background The standard adjuvant treatment of colon cancer is fluorouracil plus leucovorin (FL). Oxaliplatin improves the efficacy of this combination in patients with metastatic colorectal cancer. We evaluated the efficacy of treatment with FL plus oxaliplatin in the postoperative adjuvant setting. methods We randomly assigned 2246 patients who had undergone curative resection for stage II or III colon cancer to receive FL alone or with oxaliplatin for six months. The primary end point was disease-free survival. results A total of 1123 patients were randomly assigned to each group. After a median followup of 37.9 months, 237 patients in the group given FL plus oxaliplatin had had a cancer-related event, as compared with 293 patients in the FL group (21.1 percent vs. 26.1 percent; hazard ratio for recurrence, 0.77; P=0.002). The rate of disease-free survival at three years was 78.2 percent (95 percent confidence interval, 75.6 to 80.7) in the group given FL plus oxaliplatin and 72.9 percent (95 percent confidence interval, 70.2 to 75.7) in the FL group (P=0.002 by the stratified log-rank test). In the group given FL plus oxaliplatin, the incidence of febrile neutropenia was 1.8 percent, the incidence of gastrointestinal adverse effects was low, and the incidence of grade 3 sensory neuropathy was 12.4 percent during treatment, decreasing to 1.1 percent at one year of follow-up. Six patients in each group died during treatment (death rate, 0.5 percent). conclusions Adding oxaliplatin to a regimen of fluorouracil and leucovorin improves the adjuvant treatment of colon cancer.

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Oxaliplatin, Fluorouracil, and Leucovorin as Adjuvant Treatment for Colon Cancer

PURPOSETo determine, in women with primary operable breast cancer, if preoperative doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan; AC) therapy yields a better outcome than postoperative AC therapy, if a relationship exists between outcome and tumor response to preoperative chemotherapy, and if such therapy results in the performance of more lumpectomies.PATIENTS AND METHODSWomen (1,523) enrolled onto National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 were randomly assigned to preoperative or postoperative AC therapy. Clinical tumor response to preoperative therapy was graded as complete (cCR), partial (cPR), or no response (cNR). Tumors with a cCR were further categorized as either pathologic complete response (pCR) or invasive cells (pINV). Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were estimated through 5 years and compared between treatment groups. In the preoperative arm, proportional-hazards models were used to investigate the relationship b...

Effect of preoperative chemotherapy on the outcome of women with operable breast cancer.

Purpose Three-year disease-free survival (DFS) was significantly improved in patients who had undergone resection with curative intent for stage II or III colon cancer who received bolus plus continuousinfusion fluorouracil plus leucovorin (LV5FU2) with the addition of oxaliplatin (FOLFOX4). Final results of the study, including 6-year overall survival (OS) and 5-year updated DFS, are reported. Patients and Methods A total of 2,246 patients were randomly assigned to receive LV5FU2 or FOLFOX4 for 6 months. The primary end point was DFS. Secondary end points were OS and safety. Results Five-year DFS rates were 73.3% and 67.4% in the FOLFOX4 and LV5FU2 groups, respectively (hazard ratio [HR] 0.80; 95% CI, 0.68 to 0.93; P .003). Six-year OS rates were 78.5% and 76.0% in the FOLFOX4 and LV5FU2 groups, respectively (HR 0.84; 95% CI, 0.71 to 1.00; P .046); corresponding 6-year OS rates for patients with stage III disease were 72.9% and 68.7%, respectively (HR 0.80; 95% CI, 0.65 to 0.97; P .023). No difference in OS was seen in the stage II population. The incidence of second noncolorectal cancers was 5.5% and 6.1% in the FOLFOX4 and LV5FU2 groups, respectively. Among patients receiving oxaliplatin, the frequency of grade 3 peripheral sensory neuropathy was 1.3% 12 months after treatment and 0.7% at 48 months. Conclusion Adding oxaliplatin to LV5FU2 significantly improved 5-year DFS and 6-year OS in the adjuvant treatment of stage II or III colon cancer and should be considered after surgery for patients with stage III disease. J Clin Oncol 27:3109-3116. © 2009 by American Society of Clinical Oncology

http://marc.porneuf.pagesperso-orange.fr/biblio/references/Improved%20Overall%20Survival%20With%20Oxaliplatin%2C%20Fluorouracil%2C%20and%20Leucovorin%20As%20Adjuvant%20Treatment%20in%20Stage%20II%20or%20III%20Colon%20Cancer%20in%20the%20MOSAIC%20Trial.pdf

Improved Overall Survival With Oxaliplatin, Fluorouracil, and Leucovorin As Adjuvant Treatment in Stage II or III Colon Cancer in the MOSAIC Trial

Background Tumorigenic breast cancer cells that express high levels of CD44 and low or undetectable levels of CD24 (CD44+/CD24 -/low ) may be resistant to chemotherapy and therefore responsible for cancer relapse. These tumorigenic cancer cells can be isolated from breast cancer biopsies and propagated as mammospheres in vitro. In this study, we aimed to test directly in human breast cancers the effect of conventional chemotherapy or lapatinib (an epidermal growth factor receptor [EGFR]/HER2 pathway inhibitor) on this tumorigenic CD44 + and CD24 -/low cell population. Methods Paired breast cancer core biopsies were obtained from patients with primary breast cancer before and after 12 weeks of treatment with neoadjuvant chemotherapy (n = 31) or, for patients with HER2-positive tumors, before and after 6 weeks of treatment with the EGFR/HER2 inhibitor lapatinib (n = 21). Single-cell suspensions established from these biopsies were stained with antibodies against CD24, CD44, and lineage markers and analyzed by flow cytometry. The potential of cells from biopsy samples taken before and after treatment to form mammospheres in culture was compared. All statistical tests were two-sided. Results Chemotherapy treatment increased the percentage of CD44 + /CD24 -/low cells (mean at baseline vs 12 weeks, 4.7%, 95% confidence interval [Cl] = 3.5% to 5.9%, vs 13.6%, 95% Cl = 10.9% to 16.3%; P <.001) and increased mammosphere formation efficiency (MSFE) (mean at baseline vs 12 weeks, 13.3%, 95% Cl = 6.0% to 20.6%, vs 53.2%, 95% Cl = 42.4% to 64.0%; P <.001). Conversely, lapatinib treatment of patients with HER2-positive tumors led to a non-statistically significant decrease in the percentage of CD44+/CD24 -/low cells (mean at baseline vs 6 weeks, 10.0%, 95% Cl = 7.2% to 12.8%, vs 7.5%, 95% Cl = 4.1% to 10.9%) and a non-statistically significant decrease in MSFE (mean at baseline vs 6 weeks, 16.1%, 95% Cl = 8.7% to 23.5%, vs 10.8%, 95% Cl = 4.0% to 17.6%). Conclusion These studies provide clinical evidence for a subpopulation of chemotherapy-resistant breast cancer-initiating cells. Lapatinib did not lead to an increase in these tumorigenic cells, and, in combination with conventional therapy, specific pathway inhibitors may provide a therapeutic strategy for eliminating these cells to decrease recurrence and improve long-term survival.

Intrinsic Resistance of Tumorigenic Breast Cancer Cells to Chemotherapy

Colorectal cancer is a major cause of death in Japan, where it accounts for the largest number of deaths from malignant neoplasms in women and the third largest number in men. Many new treatment methods have been developed over the last few decades. The Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2010 for the treatment of colorectal cancer (JSCCR Guidelines 2010) have been prepared to show standard treatment strategies for colorectal cancer, to eliminate disparities among institutions in terms of treatment, to eliminate unnecessary treatment and insufficient treatment, and to deepen mutual understanding between health-care professionals and patients by making these Guidelines available to the general public. These Guidelines have been prepared by consensuses reached by the JSCCR Guideline Committee, based on a careful review of the evidence retrieved by literature searches and in view of the medical health insurance system and actual clinical practice settings in Japan. Therefore, these Guidelines can be used as a tool for treating colorectal cancer in actual clinical practice settings. More specifically, they can be used as a guide to obtaining informed consent from patients and choosing the method of treatment for each patient. As a result of the discussions held by the Guideline Committee, controversial issues were selected as Clinical Questions, and recommendations were made. Each recommendation is accompanied by a classification of the evidence and a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here we present the English version of the JSCCR Guidelines 2010.

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Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2010 for the treatment of colorectal cancer

PURPOSETo determine whether preoperative doxorubicin and cyclophosphamide (AC) permits more lumpectomies to be performed and decreases the incidence of positive nodes in women with primary breast cancer.PATIENTS AND METHODSWomen (n = 1,523) were randomized to National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18; 759 eligible patients received postoperative AC and 747, preoperative AC. The clinical size of breast and axillary tumors was determined before each of four cycles of AC and before surgery. Tumor response to preoperative therapy was clinically complete (cCR), partial (cPR), stable (cSD), or progressive disease (cPD). Tissue from patients with a cCR was evaluated for a pathologic complete response (pCR).RESULTSBreast tumor size was reduced in 80% of patients after preoperative therapy; 36% had a cCR. Tumor size and clinical nodal status were independent predictors of cCR. Twenty-six percent of women with a cCR had a pCR. Clinical nodal response occurred in 89% of node-positive patients:...

Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18.

PURPOSE: Although the benefit from adjuvant chemotherapy has been clearly established in patients with Dukes' C colon cancer, such benefit has been questioned in patients with Dukes' B disease. To determine whether patients with Dukes' B disease benefit from adjuvant chemotherapy and to evaluate the magnitude of the benefit, compared with that observed in Dukes' C patients, we examined the relative efficacy of adjuvant chemotherapy according to Dukes' stage in four sequential National Surgical Adjuvant Breast and Bowel Project trials (C-01, C-02, C-03, and C-04) that compared different adjuvant chemotherapy regimens with each other or with no adjuvant treatment. PATIENTS AND METHODS: The four trials included Dukes' B and C patients and were conducted between 1977 and 1990. The eligibility criteria and follow-up requirements were similar for all four trials. Protocol C-01 compared adjuvant semustine, vincristine, and fluorouracil (5-FU) (MOF regimen) with operation alone. Protocol C-02 compared the periope...

Comparative Efficacy of Adjuvant Chemotherapy in Patients With Dukes' B Versus Dukes' C Colon Cancer: Results From Four National Surgical Adjuvant Breast and Bowel Project Adjuvant Studies (C-01, C-02, C-03, and C-04)

LBA4005 Background: We previously reported that FULV + oxaliplatin (FLOX) significantly prolonged 3-year disease-free survival when compared to FULV (ASCO 2005; J Clin Oncol 2007) A secondary end point of this study was overall survival (S) at five years; the data are presented herein. Methods: Between February 2000 and November 2002, 2,409 eligible patients with follow-up (1209 FULV and 1200 FLOX) with stage II (28.9%) or III carcinoma of the colon were randomized to receive either FULV (5-FU, 500 mg/m2 iv bolus weekly×6; LV, 500 mg/m2 iv weekly×6, each 8 week cycle×3) or FLOX (same FULV regimen with oxaliplatin 85 mg/m2 iv administered on weeks 1, 3, and 5 of each 8 week cycle×3). A planned secondary end point of this study was overall survival 5 years after the completion of accrual. The hazard ratio estimate is from a Cox model stratified by positive nodes (0, 1–3, 4+). The p-value is from a log-rank test stratified by positive nodes. Results: The median follow-up for patients who were still alive was...

A phase III trial comparing FULV to FULV + oxaliplatin in stage II or III carcinoma of the colon: Survival results of NSABP Protocol C-07

3505 Background:Chemoradiation is considered standard treatment for operable rectal cancer but the optimal time to deliver this therapy is unknown. NSABP R-03 trial compared preoperative neoadjuvant to postoperative adjuvant chemoradiation. Methods:Patients were randomized to preoperative therapy (1 cycle of 5-FU[FU] and leucovorin[LV], 2 cycles of FU/LV and concomitant radiation therapy[RT], surgery, 4 cycles FU/LV) or postoperative therapy (surgery, 1 cycle of FU/LV, 2 cycles of FU/LV and concomitant RTX, 4 cycles FU/LV). The endpoints were overall (OS), disease-free (DFS) and relapse-free (RFS) survival. OS, DFS, and RFS were estimated using Kaplan-Meier curves. P-values were calculated using Greenwood's variance estimator. Results:From June 1993 to June 1999, 123 patients in the preoperative and 130 patients in the postoperative group were eligible for evaluation. Among the 78 preoperative patients evaluable for response, 25.6% had a complete clinical response (CR), 48.7% had partial (PR), 23.1% stabl...

Response to preoperative multimodality therapy predicts survival in patients with carcinoma of the rectum

3508 Background: The primary aim of this two-arm randomized prospective study was to compare the relative efficacy of oral UFT+LV with that of FULV in prolonging disease-free survival (DFS) and survival (S). Methods: Between February 1997 and March 1999, 1,608 patients (805 and 803 in each arm) with stage II and III carcinoma of the colon were randomized to receive either oral UFT+LV (tegafur, 300 mg/m2/day and uracil in a 1:4 molar ratio p.o. x 28 days; leucovorin 90 mg/day p.o. x 28 days, each 35 day cycle x 5) or FULV (5-FU, 500 mg/m2 iv bolus weekly x 6; LV, 500 mg/m2 iv weekly x 6, each 8 week cycle x 3 Results: With a mean time on study of 64 months for patients with follow-up there were no significant differences in disease-free survival or overall survival between the two treatment arms. Results (%) at 5 years were: The two regimens were equitoxic and well tolerated. The Fact C quality of life metric disclosed no significant difference; other secondary quality of life measurements during chemother...

S. Wieand

Papers

Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18.

Comparative Efficacy of Adjuvant Chemotherapy in Patients With Dukes' B Versus Dukes' C Colon Cancer: Results From Four National Surgical Adjuvant Breast and Bowel Project Adjuvant Studies (C-01, C-02, C-03, and C-04)

A phase III trial comparing FULV to FULV + oxaliplatin in stage II or III carcinoma of the colon: Survival results of NSABP Protocol C-07

Response to preoperative multimodality therapy predicts survival in patients with carcinoma of the rectum

A phase III trial comparing oral UFT to FULV in stage II and III carcinoma of the colon: Results of NSABP Protocol C-06