Association of Molecular Markers With Toxicity Outcomes in a Randomized Trial of Chemotherapy for Advanced Colorectal Cancer: The FOCUS Trial

2009 ◽  
Vol 27 (33) ◽  
pp. 5519-5528 ◽  
Author(s):  
Michael S. Braun ◽  
Susan D. Richman ◽  
Lindsay Thompson ◽  
Catherine L. Daly ◽  
Angela M. Meade ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Randomized Trial ◽  
Thymidylate Synthase ◽  
Primary Outcome ◽  
Outcome Measure ◽  
Advanced Colorectal Cancer ◽  
Secondary Outcome ◽  
Second Line ◽  
First Line ◽  
End Point

PurposePredicting efficacy and toxicity could potentially allow individualization of cancer therapy. We investigated putative pharmacogenetic markers of chemotherapy toxicity in a large randomized trial.Patients, Materials, and MethodsPatients were randomly assigned to different sequences of chemotherapy for advanced colorectal cancer. First-line therapy was fluorouracil (FU), irinotecan/FU (IrFU) or oxaliplatin/FU (OxFU). Patients allocated first-line FU had planned second-line irinotecan alone, IrFU, or OxFU. The primary toxicity outcome measure was toxicity-induced delay or dose reduction; the secondary outcome was Common Terminology Criteria of Adverse Events grade ≥ 3 toxicity. DNA was analyzed in 1,188 patients; 1,036 were assessable for the primary outcome, including 688 treated with FU, 270 with IrFU (first or second line), 280 with OxFU (first or second line), 184 with irinotecan alone, and 454 with any irinotecan-containing regimen. Ten polymorphisms were assessed: thymidylate synthase–enhancer region (TYMS-ER), thymidylate synthase 1494 (TYMS-1494), dihydropyrimidine dehydrogenase (DPYD), methylenetetrahydrofolate reductase (MTHFR), mutL homolog 1 (MLH1), UDP glucuronyltransferase (UGT1A1), ATP-binding cassette group B gene 1 (ABCB1), x-ray cross-complementing group 1 (XRCC1), glutathione-S-transferase P1 (GSTP1), and excision repair cross-complementing gene 2 (ERCC2).ResultsUsing the primary outcome measure, no polymorphism was significantly associated (P < .01) with the toxicity of any regimen or with the difference in toxicity of IrFU or OxFU versus FU alone. Trends (of doubtful significance) were seen for associations of XRCC1, ERCC2, and GSTP1 with toxicity during irinotecan regimens: XRCC1, primary end point, any irinotecan-containing regimen (P = .045); ERCC2, secondary end point, irinotecan alone (P = .003); GSTP1, secondary end point; IrFU (P = .039); and irinotecan alone (P = .05). There was no evidence of association of UGT1A1*28 with irinotecan toxicity.ConclusionThese results do not support the routine clinical use of the evaluated polymorphisms, including UGT1A1*28. Further investigation of XRCC1, ERCC2, and GSTP1 as potential predictors of irinotecan toxicity is warranted.

Survival of Patients With Advanced Colorectal Cancer Improves With the Availability of Fluorouracil-Leucovorin, Irinotecan, and Oxaliplatin in the Course of Treatment

2004 ◽  
Vol 22 (7) ◽  
pp. 1209-1214 ◽  
Author(s):  
Axel Grothey ◽  
Daniel Sargent ◽  
Richard M. Goldberg ◽  
Hans-Joachim Schmoll
Keyword(s):  
Colorectal Cancer ◽  
Advanced Colorectal Cancer ◽  
Cytotoxic Agents ◽  
Phase Iii ◽  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
First Line Therapy ◽  
Line Therapy ◽  
Phase Iii Trials

Purpose Fluorouracil (FU)-leucovorin (LV), irinotecan, and oxaliplatin administered alone or in combination have proven effective in the treatment of advanced colorectal cancer (CRC). Combination protocols using FU-LV with either irinotecan or oxaliplatin are currently regarded as standard first-line therapies in this disease. However, the importance of the availability of all three active cytotoxic agents, FU-LV, irinotecan, and oxaliplatin, on overall survival (OS) has not yet been evaluated. Materials and Methods We analyzed data from seven recently published phase III trials in advanced CRC to correlate the percentage of patients receiving second-line therapy and the percentage of patients receiving all three agents with the reported median OS, using a weighted analysis. Results The reported median OS is significantly correlated with the percentage of patients who received all three drugs in the course of their disease (P = .0008) but not with the percentage of patients who received any second-line therapy (P = .19). In addition, the use of combination protocols as first-line therapy was associated with a significant improvement in median survival of 3.5 months (95% CI, 1.27 to 5.73 months; P = .0083). Conclusion Our results support the strategy of making these three active drugs available to all patients with advanced CRC who are candidates for such therapy to maximize OS. In addition, our findings suggest that, with the availability of effective salvage options, OS should no longer be regarded as the most appropriate end point by which to assess the efficacy of a palliative first-line treatment in CRC.

Supporting Treatment Decision Making in Advanced Cancer: A Randomized Trial of a Decision Aid for Patients With Advanced Colorectal Cancer Considering Chemotherapy

2011 ◽  
Vol 29 (15) ◽  
pp. 2077-2084 ◽  
Author(s):  
Natasha B. Leighl ◽  
Heather L. Shepherd ◽  
Phyllis N. Butow ◽  
Stephen J. Clarke ◽  
Margaret McJannett ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Decision Making ◽  
Randomized Trial ◽  
Advanced Cancer ◽  
Decision Aid ◽  
Advanced Colorectal Cancer ◽  
Treatment Options ◽  
Decisional Conflict ◽  
First Line ◽  
Line Chemotherapy

Purpose Decision making in advanced cancer is increasingly complex. We developed a decision aid (DA) for patients with advanced colorectal cancer who are considering first-line chemotherapy and reviewing treatment options, prognostic information, and toxicities. We examined its impact on patient understanding, treatment decisions, decisional conflict, decision making, consultation satisfaction, anxiety, and quality of life by using a randomized trial design. Patients and Methods In all, 207 patients with colorectal cancer who were considering first-line chemotherapy for metastatic disease were randomly assigned to receive a standard medical oncology consultation or a consultation in which the DA (take-home booklet with audio recording, reviewed by an oncologist) was used. Participants completed questionnaires postconsultation, postdecision, and 1 month later. Results In this study, 100 patients were randomly assigned to the control arm, and 107 received the DA. Median age of the sample was 62 years, 58% were male, 89% had a performance status of 0 or 1, and 36% had received prior adjuvant chemotherapy. Patients receiving the DA demonstrated a greater increase in understanding of prognosis, options, and benefits, with higher overall understanding (P < .001). Decisional conflict, treatment decisions, and achievement of involvement preferences were similar between the groups. Anxiety was similar across groups and decreased over time. Most patients were confident in a decision during the first consultation; 74% chose chemotherapy, 7% supportive care alone, and 10% observation. Conclusion This randomized trial of a decision aid in advanced cancer showed that its use in advanced colorectal cancer improved patient understanding of prognosis, treatment options, risks, and benefits without increasing anxiety. DAs can improve informed consent and can be tested through randomized trials even in the advanced cancer setting.

scholarly journals Efficacy and Safety of Bevacizumab in Combination with Chemotherapy for Colorectal Cancer – A Real World Study in China

2020 ◽  
Author(s):  
Tao Shen ◽  
Xian-Shuo Cheng ◽  
Wei-Xun Chunyu ◽  
Hong-Tao Zhang ◽  
Cui-Feng Xia ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adverse Events ◽  
Real World ◽  
Large Scale ◽  
Progression Free Survival ◽  
Secondary Outcome ◽  
Second Line ◽  
Efficacy And Safety ◽  
First Line ◽  
Demographic Subgroups

Abstract Background Large scale randomized trials have demonstrated that bevacizumab in addition to chemotherapy as first-line or second-line treatment has significant survival benefits. We aim to explore the clinical impact of bevacizumab in combination with chemotherapy in first-line or second-line in patients with colorectal cancer (CRC). Methods The medical records of patients with CRC who received bevacizumab at first or second-line of treatment were collected retrospectively. The primary outcome of the study was to evaluate the efficacy of bevacizumab in combination with chemotherapy by survival endpoints i.e. overall survival (OS) and progression-free survival (PFS) and the secondary outcome was to evaluate its safety by incidence of adverse events (AE). Results Fifty-one patients with CRC had met the selection criteria for treatment with bevacizumab to either cetuximab or FOLFOX or both. The median age was 54 years. During follow-up, ten patients had exhibited progression after treatment while 5 patients died. The median OS and PFS of the overall population were not reached. The Cox proportional regression analysis revealed no significant prognostic factors of OS and PFS for treatment with bevacizumab in various demographic subgroups. The 1-year PFS rates of all 51 patients was 76%. The 1-year and 3-year OS rates for all 51 patients were 95% and 88%, respectively. Toxicities were usually mild in nature, with nausea, vomiting, hand and foot syndrome, neutropenia, asthenia and palpitation being the commonly reported adverse events. Conclusion In this real-world setting, the efficacy and safety of bevacizumab in combination with chemotherapy is limited and further research is warranted as to whether bevacizumab with chemotherapy is an optimal treatment as first-line or second-line therapy in Chinese CRC patients.

Maintenance treatment with cetuximab in a series of patients treated with standard chemotherapy and cetuximab in metastatic colorectal cancer.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 624-624
Author(s):  
G. Quintero-Aldana ◽  
S. Varela ◽  
B. Campos ◽  
S. Vazquez-Estevez ◽  
O. Maseda ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Disease Progression ◽  
Advanced Colorectal Cancer ◽  
Single Agent ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Standard Chemotherapy ◽  
Cutaneous Toxicity

624 Background: New strategies are needed to improve outcomes and reduced toxicities of currently treatments for patients with advanced colorectal cancer. Nowadays maintaining treatment until disease progression is the standard option for these patients. Cetuximab is a recombinant humanized monoclonal antibody that neutralizes epidermal growth factor receptor and it has shown benefit not only in combination with standard chemotherapy in first- and second-line treatment or as a single agent in progression to standard chemotherapy in KRAS wild-type metastatic colorectal cancer (mCRC). Methods: This data describes patients who received standard chemotherapy with cetuximab every two weeks. For patients with response or stable disease, cetuximab was continued until disease progression or unacceptable toxicity. Results: Twelve patients are reported, nine were male (75%). The median age was 62 years (range, 46 to 78 years). All patients had stage IV, and liver was the most common location (75%). The majority of patients (75%) received FOLFOX VI as a first-line treatment in combination with cetuximab; only two patients were treated with FOLFIRI. Cetuximab was maintained after the first line of treatment in the 75% of patients. The median of cycles of chemotherapy and cetuximab was 12. Best response achieved in this setting was complete response (58.3%, 7/12). Median of monotherapy with cetuximab treatment was 7.5 cycles (range 3 to 12). At the moment of this analysis seven of twelve patients continued with the maintenance. In the rest of patients the treatment was followed until progression (33%, 3/12). No grade 3-4 toxicities were seen during maintenance cetuximab. The most common adverse effect during maintenance was cutaneous toxicity but the majority of patients had minor toxicity (50% grade 1). Conclusions: Cetuximab has significant antitumor activity not only as a single agent or in combination with standard chemotherapy but may also when it is used as maintenance therapy after a complete or partial response to first or second line based chemotherapy in mCRC. Maintenance cetuximab is feasible, safe, and worthy of future study in advanced colorectal cancer. No significant financial relationships to disclose.

scholarly journals Effectiveness of bevacizumab in first- and second-line treatment for metastatic colorectal cancer: ITACa randomized trial

2020 ◽  
Vol 12 ◽  
pp. 175883592093742
Author(s):  
Elisabetta Petracci ◽  
Emanuela Scarpi ◽  
Alessandro Passardi ◽  
Annibale Biggeri ◽  
Carlo Milandri ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Randomized Trial ◽  
Risk Reduction ◽  
Treatment Strategies ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Weighting Method ◽  
Line Chemotherapy

Background: Cancer trials involving multiple treatment lines substantially increase our understanding of therapeutic strategies. However, even when the primary end-point of these studies is progression-free survival (PFS), their statistical analysis usually focuses on each line separately, or does not consider repeated events, thus missing potentially relevant information. Consequently, the evaluation of the effectiveness of treatment strategies is highly impaired. Methods: We evaluated the potentially different effect of bevacizumab (B) administered for the first- or second-line treatment of metastatic colorectal cancer (mCRC) in the ITACa (Italian Trial in Advanced Colorectal Cancer) randomized trial. The ITACa trial consisted of two arms: first-line chemotherapy (CT)+B followed by second-line CT alone versus first-line CT alone followed by second-line CT+B or CT+B+cetuximab according to KRAS status. Cox models for repeated disease progression were performed, and potential selection bias was adjusted using the inverse probability of censoring weighting method. Hazard ratios (HR) [95% confidence interval (CI)] for PFS (primary endpoint) were reported. Results: The overall effect of B across the two lines resulted in a HR = 0.80 (95% CI 0.68–0.95, p = 0.008). Evaluating the differential effect of B in first- and second-line, the addition of B to first-line chemotherapy (CT) produced a 10% risk reduction (HR = 0.90, 95% CI 0.72–1.12, p = 0.340) versus CT alone; B added to second-line CT produced a 36% risk reduction (HR = 0.64, 95% CI 0.49–0.84, p = 0.0011) versus CT alone. Conclusion: Our results seem to suggest that B confers a PFS advantage when administered in combination with second-line chemotherapy, which could help to improve current international guidelines on optimal sequential treatment strategies.

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