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A 40-year-old male patient with carcinoma of the tonsil was put on a 5-fluorouracil and cisplatinum regimen. On day 2 during 5-fluorouracil infusion, he had features of myocardial ischemia manifesting as angina and ST-elevation in ECG. These vasospastic ischemic changes subsided after nitroglycerine plus nifedipine therapy. Such vasospastic toxicity of 5-fluorouracil is rare and few such cases have been reported.
Thirteen patients with localized unresectable pancreas carcinoma were treated with a combination of accelerated radiotherapy and 5-fluorouracil. Radiotherapy consisted in 3 fractions of 1.1 Gy per day during 3 weeks up to a total dose of 45-50 Gy. 5-Fluorouracil was administered as continuous infusion in a dosis of 25 mg/kg/24 h the first and the third week concomitantly to radiotherapy. Grade 3 mucositis, diarrhoea and nausea/vomiting were observed in 15% of the patients. Eleven patients completed the treatment without modifications and in two patients the dose of 5-fluorouracil was reduced to 75% during the third week of treatment. Radiotherapy was always administered as planned. Median survival was 36 weeks.
The possible synergism of cisplatin (P) and 5-fluorouracil was studied in 38 consecutive patients with advanced or metastatic colorectal carcinoma. Cisplatin 60 mg/m2 i.v.q. 4 weeks and fluorouracil 600 mg/m2 i.v. weekly were administered for at least 2 cycles, on an out-patient basis, to 24 males and 14 females with a median age of 57 years and a median PS of 80 (Karnofsky). Evaluable lesions were: primary unresectable tumor in 2 patients, local recurrence in 11, liver, lung, bone and soft tissue metastases in 21, 7, 2 and 3 patients respectively. With a median number of 3 cycles administered to 35 evaluable patients, 6 partial responses, 16 unchanged and 13 progressions were observed. Responses were observed in the liver (2 patients), lungs (1) and soft tissues (3). Median remission duration was 15 weeks, median duration of 'unchanged' was 12 weeks. The overall median survival was 24 weeks (30.5 weeks for responders and 22.5 weeks for non-responders). Six patients were pretreated with chemotherapy not containing cisplatin (mainly adjuvant 5-FU). None of them responded. Toxicity was very tolerable with moderate nausea, vomiting and alopecia in the majority of the patients; bone marrow toxicity was generally mild with no blood transfusions required, no complications of myelosuppression (sepsis or bleeding) and no chemotherapy-related deaths. In this experience the combination of low dose cisplatin with fluorouracil, does not appear to significantly enhance 5-FU toxicity and the response rate is not superior to that reported with 5-FU alone. However, better designed schedule combinations with optimal doses, sequences and exposure time of the 2-drug regimen, seem necessary to obtain the biochemical events that support the potentiation.
The scheduling of chemotherapeutic agents may be important in optimising their antitumour actions. This has been explored in non-Hodgkin lymphoma, osteogenic sarcoma and bladder cancer with improved results using intensive, weekly dosing schemas. We began a phase II study of cisplatin, 5-fluorouracil and vinblastine in non-small cell lung cancer (NSCLC) on a weekly schedule. 38 patients with advanced or metastatic NSCLC were entered; 32 are evaluable for response. 11 patients were treated with 5-fluorouracil 1.5 g/m2 and vinblastine 4 mg/m2 by 24-h continuous infusion, and cisplatin 30 mg/m2 over 30 min, 6-8 h after the start of the infusion. Because of prohibitive myelotoxicity, the next 27 patients received 5-fluorouracil 1.2 g/m2 and vinblastine 3 mg/m2. None had had prior chemotherapy while 6 had had previous radiation therapy. Myelosuppression was the predominant toxic effect. Other side-effects included neuropathy, diarrhoea, mucositis, nausea and vomiting. 32 patients are evaluable for response: there have been 14 partial remissions (44%). Responses have occurred chiefly in lung and lymph nodes. The median survival on this study is 7 months, and responders did not live longer than non-responders. While this regimen is well tolerated by the majority of patients and has a response rate comparable to other active regimens identified in single institution studies, survival does not appear to be enhanced. We conclude that the schedule manipulation described here does not enhance the therapeutic index of these drugs in NSCLC.
The injection of 5-fluorouracil to partial hepatectomized rat prevented the rise of activities of thymidylate synthase and thymidine kinase as well as DNA synthesis in 24-h regenerating liver in a dose-dependent manner. The extent of the decrease of thymidine kinase activity was more than that of thymidylate synthase level. The immunoblotting assay showed the existence of fluorodeoxyuridine monophosphate bound thymidylate synthase in 5-fluorouracil injected rat liver. These results indicate that the reduction of DNA synthesis in regenerating liver by 5-fluorouracil result from the inhibitions of the rise of activities of both thymidylate synthase and thymidine kinase, while the mechanisms in their inhibitions may be different.
Clinical studies have reported reduced response rates to subsequent chemotherapy in certain tumors recurring after radiotherapy. We have investigated whether there are any correlations between radiation and drug responses in vitro using a range of murine and human tumor cell lines. We have compared sensitivities to X-irradiation and to 24 hr exposures to two widely used antitumor drugs, methotrexate and 5-fluorouracil. The 4 murine lines selected showed a range of radiation responses with Do values of 0.48-0.76 Gy. Methotrexate sensitivities also exhibited an 800-fold difference (IC50 values of 0.018-14.9 micrograms/ml) which appeared to correlate inversely with radiation response. Sensitivity to 5-FU was less variable in these cells with a range of IC50 values of 0.056-0.43 microgram/ml and was unrelated to radiation response. In contrast, in the human lines tested, no correlations were observed between drug sensitivities and radiation response. The six lines tested (3 derived from epidermoid head and neck tumors, 2 from neuroblastomas and 1 from a colon carcinoma) showed a range of radiation responses with Do values of 0.66-1.59 Gy. Methotrexate sensitivities ranged only over a 150-fold concentration but, contrasting with data from the murine cells, no correlation with radiation response was apparent. Similarly, no correlations between response to 5-fluorouracil and radiation or 5-fluorouracil and methotrexate were noted, which is inconsistent with results using murine cells.
One hundred ninety-two patients with primary epidermoid cancer of the anal canal were treated by a series of prospectively designed, sequential non-randomized protocols of radiation alone (RT), radiation with concurrent 5-Fluorouracil and Mitomycin C (FUMIR), or radiation with concurrent 5-Fluorouracil only (FUR). The 5-year cause-specific survival rates were 69% overall, 68% RT, 76% FUMIR, 64% FUR. The primary tumor was controlled by radiation with or without chemotherapy in 68% (130/191) overall, 56% (32/57) by RT, 86% (59/69) by FUMIR, 60% (39/65) by FUR. The results with FUMIR were significantly better than with either RT alone or FUR, and except in tumors up to 2 cm in size, this superiority was found in all T stages. Regional lymph node metastases were controlled in 33 of 38 (87%) overall. The finding of clinically detectable regional lymph node metastases at presentation did not affect survival significantly in any treatment group. Anorectal function was preserved in 88% of the patients in whom the primary tumor was controlled, and in 64% overall. The delivery of 5FU and MMC concurrently with uninterrupted radical irradiation, 50 Gy in 20 fractions in 4 weeks, produced severe acute and late normal tissue morbidity. Split course treatment, and reduction of the daily fractional dose to 2 Gy, diminished the severity of normal tissue damage. Omission of Mitomycin C reduced acute hematological toxicity, but was associated with a decreased primary tumor control rate. The most effective treatment protocols as measured by survival rates, primary anal tumor control rates, and the likelihood of conservation of anorectal function included the administration of both Mitomycin C and 5-Fluorouracil concurrently with radiation therapy.
An examination of the effects of radiation combined with either 5-fluorouracil, Mitomycin C, or both drugs in vitro has been made using a mouse squamous tumor cell line SCC VIITo and cell viability as an endpoint. Depending on how the survival endpoint was calculated, the interaction of 5-fluorouracil, Mitomycin C, or 5-fluorouracil plus Mitomycin C with radiation was greater than additive (plating efficiency) or only additive (viable cells per flask). These results suggest that the cytostatic effect of these drugs may be an important aspect of their action clinically.
A consecutive phase I and phase II study of a 14-days continuous infusion schedule of 5-fluorouracil with weekly bolus injection leucovorin was performed in 10 and 21 patients, respectively. Chemotherapy courses were repeated every 4 weeks. 1 patient in the phase I study was pretreated, all the others had no prior chemotherapy. 300 mg/m2 continuous infusion of 5-fluorouracil for 14 days could not be combined with any dose of leucovorin 20-200 mg/m2 without severe toxicity, mainly gastrointestinal. A 5-fluorouracil dose of 200 mg/m2 day for 2 weeks, combined with weekly bolus injection of 200 mg/m2 leucovorin was found to be feasible. The phase II study was performed at this dose level. In 21 patients a response rate of 5/21 [23.8%, 95% confidence interval (CI) 8.2-47.1%] was observed, and the overall response rate was 8/29 (27.6%, 95% CI 12.7-47.2%). Responses were observed in patients with liver (4), lung (1), abdominal (1), and multiple (2) metastases. Median survival was 14.5 months. Toxicity was low, mucositis WHO grade 1-2 being most frequent (36/113 courses = 31.9%). Patients' acceptance of this continuous infusion schedule was generally good.
60 patients with metastatic breast cancer were entered in a phase II study using folinic acid, 5-fluorouracil bolus and infusion and mitoxantrone with or without cyclophosphamide. 47 had measurable visceral metastases and 13 had exclusively bone metastases. 36 had received previous adjuvant or metastatic treatment (33/36 with anthracycline-based regimens). Overall response rate in visceral metastatic patients was 57.1% [95% confidence interval (CI) 35.4-78.8%]; 45.5% and 70% in previously and non-previously treated patients, respectively; duration of response was 9 and 13 months, respectively. 10 out 13 patients with exclusive bone metastases improved for a median time of 18 months. Median survival was 22 months for the 60 patients; 18 and 31 months for previously and non-previously treated patients, respectively. Cyclophosphamide was scheduled only in the absence of nadir grade 4 neutropenia. However, this toxicity occurred in the first 7 patients. For this reason, we chose to avoid cyclophosphamide in patients over 60 years, or with a performance status of 1-2, or who had received previous chemotherapy. Overall, cyclophosphamide was stopped due to nadir grade 4 neutropenia in 17/24 patients for whom this drug was planned. When mitoxantrone, 5-fluorouracil and folinic acid were used at the doses scheduled, the addition of cyclophosphamide appeared feasible in only about 25% of the patients. Furthermore, survival was identical for patients receiving or not receiving cyclophosphamide. Therefore, cyclophosphamide does not contribute substantially to this regimen. This study confirms the value of folinic acid, 5-fluorouracil and mitoxantrone in metastatic breast cancer.
Cisplatin is an effective antineoplastic agent, but can cause renal tubular damage leading to urinary magnesium wasting and hypomagnesaemia. Cisplatin and 5-fluorouracil, when used in combination, have synergistic antitumour activity in upper gastrointestinal malignancies, but it is unclear whether they have additive effects on renal magnesium loss. To determine the optimal regimen for magnesium supplementation in these patients, we have conducted a randomised trial of routine intravenous magnesium supplements compared with magnesium given on an 'as required' basis. 32 patients were randomised to receive magnesium intravenously in prehydration and posthydration fluids with cisplatin chemotherapy, or to receive magnesium only when the serum level was low. 5-fluorouracil was given as a continuous infusion. Serum magnesium was measured on admission for each cycle of chemotherapy and an interim measurement performed between each cycle. 28 patients were evaluable. All patients randomised to receive magnesium on an 'as required' basis had at least one episode of hypomagnesaemia. On subsequent admissions for chemotherapy (cycles 2 and 3), the mean serum magnesium level was significantly lower in these patients compared with patients who received magnesium routinely (P < 0.05). After omission of magnesium from the first cycle of cisplatin, magnesium supplements were necessary in 50% of subsequent cycles, usually by the second or third cycle. Moreover, there were several instances of symptomatic hypomagnesaemia requiring further intravenous supplements in mid-cycle. Patients treated with a combination of cisplatin and 5-fluorouracil should be given intravenous magnesium supplements with each cycle of cisplatin chemotherapy. Nevertheless, episodes of hypomagnesaemia still occur, and additional intravenous supplements may be required, highlighting the importance of measuring this electrolyte.
Dipyridamole is known as a potent inhibitor of facilitated diffusion-mediated nucleoside transport as well as a modulator of 'classical' multidrug resistance. BIBW22BS, a derivative of dipyridamole, has been found to be 20- to 100-fold more potent in the reversal of multidrug resistance when compared to the parent compound. In parallel, we studied the efficacy of BIBW22BS in the modulation of the antiproliferative effects of 5-fluorouracil, methotrexate and gemcitabine in human cancer cell lines. BIBW22BS, at non-toxic concentrations up to 1.0 microM, increased the antiproliferative effects of 5-fluorouracil 2- to 6-fold in seven of the eight colon cancer cell lines tested in a dose-dependent manner. The addition of 1.0 microM BIBW22BS to methotrexate resulted in a slight increase in the antiproliferative effects, but inhibited the activity of gemcitabine 30- to 100-fold in various cancer cell lines. In vitro, no notable difference was found between BIBW22BS and dipyridamole in their capacity to modulate the activity of the antimetabolites studied. BIBW22BS did not affect the growth inhibition induced by 5-fluorouracil or gemcitabine in human tumour xenografts grown subcutaneously in nude mice. We confirmed the higher potency of BIBW22BS when compared to dipyridamole in the reversal of drug resistance in the Pgp-positive COLO 320 cell line.
RATIONALE AND OBJECTIVES: The association between hepatic steatosis and oral 5-fluorouracil (5-FU) agents is clinically recognized but has not been systematically studied. The aim of this study was to determine the effects of 5-FU on hepatic fat content in patients undergoing oral 5-FU therapy and to compare the effects in three subgroups of 5-FU drugs. MATERIALS AND METHODS: Fifty-one patients with postoperative colon cancer (mean 61.1 years) were retrospectively studied. Forty-three patients were given adjuvant oral 5-FU therapy for a mean 3.3 years (5-FU group), and eight patients were not (control group). All patients underwent preoperative and postoperative abdominal computed tomography (CT) studies. The liver/spleen ratio was calculated from the CT attenuation values for the liver and spleen. We also compared the effects on hepatic appearance under CT of three 5-FU drugs: fluorouracil (n = 13), doxifluridine (n = 14), or UFT (a mixture of tegafur and uracil; n = 9). RESULTS: In the 5-FU group, the mean CT values for the liver were significantly reduced relative to values before therapy (P < .01) and to those of the control group (P < .0001). Fifteen of 43 patients (34.9%) developed steatosis. Of the three 5-FU drugs, fluorouracil and doxifluridine caused a significant decrease in hepatic CT values. CONCLUSION: 5-FU caused a significant decrease in CT attenuation, indicating an increase in hepatic fat content, and was associated with very frequent hepatic steatosis. UFT seemed less likely to cause hepatic fatty infiltration. CT examination was useful for early detection of drug-induced side effects on liver even before lab abnormality or clinical manifestation is observed.
In vitro transdermal permeation of 5-fluorouracil (antineoplastic), a hydrophilic drug encapsulated in AOT/water/isopropylmyristate water-in-oil microemulsions (MEs), were studied using a modified Keshary and Chien diffusion cell. AOT (aerosol-OT or sodium bis(2-ethylhexyl) sulfosuccinate) is an anionic surfactant, which forms 'water-in-oil' ME in non-aqueous medium. The effect of water and AOT concentrations in MEs to the transdermal permeation of 5-fluorouracil through hairless mouse skin was investigated. MEs with 5:95 weight ratio of AOT:isopropylmyristate, containing 0.9, 1.8, 2.7 and 3.6% w/w of water have showed 1.68-, 2.36-, 3.58- and 3.77-fold increases in the skin flux of 5-fluorouracil (5-FU) respectively, compared to the aqueous solution of drug. The MEs with 5:95, 9:91 and 13:87 weight ratio of AOT:isopropyl myristate at fixed water content W0=15 (W0=[H2O]/AOT]) gave 3.58-, 5.04- and 6.3-fold enhancement of drug. In addition, attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy was used to examine the effect of ME on lipid alkyl chain, hydration level, and corneocyte cells of the stratum corneum (SC). Results reveal that the ME interacts with a component of the SC and perturbs its architectural structure. The extent of perturbation in the SC depends on the concentration of water and AOT in the ME. Preliminary dermal toxicity studies indicate that the AOT/water/isopropylmyristate ME be safe for the transdermal permeation of 5-FU.
Our preliminary data indicate that rosiglitazone may be myeloprotective. We investigated whether it can modify bone marrow recovery. Five-day pre-treatment with rosiglitazone significantly accelerated recovery of 5-fluorouracil-damaged bone marrow in mice. Frequency and femoral content of granulocyte-macrophage progenitors reached mean baseline faster in pre-treated groups than in 5-fluorouracil-treated controls. Consequently, neutropenia was milder. Five-day insulin pre-treatment had similar effects in vivo. Insulin supports in vitro hematopoiesis. The observed myeloprotection demonstrated the importance of insulin in vivo. Clinical use of insulin to moderate myelotoxicity is impractical but rosiglitazone, an insulin sensitizer, could offer hope. Although rosiglitazone tends to increase plasma insulin levels, the significant myeloprotection was partly due to direct effects on progenitors. In vitro rosiglitazone enhanced the survival of both murine progenitor and human mobilized blood stem cells in the presence of 5-fluorouracil, the effect of which was neutralized by a peroxisome-proliferator-activated receptor-gamma antagonist.
PURPOSE: To define the maximum-tolerated dose of oxaliplatin given with cisplatin, protacted 96-h infusion of fluorouracil, and radiotherapy for patients with advanced esophageal cancer. PATIENTS AND METHODS: Seventeen patients with locally advanced esophageal cancer and 2 patients with local recurrence were treated. Escalating doses of oxaliplatin, cisplatin, and fluorouracil were administered on Days 1 and 29 of radiotherapy. Radiotherapy was delivered in 1.8 Gy daily fractions to a total dose of 50.4 Gy. Dose-limiting toxicity was defined as a Grade 4 hematologic or Grade 3-4 nonhematologic toxicity. RESULTS: Dose-limiting toxicity caused by diarrhea and asthenia was observed at the IV level. The recommended dose was 85 mg/m- oxaliplatin, 55 mg/m2 cisplatin, and 3000 mg/m2 96-h fluorouracil infusion. Two pathologic complete responses were observed in 12 patients selected for surgery (16%). CONCLUSIONS: Oxaliplatin, cisplatin, fluouracil, and radiotherapy can be administered together with acceptable toxicity. A Phase II trial is ongoing with resectable esophageal and gastric carcinoma.
OBJECTIVE: To determine the efficacy of a combination of 5-fluorouracil and low-molecular-weight heparin (LMWH) to improve the outcome of surgery for established proliferative vitreoretinopathy (PVR). DESIGN: Double-masked, prospective, randomized, placebo-controlled clinical trial. SETTING: Three tertiary-referral teaching hospital vitreoretinal surgical units. PATIENTS: One hundred fifty-seven patients with established PVR (grade C, anterior or posterior) undergoing vitrectomy surgery. INTERVENTION: All patients underwent vitreoretinal surgery and silicone oil exchange with or without membrane peeling and/or retinectomy. Patients were randomly allocated to perioperative infusion with or without 5-fluorouracil (200 microg/ml) and LMWH (5 IU/ml) in Hartmann's solution for 1 hour. OUTCOME MEASURES: The primary outcome measure was defined as posterior retinal reattachment after removal of silicone oil without any reoperations at 6 months. Secondary outcome measures recorded were posterior retinal reattachment, localized/tractional retinal detachment, visual acuity, macular pucker, hypotony, glaucoma, keratopathy, and cataract. Removal of silicone oil and reoperations were also recorded. RESULTS: Overall, at 6 months 84% of patients had full retinal reattachment and 94% had stable posterior retinal reattachment. There was no significant difference in success in the primary outcome measure (56%, treatment group; 51%, placebo group; P = 0.59) or in secondary outcome measures or rates of complications. Secondary macular pucker occurred less often in the treatment group (6% vs. 17% at 6 months, P = 0.068). CONCLUSIONS: A perioperative infusion of combined 5-fluorouracil and LMWH does not significantly increase the success rate of vitreoretinal surgery for established PVR.
OBJECTIVE: To study the efficacy of subconjunctival 5-fluorouracil (5-FU) and triamcinolone injection in halting the progression of impending recurrent pterygium. DESIGN: Randomized, prospective, controlled clinical trial. PARTICIPANTS: One hundred nine patients who had undergone pterygium excision within the previous 6 months and developed grade 3 characteristics (impending recurrent pterygium). METHODS: A total of 109 eyes with impending recurrent pterygium were stratified randomly into 3 groups by treatment: 35 eyes served as the control group, 39 eyes received a 5-mg intralesional injection of 5-FU weekly for 2 weeks, and 35 eyes received one 20-mg intralesional injection of triamcinolone. All groups received 1% prednisolone acetate eye drops 4 times daily for 8 weeks. MAIN OUTCOME MEASURES: Recurrence rate, success rate, and survival analysis were compared among the groups. RESULTS: With a mean follow-up time of 10.9+/-5.5 months (range, 6-26 months), the success rates of the 5-fluorouracil and triamcinolone groups were higher than the control group (87.2%, 71.4%, and 48.6%, respectively). 5-fluorouracil was significantly (P = 0.001) more effective in inhibiting the recurrence of pterygium compared with the control group at all time points during follow-up. Kaplan-Meier survival analysis showed that the recurrence-free period of pterygium in the 5-FU group was significantly (P = 0.005) longer than that of the control group but not in the triamcinolone group compared with the controls (P = 0.063). There was no significant difference between the 5-FU group and the triamcinolone group (P = 0.362). Minimal reversible complications such as steroid-induced glaucoma and superficial punctate epitheliopathy developed during the study. CONCLUSIONS: Intralesional injection of 5-FU and triamcinolone was more effective in inhibiting the recurrence of pterygium than topical steroid alone, with the results in the 5-FU group reaching statistical significance.