Usefulness of pharmacokinetic modulating chemotherapy (PMC) for the postoperative adjuvant therapy of colorectal carcinoma: a preliminary report

Pharmacokinetic modulating chemotherapy (PMC) using oral UFT and continuous venous 5-FU infusion was administered to 22 resectable patients with Dukes' B2-D colorectal carcinomas. The regimen was arranged as follows: Group A (n = 12) UFT 300-450 mg/day, 5 days a week and 5-FU 440-600 mg/m2/24 hr (750-1,000 mg/body/24 hr) once a week, Group B (n = 10), UFT less than 300 mg/day, 5 days a week, and/ or 5-FU less than 440 mg/m2/24 hr (750 mg/body/ 24 hr) once a week. The control group (Group C, n = 26) was selected at random from among non-PMC cases matched for other background factors and in which surgery had been performed during the past 4 years. Fifteen out of 26 patients in Group C were treated with 5-FU masked compounds orally. The cumulative 2 year recurrent rates of Groups A, B and C were 8.3%, 52.0% and 50.0%, respectively; the rate of Group A was significantly lower than that of Group B (p < 0.05). Four patients who suffered from PMC-related side effects of grade 1-2 wanted to decrease their dosage of UFT and/or 5-FU. They were registered in Group B. These results suggest that the regimen of Group A was advantageous in improving the prognosis after resection of Dukes' B2-D colorectal carcinoma.     

Dose intensity and clinical response in head and neck carcinoma treated with cisplatin + 5-fluorouracil

Chemotherapy dose adjustment has been associated with cancer treatment failure in some types of cancer. The aim of this study was to evaluate the impact of dose intensity in the efficacy of neoadjuvant treatment of locally advanced squamous cell carcinoma of head and neck (SCCHN). We reviewed the records of seventy patients with locally advanced SCCHN (stage III or IV) treated with three cycles of CDDP (100 mg/m²) plus 5-day continuous infusion of 5-FU (1,000 mg/m²/day) before local therapy. Planned and received dose intensity were both calculated, and clinical response and survival were assessed. Median dose intensity received was 28.38 mg/m²/week for CDDP (range: 7.45–35) and 278.16 for 5-FU (range: 74.47–350). Overall response rate to the chemotherapy combination was 76%. Cisplatin was administered ≥75% of the planned dose in 80% of the patients, and 5-FU was administered ≥75% in 76% of cases. The response rate was significantly higher in the patients that received ≥75% of the planned dose of CDDP (82% vs 50%, p=0.004), and in patients receiving ≥75% of the planned dose of 5-FU (83% vs 53%, p=0.028). Overall survival also correlated with the dose intensity of chemotherapy. Median survival of patients receiving ≥75% of CDDP was significantly longer that patients receiving <75% of CDDP (32 vs 18 months, p=0.03). Similarly, median survival of patients receiving ≥75% of 5-FU was significantly longer that patients receiving <75% of 5-FU (33 vs 21 months, p=0.02). Maintaining a dose-intensity of CDDP and 5-FU above 75% in patients with locally advanced head and neck cancer results in an improved treatment benefit, both in terms of response rate and overall survival.     

Sequence-dependence of cisplatin and 5-fluorouracil in advanced and recurrent gastric cancer

This randomized controlled clinical trial was designed to compare the safety and effectiveness of different sequences of treatment with cisplatin (CDDP) and 5-fluorouracil (5-FU) in patients with unresectable advanced and post-operative recurrent gastric cancer. Patients with unresectable advanced or post-operative recurrent gastric cancer were randomly assigned by a registration center to group A or B. Group A received CDDP (80 mg/m(2)) as a continuous 2-h intravenous infusion on day 1 and 5-FU (700 mg/m(2)) as a continuous intravenous infusion on days 2-5. Group B was given 5-FU (700 mg/m(2)) as a continuous intravenous infusion on days 1-4, followed by CDDP (80 mg/m(2)) as a continuous 2-h intravenous infusion on day 5. Each course of chemotherapy was repeated every 28 days. A total of 74 patients were enrolled. One patient died accidentally, and 5 could not be evaluated. Response was assessable in 68 patients. The response rate was 31.3% (10/32) in group A as compared with 13.9% (5/36) in group B. Although the response rate was higher in Group A, the difference was not significant (p=0.085). The response rate in patients with diffuse type tumors was significantly lower in group B. There was no difference between the groups in response among patients with intestinal type tumors. The median overall survival was 239 and 174 days and time to progression was 175 and 140 days in group A and group B, respectively. Although there were trends toward longer survival and time to progression in group A, the differences between the groups were not statistically significant. There was also no difference in the type or incidence of adverse reactions. The results of this controlled study indicate that the overall response rate was slightly but not significantly higher in patients who received CDDP before 5-FU. Among patients with diffuse type tumors, the response rate was significantly lower when 5-FU was administered before CDDP. Our results suggest that CDDP should be given before 5-FU in patients with gastric cancer when treated with a combination of CDDP and 5-FU.     

A new systemic combination chemotherapy to be provided at home for patients with unresectable recurrent colorectal cancer

We compared the effectiveness of 5-FU + l-LV with CDDP + 5-FU as a systemic chemotherapy for unresectable recurrence of colorectal cancer. The protocol we carried out in one group was as follows: (Group 1) 5-FU 2,000 mg mixed with l-LV 100-200 mg in the disposable balloon pump was administered continuously for 1 week. In the other group, (Group 2) we administered CDDP 5 mg/day every 5 days for a week and continuous 5-FU 500 mg/day for 3 weeks in the hospital, and in the outpatient clinic CDDP 5 mg/day every 2 days for a week with UFT-E 300-600 mg/day, orally, everyday. The response rate of Group 1 was 18.8% and that of Group 2 was 19.3%; the median survival time (MST) was 10.8 months for Group 1 and 8.4 months for Group 2. There were no significant differences between the 2 groups regarding these parameters. Hand foot syndrome (HFS) was observed in 43.8% of the patients, and stomatitis in 37.5% of all cases as adverse effect of systemic chemotherapy using 5-FU + l-LV. But the grade of the adverse effect was low and patients could continue with this systemic chemotherapy.     

Optimisation of irinotecan dose in the treatment of patients with metastatic colorectal cancer after 5-FU failure: results from a multinational, randomised phase II study

Although irinotecan 350 mg m(-2) is a standard option for relapsed/refractory advanced colorectal cancer, there is some evidence that suggests that a higher dose may be more effective, with acceptable tolerability, following 5-fluorouracil (5-FU). This study assessed the optimal dosing strategy for irinotecan, along with treatment efficacy and safety. A total of 164 patients with metastatic colorectal cancer progressing after failure on 5-FU or raltitrexed received either 350 mg m(-2) irinotecan (Group A; n=36) or 250, 350 or 500 mg m(-2), according to individual patient tolerance (Group B; n=62) or based on risk factor optimisation (Group C; n=66). There were no complete responses. There was a trend towards a higher overall response rate in Group B (13%) than in Groups A (8%) and C (9%). Tumour control growth rate was high in all three groups: 58% in group A, 60% in Group B and 50% in Group C. A total of 34% of patients in Group B and 9% in Group C were able to receive a dose of 500 mg m(-2). Median duration of response and time to progression were significantly longer in Groups A and B compared with Group C. No significant between-group differences for any adverse events were seen, although there was a small trend towards better tolerability in Group B. Individual dose escalation based on patient tolerance may allow more patients to receive a higher irinotecan dose without causing additional toxicity and can be an appropriate patient management strategy.     

Results of pharmacokinetic modulating chemotherapy in combination with hepatic arterial 5-fluorouracil infusion and oral UFT after resection of hepatic colorectal metastases

BACKGROUND: Pharmacokinetic modulating chemotherapy (PMC) is a new therapeutic concept in combination with continuous 5-fluorouracil (5-FU) infusion and UFT. UFT enhanced plasma 5-FU concentration and antitumor effects during 5-FU infusion. The authors report on their experiences with arterial 5-FU infusion and UFT after resection of hepatic colorectal secondaries. METHODS: Fifty-eight patients were divided into two groups after hepatectomy. Group A, 30 patients, underwent hepatic arterial infusion (HAI) via implantable port system with perfusion 5-FU for 2 consecutive days per week at 600 mg/m(2)/day, and oral administration of UFT at 400 mg/day for 5-7 days per week, repeated 10 times, and Group B, 28 patients, underwent oral administration of UFT at 400 mg/day for 6 months. All the patients were managed at the outpatient clinic at Hyogo College of Medicine, and recurrence, survival, and toxicity were documented. Plasma 5-FU concentrations during chemotherapy were detected using high performance liquid chromatography. RESULTS: Maximum plasma concentrations of 5-FU in Group A reached 144.0 ng/mL and in Group B 58.7 ng/mL. Cumulative 5-year survival rate after hepatectomy in Group A was 59% and in Group B was 27%. (P = 0.00001) HAI-PMC drastically decreased hepatic recurrence (median hepatic recurrence free times were 34.2 months in Group A vs. 18.4 months in Group B; P = 0.00002). Grade 3 toxicity in Group A was found in 3 patients CONCLUSIONS: Pharmacokinetic modulating chemotherapy was designed as a uracil-related biochemical modulation. HAI-PMC significantly decreased hepatic recurrence after curative resection. This new chemotherapy concept significantly improved prognosis in patients with hepatic colorectal metastases.     

Five-day continuous infusion of 5-fluorouracil for advanced colorectal, gastric, and pancreatic adenocarcinoma.

In a retrospective study, 58 patients with advanced colorectal carcinoma received one or more 5-day infusions of 5-FU at 20 mg/kg per 24 hours followed by weekly IV 5-FU at 15 mg/kg. In 36 patients who received the infusion as first treatment (Group A), the response rate was 23% with a median duration of response of 8.0 months. No improvement in survival was noted. In 22 patients treated with the infusion after relapse on weekly 5-FU (Group B), the response rate was 10.5% with a median duration response of 4.5 months. Stable disease for 3-6 months was seen in 21%. Survival in Group B was improved when compared with a similar group of patients treated by weekly 5-FU without infusion (Group CB), but statistical significance was not obtained. Twenty percent of patients were alive two years after relapsing on weekly 5-FU when given the five-day infusion 5-FU and re-initiated on weekly 5-FU. Toxicity to the five-day infusion of 5-FU was minimal. Three of 69 (4.3%) infusions were not completed because of toxicity. A separate review of procarbazine indicated that it was minimally active in colorectal carcinoma. Other patients with gastric and pancreatic carcinoma were reviewed but no statistical significance for 5-FU infusion was seen for survival. A five day continuous infusion of 5-FU is recommended for colorectal cancer patients who relapse on weekly 5-FU therapy. Further study of the infusion in combination with other chemotherapy is warranted.     

Three successful case reports of advanced gastric cancer with chemotherapy

We report three successful cases with continuous systemic chemotherapy for advanced gastric cancer. Case 1: A 67-year-old male with gastric cancer. Abdominal CT showed the invasion in the pancreas and as a result, continuous systemic infusion of low-dose cisplatin (CDDP 20 mg/day) and 5-fluorouracil (5-FU 1,000 mg/day) was performed. This infusion chemotherapy, CDDP and 5-FU, was continued for 5 days and discontinued for 25 days. Three months after the chemotherapy, the main tumor was remarkably reduced (downstaging was obtained), and consequently, total gastrectomy was performed. Case 2: A 78-year-old male with gastric cancer and hepatic multiple metastases. Abdominal CT scan before operation did not reveal the hepatic metastasis. In the operation for distal gastrectomy, we found multiple metastases on the surface of the liver. Continuous systemic infusion of low-dose CDDP (20 mg/day) and 5-FU (1,000 mg/day) was performed. This infusion chemotherapy, CDDP and 5-FU, was continued for 5 days and discontinued for 2 days. One month after the chemotherapy, Liver metastases had almost disappeared. Case 3: A 73-year-old male had received a distal gastrectomy based on the diagnosis of gastric cancer. The tumor marker, CA19-9, immediately decreased after the operation, but had increased again. He was treated with a combination chemotherapy of TS-1 and CDDP. The treatment consisted of 4 weeks of TS-1 administration (100 mg daily) followed by a 2-week break. CDDP of 10 mg/day was infused intravenously (day 1-5). Four weeks after the infusion, CA19-9 had returned to almost normal. We conclude that the combination chemotherapy of 5-FU (or TS-1) and CDDP might be an effective treatment for advanced and metastatic gastric cancer.     

Intra-arterial infusion of 5-fluorouracil plus granulocyte-macrophage colony-stimulating factor (GM-CSF) and chemoembolization with melphalan in the treatment of disseminated colorectal liver metastases.

AIMS: We compared two prospective trials of intra-arterial cytokine/chemotherapeutic infusion plus chemoembolization in the treatment of inoperable colorectal liver metastases. MATERIALS AND METHODS: One hundred and three patients with disseminated inoperable colorectal liver metastases received intra-arterial chemotherapy with 5-FU and granulocyte-macrophage colony-stimulating factor (GM-CSF) plus chemoembolization via an angiographically positioned hepatic artery catheter. Two different regimens were used in two consecutive studies. Group A: short-term i.a. infusion of 550 mg/m(2)5-FU (days 1-4) plus 80 microg/m(2)GM-CSF (day 1+2) combined with chemoembolization with 25 mg/m(2)melphalan plus Lipiodol and Gelfoam (day 5). Group B: continuous circadian intra-arterially administered 1400 mg/m(2)5-FU infusion plus 60 mg/m(2)i.v. leucovorin and 80 microg/m(2)GM-CSF (day 1+2) combined with chemoembolization with 25 mg/m(2)melphalan plus Lipiodol and Gelfoam (day 3). RESULTS: One hundred and three patients (62 male/41 female) with a median age of 59.9 and a median Karnofsky index of 88.5 were treated with 447 cycles of immuno-chemoembolization (group A 299, group B 148 cycles). Fifty-seven percent of these patients had received prior systemic chemotherapy. Side-effects were seen in all patients, mainly upper abdominal pain lasting 1-4 days and grade 1 or 2 vomiting. Systemic side-effects were mild and transient with a very low rate of leukopenia. Using World Health Organization response criteria, the following responses could be demonstrated: group A: CR 2.7%, PR 32.4%, MR 21.6%, SD 12.7%, NR 16.2%; group B: CR 1.0%, PR 42.4%, MR 24.2%, SD 18.2%, NR 12.1%. Time to progression was 7 as compared to 8 months. Median survival was 17 months in group A, whereas it has not been reached after 28 months (P=0.0095) in group B. There was no statistically significant difference between chemo-naive patients and patients who had received prior systemic therapy. CONCLUSION: Immuno-chemoembolization combined with 2-day circadian administration of 5-FU is an effective tool in the treatment of disseminated colorectal liver metastases. This regimen is also effective as second-line treatment.     

Neoadjuvant chemotherapy with CDDP and 5-fluorouracil for gastric cancer with serosal invasion

Many gastric cancer patients who recur peritoneally are initially diagnosed with serosal invasion. To clarify the usefulness of neoadjuvant chemotherapy with 5-fluorouracil (5-FU) +/- cisplatin (CDDP), neoadjuvant versus no preoperative chemotherapy for gastric cancer with preoperative serosal invasion was investigated. The patients were treated preoperatively with 5-FU 300 mg/m(2)/day for 2 weeks (F group; n=40), 5-FU 300 mg/m(2)/day for 2 weeks + CDDP 15 mg/m(2)/day for 2 days (FP group; n=80) or nothing (C group; n=100). A total of 78% of patients in C, 65.0% in F and 67.5% in FP group were classified as T3 or higher surgically. In patients without peritoneal metastasis, the positive peritoneal lavage cytology was 29.2% in C, 11.8% in F, and 12.2% in FP patients (p=0.0279). Serosal invasion was found histologically in 60.0% of C, 30.0% of F, and 33.8% of FP patients (p=0.001). There were no serious drug reactions and no increases in morbidity or mortality using either regimen. The 5-year survival rate was 47.0% in F and 50.9% in FP patients, but only 33.2% in C patients (p=0.0042). In conclusion, neoadjuvant chemotherapy with 5-FU +/- CDDP for gastric cancer patients with serosal invasion may reduce positive peritoneal cytology, eliminate cancer cells from the serosal surface, and improve prognosis.     

The 5-fluorouracil hepato-arterial infusion with oral UFT therapy for the hepatic and extra hepatic metastases of colorectal cancer

BACKGROUND: The 5 fluorouracil hepato-arterial infusion (5-FU HAI) therapy has a good effect on the liver metastases of colorectal cancer. To gain the antitumor effect of the extra-hepatic lesion, an oral UFT was combined with 5-FU HAI (pharmacokinetic modulating chemotherapy, PMC) to enhance the plasma 5-FU concentration. METHODS: UFT (200-400 mg/day) was orally administered daily and a continuous infusion of 5-FU (1,000-1,500 mg/5 h) was given once a week. Eight patients were treated with this regimen. Five of the eight have extra-hepatic lesions with liver metastases when this treatment was started. The response, time to progression, survival, and toxicity were detected. RESULTS: Four of the five patients with extra-hepatic lesion were evaluated. The response rate was 50% (1 CR, 1 PR, and 2 SD). For the liver metastases, the response rate was 62.5% (1 CR, 4 PR, 2 SD, and 1 PD). Grade 2 leukopenia was found in 1 patient. CONCLUSIONS: The 5-FU HAI with an oral UFT therapy had a good effect on the extra-hepatic lesions as well as hepatic metastases of colorectal cancer.     

Long-term administration of low-dose cisplatin plus 5-fluorouracil prolongs the postoperative survival of patients with esophageal cancer

To evaluate the efficacy of long-term postoperative adjuvant chemotherapy with low-dose cisplatin (CDDP) plus 5-fluorouracil (5-FU) (CDDP/5-FU), we retrospectively examined 167 patients with squamous cell carcinoma of the esophagus who received the treatment after curative surgery (R0 resection). We classified the patients into the following three groups according to their postoperative therapies and analyzed their outcomes: a) low-dose CDDP (10 mg body(-1) day(-1) x 5 days) plus 5-FU (250-500 mg body(-1) day(-1) x 5 days) repeated every 6 months for 3 years, with an oral fluoropyrimidine (5-FU 150-200 mg body(-1) day(-1) or UFT 300-400 mg body(-1) day(-1)) administered between each treatment cycle (low-dose CDDP/5-FU group, 98 patients); b) high-dose CDDP (80 mg body(-1) day(-1) x 1 day) plus 5-FU (750-1,000 mg body(-1) day(-1) x 5 days) administered once only, followed by treatment with an oral fluoropyrimidine (5-FU 150-200 mg body(-1) day(-1) or UFT 300-400 mg body(-1) day(-1)) for 3 years (high-dose CDDP/5-FU group, 17 patients); or c) surgery alone (surgery alone group, 52 patients). The 3-year survival rates were 83.7% in the low-dose CDDP/5-FU group, 61.4% in the high-dose CDDP/5-FU group, and 62.2% in the surgery alone group; the difference between the low-dose CDDP/5-FU group and surgery alone group was significant (log-rank, p<0.05). A significantly better outcome in the low-dose CDDP/5-FU group than in the surgery alone group was associated with pStage III disease (p<0.001), pN1 lymph node metastasis (p<0.001), and lymphatic invasion (p<0.01). We conclude that long-term postoperative treatment with low-dose CDDP/5-FU is therapeutically beneficial and prolongs survival in patients with esophageal cancer who have regional lymph node metastasis or lymphatic invasion.     

Postoperative chemotherapy vs chemoradiotherapy for thoracic esophageal cancer: a prospective randomized clinical trial.

BACKGROUND: Neither postoperative radiotherapy nor chemotherapy alone provided a survival benefit after curative esophagectomy for esophageal squamous carcinoma. MATERIAL AND METHODS: Of 103 consecutive patients who underwent potentially curative esophagectomy for esophageal squamous carcinoma, 45 patients with advanced cancers without preoperative adjuvant treatments were prospectively randomized to two groups; postoperative chemotherapy alone (Group A, n=23) and postoperative radio/chemotherapy (Group B, n=22). In Group A, cisplatin (CDDP) (50 mg/m(2)) was given by intravenous infusion on days 1 and 15, and 5-fluorouracil (5-FU) (300 mg/m(2)) was given daily by continuous intravenous infusion for 5 weeks. In Group B, in addition to the same chemotherapeutic regimen of Group A, 50 Gy of radiotherapy was given to the mediastinum over 5 weeks. The immunohistochemical staining of tumoral p53 and microvessel density was undertaken to correlate to the radio/chemosensitivity. RESULTS: There were no significant differences in the clinicopathologic characteristics between the two groups. The median dose of 5-FU and CDDP administered were not significantly different between the two groups. The mean (SD) dose of radiotherapy in Group B was 42+10 Gy. The 1-, 3- and 5-year survival rates in Group A were 100, 63 and 38% and those in Group B were 80, 58 and 50%, respectively (P=0.97). In each group, four patients succumbed to locoregional recurrences.Tumoral p53 was immunohistochemically negative in 43% in Group A and 77% in Group B (P=0.03), indicating that many patients in Group B might be potentially sensitive to radiochemotherapy. The 3- and 5-year survival rates (75 and 64%) of patients with p53 negative expression (n=18) were significantly (P=0.03) better than those with p53 positive expression (n=27, 44 and 26%). The long-term survival was better for patients with p53 negative tumours than those with p53 positive tumours in Group B (P=0.06 by long-rank test, P<0.05 by Generalized-Wilcoxon test). However, the long-term survival was not different between the patients who had p53 negative and positive tumours in Group A (P=0.19). These data suggest that there were no survival advantage for patients receiving radiotherapy in Group B, instead p53 negative tumours appeared to have a favorable prognosis. CONCLUSION: Postoperative radiotherapy administered concurrently with chemotherapy does not provide a survival benefit compared with chemotherapy alone. Tumoral p53 expression has a predictive value for survival in patients treated with postoperative radio/chemotherapy.     

Irinotecan combined or alternated with bolus 5-fluorouracil and folinic acid versus the Mayo Clinic regimen in the first-line therapy of advanced colorectal cancer

The objective of this study was to assess the efficacy and safety of two regimens of irinotecan, combined or alternated with bolus 5-fluorouracil (5-FU) and folinic acid (FA), and the Mayo Clinic regimen as first-line therapy for colorectal cancer (CRC). A total of 152 patients with advanced CRC were randomised, and 149 patients were treated intravenously by irinotecan 125 mg/m2, FA 20 mg/m2 followed by 5-FU 500 mg/m2 bolus, weekly for 4 weeks (arm A, Saltz regimen; n=46), or irinotecan 350 mg/m2 alternating with FA 20 mg/m2/day followed by 5-FU bolus 425 mg/m2/day for 5 days (arm B; n=53), or FA 20 mg/m2/ day followed by 5-FU bolus 425 mg/m2/day over 5 days every 4 weeks (arm C, Mayo Clinic regimen; n=50). Patients were analyzed for tumor response, time to progression, overall survival, safety and quality of life. The overall response rate for evaluable patients in arm A was 33% [95% confidence interval (CI), 17-49%], in arm B was 32% (95% CI, 16-49%) and in arm C was 26% (95% CI, 12-40%). Median times to progression were 7.9, 7.0 and 6.9 months and median survival times were 22.2, 17.0 and 18.2 months for arms A, B and C, respectively, in the intention-to-treat population. The main grade 3-4 adverse events were neutropenia (7%, 39% and 12%) and diarrhea (6%, 21% and 18%). In conclusion, both regimens containing irinotecan were active and well tolerated in patients with advanced CRC.     

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.     

A multicenter evaluation of intensified, ambulatory, chronomodulated chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin as initial treatment of patients with metastatic colorectal carcinoma. International Organization for Cancer Chronotherapy.

BACKGROUND: The combination of 5-fluorouracil (5-FU), leucovorin (LV), and oxaliplatin (I-OHP) was shown to be both more active against metastatic colorectal carcinoma and better tolerated if the drug delivery rate was chronomodulated according to circadian rhythms rather than constant. This allowed the authors to intensify the three-drug chronotherapy regimen and to assess its activity as the initial treatment of metastatic colorectal carcinoma patients in ten centers from four countries. METHODS: Patients with previously untreated and inoperable measurable metastases from colorectal carcinoma received a daily administration of chronomodulated 5-FU (700 mg/m2/day, peak delivery rate at 04:00 hours), LV (300 mg/m2/day, peak delivery rate at 04:00 hours), and 1-OHP (25 mg/m2/day, peak delivery rate at 16:00 hours) for 4 days every 14 days. Intrapatient escalation of 5-FU dose was performed if toxicity was less than World Health Organization (WHO) Grade 2. RESULTS: Of 90 enrolled patients, 35 had a WHO performance status of 1 or 2; 49 had metastases in > or = 2 organs. The liver was involved in 79 patients, 30 of whom had clinical hepatomegaly. The main dose-limiting toxicities were WHO modified Grade 3 or 4 diarrhea (41% of patients, 8.2% of courses), stomatitis (30% of patients, 5.1% of courses), and Grade 2 cumulative peripheral sensory neuropathy (19% of patients after 12 courses). Two patients died with severe gastrointestinal toxicity. Using the intent-to-treat method, the overall objective response rate was 66% (95% confidence limits, 56-76%). Surgical removal of previously inoperable metastases was successful in 31 patients (34%). Histologic necrosis of metastases was >90% in 7 patients and complete in 1 patient. The median progression free survival and survival durations were 8.4 months (range, 5.9-10.9 months) and 18.5 months (range, 13.2-23.8 months), respectively, with 38% of the patients alive at 2 years of follow-up. CONCLUSIONS: The objective response rate appeared to be approximately 3-fold as high as that achieved with current 5-FU-based regimens and translated into an approximately 50% increase in median survival. The hypothesis that this intensified, ambulatory, chronotherapy regimen can increase survival currently is being investigated in a multicenter randomized study conducted by the European Organization for Research and Treatment of Cancer Chronotherapy Study Group.     

结直肠癌5-FU和亚叶酸辅助化疗的评价

目的：评估5－FU和亚叶酸辅助化疗能否提高结直肠癌根治术的疗效。方法：自1988年以来共有225例结直肠癌根治术后应用5－FU利亚叶酸辅助化疗，术后每月一次，连续5天给予亚叶酸150mg和5－FU1．0g／日，6～9个疗程。其中随访满5年可作评估者66例，包括结肠癌38例和直肠癌28例。结果：66例的5年生存率为66．67％，结肠癌为73．68％．直肠癌为57．14％。Dukes—中国改良分期A期的5年生存率结肠癌为100％，直肠癌为80％；B期结肠癌为90．91％．直肠癌为50％；C期结肠癌为60．87％，直肠癌为42．85％，但统计学上结肠癌与直肠癌的差异不显著（P＞0．05）。术后复发率B期结肠癌为18．18％．直肠癌为50％（P＞0．05）；C期结肠癌34．78％．直肠癌71．43％（P＝0．032）。复发病例B期和C期各有1例生存5年以上。结论。提示5－FU和亚叶酸辅助化疗对降低Dukes’C期结肠癌术后复发有肯定疗效。至于对Dukes’B期术后复发车以及对5年生存率的作用，由于病例数偏少，尚不能得出有统计学意义的结论，有待进一步积累病例。     

Low-dose CDDP and 5-FU for head and neck cancer patients]

Combination chemotherapy with CDDP and 5-FU is one of the most effective regimens for head and neck cancer. Recent studies have focused on biochemical modulation in the combination of CDDP and 5-FU. We studied the difference in effectiveness and adverse effects between two CDDP administration schedules for CDDP-5-FU combination chemotherapy. For regimen A, CDDP was administered on 5 consecutive days from day 1 to day 5, with a daily dose of 16 mg/m2. For regimen B, CDDP was administered at 80 mg/m2 on day 1. 5-FU was administered at 600 mg/m2/day in a continuous drip infusion for 120 hours from day 1 to day 5 for regimens A and B. Twenty-seven patients with head and neck squamous cell carcinoma were included in this study, and received either regimen A or B. Thirteen patients were given regimen A and 14 regimen B. With regimen A, 3 patients showed CR and the response rate was 76.9%. With regimen B, 3 patients showed CR and the response rate was 64.3%. The rates of efficacy were not different between regimen A and B. In contrast, a difference was seen with organ toxicity. Regimen B was more toxic for renal function than regimen A, while regimen A showed greater toxicity to bone marrow function. Acute nausea and vomiting were observed more frequently with regimen B. The difference in organs and symptoms of adverse effects, according to the schedule of CDDP administration would seem to be important in the treatment of head and neck cancer patients. The schedule of CDDP administration should be adjusted depending on the renal and bone marrow functions of the patients. Because multiple infusion of CDDP proved to be efficacious, low-dose CDDP and 5-FU will have a role for patients with head and neck squamous cell carcinoma. We also introduce other reports on the efficacy of low-dose CDDP and 5-FU.     

Downstaging by regional chemotherapy of non-resectable isolated colorectal liver metastases.

AIMS: To improve the course of isolated non-resectable colorectal liver metastases (CRLM) by hepatic arterial infusion treatment. Patients with CRLM have a worse prognosis than those whose liver metastases are resectable. Systemic (i.v.) chemotherapy for CRLM/colorectal metastases with 5-fluorouracil+folinic acid (5-FU+FA) i.v. may result in median survival times of 6.4-14.3 months. Hepatic artery infusion (HAI) with 5-fluorodeoxyuridine (5-FUDR) has been demonstrated in a meta-analysis of randomized trials to be superior to i.v. treatment/palliative care (median survival 15 vs. 10 months). The benefit of HAI with 5-FUDR, although recommended as treatment for CRLM, is severely compromised by the 5-FUDR induced hepatotoxicity, leading eventually to sclerosing cholangitis (SC)/liver cirrhosis. We have developed a stepwise protocol for HAI in CRLM, which is superior to HAI with 5-FUDR and to systemic chemotherapy. METHODS: Between 1982 and 1997, 168 CRLM patients were treated within the following protocols. In protocol A, 48 CRLM patients received HAI with 5-FUDR. In protocol B, 46 patients received 5-FUDR i.a. (HAI)+i.v. In protocol C 5-FU+FA were delivered via HAI in 24 patients with CRLM. In protocol D, based on in vitro phase II studies and the results of protocol C, mitoxantrone and mitomycin C were added to 5-FU+FA (MFFM). Fifty (50) CRLM patients received HAI with HFFM. RESULTS: The response rates, median survival time, systemic toxicity and SC rate were: 42%, 20.8 months, 0-19% and 38% for protocol A; 46%, 20.8 months, 0-20% and 41% for protocol B; 45%, 19.8 months, 4-25% and 0% for protocol C; and 66%, 27.4 months, 2-26% and 0% for protocol D. The surgically placed ports for HAI in protocols C and D functioned in 90%, 82% and 76% of patients, 6, 9, and 11 months after beginning HAI. Quality of life in protocol D was high. Nine patients from protocols C and D with either partial (PR, seven patients) or complete (CR, two patients) remissions received a secondary liver resection without hospital mortality, and seven of nine patients are alive 2-58 months after liver resection. The other two died 11 and 22 months after resection. CONCLUSIONS: Optimal treatment of CRLM was found to be protocol D: HAI with MFFM. The results of this protocol, including high remission rate, long median survival time, good port function, good quality of life and, interestingly, the possibility of downstaging and resecting primarily non-resectable metastases, seem to be superior to HAI with 5-FUDR or 5-FU+FA and to systemic chemotherapy with 5-FU+FA. This hypothesis is currently being examined in a phase III study (HAI with MFFM vs. 5-FU+FA i.v.).     

Biweekly low-dose cisplatin and 5-fluorouracil combination chemotherapy for advanced gastrointestinal carcinoma

Biweekly intravenous infusions of low-dose cisplatin (CDDP) and 5-fluorouracil (5-FU) were evaluated in 80 patients with advanced or recurrent gastric, colorectal, pancreatic or gallbladder adenocarcinoma. CDDP was given biweekly at a dose of 15 mg/m2 infused for 30 minutes, and 5-FU 375 mg/m2 was infused for 2 hours as many times as possible. The response rate among patients with gastric cancer was 26%, colorectal cancer 10%, pancreatic cancer 7.7%, and gallbladder cancer 42.9%. The response rates were not so high, but the median survival time of patients with recurrent gastric cancer was 17.3 months, pancreatic cancer 6.7 months, and gallbladder cancer 10.7 months. A patient with unresected advanced pancreatic head cancer with liver and para-aortic lymph node metastases received this therapy 38 times, and lived for 54 months. No severe side effects occurred in any of these cases. Thus, this chemotherapy could well be effective for the outcome of cases of advanced gastrointestinal carcinoma.