Clinical efficacy of administration with S-1 alone for head and neck carcinoma

Most head and neck carcinomas are squamous cell carcinomas (HNSCCs). The combination of cisplatin with a continuous infusion of 5-fluorouracil (5-FU) has been a standard chemotherapy regimen for HNSCC. Based on basic and clinical studies, the critical plasma concentration of 5-FU is suspected to be about 0.1 microg/ml. The administration of the conventional dose of S-1 including dihydropyrimidine dehydrogenase (DPD), an metabolic inhibitor of 5-FU, results in exceeding the critical plasma concentration of 5-FU, and the long-term administration with high plasma concentration of 5-FU is considered to show clinical effectiveness in head and neck cancer. The results of early and late phase II studies on head and neck carcinoma were also described in the present paper.     

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.     

Radiation Therapy With 5-fluorouracil in Head and Neck Cancer

5-Fluorouracil (5-FU) alone or combined with other drugs, most frequently cisplatin, has been used concurrently or as induction or adjuvant therapy with radiotherapy with or without surgery in the treatment of head and neck cancer. Improved local-regional control and disease-free survival or overall survival have been shown in several randomized trials using a concurrent approach. However, acute mucositis is usually increased with simultaneous 5-FU and radiation administration, especially when other drugs are used in addition to 5-FU. Alternating radiotherapy with 5-FU and cisplatin was shown to improve the local-regional relapse-free, progression-free, and overall survival of unresectable squamous cell carcinoma of the head and neck compared with radiotherapy alone in one randomized trial. Further evaluation of the alternating chemotherapy and radiotherapy approach is needed, however, before one can accept this as a standard of practice. Induction chemotherapy with 5-FU infusion and cisplatin followed by definitive radiotherapy in the chemotherapy responders in an alternative treatment option for patients with locally advanced resectable squamous cell carcinoma of the larynx or hypopharynx who wish to preserve organ function. Induction or adjuvant chemotherapy with 5-FU infusion and cisplatin may also decrease or delay the occurrence of distant metastasis. Induction chemotherapy, however, has not been shown to improve local-regional control or overall survival. Further clinical trials combining 5-FU and its biochemical modulators using innovative radiation and drug dose schedules and other treatment modifiers are needed to improve the therapeutic ratio.     

Status of treatment for advanced gastric carcinoma

Gastric cancer is the second most common cause of cancer death worldwide. Advanced gastric cancer is incurable. The most widely investigated single-agent chemotherapy is 5-fluorouracil (5-FU), with partial response rates up to 20%. Pilot phase II studies investigating combinations of 5-FU, anthracyclines, mitomycin, methotrexate, and platinums achieved higher response rates; however, the response rates declined in subsequent larger trials. Furthermore, toxicity was substantially higher in confirmatory trials, emphasizing the need to develop well-tolerated regimens prior to multi-institutional testing. Although phase III studies of combination regimens have not achieved a clear worldwide standard, the regimen of epirubicin, cisplatin, and continuous-infusion 5-FU achieved a survival benefit, possibly through the increased activity of infusional 5-FU combined with cisplatin. The taxanes, irinotecan and oxaliplatin, have recently shown important activity in gastric cancer. Patient accrual to a phase III trial comparing a docetaxel-based combination regimen with the regimen of cisplatin and 5-FU has completed accrual. Whether patients with adenocarcinomas of the proximal stomach and gastroesophageal junction will have the same response rates to these new agents as did patients with classical body and distal gastric cancers is unknown. It is anticipated that the development of these active new agents will ultimately improve survival for patients with advanced gastric cancer.     

A phase II trial of weekly intravenous gemcitabine and cisplatin with continuous infusion fluorouracil in patients with metastatic renal cell carcinoma.

BACKGROUND: We reported previously that the combination of gemcitabine and continuous infusion fluorouracil (5-FU) has activity in renal cell carcinoma. Based upon in vitro synergy of gemcitabine/cisplatin and 5-FU/cisplatin, we hypothesized that the addition of cisplatin could improve the objective response rate of gemcitabine and 5-FU with manageable toxicity. PATIENTS AND METHODS: Twenty-one patients with metastatic renal cell carcinoma (RCC) and a Cancer and Leukemia Group B performance status of 0 to 2 were enrolled. Ten had received prior systemic therapy. Treatment consisted of gemcitabine 600 mg/m2 and cisplatin 20 mg/m2 on days 1, 8 and 15 of each 28-day cycle. Continuous infusion 5-FU was given from day 1 to day 21. RESULTS: No complete responses and one partial response were observed for an objective response rate of 5% (95% confidence interval 0% to 24%). Two minor responses (25% to 50% regression) were also observed. The median overall survival was 10 months with 35% of patients surviving at 1 year. Grade 3-4 myelosuppression (mostly thrombocytopenia) occurred in nine (43%) patients. Nausea/vomiting and neuropathy were dose-limiting in an additional five patients. Only 51% of treatment cycles were delivered on time and without dose reduction. CONCLUSIONS: The addition of cisplatin to gemcitabine and 5-FU did not improve the objective response rate of gemcitabine and 5-FU alone and added to the toxicity. Due to the cumulative toxicity, further trials with this cisplatin-containing regimen in RCC are not indicated.     

Latest progress on chemotherapy for advanced gastric cancer

Although recent phase II studies have demonstrated high antitumor activity in the treatment of advanced gastric cancer, no significant survival benefit has been clearly demonstrated yet, when compared with 5-FU alone. More recently, a number of new agents including irinotecan and S-1 have demonstrated significant activity against gastric cancer as single agent or in combination with other chemotherapeutic agents. A phase III trial of 5-FU alone versus irinotecan plus cisplatin versus S-1 alone in advanced gastric cancer patients will be initiated in Japan Clinical Oncology Group (JCOG) within a few months. These new regimens have a potential becoming a new standard chemotherapy for the treatment of gastric cancer. The patients with peritoneal dissemination has usually not yet evaluated and explored from clinical study because of risk of toxicity and having no measurable disease. A next randomized phase III trial comparing 5-FU alone with sequential methotrexate and 5-fluorouracil in patients with peritoneal metastasis will be initiated in JCOG next year. The development of molecular biology has demonstrated the molecular mechanisms of chemoresistance or chemosensitivity, as well as a number of molecular targets against cancer cells. To date, many molecular targeted agents are being evaluated in various stages of clinical testing. These advances may provide a possibility of tailor made treatment.     

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.     

Oxaliplatin: A review of preclinical and clinical studies

Of the new generation platinum compounds that have been evaluated, those with the 1,2-diaminocyclohexane carrier ligand – including oxaliplatin – have been focused upon in recent years. Molecular biology studies and the National Cancer Institute in vitro cytotoxic screening showed that diaminocyclohexane platinums such as oxaliplatin belong to a distinct cytotoxic family, differing from cisplatin and carboplatin, with specific intracellular target(s), mechanism(s) of action and/or mechanism(s) of resistance.In phase I trials, the dose-limiting toxicity of oxaliplatin was characterized by transient acute dysesthesias and cumulative distal neurotoxicity, which was reversible within a few months after treatment discontinuation. Moreover, oxaliplatin did not display any, auditory, renal and hematologic dose-limiting toxicity at the recommended dose of 130 mg/m2 q three weeks or 85 mg/m2 q two weeks given as a two-hour i.v. infusion. Clinical phase II experiences on the antitumoral activity of oxaliplatin have been conducted in hundreds of patients with advanced colorectal cancers (ACRC). Single agent activity reported as objective response rate in ACRC patients is 10% and 20% overall in ACRC patients with 5-fluorouracil (5-FU) pretreated/refractory and previously untreated ACRC, respectively.Synergistic cytotoxic effects in preclinical studies with thymidylate synthase inhibitors, cisplatin/carboplatin and topoisomerase I inhibitors, and the absence of hematologic dose-limiting toxicity have made oxaliplatin an attractive compound for combinations. Phase II trials combining oxaliplatin with 5-FU and folinic acid ACRC patients previously treated/refractory to 5-FU showed overall response rates ranging from 21% to 58%, and survivals ranging from 12 to 17 months. In patients with previously untreated ACRC, combinations of oxaliplatin with 5-FU and folinic acid showed response rates ranging from 34% to 67% and median survivals ranging from 15 to 19 months. Two randomized trials totaling 620 previously untreated patients with ACRC, comparing 5-FU and folinic acid to the same regimen with oxaliplatin, have shown a 34% overall response rate in the oxaliplatin group versus 12% in the 5-FU/folinic acid group for the first trial; and 51.2% vs. 22.6% in the second one. These statistically significant differences were confirmed in time to progression advantage for the oxaliplatin arm (8.7 vs. 6.1 months, and 8.7 vs. 6.1 months, respectively). A small but consistent number of histological complete responses have been reported in patients with advanced colorectal cancer treated with the combination of oxaliplatin with 5-FU/folinic acid, and secondary metastasectomy is increasingly done by oncologists familiar with the combination.Based on preclinical and clinical reports showing additive or synergistic effects between oxaliplatin and several anticancer drugs including cisplatin, irinotecan, topotecan, and paclitaxel, clinical trials of combinations with other compounds have been performed or are still ongoing in tumor types in which oxaliplatin alone showed antitumoral activity such as ovarian, non-small-cell lung, breast cancer and non-Hodgkin lymphoma. Its single agent and combination therapy data in ovarian cancer confirm its non-cross resistance with cisplatin/carboplatin. While the role of oxaliplatin in medical oncology is yet to be fully defined, it appears to be an important new anticancer agent.     

Effects of Intermittent 5-Fluorouracil and Low-dose Cisplatin Therapy on Advanced and Recurrent Gastric Cancer

BACKGROUND: Although combination therapy consisting of 5-fluorouracil (5-FU) and cisplatin for the treatment of gastric cancer has been reported, no consistent regimen has been established. Our aim was to determine the optimal treatment schedule of this therapy, for patients with advanced or recurrent gastric cancer. PATIENTS AND METHODS: We conducted a phase II study to evaluate the efficacy and safety of combination therapy consisting of intermittent 5-FU and low-dose cisplatin in 26 patients with advanced or recurrent gastric cancer. The treatment cycle consisted of intravenous cisplatin at 3.3 mg/m(2)/day for 5 consecutive days. 5-FU was administered as a continuous intravenous infusion at 300-500 mg/body every other day (days 1, 3, 5) for 4 weeks. RESULTS: The partial response rate was 34.6%. The median survival duration was 12.8 months and the one-year survival was 53.1%. There were a few adverse effects. CONCLUSION: Our results suggest that this mode of combination therapy led to a fairly favorable outcome for patients with advanced or recurrent gastric cancer.     

Combination therapy with TS-1

The combination with cisplatin (CDDP) and 5-FU is considered the chemotherapy of choice for squamous cell carcinoma of the head and neck (HNSCC). TS-1, a modulation of tegafur developed in Japan, is an orally administered active agent for HNSCC. Some clinical phase I/II studies on the combination of CDDP and TS-1 have been reported. The combination showed a good response rate, 67.6% for both advanced and recurrent HNSCC, in our clinical phase II study. Regimens of TS-1 combined with carboplatin or nedaplatin are also reported.TS-1 containing regimens appear to be effective for HNSCC, and multi-institutional phase II studies with large sample size are needed in future.The combination TS-1 and radiotherapy, its dose and schedule,are being studied in phase I trials for advanced HNSCC. Patient compliance is better than with 5-FU injection because TS-1 is orally administered.The adverse effect, especially in terms of bone marrow toxicity, is equal or better than with 5-FU injection. The TS-1 combination with radiotherapy is a useful regimen for outpatients. The efficacy and adverse effects should be studied in carefully designed phase I/II trials. TS-1 will be one of the key drugs for HNSCC in future.     

Current combination chemotherapy containing paclitaxel for advanced, recurrent gastric cancer

5-FU has been a key chemotherapeutic agent in the treatment of advanced or recurrent gastric cancer. In order to enhance the effect of 5-FU, biochemical modulation or combination chemotherapy has been developed. Although several phase III studies were reported in the 1990s, a standard chemotherapeutic regimen has not been established worldwide. Recently, a newly developed anticancer agent, Paclitaxel, can be clinically used for advanced gastric cancer either as a single agent or in combination with such as 5-FU, cisplatin, and TS-1. It may well further improve the quality of life and prolong the survival of patients with gastric cancer. Further assessment for the well design phase III clinical trials will be necessary to establish the availability of such combination modalities for the treatment of advanced, recurrent gastric cancer.     

European experience of docetaxel and cisplatin in advanced gastric cancer

The combination of docetaxel with cisplatin in gastric cancer is a promising development. In a phase II study, 85-100 mg/m2 docetaxel plus 75 mg/m2 cisplatin was established as an active regimen in advanced gastric cancer (with an overall response rate of 56%) with a manageable safety profile. Up to 300 mg/m2 5-fluorouracil (5-FU) given by continuous infusion for 2 of 3 weeks can be added to this regimen without an increase in appreciable toxicity. The efficacy of docetaxel-based regimens remains to be established by a randomized phase III study. However, the results of such trials are eagerly awaited, as are data from studies of docetaxel-based combinations in the adjuvant and neoadjuvant settings.     

Phase I clinical and pharmacologic study of intraperitoneal cisplatin and fluorouracil in patients with advanced intraabdominal cancer

Fluorouracil (5-FU) and cisplatin display marked therapeutic synergy in preclinical models and are effective in the treatment of a number of solid tumors when combined and administered intravenously (IV). Each drug has also been administered intraperitoneally (IP) and displays a favorable pharmacologic profile and acceptable clinical toxicity. We therefore undertook a phase I study to determine the feasibility and toxicity of combination IP chemotherapy with these agents. Thirty-one patients with histologically documented malignancy confined to the peritoneal space were treated with cisplatin 90 mg/m2 mixed with 5-FU in 2 L of lactated Ringer's solution and given IP for 4 hours every 28 days. Cohorts of at least three patients received starting 5-FU concentrations ranging from 5 mmol/L (1,300 mg in 2 L) to 20 mmol/L. The dose-limiting toxicity was neutropenia with a median granulocyte nadir of 156 cells per microliter occurring at a 5-FU dose of 20 mmol/L. Intrapatient escalation of the 5-FU dose was permitted and 15 cycles of chemotherapy were delivered at 5-FU concentrations greater than 20 mmol/L, the highest concentration being 30.7 mmol/L (8 g of 5-FU in 2L). Other toxicities included mild to moderate nausea during all cycles of therapy, vomiting in 54% of cycles, and diarrhea in 15% of cycles. Abdominal pain, renal dysfunction, peripheral neuropathy, and oral mucositis occurred infrequently and were not related to the 5-FU dose. Peritoneal fluid and plasma 5-FU concentrations were measured by high-performance liquid chromatography (HPLC) in selected patients. Mean peak plasma 5-FU concentrations ranged from 6.19 mumol/L to greater than 60 mumol/L, and peritoneal fluid to plasma 5-FU area under the curve (AUC) ratios ranged from 85 to 1,150. Nine of 15 patients with nonbulky disease had resolution of malignant ascites or at least a 50% reduction of peritoneal studding by tumor at repeat laparotomy. We conclude that combination IP chemotherapy with cisplatin and 5-FU is technically feasible and has acceptable clinical toxicity and a favorable pharmacologic profile. The recommended starting 5-FU dose for phase II trials is 3,900 mg mixed with 90 mg/m2 of cisplatin in 2 L of isotonic fluid.     

Phase II study of oxaliplatin, 5-fluorouracil and leucovorin in previously platinum-treated patients with advanced gastric cancer.

BACKGROUND: Oxaliplatin shows preclinical activity in many cancer cell lines that are resistant to cisplatin, and also has synergism with 5-fluorouracil (5-FU). We undertook this study to evaluate the efficacy and toxicities of a combined oxaliplatin, 5-FU and leucovorin (LV) continuous infusion regimen in patients with advanced gastric cancer who progressed during or after treatment with 5-FU and platinum compounds. PATIENTS AND METHODS: Twenty-six patients with advanced gastric cancer, whose disease progressed while receiving, or after discontinuing, chemotherapy with a 5-FU and platinum regimen, were enrolled in this study. Treatment comprised oxaliplatin (85 mg/m2 on day 1) as a 2-h infusion followed by bolus 5-FU (400 mg/m2 on day 1), and 48-h infusion of 5-FU 2.4-3.0 g/m2 concurrently with LV 150 mg/m2. Cycles were repeated at 2-week intervals. RESULTS: Of the 23 evaluable patients, there were six partial responses (response rate 26%). All responding patients were among those who entered into this trial immediately after failure of previous chemotherapy with 5-FU and cisplatin. The median time to progression was 4.3 months and the median overall survival was 7.3 months. The most common hematologic toxicity was grade 1-2 anemia in 39 cycles (39%). No grade 4 leukopenia or thrombocytopenia were observed. The most common non-hematologic toxicity was nausea/vomiting (33%). Peripheral neuropathy of grade 1 or 2 was noted (27%), but there was no grade 3 or 4 neurotoxicity. CONCLUSIONS: This phase II study of oxaliplatin, 5-FU and LV continuous infusion showed activity in previously platinum-treated patients with advanced gastric cancer, with acceptable toxicities.     

Phase I trial of 5-fluorouracil,leucovorin, and cisplatin in combination

Summary The ongoing evaluation of combination chemotherapy with 5-fluorouracil (5-FU) and cisplatin in several tumors prompted a phase I clinical trial of cisplatin with 5-FU modulated by leucovorin. A total of 26 patients were treated with varying doses of 5-FU by continuous i.v. infusion for 5 days; 200 mg/m² leucovorin was given by daily bolus injection for 5 days; and 20 mg/m² cisplatin was infused over 2 h on each day of treatment. Courses were repeated every 21–28 days. The starting dose of 5-FU was 300 mg/m². Poor-risk patients (extensive prior radiation, performance status of 2 or worse) did not tolerate the initial dose; the maximum tolerated dose of 5-FU in this group was 200 mg/m² daily. Good-risk patients tolerated 300 mg/m², but a majority had excessive toxicity at higher doses. The dose-limiting toxicity was gastrointestinal (mucositis/diarrhea) and/or myelosuppression; additional side effects included were nausea and vomiting (grade 2) and ataxia (one patient). Among 13 patients with colorectal cancer, 4 partial responses were observed. The marked reduction in the tolerable dose of 5-FU occasioned by the addition of modulating doses of leucovorin is noteworthy. The response observed support further investigation of this regimen in phase II trials.     

Chemotherapeutic advances in pancreatic cancer

Advances in chemotherapy for pancreatic cancer have been limited. In the past decade, the standard therapy for metastatic disease has switched from 5-fluorouracil (5-FU) to gemcitabine. However, several other cytotoxic agents have shown limited but promising efficacy in pancreatic cancer, and many of these appear to be well suited for combination chemotherapy. Although 5-FU and cisplatin have not demonstrated substantial survival benefits when combined with gemcitabine, results of several phase III trials with other agents are still pending. For locally advanced disease, most recent studies have incorporated gemcitabine into combined-modality therapy. Similarly, in surgically resectable disease, current trials are incorporating gemcitabine into adjuvant therapy. Other trials are using neoadjuvant therapy as a possible means to improve upon current surgical results. However, much hope comes from the development of newer “targeted” therapies for this disease. Although matrix metalloproteinase inhibitors and farnesyl transferase inhibitors did not appear to be effective in initial studies, other targeted therapies are beginning to enter clinical trials.     

Capecitabine (Xeloda): from the laboratory to the patient's home

Attempts at improving the efficacy of 5-fluorouracil (5-FU) by protracted continuous infusion and/or biochemical modulation have been hindered by the need for indwelling central venous catheters and their associated toxicity. Capecitabine, an oral fluoropyrimidine carbamate, has been rationally synthesized as an inactive precursor that is absorbed intact through the intestinal mucosa and is sequentially converted by an enzymatic cascade involving 3 distinct enzymes to 5'-deoxy-5-fluorocytidine, to 5'-deoxy-5-fluorouridine (5'-DFUR), and finally to 5-FU. Preclinical studies provided evidence of preferential intratumoral conversion of inactive 5'-DFUR to active 5-FU due to the relative overexpression of the final anabolizing enzyme, thymidine phosphorylase, in tumor tissues, with a resultant decrease of 5-FU exposure in normal tissues. The safety of capecitabine and optimal dosing schedules have been explored in phase I/II studies, resulting in the evaluation of the intermittent schedule (1250 mg/m2 twice daily for 14 days, every 3 weeks) in most subsequent clinical trials. Two large randomized phase III studies in patients with metastatic colon cancer established at least equivalent efficacy and improved tolerability with capecitabine compared to the Mayo Clinic bolus 5-FU/leucovorin regimen. The most common treatment-related adverse events are palmar-plantar erythrodysesthesia, diarrhea, and stomatitis, with grade 3/4 events occurring in 17%, 15%, and 2%-8% of patients, respectively. Myelosuppression was minimal. Overall toxicity was easily managed, with a significant reduction in the frequency of hospitalizations and medical resource use. The spectrum of clinical efficacy of capecitabine is expected to encompass other tumor types and administration in the adjuvant setting. As a home-based outpatient regimen, capecitabine represents a safe and effective advance in modern drug development.     

Raltitrexed (Tomudex) in combination with 5-fluorouracil for the treatment of patients with advanced colorectal cancer: preliminary results from phase I clinical trials

The potential of raltitrexed (Tomudex) in combination with 5-fluorouracil (5-FU) as treatment for advanced colorectal cancer has been investigated in two phase I clinical trials. In the first study, raltitrexed was combined with bolus 5-FU; patients received raltitrexed as a 15-min infusion followed 24 h later by bolus 5-FU every 3 weeks. In the second study, 5-FU was administered as a weekly 24-h infusion for 5 weeks of a 6-week cycle and raltitrexed was given 15-min prior to 5-FU on days 8 and 29. The recommended dose for bolus 5-FU in combination with raltitrexed is likely to be 1200 mg/m2 as dose-limiting toxicity (DLT) of febrile neutropenia was observed at 1350 mg/m2, but escalation of raltitrexed above the dose used for single-agent use (3.0 mg/m2) continues. In the raltitrexed/infusional 5-FU study, dose escalation is also still continuing, but only in men as no DLT has been observed in men; 2 of 3 female patients had DLT of myelosuppression and diarrhoea at raltitrexed 3.0 mg/m2 and infusional 5-FU 2400 mg/m2. Raltitrexed had a significant effect on the pharmacokinetics of 5-FU irrespective of 5-FU regimen. Preliminary response data is encouraging with 53% of patients receiving raltitrexed/infusional 5-FU showing a partial response. In addition, significant disease stabilisation was observed in patients receiving raltitrexed combined with bolus 5-FU who had previously failed 5-FU therapy. Recruitment has recently commenced in two studies in which raltitrexed is combined with oral derivatives of 5-FU. In conclusion, preliminary data from these phase I studies indicate that the combination of raltitrexed and 5-FU is well tolerated and has encouraging clinical activity.     

European experience of docetaxel and cisplatin in advanced gastric cancer

The combination of docetaxel with cisplatin in gastric cancer is a promising development. In a phase II study, 85–100?mg/m² docetaxel plus 75?mg/m² cisplatin was established as an active regimen in advanced gastric cancer (with an overall response rate of 56%) with a manageable safety profile. Up to 300?mg/m² 5-fluorouracil (5-FU) given by continuous infusion for 2 of 3 weeks can be added to this regimen without an increase in appreciable toxicity. The efficacy of docetaxel-based regimens remains to be established by a randomized phase III study. However, the results of such trials are eagerly awaited, as are data from studies of docetaxel-based combinations in the adjuvant and neoadjuvant settings.     

Irinotecan plus oxaliplatin: a promising combination for advanced colorectal cancer

The standard treatment for advanced colorectal cancer (CRC) has been 5-fluorouracil (5-FU)-based chemotherapy. However, addition of irinotecan, a topoisomerase I inhibitor, to the combination of 5-FU and leucovorin (LV) has proven to be superior to treatment with 5-FU/LV alone in both chemonaive as well as previously treated patients. Oxaliplatin, a 1,2 diaminocyclohexane platinum compound, in combination with 5-FU and LV, has demonstrated superiority as first-line therapy over 5-FU and LV in terms of response rate and time to progression. The irinotecan/oxaliplatin combination showed synergistic activity in vitro, and the optimal dose safety profile has been explored in several phase I studies. Neutropenia and diarrhea were the dose-limiting toxicities. The recommended dose of irinotecan/oxaliplatin in every-2-week and every-3-week schedules ranged from 150-200 mg/m2 and 85 mg/m2, respectively. In the weekly schedule, the recommended doses of irinotecan/oxaliplatin were 65 mg/m2 and 60 mg/m2. Promising clinical efficacy in CRC was observed in all studies. A recent randomized phase II study revealed that the irinotecan/oxaliplatin combination has equivalent clinical activity to other 5-FU-based combinations and a manageable toxicity profile. The evaluation of irinotecan/oxaliplatin in phase III trials as well as in combination with 5-FU is ongoing.