Combined 5-FU and CDDP in a gastric cancer patient undergoing hemodialysis--pharmacokinetics of 5-FU and CDDP

The pharmacokinetics of 5-FU and CDDP was examined in a gastric cancer patient receiving regular hemodialysis (HD) for renal failure. The patient received combination chemotherapy of 5-FU and CDDP, then on the day of HD we measured the plasma concentration of 5-FU, total platinum, and non-protein-bound platinum of the patient. In the present case, the 5-FU concentration was kept at an almost even level during HD. Non-protein-bound platinum disappeared after being maintained in blood for a certain time when HD was started 30 minutes after the end of CDDP administration. From these findings, we conclude that combined 5-FU and low-dose CDDP therapy should be done by decreasing the dose of 5-FU, administrating CDDP only on the day the patient undergoes HD, and starting HD 30 minutes after the end of CDDP administration.     

Theoretical basis for low-dose CDDP/5-FU therapy]

The theoretical basis for low-dose cisplatin (CDDP)/5-fluorouracil (5-FU) therapy is rather clear. CDDP can inhibit methionine-uptake into tumor cells and cause depletion of folate cofactors including 5-CH3FH4 and FH4, which are essential for the formation of a ternary complex with thymidylate synthetase and 5-fluorodeoxyuridine, an active metabolite of 5-FU. The literature on this mechanism are reviewed herein, and the methionine-dependency of human cancer xenografts and the modulation of 5-FU-cytotoxicity through methionine-depletion are reported.     

Multi-institutional cooperative study on combination chemotherapy with THP, CDDP and 5-FU for squamous cell carcinoma of the head and neck]

Combination chemotherapy with THP, CDDP and 5-FU for squamous cell carcinoma of the head and neck was conducted in 13 institutions in Hyogo Prefecture as a multi-institutional cooperative study. In the initial study (Nov. 1990-Nov. 1993), THP was administered intravenously at 20 mg/m2 on day 1, CDDP at 80 mg/m2 on day 2, and 5-FU at 1,000 mg/body/day in a continuous drip infusion for 120 hours from day 2 to day 6. In the second study (May, 1996-Mar. 1998), THP was administered at 20 mg/m2 on day 1, 5-FU at 10 mg/kg/day from day 1 to day 5, and CDDP at 70 mg/m2 on day 6 in the same way as the initial study. Forty-nine patients (Stage I in 3, Stage II in 12 including 2 recurrent cases, Stage III in 6, Stage IV in 28 including 3 recurrent cases; 1 course chemotherapy in 13 and 2 or more courses in 36) were subjected as complete cases in the initial study, and 36 patients (Stage I in 5 including one recurrent case, Stage II in 11 including 1 recurrent case, Stage III in 9 including 2 recurrent cases, Stage IV in 11 including one recurrent case; 1 course in 18 and 2 or more courses in 18) in the second. The overall response rate was 65.3% (CR in 3 cases) in the initial study and 63.9% (CR in 5 cases) in the second. Primary cases showed a response rate of 65.9% (29/44) in the initial study and 71.0% (22/31) in the second, whereas recurrent cases showed a 60.0% (3/5) response rate in the initial study and a 20.0% (1/5) rate in the second. Treatment-naive patients showed a response rate of 72.7% (24/33) in the initial study and 71.0% (22/31) in the second, whereas previously treated patients showed a 50.0% (8/16) response rate in the initial study and a 20.0% (1/5) rate in the second. Adverse reactions of more than Grade 3 in the initial study were leukopenia in 18.4%, thrombocytopenia in 8.2%, decrease of hemoglobin in 6.1%, loss of hair in 6.1%, anorexia in 36.7%, nausea and vomiting in 26.5%, and diarrhea in 4.1%, whereas those of Grade 3 in the second study were decrease of hemoglobin in 2.8%, anorexia in 22.2% and nausea and vomiting in 8.3%. From these results, it is suggested that the regimen in the second study was more useful than that in the initial study.     

A randomized trial between two neoadjuvant chemotherapy protocols: CDDP + 5-FU versus CDDP + VP16 in advanced cancer of the head and neck

We investigated a phase III randomized trial to compare efficacy and tolerance of CDDP + 5-FU to CDDP + VP16, both given intravenously in patients with unresectable advanced head and neck cancer. The 197 eligible patients were paired off successively on the basis of tumor sites and UICC stage. Comparisons were made through sequential closed plans. In 179 patients, tumor beds and cervical lymph nodes were irradiated, and 20 patients underwent salvage surgical procedures. Cisplatin plus 5-fluorouracil showed a response (CR + PR) rate of 15% greater than that observed with cisplatin plus etoposide (alpha=0.05, power 70%). Complete responses played a major role in the CDDP + 5-FU regimen. Furthermore, we noted a higher cervical node regression with this chemotherapy combination. Because radiotherapy was administered after chemotherapy, we could not analyze the mean duration response for each protocol. No significant difference in survival existed between the two groups. Myelosuppression was the most frequent sign of toxicity observed, especially with the CDDP + VP16 regimen. Mucositis was rare with allopurinol protection. In the CDDP + 5-FU group, one patient had grade 4 cardiac dysfunction, and 3 patients exhibited unconsciousness that may be related to cerebral vascular damage. Thirteen patients died, with 8 cases related to septic shock (5 CPPP + VP16 and 3 CDDP + 5-FU). Cisplatin plus 5-FU chemotherapy showed a satisfactory efficacy and acceptable toxicity profile compared with CDDP + VP16, with caution to patients with a cardiac or vascular history. Although we could not show a benefit in survival with the CDDP + 5-FU protocol, this trial supports literature data and confirms that this regimen may be proposed as a first-line therapy in advanced cancer of the head and neck.     

Combination chemotherapy with 5-FU and low-dose CDDP for urogenital tumors]

Chemotherapy with 5-FU and low-dose CDDP, MTX or LV has not been fully evaluated in urogenital tumors. In a study of advanced renal cell carcinoma, the response rate of the combination of 5-FU, CDDP and IFN-alpha was 9%. In urinary bladder cancer, the combination chemotherapy with 5-FU and low-dose CDDP has been used as a radiosensitizer. This combination chemotherapy with radiation introduced a high response rate and has been used for the preservation of bladder function with minimum invasive surgery. There are very few effective chemotherapies for advanced androgen independent prostate cancer. However, some oral fluoripyrimidine, like UFT, was shown to be effective to some extent for prostate cancer in a phase II study. Thus, combination therapies of 5-FU and low-dose CDDP for prostate cancer as a biochemical modulator may be expected.     

Clinical pharmacokinetic study of 5-FU in continuous 5-day infusions for head and neck cancer

Summary Twenty-nine previously untreated patients with head and neck carcinoma received a total of 63 cycles of an initial chemotherapy protocol combining cis-platinum (100 mg/m² on day 1) and continuous 5-day infusion of 5-FU (1000 mg/m²/24 h) from day 2 to day 6. This protocol was repeated on day 16 and day 31. Two daily blood samples obtained from all patients every day during 5-FU administration were analyzed by HPLC to determine the 5-FU concentrations. In the majority of cases a constant elevation was observed in total 5-FU cycle exposure (CxT) from cycle to cycle. A close relationship was demonstrated between elevated 5-FU CxT values (over 30 000 ng h ml^-1) and the frequency of cycles in which signs of toxicity (myelosuppression, mucositis, diarrhea) were observed. By contrast, no obvious association was noted between response to treatment and systemic 5-FU exposure.     

Clinical experience of intermittent administration of 5-FU and CDDP to patients with advanced and recurrent gastric cancer]

We administered 5-FU and CDDP (FP) intermittently to four patients with advanced and recurrent gastric cancer. A minor response (MR) and partial response (PR) were achieved in two of four patients who had evaluable lesions for this treatment, and few side effects were observed. Only one patient among six showed grade 2 leucocytopenia after 15 administrations of this chemotherapy, when she had attained a partial response in a lung metastasis. The other patients had no side effects such as bone marrow suppression or digestive symptoms. This intermittent FP treatment may be an effective and promising therapy with few side effects even for the patients with serious conditions.     

Combined MTX.5-FU.CDGP for the treatment of head and neck cancer

Combination chemotherapy including 5-fluorouracil (5-FU) and nedaplatin (CDGP) with methotrexate (MTX) and leucovorin (LV) was administered for modulation in patients with head and neck cancer. We treated 19 patients with MTX.5-FU.CDGP consisting of 150 mg/body of MTX on day 1 followed by a 3-day continuous infusion of 5-FU at 3,500 mg/m2 and 17 injections of LV at 15 mg and infusion of CDGP at 100 mg/m2. Six patients had recurrent head and neck cancer, and 13 had newly diagnosed disease. Eleven of the new patients were concurrently treated with radiation therapy. Treatment-associated toxicity was significant, including mucositis and myelosuppression, but acceptable. Sixteen patients were eligible for evaluation of response. The overall complete response rate was 75.0% (12/16). Patients treated with radiotherapy had a 90.0% (9/10) overall complete response rate.     

Combination therapy with S-1 and CDDP for head and neck cancer

The combination with cisplatin (CDDP) and 5-FU is considered the first choice chemotherapy for squamous cell carcinoma of the head and neck (HNSCC). S-1, a modulation of tegafur developed in Japan, is an active agent for HNSCC. Some clinical phase I/II studies about the combination with CDDP and S-1 have been reported. The combination showed a good response rate of 67.6% for advanced and recurrent HNSCC in our clinical phase I/II study. The regimens of S-1 combined with carboplatin or nedaplatin have also been reported. Regimens containing S-1 appear to have been effective for HNSCC. Multi-institutional phase II studies with a large sample size are needed in the future. The compliance for patients is better than a 5-FU injection because S-1 is orally administrated. The adverse effect, especially for bone mallow toxicity, is equal or upgraded compared with a 5-FU injection. The efficacy and adverse effects of CDDP plus S-1 should be studied in carefully designed phase II/III trials. S-1 will be one of the key drugs for HNSCC in the future.     

Chemotherapy with consecutive low-dose CDDP combined with 5-FU for gynecologic malignancies]

CDDP is generally given in a bolus fashion because it has been considered to act in a dose-dependent manner. However, early studies demonstrated anti-tumor activity of CDDP was both dose- and time-dependent. This indicated that the anti-tumor effect of CDDP dependent on the area under the concentration of filterable platinum-time curve (AUC) obtained following an administration of the agent, but not on the maximum concentration (C max) of the agent. To increase the AUC and treatment compliance, we designed a consecutive low-dose CDDP dosing method (10 mg/m2, days 1-7). This method was found to be accompanied by a good treatment compliance and high dose intensity due to significantly reduced toxic effects when CDDP was combined with several other agents. 5-FU alone has been reported to be effective in approximately 20-25% of gynecologic malignancies. Moreover, CDDP can augment the cytotoxic activity of 5-FU through biochemical modulation. Accordingly, combination treatment with consecutive low-dose CDDP with 5-FU could be designed. The present report reviews the efficacy of this combination chemotherapy for cervical carcinoma.     

Preoperative chemotherapy for patients with advanced head and neck cancer]

Cases with head and neck squamous cell carcinoma (HNSCC) have clinically advanced tumors. The curative treatments for advanced HNSCC are radiotherapy and/or surgical resection. However, standard treatment alone is less successful for advanced HNSCC. Accordingly, two modalities using chemotherapy are applied as preoperative treatment for HNSCC. First, multi-drug chemotherapy has been administered as neoadjuvant chemotherapy (NAC). As a result during the past 20 years, NAC without a high complete response (CR) rate has never improved the long-term outcome of advanced cases. Therefore, the development of intensive chemotherapy regimen with a high CR rate including taxanes is ongoing. On the other hand, organ preservation modality has been under investigation using combined radiotherapy with NAC regimen with a dose reduction of administered chemotherapeutic drugs or a new chemotherapy regimen including taxanes (concomitant or concurrent chemoradiotherapy). In this strategy, impact chemotherapy with almost the same anti-tumor effect as NAC and with a potential of radiation sensitizer is necessary.     

Preliminary clinical evaluation of low-dose CDDP and continuous 5-FU therapy for advanced gallbladder cancer

5-fluorouracil (5-FU) has been widely used for the treatment of gastrointestinal cancers. Low-dose cisplatin (CDDP) and continuous venous infusion of 5-FU have recently shown additive or synergistic antitumor effects in experimental models. In this study, we evaluated the clinical effects of low-dose CDDP and 5-FU (low-dose FP therapy) in patients with advanced gallbladder cancer. From December, 1993 to June, 1998, 13 patients with advanced gallbladder cancer were treated with low-dose FP therapy. Patients were eligible for this study if they had a bidimensionally measurable tumor. 5-FU (160 mg/m2/day) was continuously infused over 24 hours using an implantable port, and CDDP (3 mg/m2/day) was infused for one hour. The administration schedule consisted of 5-FU for 7 consecutive days and CDDP for 5 days followed by a 2-day rest, each for four weeks according to response and tolerance. Low-dose FP therapy was given to 12 patients (92.3%). The response rate was 66.7% and the median survival time was 151 days. The regimen was tolerable, with the most common toxicity being nausea (38.5%). There were no severe side effects except for one patient who suffered from grade 3 nausea. We conclude that low-dose FP therapy may be useful as a palliative chemotherapy for cases of advanced gallbladder cancer.     

DPD-based adaptive dosing of 5-FU in patients with head and neck cancer: impact on treatment efficacy and toxicity

Background

Fluoropyrimidine drugs are widely used in head and neck cancer (HNC). DPD deficiency is a pharmacogenetics syndrome associated with severe/lethal toxicities upon 5-FU or capecitabine intake. We have developed a simple, rapid, and inexpensive functional testing for DPD activity, as a means to identify deficient patients and to anticipate subsequent 5-FU-related toxicities. We present here the impact of fluoropyrimidine dose tailoring based on DPD functional screening in a prospective, open, non-controlled study, both in term of reduction in severe toxicities and of treatment efficacy.

Methods

About 65 patients with HNC (59?±?9?years, 52M/13F, Prospective Group) were entered into the study. Screening for DPD deficiency was performed prior to the beginning of the chemotherapy or radiochemotherapy. DPD status was evaluated by monitoring U/UH2 ratio levels in plasma as a surrogate marker for enzymatic functionality. 5-FU doses were reduced according to the extent of the detected DPD impairment, and adjusted on the basis of age, general condition, and other clinical/paraclinical covariates, if required. Treatment-related toxicities and subsequent impact on treatment delay were carefully monitored next for comparison with a retrospective, Reference subset of 74 other patients with HNC (mean age: 59?±?10, 58M/16F, Reference Group), previously treated in the same institute with similar schedule but using standard 5-FU dosage.

Results

Thirty-one out of 65 patients (48%) were identified as mildly (28%) to markedly (20%) DPD deficient. Subsequently, dose reductions ranging from 10 to 100% with 5-FU were applied in those patients. In this group, six patients (9%) experienced severe toxicities, none of them being life threatening, and no toxic death was encountered. In comparison, 16 out of 74 patients (22%) of the Reference Group displayed severe side effects after standard 5-FU administration, 13% being life-threatening toxicities (e.g., G4 neutropenia?+?sepsis). Moreover, one toxic death was observed in this Reference Group. No postponement or cancelation of forthcoming chemoradiotherapy courses occurred in the Prospective Group, whereas treatment had to be disrupted in six patients (8%) from the Reference Group. No difference in first-line therapy efficacy was evidenced between the two subsets (78 vs. 79% response, P?=?0.790).

Conclusions

Although non-randomized, this study strongly suggests that prospective determination of DPD status has an immediate clinical benefit by reducing the drug-induced toxicities incidence in patients treated with 5-FU, allowing an optimal administration of several courses in a row, while maintaining efficacy. Our preliminary results thus advocate for systematic DPD screening in patients eligible for treatment with fluoropyrimidine drugs in HNC.     

Chemotherapy with low-dose CDDP and continuous 5-FU for the treatment of advanced gastric cancers]

INTRODUCTION: 5-fluorouracil (5-FU) has been widely used for the treatment of gastrointestinal cancers. On the basis of recent findings, low-dose Cisplatin (CDDP) and continuous venous infusion of 5-FU have shown additive or synergistic antitumor effects in experimental models. We evaluated clinical effects of low-dose CDDP and 5-FU (low-dose FP therapy) in patients with advanced gastric cancers. PATIENTS AND METHODS: In December 1993 and June 1998, 52 patients with advanced gastric cancer were entered in this study. Patients were considered eligible if they had a bidimensionally measurable tumor. 5-FU (160 mg/m2/day) was continuously infused over 24 hours using an implantable port, and CDDP (3 mg/m2/day) was infused for half an hour. The administration schedule consisted of 5-FU for 7 consecutive days and CDDP for 5 days followed by a 2-day rest every four weeks according to response and tolerance. RESULTS: Low-dose FP therapy was given 44 patients (85%). The response rate was 65.9% and median survival time was 249 days. The responder group showed good survival compared with the non-responder group. The regimen was tolerable, and the most common toxicity was anorexia (40.3%). Three patients suffered from grade 3 anorexia, leukopenia and mucositis. On the other hand, renal dysfunction occurred in 50% (two of four patients administered over 1,000 mg CDDP). These results raise the possibility that the dose-limiting factor of low-dose FP therapy may account for the total dosage of CDDP. CONCLUSION: Low-dose FP therapy promises to be effective in the clinical management of advanced gastric cancer.     

Immune homeostasis in patients with head and neck cancer]

Immunologic parameters in head and neck cancer patients measured prior to treatment, in remission, at relapse and in cases of lymph node metastases developing 1-3 years following radiation treatment proved different. Evaluation of immune status, alongside with other diagnostic methods, can be used to confirm remission and diagnose relapse.     

Evaluation of high-dose cisplatin and 5-FU infusion as initial therapy in advanced head and neck cancer

The combination of cisplatin and 5-fluorouracil (5-FU) infusion in head and neck cancer patients produces an overall response rate of 90% for advanced disease and 70% for recurrent disease. Whether or not escalating the platinum dose in combination with other agents, as has been done with refractory ovarian and testicular patients, would improve the response rates in patients with advanced head and neck cancer has not been evaluated. We undertook a study to determine the most efficacious dose of cisplatin that could be administered with 5-FU infusion in head and neck cancer patients. Eleven patients entered the study. Initial dose of cisplatin was 40 mg/m2 (in hypertonic saline) on days 1-5 plus 5-FU 1,000 mg/m2 on days 1-5 as a continuous infusion. Subsequent cisplatin doses were adjusted for the main toxicity, which was myelosuppression. The safest tolerable dose was 30 mg/m2 for 5 days. Overall response was 90% [45% complete response (CR) (5/11) plus 45% (5/11) partial response (PR)] which is comparable to that seen with cisplatin 100 mg/m2 and 5-FU in a 120-h infusion. Although patient numbers are small, there was no appreciable difference in response rate with higher dose cisplatin and there was a significant increase in serious toxicity.     

Evaluation of docetaxel, CDDP and 5-FU combined therapy as second-line chemotherapy for esophagus cancer

The combined therapy of docetaxel (70 mg/m(2), day 1), CDDP (80 mg/m(2), day 1) and 5-FU (800 mg/m(2), day 1-5) is used as second-line chemotherapy for esophagus cancer. First-line chemotherapy for 32 advanced squamous cell carcinomas of the esophagus is not effective, and early recurrences after chemotherapy were examined. Pretreatment surgery was used in 20 cases,radiation therapy in 19 and chemotherapy by 3.1 courses (1-9) on average. PR was found in 16 patients (response rate 50%) in the first course, MR in 2, NC in 6, and PD in 7 cases. Among 16 patients,one was discontinued due to aspiration pneumonia and two by leukopenia. Thirteen patients received 3-5 courses. The operation was continuously enforced in three patients among 13, radiation therapy was added in three, and they survived for one year or more. Five for whom imaging became virtually impossible lived for six months or more. Additional treatment proved ineffective in 2, so it was discontinued. There were 18 lymph node examples of lesions effectively treated, 6 main lesions, 1 pulmonary metastasis and 1 bone metastasis. As for deleterious events, leukopenia was admitted in 95%. G-CSF was needed by 68% during use and 3 days on average. The CDDP+5-FU+docetaxel therapy was comparatively safe in patients with much pre-treatment and demonstrated a maximum effect at more than the expected rate.     

A case of recurrent gallbladder cancer responding to low-dose 5-FU and CDDP therapy

We treated a patient with a postoperative local recurrence of gallbladder cancer who showed a long-term response to low-dose 5-fluorouracil (5-FU) and cisplatin (CDDP) therapy. A 60-year-old woman was diagnosed with advanced gallbladder cancer, for which she underwent an extended cholecystectomy, bile duct resection and a partial resection of the duodenum in March 2000. The pathological diagnosis was well differentiated tubular adenocarcinoma of si, ly1, v1, hinf2, binf2, n0. Eight months later, she presented with cholangitis and obstructive jaundice due to a local recurrence of the gallbladder cancer and her serum CA19-9 level had increased to 1,991.6 U/ml. The biliary obstruction was treated by PTCD and a subsequent self-expanding metallic stent. In addition, she was also placed on combined chemotherapy with low-dose 5-FU and CDDP. Her serum CA19-9 level thereafter gradually decreased, so that after eight months it was within the normal range, and the recurrent tumor at the hepatic hilus was also observed to have decreased in size on the CT scan. As of this writing she has undergone eight courses of low-dose 5-FU and CDDP therapy over about a year and has been able to maintain a good quality of life without any severe adverse effects.     

Combination chemotherapy of continuous infusion 5-FU and daily low-dose CDDP in colorectal carcinoma]

Continuous intravenous infusion (CVI) of 5-fluorouracil (5-FU) plus daily low-dose cisplatin (CDDP) was evaluated in 59 patients with advanced and unresectable colorectal carcinoma. The procedure consisted of 5-FU 320 mg/m2/day, CVI and CDDP 2.5-3.5 mg/m2/day, infused for one hour five times a week (low-dose FP therapy) was performed for at least four weeks. The rates of complete and partial response, along with side effects were studied. Also, the effect of low-dose FP therapy on the prognosis of patients with colorectal carcinoma was investigated. The rate of complete and partial response was 57.1%. The frequency of severe side effects (grade 3 and 4) was 10.5%, and no death from side effects was noted. The effect of low-dose FP therapy on the prognosis of advanced and unresectable colorectal carcinoma was studied. It is suggested that this chemotherapy might contribute to the survival of patients with colorectal carcinoma. We designed the chemotherapy of intermittent administration (day by day) of 5-FU 600 mg/m2/day and daily CDDP 2.5-3.5 mg/m2/day (intermittent FP) in order to decrease the rate of side effects and their severity. No cases with grade 3 or 4 side effects were experienced, but the response rate was mostly similar to that of low-dose FP therapy. We concluded that low-dose FP and intermittent FP therapy might be fairly effective for advanced and unresectable colorectal carcinoma.