mg/m², and leucovorin (LV) 20mg/m² (Saltz regimen; treatment on days 1, 8, 15, and 22 every 6 weeks) is widely used for the treatment of metastatic colorectal cancer. A modified schedule with chemotherapy on days 1 and 8 of a 21-day cycle was recommended in 2001 because of early treatment-related mortality. We conducted a phase I/II study of this modified Saltz regimen as first-line therapy in Japanese patients with metastatic colorectal cancer to assess the maximum tolerated dose (MTD) and the recommended dose of 5-FU when given with fixed doses of l-LV and irinotecan, and to evaluate the efficacy and the feasibility of this regimen.Methods Irinotecan, 5-FU, and l-LV were administered on days 1 and 8 of a 21-day cycle. Irinotecan 100mg/m² was given intravenously over the course of 90min on day 1, followed by l-LV 10mg/m², and then 5-FU. The dose of 5-FU was escalated from 400mg/m² (level 1) to 500mg/m² (level 2). If neither level met the criteria for the MTD, the recommended dose was defined as level 2, and dose escalation was discontinued, because the maximum approved weekly dose of irinotecan alone in Japan is 100mg/m² and the dose of 5-FU in the original Saltz regimen was 500mg/m².Results One patient had grade 4 neutropenia with fever at level 1, and four patients had grade 3 neutropenia at level 2. There was no treatment-related death. Level 2 did not meet the criteria for the MTD. The relative dose intensities of the first five cycles were 91% for both 5-FU and irinotecan at level 1 and 86% for 5-FU and 93% for irinotecan at level 2. The response rates were 58% for all patients, and 69% for patients at level 2.Conclusion Our results confirm that the modified Saltz regimen is safe and efficacious for Japanese patients. The recommended doses for phase II studies are irinotecan 100mg/m², 5-FU 500mg/m², and l-LV 10mg/m².