A combination of gemcitabine and 5-fluorouracil in advanced pancreatic cancer, a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD).

In a randomized clinical trial, gemcitabine (GEM) was more effective than 5-fluorouracil (5-FU) in advanced pancreatic cancer patients. GEM and 5-FU have different mechanisms of action and their combination, from a theoretical point of view, could result in a higher activity. To test activity and feasibility of such a combination, a multi-institutional phase II study was initiated in November 1996 by the Italian Group for the study of Digestive Tract Cancer (GISCAD). Primary objectives of this study were to determine the activity in terms of response rate and clinical benefit, while the secondary objective was toxicity. According to the optimal two-stage phase II design, 54 patients were enrolled. Schedule was: GEM 1000 mg m(-2) intravenous (i.v.), and 5-FU 600 mg m(-2) bolus i.v. weekly for 3 weeks out of every 4. All the 54 patients were symptomatic (pain, weight loss, dyspepsia). A clinical benefit was obtained in 28 patients (51%) (95% confidence interval (CI) 38-64%). Two patients achieved a partial response and 34 a stable disease. Median survival for all the patients was 7 months. Side-effects were mild: no gastrointestinal or haematological grade 3-4 toxicity (WHO) were recorded. We observed only six episodes of grade 2 (WHO) leukopenia and seven episodes of thrombocytopenia. Although the non-randomized design of this study suggests caution in the interpretation of these data, in consideration of the low incidence of toxicity and the favourable results obtained in terms of clinical benefit, it may be worthwhile to test more active schedules of 5-FU (continuous infusion) in combination with gemcitabine.     

High- versus low-dose levo-leucovorin as a modulator of 5-fluorouracil in advanced colorectal cancer: A 'GISCAD' phase III study

Background: Although leucovorin (LV) + 5-fluorouracil (5-FU) isconsidered the treatment of choice for advanced colorectal cancer in mostcountries, the optimal schedule of this combination has not yet beenestablished. Low-dose LV appears to be as active as high-dose LV in thedaily-times-five regimen, but no randomized study of the levorotatorystereoisomer (6S-LV) given at two different dose levels has been published.Patients and methods: Between November 1991 and June 1994, 422patients (all with measurable disease previously untreated with chemotherapy)were randomized to 6S-LV (100 mg/sqm/i.v.) + 5-FU (370 mg/sqm/15 min i.v.infusion), both administered for 5 days every 28 days (arm A), or to 6S-LV (10mg/sqm/i.v.) + 5-FU (doses as above), also given for 5 days every 28 days (armB). The primary endpoint of the study was the comparison of response rates(WHO criteria); the secondary endpoint was the assessment of survival andtolerability. No evaluation of the quality of life or the symptomatic effectof treatment was planned.Results: The response rate was 9.3% in arm A (95% CI:5.4–13.1), with 2 CR and 18 PR, and 10.7% in arm B (95%CI: 6.5–14.9), with 3 CR + 19 PR, without any significant difference(P = 0.78). The median time to progression was eight months in bothgroups and overall survival was 11 months, with no difference betweentreatments. Toxicity mainly consisted of gastrointestinal side effects(mucositis and diarrhoea), which were rarely severe (grade 3–4:5%–10% of patients) and similar in the two groups.Conclusions: In this large-scale multicentre trial, the low and highdoses of 6S-LV appeared to be equivalent in terms of the biochemicalmodulation of 5-FU in advanced colorectal cancer although, for several reasons(including the timing and the strict criteria of response evaluation, the highnumber of patients with unfavourable prognostic factors, themulti-institutional nature of the study, the dose and modality of 5-FUadministration), the response rate was lower than that reported in some of theother published studies. Given the considerable difference in economic costbetween the two dosages, the use of high-dose 6S-LV in the daily-times-fiveregimen is not recommended in clinical practice.     

Sequential methotrexate-5-fluorouracil (MTX-5-FU) treatment of patients with advanced gastric and colorectal cancer. Sequential Methotrexate-5-FU Study Group

A multicenter cooperative study was conducted from July 1984 to March 1986 to evaluate the clinical efficacy of sequential MTX-5-FU treatment in 96 cases of advanced gastric cancer and 39 cases of colorectal cancer. 5-FU 600 mg/m2 i.v. was given and MTX 30 mg/m2 (A), 100 mg/m2 (B) and 300 mg/m2 (C) i.v. were given, and the administration interval between MTX and 5-FU was 1 to 3 h for the gastric cancer group, and 7 h for the colorectal cancer group. Leucovorin rescue of 10 mg/m2 p.o. was given 24 h after MTX administration. In the gastric cancer group, the response rate for Regimen A was 23.2% (CR 1 and PR 12) out of 56 evaluable cases, and for Regimen B, 40.5% (CR 1 and PR 14) out of 37 evaluable cases. In the colorectal cancer group, the response rate for Regimen A was 28.6% (PR 6) out of 21 evaluable cases and for Regimen B, 20.0% (PR 3) out of 15 cases. Median survival time for the gastric cancer group was 5.5 months with Regimen A and 7.6 months with Regimen B, and for the colorectal cancer group 10.9 months with Regimen A and 7.9 months with Regimen B. Main adverse effects were marrow impairment and gastrointestinal symptoms such as nausea, diarrhea, and stomatitis. In this study Regimen B showed relatively good results. In order to evaluate the biochemical modulation occurring with sequential MTX-5-FU treatment, a further phase III study in gastric cancer patients should be conducted.     

A prospective randomized trial of continuous infusion 5-fluorouracil (5-FU) versus 5-FU plus cisplatin in patients with advanced colorectal cancer. A trial of the Spanish Cooperative Group for Digestive Tract Tumor Therapy (T.T.D.).

One hundred sixty consecutive patients with histologically confirmed colorectal cancer (advanced disease) without prior chemotherapy were entered in a randomized trial comparing 5-fluorouracil (5-FU) 1,000 mg/m2 intravenously per day for 5 consecutive days in continuous infusion versus cisplatin (CP) 100 mg/m2 on day 1 plus 5-FU as described on days 2 to 6. In both arms, treatment was recycled every 4 weeks. Both groups were well balanced for age, sex, colon or rectal origin, median time between diagnosis to advanced disease, performance status at entry, and visceral involvement. The overall response rate in the combination and in the single arm were 18 and 23%, respectively. There were no differences in time to progression (a median of 17.8 and 14.9 weeks for CP-5-FU and 5-FU, respectively) and in overall survival (a median of 71.2 and 59.6 weeks, respectively). The incidence of grade 3-4 emesis was significantly higher in the CP-containing chemotherapy (p = .00001). Our study has failed to demonstrate any clinical benefit from adding cisplatin to 5-FU in patients with cancer of the colon and rectum.     

Etoposide,leucovorin (LV) and 5-fluorouracil (5-FU) in 5-FU+LV pre-treated patients with advanced colorectal cancer

In the present study, we evaluated the efficacy and safety of the weekly combination of etoposide, leucovorin (LV) and 5-fluorouracil (5-FU) when administered as second-line chemotherapy in patients with relapsed/refractory advanced colorectal cancer (ACC), previously treated with weekly LV+5-FU. Etoposide was administered at 3 different dose levels (DLs), in 3 groups of 20 patients each (total: 60); DL-I: etoposide 80 mg/m2, DL-II: etoposide 120 mg/m2, and DL-III: etoposide 180 mg/m2, in 45 min i.v. infusion, and followed in all levels by LV 100 mg/m2 i.v. over 1 hour and 5-FU 500 mg/m2 i.v. bolus. Treatment was administered weekly until disease progression or unacceptable toxicity. No patients at DL-I responded, while 2 patients at DL-II and 3 at DL-III had a partial response (PR). Stable disease (SD) rates were as follows; at DL-I: 2, DL-II: 8 and DL-III: 9. More patients in DL-I progressed (n = 19) compared to DL-II (n=10) and DL-II (n = 8) (p < 0.0007). Time to progression was for DL-I, -II, -III: 17, 15, and 14 weeks, respectively. Median survival was DL-I, -II, -III: 30, 30, and 32.5 weeks, respectively. Toxicity consisted mainly of neutropenia, diarrhea and mucositis at all DLs, and was significantly more severe in DL-III. No difference was noted in responses between DL-II and DL-III. The authors conclude that the combination of etoposide with LV+5-FU has limited activity when administered after failure of weekly LV+5-FU in patients with ACC and should not be recommended for further evaluation.     

High-dose leucovorin and 5-fluorouracil in advanced gastric and colorectal cancer. High-Dose Leucovorin and 5-FU Study Group

A multicenter cooperative study was conducted from June 1988 to July 1989 to evaluate the clinical efficacy of high-dose dl-Leucovorin (dl-LV) and 5-FU treatment in 61 cases of advanced gastric and colorectal cancer. The administration schedule was a 2-hour infusion of dl-LV (500 mg/m2) and an IV bolus of 5-FU (600 mg/m2), given 1 hour after the beginning of LV infusion. Patients (pts.) were treated q week x 6 then evaluated for response. Thirty one gastric cancer pts. were divided into two groups; nine pts. treated with 30 min. infusion of 5-FU, and the remaining 23 pts. treated with IV bolus. PR was obtained in 2/9 (22.2%) and in 7/22 (31.8%) of the first and second group, respectively. An overall response rate was 9/31 (29%). Thirty colorectal cancer pts. were divided the same: 13 pts. treated with 30 min. infusion of 5-FU and the remaining 17 pts. treated with IV bolus. PR was obtained in 2/13 (15.4%) and in 7/17 (41.2) of the first and second groups, respectively. An overall response rate was 9/30 (30%). Median survival time for the gastric cancer group was 9.4 months, and for the colorectal cancer group was 13.6 months. Toxicity was within acceptable limits. Toxic effects included diarrhea, stomatitis, anorexia and myelohypoplasia. Our data suggests that high dose LV and 5-FU seems to be a very promising combination and warrants a further investigation.     

Phase III evaluation of octreotide versus chemotherapy with 5-fluorouracil or 5-fluorouracil plus leucovorin in advanced exocrine pancreatic cancer: a North Central Cancer Treatment Group study.

There continues to be a need for new systemic approaches for the treatment of advanced pancreatic cancer. The purpose of this study was to compare the antitumor activity of the somatostatin analogue octreotide to 5-fluorouracil chemotherapy in a Phase III setting. Eighty-four patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 and limited tumor volume were randomized to receive octreotide 200 microg three times daily or 5-fluorouracil with or without leucovorin. After the first 12 patients had been randomized to octreotide, we increased the dose in the remaining patients to 500 microg three times daily. This change was based on early reports in other studies, suggesting that our original dose may not have been effective and that higher doses of octreotide were well tolerated. A planned interim analysis performed after 84 patients were enrolled demonstrated inferior time to progression and survival for the patients randomized to octreotide. Further accrual to the octreotide arm of this protocol was therefore terminated. Octreotide in doses of 200-500 microg three times daily does not delay progression or extend survival in patients with advanced pancreatic cancer compared with treatment with 5-fluorouracil with or without leucovorin.     

A phase III study of 5-fluorouracil versus 5-fluorouracil plus interferon alpha 2b versus 5-fluorouracil plus leucovorin in patients with advanced colorectal cancer: a Hellenic Cooperative Oncology Group (HeCOG) study

We conducted a phase III study in patients with advanced colorectal carcinoma (ACC). The total number of patients randomized from October 1993 until July 1998 was 192, whereas therapy was started on 179 and 158 (82.3%) have been evaluable. The treatment schedules consisted of weekly bolus administration for 6 weeks of 5-fluorouracil (5-FU), 600 mg/m2 (arm I) versus 5-FU (500 mg/m2) intravenous bolus and interferon-alpha, 5 MU subcutaneously, three times a week (arm II) versus leucovorin 200 mg/m2 in 2-hour infusion and 5-FU 500 mg/m2 intravenous bolus at the midtime of leucovorin infusion (arm III) followed by a 2-week rest period. Treatment was continued for six cycles or until progression. This study failed to show any superiority of the modulated 5-FU versus single administration of 5-FU. There were no significant differences between the three arms in the overall response rate (10.3% versus 11.3% versus 12.9%, p = 0.95), the time to tumor progression (median, 3.9 versus 3.8 versus 6.0 months, p = 0.59), or survival duration (median, 14.7 versus 12.4 versus 16.3 months, p = 0.71). The incidence of severe (grades III and IV) toxicity was significantly higher in patients in arm II and III (24.5% and 18.6%) versus arm I (6.0%) (p = 0.01). Because modulated 5-FU failed to show superiority versus 5-FU, new agents and new strategies are needed for the treatment of advanced colorectal carcinoma.     

A phase I-II study of gemcitabine and docetaxel in advanced pancreatic cancer: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD).

Background: Gemcitabine and docetaxel have been claimed to be active single agents in advanced pancreatic cancer. We determined the maximum tolerable dose of docetaxel combined with a weekly fixed dose of gemcitabine and assessed the activity of this combination in advanced pancreatic cancer.Patients and methods: Phase I. Patients were treated with gemcitabine on days 1 and 8, every three weeks, at a fixed dose of 1,000 mg/m²; docetaxel was given at escalating doses starting from 70 mg/m² on day 8. Phase II. In accord with the optimal two-stage phase II study design, 18 patients were treated with gemcitabine (1000 mg/m²) and the maximum tolerable dose of docetaxel (70 mg/m²).Results: Phase I. Dose-limiting toxicities occurred at the second dose level of docetaxel (80 mg/m²), with all three patients developing grades 3 or 4 neutropenia. Consequently, the dose tested in the phase II study was 70 mg/m². Phase II. In the 18 patients enrolled in the study, we registered only one partial response. The time to progression was 3 months, and the median treatment survival was 5.4 months. Grade 3–4 toxicities consisted of neutropenia (three episodes) and thrombocytopenia (two episodes). Furthermore, 10 patients complained of grade 3 fatigue.Conclusions: The addition of docetaxel to gemcitabine does not appear to be useful in advanced pancreatic cancer, since gemcitabine alone achieves similar results.     

Phase II trial of continuous-infusion iproplatin (CHIP) and 5-fluorouracil (5-FU) in advanced colorectal carcinoma

Summary Following the observation of antitumor activity for the combination of 5-fluorouracil (5-FU) and cisplatin in metastatic colorectal carcinoma, the combination of 5-FU and iproplatin was tested, also in colorectal carcinoma, in the hope of attaining equivalent activity without the nephrotoxicity observed with 5-FU/cisplatin. However, no responses were achieved with 5-FU/iproplatin.     

120-hour 5-fluorouracil (5-FU) continuous infusion (CI) plus BCNU in advanced colorectal cancer

Seventy-five previously untreated patients with measurable advanced colorectal cancer were treated with 5 fluorouracil 1,000 mg/m2 as a 24-hour intravenous (i.v.) continuous infusion during days 1-5 and 28-32 every cycle, plus 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), 200 mg/m2 i.v. bolus on day 1, all given every 8 weeks up to 6 cycles. Median Karnofsky performance status (KPS) was 100. Sites of disease at entry were mainly the abdomen (45%) and liver (33%). All patients were evaluable for response and survival. There were two complete responses and seven partial responses (PR) for an overall response rate of 12% (95% confidence limits: 5-20%). Four out of 25 patients with liver metastases alone had PR. Stabilization was seen in 40 patients (53%). Median time to progression was 9.3 months and overall median survival was 12.5 months, whereas median survival for patients with liver metastases alone was 16 months. Toxicity was mild except for 8% with WHO grade 4 mucositis. Only KPS had statistical significance in the multivariate analysis of prognostic factors. It is concluded that this regimen is relatively active and well tolerated in patients with advanced colorectal cancer.     

Intensive weekly chemotherapy for locally advanced gastric cancer using 5-fluorouracil, cisplatin, epidoxorubicin, 6S-leucovorin, glutathione and filgrastim: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD).

Local extension prevents curative resection in more than two-thirds of gastric cancer patients. Unfortunately, resectability is one of the main prognostic factors in these patients, and survival is longer when tumours are completely removed. Preoperative chemotherapy is an attractive concept for obtaining curative resection. Thirty-two locally advanced unresectable gastric cancer patients were enrolled in five Italian Group for the Study of Digestive Tract Cancer (GISCAD) centres. For 16 patients, surgical unresectability was based on computerized tomography scan evaluation of tumour size (four patients) and invasion of adjacent structures (12 patients), whereas in another 16 patients locally advanced disease was confirmed by laparotomy. They received weekly administration of cisplatin 40 mg m(-2), 5-fluorouracil 500 mg m(-2), epidoxorubicin 35 mg m(-2), 6S-stereoisomer of leucovorin 250 mg m(-2) and glutathione 1.5 g m(-2). From the day after to the day before each chemotherapy administration, filgrastim was administered by subcutaneous injection at a dose of 5 microg kg(-1). One cycle of therapy consisted of eight weekly treatments. Fifteen of 32 patients (47%) responded to chemotherapy, whereas 13 (41 %) had stable disease and four (12%) progressed on therapy. Of the 15 responding patients, 13 were completely resected after chemotherapy and two of them had a complete pathological response. Two clinically responding patients were found unresectable at operation because of peritoneal seeding. At a median follow-up from the start of treatment of 24 months (range 11-39 months), 10 of 13 resected patients are alive and eight are relapse free. Three patients died after 11, 12, and 14 months respectively. Toxicity was acceptable: side-effects consisted mainly of grade II National Cancer Institute common toxicity criteria (NCICTC) leucopenia and thrombocytopenia in ten patients. Neither treatment-related death nor surgical complications in patients undergoing surgery were observed. This weekly intensive regimen enabled resection in half of previously inoperable tumours with a moderate toxicity. It can be offered to patients with locally advanced unresectable gastric cancer to obtain curative resection.     

Weekly regimen of 5-FU vs 5-FU + intermediate dose folinic acid in the treatment of advanced colorectal cancer.

Sixty-four patients with advanced colorectal cancer were randomized to receive 5-fluorouracil (5-FU) at the dose of 600 mg/sm weekly or the same regimen of 5-FU administered halfway through a 1 hour i.v. infusion of folinic acid (FA) at the dose of 200 mg/sm. A partial remission (PR) was obtained in 1/30 patients (3%) treated with 5-FU and in 9/34 patients (26%) treated with 5-FU + FA (P = 0.028). The objective response was accompanied by an improvement in subjective status and general conditions. The median duration of PR in 5-FU + FA arm was 10 months (range: 6-17). The median time to progression was 5 and 6 months in patients treated with 5FU and 5FU + FA, respectively (not a statistically significant difference). There were no cases of grade 4 toxicity. A higher, but not statistically significant, incidence and intensity of diarrhoea was observed in the 5-FU + FA arm. However, 14 patients on 5-FU + FA as opposed to 3 on 5-FU had to stop the treatment temporarily because of side-effects (P = 0.011). Median survival was higher with 5-FU + FA treatment (10 vs 7 months), but the difference is not statistically significant. This study confirms that the addition of an intermediate dose of FA enhances the cytotoxicity of 5-FU. Although its clinical advantage was limited, this weekly 5-FU + FA regimen appears useful in the treatment of advanced colo-rectal cancer on a outpatient basis.     

Phase III trial of irinotecan plus infusional 5-fluorouracil/folinic acid versus irinotecan plus oxaliplatin as first-line treatment of advanced colorectal cancer

Purpose

To determine whether irinotecan plus oxaliplatin (mIROX) is superior to irinotecan plus infusional 5-fluorouracil, leucovorin (FUFIRI) as first-line therapy of patients with metastatic colorectal cancer (mCRC).

Patients and methods

A phase III, randomised, open-label multicentre study compared standard treatment with FUFIRI (irinotecan 80 mg/m², 5-fluorouracil 2000 mg/m², folinic acid 500 mg/m² weekly times 6) to mIROX using an identical schedule of irinotecan plus oxaliplatin 85 mg/m² applied on days 1, 15 and 29 of a 7-week cycle. The primary end-point was progression-free survival (PFS).

Results

A total of 479 eligible patients were randomly assigned. Progression-free survival was 7.2 months in the mIROX arm and 8.2 months in the FUFIRI arm [hazard ratio = 1.14; 95% confidence interval (CI) 0.94-1.37; P = 0.178]. Comparable results were also obtained for overall survival time with 19 months in the mIROX-arm and 22 months in the FUFIRI-arm (hazard ratio = 1.08, P = 0.276). Both regimens induced an identical objective response rate (ORR) of 41%, but disease control rate (ORR plus stable disease) was significantly greater in the FUFIRI group (81% versus 68%, P = 0.001). Most frequent grades 1-4 side-effects of mIROX and FUFIRI treatment were nausea (80% versus 73%) and delayed diarrhoea (79% versus 68%). Grades 3-4 toxicities were generally below 10%, except for diarrhoea which was more frequent in the mIROX-arm compared to the FUFIRI-arm (19% versus 30%, P = 0.006)

Conclusion

mIROX failed to show superior activity compared to high-dose 5-FU/folinic acid plus irinotecan. Due to better tolerability the combination of high-dose 5-FU/folinic acid and irinotecan remains a standard of care in first-line treatment of metastatic colorectal cancer.     

Preoperative treatment with 5-fluorouracil (5-FU) in gastric and colorectal cancer

Preoperative chemotherapy with 5-FU was carried out on patients with gastric and colorectal cancer. 5-FU was given at a dose of 500 mg daily with a drip infusion for 7 days (Group A), with a one-shot intravenous infusion daily (Group B) and orally for 7 days (Group C). Histological effects were evaluated, using the criteria proposed by Ohboshi. In group A for gastric cancer and in group C for colon cancer, the histological response was stronger at the edge of the cancer than at its surface. In group C for gastric cancer and in group A for colon cancer, the histological response was more remarkable at the surface of the cancer than at its edge. The histological effects on metastatic lymph nodes in gastric cancer were the same as for the cancer nests in groups A and C. 5-FU used as a drip infusion or orally was more effective on metastatic lymph nodes of gastric cancer than on metastatic lymph nodes of colon cancer. 5-FU was detected at a high concentration in tumor tissues of gastric cancer in group A, Grade II response being obtained in 3 of 7 patients. Changes in regional lymph nodes, plasma and other organs in cases of combined resection were not obtained with regard to either the concentration of 5-FU or the histological findings for all three groups.     

A combination of a fixed dose rate infusion of gemcitabine associated to a bolus 5-fluorouracil in advanced pancreatic cancer, a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD)

Background:Laboratory evidences suggest the possibility that aninfusion rate of 10 mg/m²/min may be more effective than thestandard 30-min infusion of Gemcitabine (GEM). Patients and methods:Thirty-four patients with histologicallyverified locally unresectable and/or metastatic pancreatic carcinoma receivedGEM at the dose of 1,500 mg/m² with an infusion rate of 10mg/m²/min, associated to 5-fluorouracil (5-FU) at the dose of 600mg/m². Both drugs were administered weekly for two consecutiveweeks out of every three weeks. Results:One complete and five partial responses have beenobserved for an overall response rate of 17% (95% CI:3%–27%). The time to progression was 3.7 months with amedian survival of 5.7 months. A clinical benefit was obtained in 5 of 29patients (17%). Grade 3–4 WHO toxicities included neutropenia(35%) and thrombocytopenia (10%). Conclusion:It is unlikely that a fixed dose rate infusion of GEM,at least with this dose, can improve palliation in comparison with thestandard 30-min infusion schedule in advanced pancreatic cancer.     

A double-blind randomized comparative study of oral 5-fluorouracil (5-FU), cyclophosphamide (CPA), and 5-FU + CPA in advanced breast cancer

A randomized trial was performed comparing the effects of oral 5-fluorouracil (5-FU), 300 mg/day, cyclophosphamide (CPA), 150 mg/day and 5-FU + CPA in advanced breast cancer. Some 181 patients were entered in the trial, with 1 ineligible, and 14 incomplete cases. Then 166 were evaluated for their rates of response in the treatment groups: 14.0% (8/57) in 5-FU, 23.6% (13/55) in CPA, and 37.0% (20/54) in 5-FU + CPA, with a P value of 0.019. The difference in response rates between 5-FU and 5-FU + CPA was shown to be significant (p = 0.005). When long NC was included in the comparison, there was a significant difference (p = 0.006) between the groups. A higher incidence of adverse effects was noted in the combination group. A significant difference was noted in TTP (time to progression) among the 3 groups (p = 0.0144), and between 5-FU and 5-FU + CPA (p = 0.0061). There were no significant differences in the overall survival among the groups (p = 0.6808). In conclusion, the combination oral treatment of 5-FU and CPA appears effective as a first line therapy for advanced breast cancer, and also in the postoperative adjuvant setting.     

The value of oxaliplatin in combination with continuous infusion +/- bolus 5-fluorouracil and levo-folinic acid in metastatic colorectal cancer progressing after 5FU-based chemotherapy: a GISCAD (Italian Group for the Study of Digestive Tract) cancer phase II trial

AIMS AND BACKGROUND: The phase II trial was designed to evaluate the activity of combined oxaliplatin (L-OHP), continuous infusion (CI) +/- bolus 5-fluorouracil (5FU) and levo-folinic acid (I-FA) in patients with metastatic colorectal cancer progressing after one or more lines of 5FU-based chemotherapy. PATIENTS AND METHODS: We designed two contemporary studies: in the former we enrolled patients previously treated with 1 line of chemotherapy, and in the latter, patients previously treated with 2, 3 and 4 lines. Seventy-six consecutive patients were enrolled: 45 received L-OHP (85 mg/m2 i.v. 2 h on day 1) + I-FA (100 mg/m2 i.v. 2 h on days 1 and 2) + 5FU i.v. bolus (400 mg/m2 days 1 and 2) + 5FU (600 mg/m2 CI 22 h days 1 and 2 (FOLFOX 4); 31 received L-OHP (100 mg/m2 i.v. 2 h on day 1) + I-FA (250 mg/m2 i.v. 2 h on days 1 and 2), followed by 5FU (1500 mg/m2 Cl 24 h days 1 and 2 (FOLFOX 2). The treatment was recycled every 2 weeks and continued until progression and/or unacceptable toxicity or patient preference. The primary end point was activity (tumor growth control [TGC]: partial response [PR] + stable disease [SD]); the secondary end points were time to progression (TTP), overall survival (OS) and toxicity. RESULTS: Forty-five patients in 2nd line (22 FOLFOX 4, 23 FOLFOX 2), 23 (17 FOLFOX 4, 6 FOLFOX 2) in 3rd, 4 in 4th and 1 in 5th line were assessable; 3 were lost to follow-up. In 15 patients (11 FOLFOX 4, 4 FOLFOX 2), disease involved the liver only. A total of 533 courses were administered with a range of 1-14 in FOLFOX4 and 1-12 in FOLFOX2; dose intensity was 92.85%, and the total dose of the administered L-OHP was 98.29%. As a 2nd line treatment, FOLFOX 4 achieved TGC in 72.8% of the patients (PR, 18.2%; SD, 54.6%), with a median TTP of 6 months and a median OS of 7 months, whereas in the FOLFOX 2 group these figures were 78.3% (PR 21.8%, SD 56.5%), and 5 and 9 months. As a 3rd line treatment, FOLFOX 4 produced TGC in 41.1% of patients (PR 23.5%, SD 17.6%), with a median TTP of 5 months and median OS of 7+ months, whereas FOLFOX 2 obtained respective values of 50% (PR 16.7%, SD 33.3%), 7 and 9 months. As a 4th line of treatment, TGC was achieved in 2 patients (1 PR, 1 SD); the patient in 5th line therapy obtained a SD. With "de Gramont" as the first-line regimen, patients assessable were 24 in FOLFOX 4 and 18 in FOLFOX 2. In the former population, TGC was 70.8% (PR 37.5%, SD 33.3%), with a TTP of 6 months and OS of 10 months, whereas with FOLFOX2 these values were 61.1% (PR 5.6%, SD 55.5), 5 and 7 months. In patients with liver involvement only, FOLFOX 4 obtained TGC in 63.6% of cases (with a TTP of 7 months and OS of 6+ months), FOLFOX 2 in 100% (with a TTP of 9.5 months and OS of 13.5+ months). Both schedules exhibited an acceptable toxicity: neurologic, hematologic and hepatic grade 3 side effects occurred in a limited number of patients, with a higher frequency in the FOLFOX 2 group. CONCLUSIONS: Treatment with L-OHP, CI +/- bolus 5FU and I-FA was well tolerated. The activity in terms of TGC was interesting and comparable with results reported in the literature for the standard treatment for 2nd line, i.e. irinotecan alone. Treatment was effective in 2nd line and in patients previously treated with more than two chemotherapy lines; in particular, treatment was active in patients with hepatic disease only. Although the two schedules seemed to achieve the same benefit with the same tolerance, we could not define from the study the better regime.     

Randomised Phase III study of biweekly 24-h infusion of high-dose 5FU with folinic acid and oxaliplatin versus monthly plus 5-FU/folinic acid in first-line treatment of advanced colorectal cancer.

BACKGROUND: A phase III study was started to compare oxaliplatin/5FU/LV in the first-line with bolus FU/LV in metastatic colorectal cancer. PATIENTS AND METHODS: 302 patients were randomised and received bolus 5-FU 425 mg/m(2) day 1-5, FA 20 mg/m(2) day 1-5, q 4 wk or oxaliplatin 85 mg/m(2), 2 h-infusion, FA 200 mg/m(2), 1-h infusion. 5-FU 2600 mg/m(2), 24-h infusion day 1, q 2 wk. The primary endpoint was response rate (RR). RESULTS: The median follow-up is 31.8 months, 90.4% of the patients have died. Confirmed RR, progression free survival (PFS; months) and median overall survival (OS; months) in 5FU/LV versus 5FU/LV/oxaliplatin were respectively 18.5% versus (vs) 33.8% (P = 0.004), 5.6 vs 6.7 (P = 0.016) and 13.3 vs 13.8 (P = 0.619). In the 5FU/LV/oxaliplatin arm less grade (3/4) toxicity was measured for diarrhoea, stomatitis, an increase in idiosyncratic side effects and neurosensory events compared with 5FU/LV. The quality of life (QOL) was equal in both arms. Second line treatment was given in 62% of the patients, crossover of 5FU/LV to 5FU/LV/oxaliplatin occurred in 14%. CONCLUSIONS: Oxaliplatin in the first-line resulted in an increased RR and PFS with less grade 3/4 mucositis/diarrhoea compared with 5FU/LV alone. Idiosyncratic side effects deserve attention with oxaliplatin. Despite a low treatment cross over rate, OS in both groups was comparable.