Rainer Porschen

Efficacy of Oxaliplatin Plus Capecitabine or Infusional Fluorouracil/Leucovorin in Patients With Metastatic Colorectal Cancer: A Pooled Analysis of Randomized Trials

PURPOSE Six randomized phase II and III trials have investigated the role of oxaliplatin (OX) in combination with capecitabine (CAP) or infusional fluorouracil (FU) in metastatic colorectal cancer. This meta-analysis compared the efficacy of CAP/OX compared with infusional FU/OX. PATIENTS AND METHODS This analysis compared all published CAP/OX versus infusional FU/OX regimens. A total of 3,494 patients (FU, n = 1,737; CAP, n = 1,757) were analyzed for response rate (RR), progression-free (PFS), overall survival (OS), and toxicity. RESULTS The fixed-effect pooled estimate for RR showed higher RR for FU-based regimens (Odds ratio [OR] = 0.85; 95% CI, 0.74 to 0.97; P = .02) whereas the analysis of chemotherapy-only trials, excluding the bevacizumab containing NO16966 and TREE 2 trials, led to an OR of 0.74 (95% CI, 0.60 to 0.92; P = .007). However, for PFS (hazard ratio [HR] = 1.04; 95% CI, 0.96 to 1.12; P = .17) and OS (HR = 1.04; 95% CI, 0.95 to 1.12; P = .41) all models suggested similar outcome within the range of noninferiority. Grade 3/4 toxicities (thrombocytopenia-HR = 2.07, 95% CI, 1.42 to 3.03; P < .0002; diarrhea-HR = 1.34; 95% CI, 1.08 to 1.66; P < .0009; and grade 2/3 hand-foot-syndrome [HFS]-HR = 3.54; 95% CI, 2.07 to 6.05; P < .00001) were less prominent with FU-based regimens whereas neutropenia (HR = 0.15; 95% CI, 0.11 to 0.19; P < .00001) was lower in the CAP regimens. CONCLUSION The combination of CAP and OX resulted in lower RR, but this did not affect PFS and OS, which were similar in both treatment arms. The toxicity analysis showed the characteristic toxicity of each of the different FU schedules, with thrombocytopenia and HFS consistently more prominent in the CAP regimens.

Fluorouracil Plus Leucovorin as Effective Adjuvant Chemotherapy in Curatively Resected Stage III Colon Cancer: Results of the Trial adjCCA-01

PURPOSE Adjuvant postoperative treatment with fluorouracil (5-FU) and levamisole in curatively resected stage III colon cancer significantly reduces the risk of cancer recurrence and improves survival. Biochemical modulation of 5-FU with leucovorin has resulted in increased remission rates in metastatic colorectal cancer, thus reflecting an increased tumor-cell kill. The impact of 5-FU plus leucovorin on survival and tumor recurrence was analyzed in comparison with the effects of 5-FU plus levamisole in the prospective multicentric trial adjCCA-01. PATIENTS AND METHODS Patients with a curatively resected International Union Against Cancer stage III colon cancer were stratified according to T, N, and G category and randomly assigned to receive one of the two adjuvant treatment schemes: 5-FU 400 mg/m(2) body-surface area intravenously in the first chemotherapy course, then 450 mg/m(2) x 5 days; 12 cycles, plus leucovorin 100 mg/m(2) (arm A), or 5-FU plus levamisole (Moertel scheme; arm B). RESULTS Six hundred eighty (96.9%) of 702 patients enrolled onto this study were eligible. After a median follow-up time of 46.5 months, the 5-FU plus leucovorin combination significantly improved disease-free survival (P =.037) and significantly decreased overall mortality (P =.0089) in comparison with 5-FU plus levamisole. In a multivariate proportional hazards model, adjuvant chemotherapy emerged as a significant prognostic factor for survival (P =.0059) and disease-free survival (P =.03). Adjuvant treatment with 5-FU plus levamisole as well as with 5-FU plus leucovorin was generally well tolerated; only a minority of patients experienced grade 3 and 4 toxicities. CONCLUSION After a curative resection of a stage III colon cancer, adjuvant treatment with 5-FU plus leucovorin is generally well tolerated and significantly more effective than 5-FU plus levamisole in reducing tumor relapse and improving survival.

S3 Guidelines for Colorectal Carcinoma

Correspondence Prof. Dr. Wolff Schmiegel Medizinische Klinik, Ruhr-Universität Bochum, Knappschaftskrankenhaus In der Schornau 23–25 44892 Bochum Tel.: ++ 49/2 34/2 993401 Fax: ++ 49/2 34/2 9934 09 meduni-kkh@rub.de www.medunikkh.de Representing the German Society for Digestiveand Metabolic Diseases (DGVS) and the German Cancer Society (DKG) In collaboration with the: ▶ German Society for Visceral Surgery (DGVC) ▶ German Society for Haematology and Oncology (DGHO) ▶ German Society of Pathology (DGP) ▶ German Society of Radio-oncology (DEGRO) ▶ Surgical Working Group for Oncology abdominal surgery (CAO-V) ▶ Germany Radiological Society (DRG) ▶ German Combined Society for Clinical Chemistry and Laboratory Medicine (DGKL) ▶ German Society of Coloproctology (DGK) ▶ Association for Stoma Patients and Persons with Colorectal Cancer (German ILCO) ▶ German Crohn’s Disease and Ulcerative colitis Association (DCCV) ▶ German Society of Internal Medicine (DGIM) ▶ Working Group for Scientific Medical Specialised Societies e.V. (AWMF) ▶ with support from the German Cancer Society e.V. (DKH) Directors 2004: W. Schmiegel, H.-K. Selbmann Leadership Update 2008: W. Schmiegel with the collaboration of: C. Pox, A. Reinacher-Schick, I. Kopp

Individual Patient Data Analysis of Progression-Free Survival Versus Overall Survival As a First-Line End Point for Metastatic Colorectal Cancer in Modern Randomized Trials: Findings From the Analysis and Research in Cancers of the Digestive System Database

PURPOSE Progression-free survival (PFS) has previously been established as a surrogate for overall survival (OS) for first-line metastatic colorectal cancer (mCRC). Because mCRC treatment has advanced in the last decade with extended OS, this surrogacy requires re-examination. METHODS Individual patient data from 16,762 patients were available from 22 first-line mCRC studies conducted from 1997 to 2006; 12 of those studies tested antiangiogenic and/or anti-epidermal growth factor receptor agents. The relationship between PFS (first event of progression or death) and OS was evaluated by using R(2) statistics (the closer the value is to 1, the stronger the correlation) from weighted least squares regression of trial-specific hazard ratios estimated by using Cox and Copula models. RESULTS Forty-four percent of patients received a regimen that included biologic agents. Median first-line PFS was 8.3 months, and median OS was 18.2 months. The correlation between PFS and OS was modest (R(2), 0.45 to 0.69). Analyses limited to trials that tested treatments with biologic agents, nonstrategy trials, or superiority trials did not improve surrogacy. CONCLUSION In modern mCRC trials, in which survival after the first progression exceeds time to first progression, a positive but modest correlation was observed between OS and PFS at both the patient and trial levels. This finding demonstrates the substantial variability in OS introduced by the number of lines of therapy and types of effective subsequent treatments and the associated challenge to the use of OS as an end point to assess the benefit attributable to a single line of therapy. PFS remains an appropriate primary end point for first-line mCRC trials to detect the direct treatment effect of new agents.

Body Mass Index Is Prognostic in Metastatic Colorectal Cancer: Pooled Analysis of Patients From First-Line Clinical Trials in the ARCAD Database

PURPOSE In recent retrospective analyses of early-stage colorectal cancer (CRC), low and high body mass index (BMI) scores were associated with worsened outcomes. Whether BMI is a prognostic or predictive factor in metastatic CRC (mCRC) is unclear. PATIENTS AND METHODS Individual data from 21,149 patients enrolled onto 25 first-line mCRC trials during 1997 to 2012 were pooled. We assessed both prognostic and predictive effects of BMI on overall survival and progression-free survival, and we accounted for patient and tumor characteristics and therapy type (targeted v nontargeted). RESULTS BMI was prognostic for overall survival (P < .001) and progression-free survival (P < .001), with an L-shaped pattern. That is, risk of progression and/or death was greatest for low BMI; risk decreased as BMI increased to approximately 28 kg/m(2), and then it plateaued. Relative to obese patients, patients with a BMI of 18.5 kg/m(2) had a 27% increased risk of having a PFS event (95% CI, 20% to 34%) and a 50% increased risk of death (95% CI, 43% to 56%). Low BMI was associated with poorer survival for men than women (interaction P < .001). BMI was not predictive of treatment effect. CONCLUSION Low BMI is associated with an increased risk of progression and death among the patients enrolled on the mCRC trials, with no increased risk for elevated BMI, in contrast to the adjuvant setting. Possible explanations include negative effects related to cancer cachexia in patients with low BMI, increased drug delivery or selection bias in patients with high BMI, and potential for an interaction between BMI and molecular signaling pathways.

Colorectal carcinoma: the management of polyps, (neo)adjuvant therapy, and the treatment of metastases.

BACKGROUND Colorectal carcinoma (CRC) is the second most common type of cancer in Germany. In view of recent major changes in the diagnosis and treatment of CRC, the S3 guideline for CRC published in its full version in 2004 was partially updated in 2008 and again in 2009. METHOD The literature was systematically searched for all articles published from 2004 onward concerning polyp management, (neo-)adjuvant treatment, and treatment of metastatic disease. Evidence-based recommendations were developed in a consensus conference. RESULTS For some patients who have undergone polypectomy, the time to follow-up with colonoscopy can be lengthened. In UICC stage III colon cancer, adjuvant chemotherapy with an oxaliplatin-based regimen is recommended. In stage II colon cancer, adjuvant chemotherapy should be considered mainly when risk factors are present. In stages II and III, neo-adjuvant therapy should be given before resection in rectal cancer. In patients with metastatic disease, the use of all possible treatment options results in a median overall survival time of 24 months. In some patients with primarily non-resectable liver metastases, systemic treatment may enable a secondary, potentially curative resection. Therapeutic agents are chosen individually on the basis of clinical factors including the goal of treatment, the patients general condition, and tumor molecular markers. CONCLUSION The S3 guideline contains evidence-based recommendations for the diagnosis and treatment of colorectal carcinoma. Broad implementation of the guideline will be essential for improved patient care.

Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants: pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group

In this pooled analysis of metastatic colorectal cancer patients, mutations in KRAS, and BRAF were associated with inferior progression-free and overall survival compared with patients with non-mutated tumors. KRAS exon 2 mutation variants were associated with heterogeneous outcome compared with unmutated tumors with KRAS G12C and G13D being associated with rather poor survival.

A randomised phase II study of irinotecan in combination with 5-FU/FA compared with irinotecan alone as second-line treatment of patients with metastatic colorectal carcinoma.

We conducted a randomised phase II study to compare irinotecan monotherapy with irinotecan in combination with infusional 5-fluorouracil/folinic acid (5-FU/FA) regarding efficacy and safety of these regimens in second-line therapy after failed fluoropyrimidine therapy in patients with metastatic colorectal cancer (mCRC). Patients and Methods: 55 patients with mCRC after failure of a first-line therapy were randomised to receive either irinotecan 80 mg/m2 followed by FA 500 mg/m2 and 5-FU 2,000 mg/m2 24 h weekly for 6 weeks, with courses repeated on day 50 (arm A), or irinotecan 125 mg/m2 weekly for 4 weeks, with cycles repeated on day 43 (Arm B). Results: Both regimens yielded a partial response rate of 11% with identical progression-free survival (3.7 months for both regimens) and similar overall survival (9.5 months for the combination therapy vs. 10.7 months for the monotherapy). Both regimens were very well tolerated, and the combination of irinotecan with 5-FU/FA did not result in increased toxicity. Conclusion: Our study confirms that irinotecan alone or in combination with infusional 5-FU/FA is an effective and safe regimen for CRC patients who failed first-line therapies. However, the role of 5-FU in addition to irinotecan for fluoropyrimidine failures remains unclear. Due to the small sample size, a decision cannot be made which therapy should be preferred, and a significant contribution to the efficacy of single-agent irinotecan is not obvious from this small randomised phase II trial.

Prognostic Value of Reduced SMAD4 Expression in Patients With Metastatic Colorectal Cancer Under Oxaliplatin-Containing Chemotherapy: A Translational Study of the AIO Colorectal Study Group

BACKGROUND SMAD4 is a polypeptide with tumor suppressor function being investigated as a prognostic biomarker in Union Internationale Contre le Cancer stages II and III in previous studies, but its role as a prognostic marker in stage IV colorectal cancer (CRC) is still undefined. We investigated the prognostic value of reduced SMAD4 expression in patients with metastatic (mCRC) under first-line oxaliplatin-containing combination chemotherapy. PATIENTS AND METHODS Tumor samples were obtained from patients who took part in a prospective randomized phase III chemotherapy trial of the Arbeitsgemeinschaft Internistische Onkologie of the German Cancer Society colorectal study group, comparing the use of capecitabine plus oxaliplatin with infusional 5-fluorouracil (5-FU) plus oxaliplatin as first-line therapy in mCRC. SMAD4 expression was determined by immunohistochemistry. RESULTS Tumor tissues from 230 patients were obtained. Reduced SMAD4 expression was identified in 34% of samples. Patients with reduced nuclear SMAD4 expression in tumor tissue showed a shorter progression-free survival (PFS; 7.0 months vs. 8.9 months; P = .024) and overall survival (OS; 13.9 months vs. 17.8 months; P = .044) compared with patients retaining SMAD4 expression. The effect of SMAD4 expression on PFS and OS could be demonstrated in univariate and multivariate analyses. CONCLUSION Our data demonstrate the importance of reduced SMAD4 expression in patients with mCRC receiving chemotherapy with oxaliplatin and 5-FU.

Phase III trial of infusional 5-fluorouracil/folinic acid plus oxaliplatin (FUFOX) versus capecitabine plus oxaliplatin (CAPOX) as first line treatment in advanced colorectal carcinoma (ACRC): Results of an interim safety analysis

3546 Background: In a previous phase III study, the FUFOX regimen has shown superior response rates and progression-free survival compared with bolus 5-FU/FA (Mayo Clinic protocol) in patients with ACRC (Grothey, ASCO 2002). The combination of capecitabine (CAP) and oxaliplatin (OX) has demonstrated good efficacy and safety results in recent phase II studies. In August 2002 we initiated a phase III trial to compare FUFOX and CAPOX as first line therapy in patients with ACRC. Here, we present the results of a planned interim safety analysis. PATIENTS AND METHODS From August 2002 to October 2003 275 (of target 420) patients (m:f = 176:99; median age 66 (range 32-85)) have been randomized to receive either FUFOX (135 pts. arm A: 5-fluorouracil 2000mg/m2 24h infusion, folinic acid 500mg/m2, oxaliplatin 50mg/m2 d1,8,15,22; q5 wks) or CAPOX (140 pts. arm B: capecitabine 1000mg/m2 bid d1-14, oxaliplatin 70mg/m2 d1 and 8; q3 wks). All patients had measurable metastatic disease, ECOG performance status 0-2, normal renal and hepatic function. RESULTS To date 783 treatment cycles (320 FUFOX, 463 CAPOX) are evaluable (median number of cycles per patient: arm A: 4, range 1-8; arm B: 4, range 1-12. Seven deaths occured within the first 60 days (3 (2.2%) in arm A : 1x bowel obstruction, 1x severe diarrhea, 1x unknown cause) and 4 (2.8%) in arm B : 1x stroke, 1x bowel obstruction, 1x severe diarrhea and sepsis, 1x unknown cause). Major toxicities grade 2-4 (NCI-CTC) are listed in the table below. CONCLUSIONS These data show that both FUFOX and CAPOX have a comparable toxicity profile as first line therapy in ACRC and are both well tolerated. Updated toxicity results will be reported at the meeting. At that time, the planned enrollment of 420 patients will have been completed. [Figure: see text] No significant financial relationships to disclose.