Medical care consumption in a phase III trial comparing irinotecan with infusional 5-fluorouracil (5-FU) in patients with metastatic colorectal cancer after 5-FU failure

We evaluated economic implications of treatment with irinotecan, following a RCT which demonstrated significantly increased survival at 1 year with irinotecan (45%) compared to infusional 5-fluorouracil (5-FU) (32%) in patients with metastatic colorectal cancer. Medical care consumption data were collected prospectively alongside the trial, with 256 patients followed for a median of 10 months. Follow-up was prolonged beyond treatment failure and medical care consumption was not protocol driven, enabling a realistic evaluation of economic implications. Medical care consumption associated with chemotherapy administration was lower with irinotecan as compared with infusional 5-FU. The cumulative number of days in hospital due to treatment toxicity and cancer complications, which is the key cost driver, was 14.4 (95% CI: 10.7-18.1) with irinotecan versus 17.5 (95% CI: 11.7-23.3) with infusional 5-FU. Thus, the survival benefit with second-line irinotecan compared to infusional 5-FU in patients with advanced colorectal cancer was achieved without increasing medical care consumption.     

Advanced colorectal cancer treatment in Europe: what have we achieved?

The goal of the present paper is to review how treatment of advanced colorectal cancer has evolved during the last 10 years and to make some suggestions on how that disease could be managed today. 5-Fluorouracil (5-FU) combined with folinic acid (FA) remains the basis for advanced colorectal cancer treatment. In Europe, infusional 5-FU is considered to be more active and better tolerated than bolus 5-FU. New agents including oral 5-FU prodrugs UFT/FA, and capecitabine, tomudex, irinotecan and oxaliplatin have been shown active in advanced colorectal cancer. At presentation the combination of infusional 5-FU/FA with irinotecan or oxaliplatin is considered to be superior to any of these agents used alone, yielding a median survival of up to 16-19 months. Second-line therapy could further prolong survival in selected patient populations. Eventually chemotherapy could allow curative resection of previously unresectable hepatic and pulmonary metastases.     

Clinical advances with topoisomerase I inhibitors in gastrointestinal malignancies

Phase III studies have shown irinotecan prolongs survival significantly when compared with either best supportive care or best infusional 5-fluorouracil (5-FU)-based chemotherapy in patients with 5-FU-resistant colorectal cancer. Phase I/II studies are investigating the combination of irinotecan with 5-FU, with thymidylate synthase inhibitors, notably raltitrexed, and with the oral fluoropyrimidines. Preliminary results suggest irinotecan and raltitrexed can safely be combined in the clinic and that this combination is active. The combination of irinotecan with the oral fluoropyrimidines also has produced promising results. A phase I study of irinotecan plus 5-FU/folinic acid showed high activity in first-line metastatic disease and further trials using the doses of 80 mg/m2 irinotecan plus 2 g 5-FU weekly are recommended. The combination of irinotecan with the De Gramont 5-FU regimen is feasible and active in patients with 5-FU-resistant metastatic disease. Alternating exposure to irinotecan and 5-FU may be as active as either treatment alone, and has been associated with overall response rates (ORRs) greater than 30% and encouraging median survival. The combination of irinotecan with oxaliplatin is also feasible and levels of response rates are in the region of 50% (especially with a 2-weekly administration schedule). In patients with advanced gastric cancer (including those with pretreated disease) ORRs of around 50% have been reported following administration of either cisplatin plus irinotecan or cisplatin plus docetaxel.     

Mitomycin C continuous infusion as salvage chemotherapy in pretreated patients with advanced gastric cancer

Our purpose was to evaluate the safety and therapeutic activity of continuously infused mitomycin C in patients with recurring or progressive metastatic gastric cancer following first-line chemotherapy. Patients were treated with mitomycin C 20 mg/m2 i.v. over a time period of 120 h followed by a 3-week rest period. All patients received prednisone 50 mg p.o. prophylactically for 5 days to prevent hemolytic uremic syndrome and pulmonary side effects. Twenty-two consecutively enrolled patients were assessable for toxicity and 20 for response evaluation completing at least one full course of chemotherapy (two patients evaluable but not measurable). Patient characteristics: median age: 63 years (39-76); Sex (M/ F): 13/9; median Karnofsky status: 70% (50-100%); resection of primary tumor n = 12 (55%); sites of metastases: liver n = 17 (77%), locally advanced n = 10 (45%), peritoneum n = 13 (59%), lungs n=5 (23%), bone n=3 (14%) and lymph nodes n=14 (64%). Previous chemotherapy regimens: bolus 5-FU/folinic acid n=6 (27%), ELF n=4 (18%), EAP n=3 (14%) and continuous 5-FU/folinic acid/cisplatin/paclitaxel n=9 (41%). In 20 evaluable patients one complete and five partial remissions were observed; overall response rate 30.0% [95% confidence interval (CI): 9.1-50.9%] with a median response duration of 2.1 months (range: 2-6). The median survival was 3.6 months (95% CI: 2.1-6.0) resulting in a 6-month survival rate of 30% since start of mitomycin C. WHO grade III/IV mucositis, diarrhea and fever/infection occurred in 9% of patients each. Cumulative thrombo- and leukocytopenia (WHO grade II/IV) were observed in four and two patients, respectively. Treatment had to be stopped early in two patients. No severe renal dysfunction, pulmonary toxicity or evidence of hemolytic uremic syndrome was observed. Fatigue during the 120 h infusion of mitomycin C was common (11 of 22 patients). We conclude that continuous infusion of mitomycin C is feasible on an outpatient basis, revealing an acceptable toxicity. Mitomycin C demonstrates single-agent activity in pretreated gastric cancer, but has only limited efficacy following cisplatin/paclitaxel-based first-line chemotherapy.     

Irinotecan and capecitabine as second-line treatment after failure for first-line infusional 24-h 5-fluorouracil/folinic acid in advanced colorectal cancer: a phase II study

The efficacy of combination therapy with irinotecan and capecitabine has been demonstrated for the first-line treatment of metastatic colorectal cancer (MCRC). The aim of this trial was to evaluate the efficacy and safety of this combination in MCRC as second-line treatment after failure of 24-h infusional 5-fluorouracil (5-FU24h) and folinic acid (FA). Patients pre-treated with 5-FU24h/FA were recruited at two institutions to receive 6 x weekly irinotecan 70 mg/m2 and capecitabine (1000 mg/m2 b.i.d. days 1-14 and 22-35). Courses were repeated on day 50. In elderly patients (>65 years) a 20% dose reduction of both drugs was scheduled. Twenty-eight patients [M/F 20/8; median age 65 years (range 44-79); median ECOG score 1] were enrolled. The most frequent sites of metastases were liver, n=20, lymph nodes and lungs, n=10, respectively. Half of the patients had two or more metastatic sites. A total of 71 treatment courses (median 2, range 1-8) were administered. Main toxicities [worst per patient (%); CTC grade 1/2/3/4] were: anaemias 18/14/-/-; leukocytopenia 11/21/-/-; thrombocytopenia 11/-/-/-; diarrhea 18/36/21/-; nausea/vomiting 43/29/4/-; mucositis 4/11/-/-; alopecia 7/25/-/-; hand-foot syndrome 7/21/-/-; fatigue 14/14/-/-; renal insufficiency (caused by diarrhea and exsiccosis) -/-/-/7. Dose intensity in the first course was [median/mean (%)]: irinotecan 92/83; capecitabine 88/82. Twenty-three patients are evaluable for response analysis (five did not complete the first course): three patients showed partial remissions (13%) and 11 patients had stable disease (48%). Median time to progression was 3.0 months for the total population (range 1.4-17.3) and 6.5 months for responders (partial response plus no change). Seventy-four percent of the patients received a third-line therapy. Overall survival was 15.7 months calculated from the start of study treatment. Second-line therapy with irinotecan and capecitabine yielded a tumor control in 61% of patients with MCRC. Efficacy and toxicity data are comparable to 5-FU/irinotecan combinations, although the likelihood of severe diarrhea appears to be higher with capecitabine/irinotecan.     

Safety and efficacy of outpatient treatment with CPT-11 plus bolus folinic acid/5-fluorouracil as first-line chemotherapy for metastatic colorectal cancer

The combination of irinotecan (CPT-11), bolus 5-fluorouracil (5-FU) and folinic acid (FA) (Saltz regimen) has recently been questioned as first-line chemotherapy for metastatic colorectal cancer after high early death rates due to gastrointestinal and thromboembolic events were reported in two US trials. Therefore, we carefully evaluated the safety and efficacy of this regimen, with high value placed on the management of delayed diarrhea. Forty-six patients with metastatic colorectal cancer received this first-line treatment in nine German outpatient clinics. Dose reductions were mandatory from the first cycle in case of toxicity grade >2. Chemotherapy was administered only to diarrhea-free patients. During a total of 175 cycles administered treatments were delayed for 1 week in 11.6% and given at a reduced dose in 14.5%. All and 40 patients were evaluable for toxicity and response, respectively. Grade 3/4 toxicities included diarrhea (n=10), leukopenia (n=9), neutropenia (n=3) and anemia (n=4). One non-fatal pulmonary embolism occurred. Four complete responses (CR) and 10 partial responses were seen, for an overall response rate of 35%. In addition, 16 patients (40%) had stable disease. Resectability of liver metastases was achieved in three patients, including one pathologically confirmed CR. Median progression-free and overall survival were 5 and 13 months, respectively. We conclude that outpatient treatment with the Saltz regimen was well tolerated. Severe gastrointestinal toxicity and thromboembolic events were rarely observed and never fatal. As down-staging was possible, combinations of CPT-11 and FA/5-FU should be further investigated in neoadjuvant protocols.     

Weekly high-dose 5-fluorouracil as 24-h infusion and folinic acid (AIO) plus irinotecan as second- and third-line treatment in patients with colorectal cancer pre-treated with AIO plus oxaliplatin

Our objective was to evaluate the efficacy and safety of high-dose 5-fluorouracil (5-FU) as a 24-h infusion and folinic acid (FA) (AIO regimen) plus irinotecan (CPT-11) after pre-treatment with AIO plus oxaliplatin (L-OHP) in colorectal carcinoma (CRC). Twenty-six patients with non-resectable distant CRC metastases were analyzed for second- or third-line treatment with AIO plus CPT-11 after pre-treatment with AIO plus L-OHP. On an outpatient basis, the patients received a treatment regimen comprising weekly 80 mg/m2 CPT-11 in the form of a 1-h i.v. infusion and 500 mg/m2 FA as a 1- to 2-h i.v. infusion, followed by 2000 mg/m2 5-FU i.v. administered as a 24-h infusion once weekly. A single treatment cycle comprised six weekly infusions followed by 2 weeks of rest. A total of 26 patients received 344 chemotherapy applications with AIO plus CPT-11. The main symptom of toxicity was diarrhea (NCI-CTC toxicity grade 3+4) occurring in five patients (19%; 95% CI 7-39%). Nausea and vomiting presented in two patients (8%; 95% CI 1-25%). The response rate of 26 patients can be summarized as follows: partial remission: n=7 (27%; 95% CI 12-48%); stable disease: n=9 (35%; 95% CI 17-56%) and progressive disease: n=10 (38%; 95% CI 20-59%). The median progression-free survival (n=26) was 5.8 months (range 3-13), the median survival time counted from the treatment start with the AIO plus CPT-11 regimen was 10 months (range 2-24) and counted from the start of first-line treatment (n=26) was 23 months (range 10-66). We conclude that the AIO regimen plus CPT-11 is practicable in an outpatient setting and well tolerated by the patients. Tumor control was achieved in 62% of the patients. The median survival time was 10 months and the median survival time from the start of first-line treatment (n=26) was 23 months.     

Weekly paclitaxel, 5-fluorouracil and folinic acid with granulocyte colony-stimulating factor support in metastatic breast cancer patients: a phase II study

We conducted a phase II study to determine the activity and tolerability of weekly paclitaxel, 5-fluorouracil (5-FU) and folinic acid plus granulocyte colony-stimulating factor (G-CSF) support in anthracycline-pre-treated or -resistant metastatic breast cancer patients. The phase II study was designed following the Simon optimal-two stage method. Patients received paclitaxel 80 mg/m, folinic acid 10 mg/m and bolus infusion of 5-FU 300 mg/m every week plus G-CSF on day 3 for 24 consecutive weeks in the absence of disease progression. From May 1998 to May 2000, 51 patients entered the study. Patients received a median relative dose intensity of 97.5% (range 81-100%). No severe toxicities were observed. Seven patients (14%) experienced neutropenia grade 2. Seven patients (14%) experienced grade 2 anemia. Two patients (4%) experienced severe asthenia. Three out of 50 evaluable patients [6%, 95% confidence interval (CI) 2-12.6%] showed a complete response, whereas 23 (46%, 95% CI 32.2-59.8%) had a partial response, with an overall response rate of 52% (95% CI 38.2-65.8%). In addition, eight patients (15.7%) had stable disease. In the 13 patients untreated for metastatic disease, the overall response rate was 92.3% (CI 77.8-100), with one complete response and 11 partial responses (84.6% CI 65-100%). In the whole group, the median time to progression and overall survival were 8 (range 1-18) and 14 months (95% CI 11-17), respectively. Thus, in metastatic breast cancer patients pre-treated with anthracyclines, the weekly administration of paclitaxel, 5-FU and folinic acid with G-CSF support seems to be extremely tolerable and active.     

Weekly treatment with irinotecan, folinic acid and infusional 5-fluorouracil (ILF) in patients with advanced gastric cancer

Although 5-fluorouracil remains the mainstay of treatment for advanced gastric cancer (AGC), no standard chemotherapy regimen exists. Combinations of irinotecan with folinic acid and infusional 5-fluorouracil (5-FU) (ILF) have shown good efficacy with acceptable toxicity in patients with metastatic colorectal cancer. At present, only sparse data on ILF are available for AGC. Therefore we conducted a prospective study of this combination in 25 consecutive patients with metastatic gastric cancer. Median age was 63 years, 10 had received prior chemotherapy and 13 presented initially with peritoneal carcinosis. Treatment consisted of irinotecan 80 mg/m2, folinic acid 500 mg/m2 and infusional 5-FU 2.0 g/m2 over 24 h, given weekly for 6 weeks followed by a 1-week rest. Grade 3/4 hematologic toxicity occurred in six patients (anemia = 4, neutropenia = 1 and leukopenia = 1). Non-hematologic toxicity consisted mainly of nausea/vomiting (grade 3/4 in six patients) and diarrhea (grade 3/4 in 10 patients). The overall response rate was 20% for first- and second-line treatment, with two complete and three partial responses. Another nine patients (36%) had stable disease, for a tumor control rate of 56%. Median time to progression was 4 months, median overall survival and survival for patients with tumor control was 7 and 13 months, respectively. We conclude that ILF is a feasible outpatient regimen with manageable toxicity that provides tumor control in a high proportion of patients with advanced gastric cancer, even among those with unfavorable prognostic features.     

Incidence and relative risk of grade 3 and 4 diarrhoea in patients treated with capecitabine or 5- fluorouracil: a meta-analysis of published trials

Aim

Capecitabine is an oral fluoropyrimidine that can effectively replace infusional 5-fluorouracil (5-FU) for treatment of colorectal, gastric and breast cancer. This study aims to analyze the incidence and the relative risk of grade 3 and 4 diarrhoea in patients treated with capecitabine or 5-FU in randomized clinical trials (RCTs).

Methods

MEDLINE and Cochrane Library were reviewed for RCTs that compared capecitabine with 5-FU for treatment of solid malignancies. The incidence and relative risk (RR) of grade 3/4 diarrhoea were estimated for each arm in the overall population and in colorectal cancer (CRC) patients

Results

Twenty-three studies and 15 761 patients were included. Among these 8303 and 7458 patients received capecitabine or 5-FU based therapies, respectively. In the overall populations severe diarrhoea was reported in 16.6% (95% CI 15.8, 17.4) and in 12.7% (95% CI 11.9, 13.4) of patients treated with capecitabine or 5-FU-based therapies, respectively. The RR was 1.39 (95% CI 1.14, 1.69, P = 0.0010). In 14 899 CRC patients, the incidence of severe diarrhoea was 17.0% (95% CI 16.2, 17.9) and 12.9% (95% CI 12.1, 13.7), respectively, with a RR of 1.46 (95% CI 1.18, 1.81, P < 0.0001). In CRC patients treated with combined chemotherapy, the RR was 1.40 (95% CI 1.07, 1.82; P = 0.01) for patients receiving oxaliplatin and 2.35 (95% CI 1.76, 3.13; P < 0.0001) for patients receiving irinotecan.

Conclusions

Treatment with capecitabine is characterized by an increased risk of severe diarrhoea, mainly in patients affected by CRC and treated with polichemotherapy. Combination treatment with irinotecan doubles the risk over 5-FU.     

Oxaliplatin: a review of its use in combination therapy for advanced metastatic colorectal cancer

Oxaliplatin (Eloxatin) is the only platinum compound to show clinical activity in colorectal cancer. The efficacy of a combination of oxaliplatin with various schedules of fluorouracil (5-FU)/folinic acid (FA) as first- or second-line treatment for advanced metastatic colorectal cancer has been investigated in large phase III trials. FOLFOX4 (an oxaliplatin/5-FU/FA regimen) as first-line therapy (n = 795) was superior to irinotecan/5-FU/FA (IFL). Response rates were 45% vs 31%, and median progression-free survival duration was 8.7 vs 6.9 months. The survival advantage shown by FOLFOX4 over the irinotecan combination (median survival duration 19.5 vs 14.8 months) may be confounded by differences in post-study treatment but equivalent efficacy is supported by another phase III trial of oxaliplatin and irinotecan combinations. As first-line therapy, oxaliplatin added to various 5-FU/FA regimens more than doubled the response rates from 16-22.6% to 48.3-53% and the median duration of progression-free survival was significantly longer with oxaliplatin/5-FU/FA than 5-FU/FA alone (7.9-9 versus 5.3-6.2 months, respectively).In disease resistant to irinotecan-based therapies, the oxaliplatin (FOLFOX4) regimen had superior efficacy to 5-FU/FA alone in a pivotal phase III trial (n = 816). Response rates and median durations of progression-free survival were 9.6% vs 0.7% and 5.6 vs 2.6 months, respectively. An oxaliplatin-induced cumulative peripheral sensory neuropathy (evident when total dose reaches approximate, equals 800 mg/m(2)) is dose limiting. The most frequently occurring grade 3 or 4 toxicities in oxaliplatin/5-FU/FA-recipients were neutropenia (up to 48%) and neurological toxicities (up to 18%). Gastrointestinal effects (diarrhoea [ approximate, equals 12%], nausea, vomiting, or mucositis/stomatitis [up to 6%]) are manageable. Withdrawals from oxaliplatin treatment were due to neuropathy (up to 10%), diarrhoea and/or vomiting (1%) or cutaneous toxicity (1%). Conclusion: As first-line therapy for metastatic colorectal cancer, oxaliplatin with 5-FU/FA consistently improves response rates and progression-free survival compared with various regimens of 5-FU/FA alone. The significant survival advantage shown by oxaliplatin/5-FU/FA (FOLFOX4) compared with first-line therapy with irinotecan/5-FU/FA (IFL) is encouraging but may require further confirmation. Oxaliplatin/5-FU/FA produces a significantly higher response rate and longer progression-free survival than 5-FU/FA in patients failing irinotecan-based therapies, and as such is also a useful second-line treatment. Although cumulative neurotoxicity is dose limiting, oxaliplatin has a manageable tolerability profile. Oxaliplatin as first- or second-line therapy is a valuable addition to the limited, but expanding, armamentarium of cytotoxic agents useful in advanced metastatic colorectal cancer.     

Adding weekly irinotecan to high-dose 5-fluorouracil and folinic acid (HD-5-FU/FA) after failure for first-line HD-5-FU/FA in advanced colorectal cancer--a phase II study

Irinotecan (CPT-11) has been shown to prolong survival and improve quality of life in comparison to best supportive care in colorectal cancer patients with pretreatment of bolus 5-fluorouracil (5-FU). After first-line 24-h high-dose (HD) 5-FU/folinic acid (FA) an objective response rate of 11% with 3-weekly CPT-11 350 mg/m was reported. In the present study we investigated weekly CPT-11 in combination with 24-h HD-5-FU/FA as second-line treatment after prior exposure to 24-h HD-5-FU. Synergy between 5-FU and CPT-11 is the rationale to combine both substances for second-line therapy in order to overcome resistance to 5-FU. Thirty-five patients were recruited in a single institution to receive 6 x weekly CPT-11 80 mg/m(2), FA 200 mg/m(2) and 24-h HD-5-FU 2000 mg/m(2). Treatment was repeated on day 57. Patient characteristics: M/F=20/15, median WHO performance status 1, range (0-2). Thirty-four patients were evaluable for response: partial response 17% and no change 40%. Median time to progression and overall survival were 3.3 and 8.4 months, respectively. All patients were evaluable for toxicity analysis (National Cancer Institute Common Toxicity Criteria grade 3): leukocytopenia 3%, diarrhea 12% and vomiting/nausea 6%. Of the assigned doses, a median 100% of 5-FU and 92% of CPT-11 were administered during the first cycle of chemotherapy. We conclude that weekly CPT-11 and HD-5-FU/FA is an active and safe combination chemotherapy resulting in response rates in the upper range of other CPT-11-based second-line regimen. The toxicity profile in our series compared to 3-weekly CPT-11 seems favorable.     

A phase II pilot study of high-dose 24-hour continuous infusion of 5-FU and leucovorin and low-dose PALA for patients with colorectal cancer: A Southwest Oncology Group study

PURPOSE: The purpose of this phase II multi-institutional study was to define the efficacy and toxicity of infusional 5-FU in combination with PALA and leucovorin in patients with advanced colorectal cancer. PATIENTS AND METHODS: Patients were required to have histologically confirmed colorectal cancer with distant metastases. The treatment regimen consisted of 5-FU 2600 mg/m(2) as a 24-hours continuous infusion given once a week, concurrently with leucovorin (LV) at 500 mg/m(2) as a 24-hour continuous infusion. PALA was administered 24 hours prior to 5-FU/LV at a dose of 250 mg/m(2) iv over 15 minutes weekly. Patients were continued on the assigned treatment regimen until progression of disease, unacceptable toxicity, or the patient declined further therapy. RESULTS: This study accrued 28 patients and all were eligible and evaluable for toxicity. Four patients had inadequate assessment of response and are considered non-responders. There was one complete response and five partial responses for an overall response rate of 6/28 or 21% (95% confidence interval 8-41%). Estimated median survival was 17.4 months (95% confidence interval 13.3-20.5 months). One patient died of a treatment related infection. This patient also had grade 4 diarrhea and vomiting. CONCLUSION: The combination of 5-FU, leucovorin, and PALA in the doses and schedule used here, produces a response rate similar to other modulated schedules of 5-FU with similar survival and toxicity profiles.     

Phase II study of combination chemotherapy with biweekly cetuximab and irinotecan for wild-type KRAS metastatic colorectal cancer refractory to irinotecan, oxaliplatin, and fluoropyrimidines

The aim of this study is to prospectively evaluate the efficacy of combination chemotherapy with every second week cetuximab and irinotecan in patients with pretreated metastatic colorectal cancer harboring wild-type KRAS. Patients with wild-type KRAS metastatic colorectal cancer that had progressed after chemotherapy with irinotecan, oxaliplatin, and fluoropyrimidine were included. Cetuximab was administered at 500 mg/m(2) biweekly with irinotecan. The primary endpoint was response rate. The pharmacokinetics of cetuximab was also evaluated in 5 patients. From May 2009 to February 2010, a total of 31 patients were enrolled from five institutions. One patient was not eligible. Among the 30 patients who were treated with biweekly cetuximab plus irinotecan, partial response was observed in 9 patients. The objective response rate was 30.0% (95% confidence interval [CI], 14.7%-49.4%) and the disease control rate (complete response, partial response, or stable disease) was 76.7% (95% CI, 57.7%-90.0%). The median progression-free survival was 5.3 months and median overall survival was 10.8 months. Grade 3 skin toxicity was observed in 3 patients (10.0%) and one treatment related death due to pneumonia was observed. Combination chemotherapy with biweekly cetuximab and irinotecan was effective for pretreated metastatic colorectal cancer with wild-type KRAS.     

Biweekly oxaliplatin plus irinotecan and folinic acid-modulated 5-fluorouracil: a phase II study in pretreated patients with metastatic colorectal cancer

Oxaliplatin (OXA) and irinotecan (IRI) are active drugs for metastatic colorectal cancer, their toxicity profiles are not overlapping, and both drugs have shown at least additivity with folinic acid-modulated 5-fluorouracil (5FU). We carried out this phase II study to assess the activity and toxicity of a biweekly regimen including OXA plus IRI on day 1, and levo-folinic acid (LFA) plus 5FU on day 2 (OXIRIFAFU) in pretreated patients with metastatic colorectal cancer. Forty-one patients, all previously treated with adjuvant and/or palliative 5FU-based chemotherapy (16 of them already exposed to IRI, OXA or both), were enrolled into this trial. On the basis of sensitivity to previous treatment, 19 patients were considered as chemo-resistant and 14 patients as chemo-refractory. OXA 110 mg/m (over 2 h) and IRI 175 mg/m (over 1 h) were delivered on day 1, followed by LFA 250 mg/m (2-h infusion) plus 5FU 800 mg/m as intravenous bolus on day 2. Cycles were repeated every 2 weeks. A total of 348 cycles were delivered, with a median of nine cycles per patient (range, 1-12 cycles per patient). Five complete and 13 partial responses were reported on 40 assessable patients, giving a response rate of 45% [95% confidence interval (CI), 29-62%]; eight of 19 (42%) resistant patients and five of 14 (36%) refractory patients achieved a major response, which was also obtained in four of eight (50%) patients pretreated with IRI and in three of eight (38%) patients pretreated with OXA. Grade 3 or higher neutropenia occurred in 68% of patients, but febrile neutropenia or infections affected only seven (17%) patients. No episodes of grade 3 or higher thrombocytopenia or anemia were recorded. Occurrence of severe non-hematologic toxicities by patients were: diarrhea, 34%; vomiting, 17%; peripheral cumulative neuropathy, 15%; stomatitis, 10%; acute cholinergic syndrome, 7%. Actually delivered dose intensities of all three drugs resulted in about two-thirds of the planned ones. After a follow-up of 39 months, median progression-free survival was 7.5 months. Median overall survival was 14.4 (95% CI, 10.4-18.4) months from the start of OXIRIFAFU and 25.3 (95% CI, 18.1-32.5) months from the diagnosis of metastatic disease. This OXIRIFAFU triplet regimen was highly effective in resistant/refractory colorectal cancer patients. A slight dose reduction of all cytotoxic drugs could be advisable in order to improve the tolerability of this regimen without jeopardizing its activity.     

Cetuximab-based or bevacizumab-based first-line treatment in patients with KRAS p.G13D-mutated metastatic colorectal cancer: a pooled analysis

KRAS p.G13D mutant metastatic colorectal cancer (mCRC) has been identified as representing a cetuximab-sensitive subtype of KRAS mutant mCRC. This analysis aims to answer the question of whether first-line treatment of p.G13D mCRCs should include cetuximab or bevacizumab. Fifty-four patients with p.G13D mutant mCRC were pooled in this analysis. All patients underwent systemic first-line treatment with a fluoropyrimidine and oxaliplatin/irinotecan that was combined with either cetuximab or bevacizumab. The analysis of cetuximab-based and bevacizumab-based regimens in mCRC patients with p.G13D-mutated tumours indicated comparable data for the overall response rate (58 vs. 57%) and progression-free survival (8.0 vs. 8.7 months; hazard ratio: 0.96, P=0.9). Overall survival (OS) was 20.1 months in patients treated with cetuximab-based first-line therapy compared with 14.9 months in patients receiving bevacizumab-containing regimens (hazard ratio: 0.70, P=0.29). Logistic regressions modelling OS revealed oxaliplatin-based first-line treatment to correlate with a poor outcome (P=0.03). Moreover, a strong trend in favour of capecitabine compared with infusional 5-FU (P=0.06) was observed. Response to treatment correlated with OS in patients receiving cetuximab-based, but not bevacizumab-based regimens. This retrospective pooled analysis suggests comparable efficacy of cetuximab-based and bevacizumab-based first-line therapy in patients with p.G13D mutant mCRC. The combination with capecitabine and irinotecan was associated with a more favourable outcome compared with infusional 5-FU and oxaliplatin.     

Pegylated liposomal doxorubicin and mitomycin C in combination with infusional 5-fluorouracil and sodium folinic acid in the treatment of advanced gastric cancer: results of a phase II trial

Mitomycin C (MMC) in combination with infusional 5-fluorouracil (5-FU) is a well-tolerated active combination therapy for advanced gastric cancer. Pegylated liposomal doxorubicin (Caelyx) has been combined with this regimen in a phase I study exhibiting promising activity in patients with upper gastrointestinal tumors. In the present study, we investigated activity and tolerability of this three-drug regimen in patients with gastric cancer. Patients with advanced or metastatic gastric cancer were recruited to receive weekly infusional 5-FU (2000 mg/m2) mixed with sodium folinic acid (FA; 500 mg/m2) in one pump (days 1, 8, 15, 22, 29, 36). On days 1 and 29, Caelyx (20 mg/m2) was given as a 1-h, and MMC (7 mg/m2) was applied as bolus injection on days 8 and 36. Treatment courses were repeated on day 57. Twenty-seven patients with a median age of 66 years were recruited in a single center; 56% had histologically proven peritoneal carcinomatosis and 26 patients are evaluable for toxicity. Common Toxicity Criteria of the National Cancer Institute grade 3 toxicity was recorded in 34% of the patients (anemia 12%, leukocytopenia 8%, febrile neutropenia 4%, thrombocytopenia 12%, nausea 15%, diarrhea 8% and mucositis 4%). One patient developed hemolytic-uremic syndrome. One complete (5%) and eight partial responses (42%) were observed in 19 patients evaluable for response according to WHO criteria. Seven patients had no change (37%) and three (16%) progressive disease. Six patients with peritoneal carcinomatosis not amenable to WHO response assessment had progression-free intervals between 8 and 21 months. Median survival for all patients was 14.7 months and median time to progression was 8.4 months. We conclude that this new three-drug combination regimen yields a promising overall response rate (47%) in patients with gastric cancer despite the inclusion of a majority of elderly patients at moderate or high risk of death in this trial. Its safety and good tolerability as established in the phase I trial was confirmed.     

Bevacizumab: a review of its use in metastatic colorectal cancer

Bevacizumab (Avastin) is a recombinant, humanized monoclonal antibody against vascular endothelial growth factor (VEGF) that is used to inhibit VEGF function in vascular endothelial cells and thereby inhibit tumour angiogenesis, upon which solid tumours depend for growth and metastasis.The addition of bevacizumab to fluoropyrimidine-based chemotherapy, with or without irinotecan or oxaliplatin, in both the first- and second-line treatment of metastatic colorectal cancer, significantly increased median progression-free survival or time to disease progression in most randomized controlled trials. Bevacizumab was generally, but not always, associated with a survival advantage; in phase III trials, the increases in median overall survival attributable to bevacizumab were 4.7 months with first-line therapy and 2.1 months with second-line therapy. In some studies, patients experienced clinical improvement without an apparent overall survival benefit. Bevacizumab had acceptable tolerability, with the majority of adverse events being generally mild and clinically manageable. However, from the UK National Health Service perspective, bevacizumab was not considered to be cost effective in combination with bolus fluorouracil/folinic acid or irinotecan/bolus fluorouracil/folinic acid. Additional pharmacoeconomic analyses from different perspectives and using clinical data for combinations with the more efficacious infusional fluorouracil/folinic acid plus oxaliplatin or irinotecan chemotherapy regimens are required. Although cost effectiveness may be a concern, the combination of bevacizumab and fluoropyrimidine-based chemotherapy has potential in the treatment of metastatic colorectal cancer.     

Phase II trial of oxaliplatin combined with leucovorin and fluorouracil for recurrent/metastatic biliary tract carcinoma

Biliary tract carcinoma is often diagnosed at an advanced stage, and there is currently no established palliative standard of care. This phase II study investigated the efficacy and safety of combination chemotherapy of oxaliplatin, leucovorin, and 5-fluorouracil (5-FU) in biliary tract carcinoma. Patients with unresectable or recurrent biliary tract carcinoma were enrolled, including pretreated and chemotherapy-naive patients. Treatment consisted of intravenous oxaliplatin (100 mg/m2, day 1) followed by leucovorin (100 mg/m2, day 1) and 5-FU (1000 mg/m2, days 1 and 2). Treatment was repeated every 3 weeks. The efficacy and safety of the treatment were determined. Twenty-eight patients were evaluable, and a total of 166 cycles were administered (median five cycles). One complete response (3.6%) and five partial responses (17.9%) were noted, with a response rate of 21.5% [95% confidence interval (CI): 6.2-36.7], according to Response Evaluation Criteria in Solid Tumors criteria. The median time to progression and overall survival was 3.5 months (95% CI: 2.7-4.3) and 10.0 months (95% CI: 7.2-12.8), respectively. The 1-year survival rate was 17.8%. Grade 3/4 neutropenia and thrombocytopenia were recorded in 18 and 4% of the patients, respectively. No treatment-related death was observed. Oxaliplatin in combination with leucovorin and 5-FU should be considered a feasible chemotherapy regimen for patients with recurrent/metastatic biliary tract carcinoma.