Relationship between 5-fluorouracil (5-FU) dose intensity and therapeutic response in patients with advanced colorectal cancer receiving infusional therapy containing 5-FU

PURPOSE: To evaluate in patients with advanced colorectal cancer (CRC) three treatment regimens of oral capecitabine in order to select the most appropriate regimen for testing in phase III. PATIENTS AND METHODS: Three capecitabine schedules were evaluated in a randomized phase II design: arm A, 1,331 mg/m2/d bid continuously; arm B, 2,510 mg/m2/d bid intermittently (2 weeks on/1 week off); and arm C, 1,657 mg/m2/d plus oral leucovorin 60 mg/d bid intermittently (2 weeks on/1 week off). RESULTS: One hundred nine patients were randomized; 39 patients were assessable for efficacy in arm A, 34 in arm B, and 35 in arm C. Patient characteristics were balanced in the arms. Confirmed tumor responses (partial response [PR] + complete response [CR]) were reported for eight patients with two CRs (21%; 95% confidence interval [CI], 9% to 36%) in arm A, eight patients with one CR (24%; 95% CI, 11% to 41%) in arm B, and eight patients with two CRs (23%; 95% CI, 10% to 40%) in arm C. Median times to progression (TTP) in arms A, B, and C were 127, 230, and 165 days, respectively. Overall, more toxicity was seen with capecitabine plus leucovorin, particularly diarrhea and hand-foot syndrome. There was no grade 3 or 4 marrow toxicity. CONCLUSION: Capecitabine offers a new, effective treatment option as an oral single agent in advanced CRC. Promising overall response rates were reported for all three regimens. The addition of leucovorin to the intermittent regimen had no marked effect on tumor response or median TTP. The intermittent single-agent capecitabine schedule is proposed for phase III evaluation, based on considerations of toxicity, dose-intensity, response rate, and TTP.

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Phase II clinical study of combination therapy with irinotecan and S-1(IRIS) for inoperable recurrent advanced colorectal cancer: Hokkaido Gastrointestinal Cancer Study Group study HGCSG-0302)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.3589 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 3589-3589

Author(s):

Y. Komatsu ◽

S. Yuki ◽

H. Akita ◽

M. Kudo ◽

M. Tateyama ◽

...

Keyword(s):

Colorectal Cancer ◽

Clinical Study ◽

Combination Therapy ◽

Survival Time ◽

Phase Ii ◽

Advanced Colorectal Cancer ◽

Response Rate ◽

Dose Intensity ◽

Outpatient Basis ◽

Phase Ii Clinical Study

3589 Background: We planned to conduct a phase II clinical study of combination therapy with irinotecan and S-1, a new oral anticancer drug of the fluorinated pyrimidine type. We reported the interium reports of this study in colorectal cancer patients at GI cancer Symposium 2006. Methods: The antitumor effect was the primary endpoint, while the safety, progression-free survival time, and median survival time were the secondary endpoints. The subjects were untreated patients with inoperable advanced colorectal cancer aged 20–75 years. Irinotecan was administered at a dose of 100 mg/m2 (on days 1 and 15) as an intravenous infusion over 90 minutes, and oral S-1 (40 mg/m2) was administered after breakfast and dinner and then withdrawn for 2 weeks. Results: Forty patients were enrolled in the present study. There were 23 men and 17 women. The median age was 62 years (range: 34 to 74 years). Two patient showed grade 4 neutropenia, but the next course could be given safely after dose reduction. Three patients had grade 3 diarrhea, but therapy could be continued with addition of an antidiarrheal drug. No other serious adverse reactions occurred (either hematological or non-hematological), and all patients could receive therapy safely on an outpatient basis. Interim analysis suggested excellent results, with a response rate of 50%. To date, 231 cycles (median 8, range 1–19) have been administered. Median relative dose intensity was 97% for S-1 and 87% for irinotecan. 36 pts are evaluable for efficacy: RR was 47.2% (95% CI, 30.9–63.5%) and Disease Control Rate (PR + SD) was seen in 94.4% of pts. PFS of this regimen is 320 days. MST is not reached. Conclusions: IRIS therapy achieved a high response rate and could be given safely. These findings suggest that the therapy has potential as first-line treatment for inoperable advanced recurrent colorectal cancer. It seems that IRIS is a good treatment equal to FOLFIRI. In addition, this regimen could qualify as a candidate for future combination therapy with a molecular-targeting drug. The latest data will be reported at the meeting. No significant financial relationships to disclose.

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Phase II comparative study of capecitabine combined with oxaliplatin (XELOX) and CPT-11 (XELIRI) for advanced colorectal cancer patients (p) previously treated with 5-FU-based chemotherapy

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.14544 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 14544-14544

Author(s):

J. L. Manzano ◽

N. Díaz ◽

C. Rolfo ◽

I. Juez ◽

J. M. Gracía-Bueno ◽

...

Keyword(s):

Colorectal Cancer ◽

Disease Control ◽

Cancer Patients ◽

Metastatic Disease ◽

Advanced Colorectal Cancer ◽

Survival Rates ◽

Dose Intensity ◽

Line Treatment ◽

Previously Treated ◽

Colorectal Cancer Patients

14544 Background: Based on the results obtained with Capecitabine (XEL), Oxaliplatin (OX), and CPT-11 (IRI), we proposed this exploratory study to asses the efficacy of XELIRI and XELOX, for advanced colorectal cancer, after a first line treatment with 5 FU plus OX (FOLFOX) or IRI (FOLFIRI). Methods: P aged = 18 with histological diagnosis of metastatic colorectal adenocarcinoma, were assigned to XELOX arm (XEL, 1000 mg/m2 BID during 14 d; OX, 130 mg/m2 d1; q3w) or XELIRI arm (XEL 1000 mg/m2 BID during 14 d; IRI 240 mg/m2 d1; q3w), depending on previous treatment (FOLFIRI or FOLFOX, respectively). Although sample size was calculated for 115 p, recruitment was premature closed due to the low inclusion rate related with cetuximab + IRI approval for second line treatment. Results: Forty three p (25 p, XELOX; 18 p, XELIRI) were enrolled: median age 63.2 years; M/F, 40.5%/59.5%; ECOG PS 0–1, 79.1%. All p have been previously treated for metastatic disease and 65.1% had stage IV. Main sites of metastatic disease were liver (71.8%), lymph nodes (7.7%), pelvis (7.7 %) and lung (5.1%). XELOX/XELIRI treatment data: total number of administered cycles was 94/85 and median relative dose intensity 100%(XEL)/99%(OX) and 96%(XEL)/94%(IRI); disease control rate (PR+SD) was 28%/33.3%, median TTP 3.4/4.1 months, median OS 10.3/11.2 months and 1-year survival, 39.1%/44.3%, respectively. Twenty p (46.5%) received further antitumoral treatment. Most frequent G3–4 toxicities per p are detailed in table 1 . Conclusions: Capecitabine based combinations show an excellent toxicity profile and good efficacy results, in terms of disease control and survival rates, for advanced colorectal cancer patients previously treated with 5-FU schedules. [Table: see text] No significant financial relationships to disclose.

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Bolus Fluorouracil and Leucovorin With Oxaliplatin as First-Line Treatment in Metastatic Colorectal Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2002.08.144 ◽

2002 ◽

Vol 20 (10) ◽

pp. 2545-2550 ◽

Cited By ~ 30

Author(s):

Alberto Ravaioli ◽

Maurizio Marangolo ◽

Enzo Pasquini ◽

Andrea Rossi ◽

Dino Amadori ◽

...

Keyword(s):

Colorectal Cancer ◽

Advanced Colorectal Cancer ◽

Performance Status ◽

Initial Dosage ◽

Dose Intensity ◽

Progression Free Survival ◽

Bolus Administration ◽

First Line ◽

First Line Therapy ◽

Duration Of Response

PURPOSE: A phase II trial investigated the activity and toxicity of a bolus administration schedule of oxaliplatin, fluorouracil (5-FU), and leucovorin (LV) therapy in patients with untreated advanced colorectal cancer. PATIENTS AND METHODS: Forty-five patients in this multicenter, open, nonrandomized study received oxaliplatin 130 mg/m2 on the first day of each course and 5-FU and LV 350 mg/m2 and 20 mg/m2, respectively, as a daily bolus for 5 days, every 21 days, for a maximum of six courses. RESULTS: Partial responses occurred in 18 patients, giving an intent-to-treat response rate of 40.0%. Median time to response was 12.7 weeks; median duration of response was 18.4 weeks. Median progression-free survival was 5.9 months; median survival was 14 months. The independent prognostic factors for improved overall survival were good performance status and negative carcino-embryonic antigen blood level. Incidences of adverse effects were reduced after the 5-FU dose was reduced to 300 mg/m2. Reversible neurologic toxicity occurred in 44.4% of patients. CONCLUSION: Bolus administration of oxaliplatin, 5-FU, and LV as first-line therapy for untreated advanced colorectal cancer is efficacious and safe. In addition to a more favorable safety profile, the 300 mg/m2 dosage offered improved dose-intensity compared with the initial dosage.

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Randomized trial assessing the addition of interferon alpha-2a to fluorouracil and leucovorin in advanced colorectal cancer. Colorectal Cancer Working Party of the United Kingdom Medical Research Council.

Journal of Clinical Oncology ◽

10.1200/jco.1996.14.8.2280 ◽

1996 ◽

Vol 14 (8) ◽

pp. 2280-2288 ◽

Cited By ~ 63

Author(s):

M T Seymour ◽

M L Slevin ◽

D J Kerr ◽

D Cunningham ◽

R D James ◽

...

Keyword(s):

Colorectal Cancer ◽

Median Survival ◽

Interferon Alpha ◽

Advanced Colorectal Cancer ◽

Objective Response ◽

Working Party ◽

Dose Intensity ◽

Progression Free Survival ◽

Ifn Alpha ◽

The United Kingdom

PURPOSE To determine the effects of interferon alpha-2a (IFN alpha) on the efficacy and toxicity of fluorouracil (FUra) and leucovorin (LV) in patients with advanced colorectal cancer. PATIENTS AND METHODS Two hundred sixty chemotherapy-naive patients were randomized to FUra/LV alone or FUra/LV plus IFN alpha. All patients received: LV 200 mg/m2 intravenous (IV) infusion over 2 hours, then FUra 400 mg/m2 i.v. bolus plus 400 mg/m2 i.v. infusion over 22 hours, all repeated on day 2. Treatment was every 2 weeks for up to 12 cycles. Patients randomized to IFN alpha received 6 x 10(6) IU subcutaneously every 48 hours throughout. Objective response (OR) and toxicity were assessed conventionally; in addition, palliative benefit and adverse effects were assessed using quality-of-life (QoL) questionnaires. RESULTS There were no differences in OR rate, progression-free survival, or overall survival. OR rates in assessable patients were as follows: FUra/LV alone (n = 104), complete or partial response (OR) = 27%, no change (NC) = 34%; FUra/LV/IFN alpha (n = 101), OR = 28%, NC = 30%. Median survival was 10 months in both arms. Dose-limiting FUra toxicities were not significantly increased by co-administration of IFN alpha, and the delivered FUra dose-intensity was not significantly reduced. However, QoL was adversely affected: patients on IFN alpha were less likely to report improvement in pretreatment physical and psychologic symptoms, and more likely to report new or worsening symptoms. CONCLUSION IFN alpha, at a dose that impaired QoL, did not improve the efficacy of FUra/LV. The power of this trial is sufficient to exclude with 95% confidence a benefit of 15% in OR or 10 weeks in median survival. Accordingly, we cannot recommend the use of IFN alpha as a clinical modulator of FUra/LV in the treatment of advanced colorectal cancer.

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Failure of orally administered dipyridamole to enhance the antineoplastic activity of fluorouracil in combination with leucovorin in patients with advanced colorectal cancer: a prospective randomized trial.

Journal of Clinical Oncology ◽

10.1200/jco.1995.13.5.1201 ◽

1995 ◽

Vol 13 (5) ◽

pp. 1201-1208 ◽

Cited By ~ 17

Author(s):

C H Köhne ◽

W Hiddemann ◽

J Schüller ◽

J Weiss ◽

H P Lohrmann ◽

...

Keyword(s):

Colorectal Cancer ◽

Randomized Trial ◽

Advanced Colorectal Cancer ◽

Objective Response ◽

Dose Intensity ◽

Antineoplastic Activity ◽

Nucleoside Transport ◽

Rank Test ◽

Pharmacokinetic Parameters ◽

Significant Difference

PURPOSE A randomized trial was performed to investigate the ability of the nucleoside transport inhibitor dipyridamole (DP) to enhance the antitumor activity of fluorouracil (5-FU)/leucovorin (folinic acid [FA]). PATIENTS AND METHODS One hundred eighty-one untreated patients with advanced colorectal cancer were randomized to receive 5-FU 600 mg/m2 plus FA 300 mg/m2 on days 2 to 4 with or without DP 75 mg orally three times daily on days 1 to 5. Cycles were repeated every 3 weeks. Only patients with documented tumor progression before therapy were eligible. 5-FU pharmacokinetics using high-performance liquid chromatography (HPLC) were assessed in 11 nonrandomized patients receiving paired cycles with or without DP. RESULTS One hundred seventy-four patients were assessable for toxicity and response. There was no significant difference in toxicity, except DP-related headache in 24% of patients. An objective response rate of 15% (one complete response [CR] and 13 partial responses [PRs]) for 5-FU/FA and 13% (two CRs and nine PRs) for 5-FU/FA/DP was observed. The dose-intensity of 5-FU delivered was significantly higher (1.09- to 1.16-fold) for the DP-containing arm. Pharmacokinetic parameters of 5-FU did not differ significantly, except for a prolonged half-life (t1/2) induced by DP. The median time to progression (P = .8) and the median survival time (11.6 months for 5-FU/FA v 9.3 months for 5-FU/FA/DP; P = .14, log-rank test) were not different between treatment arms. CONCLUSION Orally administered DP did not improve the antineoplastic activity of 5-FU/FA in patients with advanced colorectal cancer when used at this dose and schedule. The observed increase in 5-FU dose-intensity for FU/FA/DP was not clinically relevant.

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Treatment of advanced colorectal cancer with high-dose intensity folinic acid and 5-fluorouracil plus supportive care

European Journal of Cancer ◽

10.1016/0959-8049(95)00488-2 ◽

1995 ◽

Vol 31 (12) ◽

pp. 2105-2108 ◽

Cited By ~ 14

Author(s):

R. Petrioli ◽

M. Lorenzi ◽

A. Aquino ◽

S. Marsili ◽

B. Frediani ◽

...

Keyword(s):

Colorectal Cancer ◽

Supportive Care ◽

Folinic Acid ◽

Advanced Colorectal Cancer ◽

Dose Intensity ◽

High Dose ◽

High Dose Intensity

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Phase II study of oral S-1 monotherapy in metastatic colorectal cancer after failure of both irinotecan and oxaliplatin-containing regimen

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.3597 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 3597-3597

Author(s):

B. Cho ◽

H. Choi ◽

H. Jeung ◽

S. Rha ◽

J. Ahn ◽

...

Keyword(s):

Colorectal Cancer ◽

Phase Ii ◽

Advanced Colorectal Cancer ◽

Response Rate ◽

Phase Ii Study ◽

Skin Pigmentation ◽

Dose Intensity ◽

Line Therapy ◽

Number Of Patients ◽

Third Line

3597 Background: There has been a considerable increase in the number of patients (pts) with mCRC pretreated with both irinotecan and oxaliplatin. Little is known about third-line therapy in this group of pts. We conducted a phase II trial of oral S-1 in pts with advanced colorectal cancer who failed on both irinotecan and oxaliplatin. Methods: This phase II study was designed to evaluate the activity and toxicity of S-1 monotherapy in 31 advanced colorectal cancer pts (P0 = 3%, P1 = 15%; α = 0.05, power = 80%, drop-out rate 10 %). S-1 was administered orally twice daily, 70 mg/m2/day for 14 days followed by 1-week rest. Eligibility criteria included ECOG 0–2; measurable lesion; adequate organ functions; signed informed consent. Results: As of 1st September 2005, 21 pts were enrolled. Median age of all pts 55 years. There were 10 male and 11 females. Thirteen of 21 patients were treated with oxaliplatin-containing regimens as a first-line therapy for metastatic diseases. The median number of treatments was 3 courses (range, 1–10). The relative dose intensity was 1.0 (0.83 - 1.0) with a median dose of120 mg (100 -140 mg). Nineteen out of 21 patients were evaluable. The confirmed response rate was 21.1% (4/19, 1 CR, 3 PR). The median PFS was 11 weeks, and median OS was not reached. The most frequent adverse reaction was skin pigmentation (47.6%). Grade 3 toxicities was skin pigmentation in 1 patients (4.8%), neutropenia in 1 (4.8%), and anemia in 1 (4.8%), respectively. Conclusion: This results shows that S-1 produces a promising response rate with an acceptable safety profile in refractory, mCRC. S-1 has the potential to become a valuable option as a third-line salvage regimen in irinotecan and oxaliplatin pretreated mCRC pts. Clinical trial of combination therapy with S-1 will be warranted. No significant financial relationships to disclose.

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Safety and Toxicity Analysis of Oxaliplatin Combined With Fluorouracil or as a Single Agent in Patients With Previously Treated Advanced Colorectal Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2003.11.045 ◽

2003 ◽

Vol 21 (15) ◽

pp. 2904-2911 ◽

Cited By ~ 47

Author(s):

Ramesh K. Ramanathan ◽

Jeffery W. Clark ◽

Nancy E. Kemeny ◽

Heinz-Josef Lenz ◽

Kim O. Gococo ◽

...

Keyword(s):

Colorectal Cancer ◽

Treatment Failure ◽

Advanced Colorectal Cancer ◽

Single Agent ◽

Locally Advanced ◽

Dose Intensity ◽

The United States ◽

Hematologic Toxicity ◽

Eligibility Criteria ◽

Grade 3

Purpose: Two consecutive compassionate use studies of oxaliplatin were conducted in the United States and Canada in more than 5,000 patients with locally advanced or metastatic colorectal carcinoma who had experienced treatment failure after at least one prior chemotherapy regimen. Patients and Methods: The main focus was safety. Patients were assigned to treatment with either single-agent oxaliplatin or oxaliplatin in combination with fluorouracil (FU) and with or without leucovorin (LV) in various regimens. Response data collection was not a trial objective, but time to treatment failure (TTF) was recorded in the first cohort (1,370 patients). Results: All treatment regimens were well tolerated, with an overall incidence of grade 3 or 4 hematologic toxicity of 23.2%, grade 3 or 4 treatment-related gastrointestinal toxicity of 26.4% (including diarrhea, vomiting, and mucositis), and grade 3 neurosensory toxicity 3.9%. Similar results were reported in the second cohort (3,806 patients), in which the eligibility criteria were much less restrictive. In the first cohort (in which 83% received prior irinotecan), median TTF was 14 weeks, and was similar for the five regimens combining oxaliplatin and FU with or without LV, but significantly shorter for the single-agent oxaliplatin arm. The overall dose-intensity of oxaliplatin was maintained at 85.5% (range, 80.6% to 94.3%) of that prescribed by protocol (average 36.7 mg/m2/wk). Conclusion: These data in a heavily pretreated patient population confirm that oxaliplatin is safe when used as a single agent or with a variety of FU-based regimens as salvage therapy in patients with advanced colorectal cancer.

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