Ullrich Graeven

Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials.

This study evaluates the efficacy of capecitabine using data from a large, well-characterised population of patients with metastatic colorectal cancer (mCRC) treated in two identically designed phase III studies. A total of 1207 patients with previously untreated mCRC were randomised to either oral capecitabine (1250 mg m−2 twice daily, days 1−14 every 21 days; n=603) or intravenous (i.v.) bolus 5-fluorouracil/leucovorin (5-FU/LV; Mayo Clinic regimen; n=604). Capecitabine demonstrated a statistically significant superior response rate compared with 5-FU/LV (26 vs 17%; P<0.0002). Subgroup analysis demonstrated that capecitabine consistently resulted in superior response rates (P<0.05), even in patient subgroups with poor prognostic indicators. The median time to response and duration of response were similar and time to progression (TTP) was equivalent in the two arms (hazard ratio (HR) 0.997, 95% confidence interval (CI) 0.885–1.123, P=0.95; median 4.6 vs 4.7 months with capecitabine and 5-FU/LV, respectively). Multivariate Cox regression analysis identified younger age, liver metastases, multiple metastases and poor Karnofsky Performance Status as independent prognostic indicators for poor TTP. Overall survival was equivalent in the two arms (HR 0.95, 95% CI 0.84–1.06, P=0.48; median 12.9 vs 12.8 months, respectively). Capecitabine results in superior response rate, equivalent TTP and overall survival, an improved safety profile and improved convenience compared with i.v. 5-FU/LV as first-line treatment for MCRC. For patients in whom fluoropyrimidine monotherapy is indicated, capecitabine should be strongly considered. Following encouraging results from phase I and II trials, randomised trials are evaluating capecitabine in combination with irinotecan, oxaliplatin and radiotherapy. Capecitabine is a suitable replacement for i.v. 5-FU as the backbone of colorectal cancer therapy.

Phase I study of the humanised anti-EGFR monoclonal antibody matuzumab (EMD 72000) combined with gemcitabine in advanced pancreatic cancer

The humanised anti-epidermal growth factor receptor (EGFR) monoclonal antibody matuzumab (formerly EMD 72000) is active against pancreatic cancer in preclinical studies. This phase I study assessed the safety and potential benefit of combined treatment with matuzumab and standard-dose gemcitabine. Three groups of chemotherapy-naive advanced pancreatic adenocarcinoma patients (n=17) received escalating doses of matuzumab (400 mg weekly, 800 mg biweekly, or 800 mg weekly) and gemcitabine (1000 mg m–2 weekly in weeks 1–3 of each 4-week cycle). Toxicity, antitumour activity, pharmacokinetic (PK) parameters, and pharmacodynamic (PD) markers in skin biopsies were evaluated. Severe treatment-related toxicities were limited to grade 3 neutropenia (n=3), leucopenia (n=1), and decreased white blood cell count (n=1). Common study drug-related adverse events were skin toxicities (grade 2=6, grade 1=7) and fever (grade 1=4). Matuzumab inhibited phosphorylated EGFR and affected receptor-dependent signalling and transduction; effects were seen even in the lowest-dose group. Pharmacokinetic data were consistent with results of matuzumab monotherapy. Partial response (PR) or stable disease occurred in eight of 12 evaluated patients (66.7%), with three PRs among six evaluated patients in the group receiving 800 mg weekly. Matuzumab in biologically effective doses with standard gemcitabine therapy appears well tolerated. The combination is feasible and may have enhanced activity.

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

Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial

BACKGROUND The definition of a best maintenance strategy following combination chemotherapy plus bevacizumab in metastatic colorectal cancer is unclear. We investigated whether no continuation of therapy or bevacizumab alone are non-inferior to fluoropyrimidine plus bevacizumab, following induction treatment with a fluoropyrimidine plus oxaliplatin plus bevacizumab. METHODS In this open-label, non-inferiority, randomised phase 3 trial, we included patients aged 18 years or older with histologically confirmed, previously untreated metastatic colorectal cancer, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, adequate bone marrow, liver, and renal function, no pre-existing neuropathy greater than grade 1, and measurable disease, from 55 hospitals and 51 private practices in Germany. After 24 weeks of induction therapy with either fluorouracil plus leucovorin plus oxaliplatin or capecitabine plus oxaliplatin, both with bevacizumab, patients without disease progression were randomly assigned centrally by fax (1:1:1) to standard maintenance treatment with a fluoropyrimidine plus bevacizumab, bevacizumab alone, or no treatment. Both patients and investigators were aware of treatment assignment. Stratification criteria were response status, termination of oxaliplatin, previous adjuvant treatment with oxaliplatin, and ECOG performance status. At first progression, re-induction with all drugs of the induction treatment was a planned part of the protocol. Time to failure of strategy was the primary endpoint, defined as time from randomisation to second progression after maintenance (and if applicable re-induction), death, or initiation of further treatment including a new drug. Time to failure of strategy was equivalent to time to first progression for patients who did not receive re-induction (for any reason). The boundary for assessment of non-inferiority was upper limit of the one-sided 98·8% CI 1·43. Analyses were done by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov, number NCT00973609. FINDINGS Between Sept 17, 2009, and Feb 21, 2013, 837 patients were enrolled and 472 randomised; 158 were randomly assigned to receive fluoropyrimidine plus bevacizumab, 156 to receive bevacizumab monotherapy, and 158 to receive no treatment. Median follow-up from randomisation is 17·0 months (IQR 9·5-25·4). Median time to failure of strategy was 6·9 months (95% CI 6·1-8·5) for the fluoropyrimidine plus bevacizumab group, 6·1 months (5·3-7·4) for the bevacizumab alone group, and 6·4 months (4·8-7·6) for the no treatment group. Bevacizumab alone was non-inferior to standard fluoropyrimidine plus bevacizumab (hazard ratio [HR] 1·08 [95% CI 0·85-1·37]; p=0·53; upper limit of the one-sided 99·8% CI 1·42), whereas no treatment was not (HR 1·26 [0·99-1·60]; p=0·056; upper limit of the one-sided 99·8% CI 1·65). The protocol-defined re-induction after first progression was rarely done (30 [19%] patients in the fluoropyrimidine plus bevacizumab group, 67 [43%] in the bevacizumab monotherapy group, and 73 [46%] in the no treatment group. The most common grade 3 adverse event was sensory neuropathy (21 [13%] of 158 patients in the fluoropyrimidine plus bevacizumab group, 22 [14%] of 156 patients in the bevacizumab alone group, and 12 [8%] of 158 patients in the no treatment group). INTERPRETATION Although non-inferiority for bevacizumab alone was demonstrated for the primary endpoint, maintenance treatment with a fluoropyrimidine plus bevacizumab may be the preferable option for patients following an induction treatment with a fluoropyrimidine, oxaliplatin, and bevacizumab, as it allows the planned discontinuation of the initial combination without compromising time with controlled disease. Only a few patients were exposed to re-induction treatment, thus deeming the primary endpoint time to failure of strategy non-informative and clinically irrelevant. Progression-free survival and overall survival should be considered primary endpoints in future trials exploring maintenance strategies.

Capecitabine/irinotecan or capecitabine/oxaliplatin in combination with bevacizumab is effective and safe as first-line therapy for metastatic colorectal cancer: a randomized phase II study of the AIO colorectal study group

BACKGROUND This randomized phase II trial investigated the efficacy and safety of capecitabine/oxaliplatin (CapOx) plus bevacizumab and dose-modified capecitabine/irinotecan (mCapIri) plus bevacizumab as first-line therapy in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS Patients received bevacizumab 7.5 mg/kg with oxaliplatin 130 mg/m(2)/day 1 plus capecitabine 1000 mg/m(2) bid/days 1-14 or with irinotecan 200 mg/m(2)/day 1 plus capecitabine 800 mg/m(2) bid/days 1-14 both every 21 days. The primary end point was 6 months progression-free survival (PFS). RESULTS A total of 255 patients were enrolled. The intent-to-treat population comprised 247 patients (CapOx-bevacizumab: n = 127; mCapIri-bevacizumab: n = 120). The six-month PFS rates were 76% (95% CI, 69%-84%) and 84% (95% CI, 77%-90%). Median PFS and OS were 10.4 months (95% CI, 9.0-12.0) and 24.4 months (95% CI, 19.3-30.7) with CapOx-bevacizumab, and 12.1 months (95% CI, 10.8-13.2) and 25.5 months (95% CI, 21.0-31.0) with mCapIri-bevacizumab. Grade 3/4 diarrhea as predominant toxic effect occurred in 22% of patients with CapOx-bevacizumab and in 16% with mCapIri-bevacizumab. CONCLUSIONS Both, CapOx-bevacizumab and mCapIri-bevacizumab, show promising activity and an excellent toxic effect profile. Efficacy is in the range of other bevacizumab-containing combination regimen although lower doses of irinotecan and capecitabine were selected for mCapIri.

Induction chemotherapy before chemoradiotherapy and surgery for locally advanced rectal cancer : is it time for a randomized phase III trial?

Background:In the era of preoperative chemoradiotherapy (CRT) and total mesorectal excision (TME), the development of distant metastases is the predominant mode of failure in rectal cancer patients today. Integrating more effective systemic therapy into combined modality programs is the challenge. The question that needs to be addressed is how and when to apply systemic treatment with adequate dose and intensity.Material and Methods:This review article focuses on phase II–III trials designed to improve 5-fluorouracil (5-FU)-based combined modality treatment for rectal cancer patients through the inclusion of concurrent, adjuvant or, most recently, induction combination chemotherapy. Computerized bibliographic searches of PubMed were supplemented with hand searches of reference lists and abstracts of ASCO/ASTRO/ESTRO meetings.Results:After preoperative CRT and surgical resection, approximately one third of patients do not receive adjuvant chemotherapy, mainly due to surgical complications, patients’ refusal, or investigator’s discretion. In order to be able to apply chemotherapy with sufficient dose and intensity, an innovative approach is to deliver systemic therapy prior to preoperative CRT rather than adjuvant chemotherapy. Emerging evidence from several phase II trials and, recently, randomized phase II trials indicate that induction chemotherapy is feasible, does not compromise CRT or surgical resection, and enables the delivery of chemotherapy in adequate dose and intensity. Although this approach did not increase local efficacy in recent trials (e.g., pathological complete response rates, tumor regression, R0 resection rates, local control), it may help to improve control of distant disease.Conclusion:Whether this improvement in applicability and dose density of chemotherapy will ultimately translate into improved disease-free survival will have to be tested in a larger phase III trial.Hintergrund:Nach Einführung der präoperativen Radiochemotherapie (RCT) und der totalen mesoerektalen Excision manifestieren sich Rezidive beim Rektumkarzinom am häufigsten als Fernmetastasen. Daher ist die Integration einer systemisch effektiveren Therapie in das multimodale Behandlungskonzept derzeit die entscheidende Herausforderung. Die Frage ist, wann und wie diese Systemtherapie mit adäquater Dosis und Intensität verabreicht werden kann.Material und Methoden:Der Übersichtsartikel beschreibt Phase II–III Studien, deren Ziel es war, die allein 5-FU-basierte multimodale Behandlung durch Hinzunahme einer Kombinations-Chemotherapie, simultan zur Radiotherapie, adjuvant oder als Induktionstherapie, zu verbessern. Dazu diente eine Suchabfrage in Pubmed, in Referenzlisten publizierter Arbeiten sowie Abstrakts von ASCO/ASTRO/ESTRO-Konferenzen.Ergebnisse:Nach präoperativer RCT und Operation erhalten etwa ein Drittel aller Patienten wegen postoperativer Komplikationen, patientenseitiger Ablehnung oder Entscheidung des betreuenden Arztes keine adjuvante Chemotherapie. Ein innovativer Ansatz ist die Induktionschemotherapie vor präoperativer RCT und Operation, um die systemische Therapie in ausreichender Dosierung und Intensität durchführen zu können. Eine Vielzahl an Phase II-Studien, und zuletzt auch randomisierter Phase- II-Studien, zeigte, dass dieses Konzept durchführbar ist, die anschließende RCT und Operation nicht kompromittiert sowie die systemische Komponente in adäquater Dosis und Intensität applizierbar macht. Wenngleich dadurch die lokale Wirksamkeit (histopathologisch bestätigte Komplettremission, Tumorregression, R0-Resektionsrate, lokale Kontrolle) nicht verbessert wurde, könnte sich dieses Vorgehen positiv auf die systemische Tumorkontrolle auswirken.Schlussfolgerung:Eine Phase-III-Studie muss klären, ob die verbesserte Durchführbarkeit und Dosisdichte einer Induktionschemotherapie das krankheitsfreie Überleben verbessern kann.

Biomarkers of anti-angiogenic therapy in metastatic colorectal cancer (mCRC): original data and review of the literature.

INTRODUCTION Tumour angiogenesis via vascular endothelial growth factor (VEGF) is essential for promoting tumour progression and is overexpressed in colorectal cancer. The humanised monoclonal anti-VEGF antibody bevacizumab (Avastin®, Genentech Inc., South San Francisco, CA) has shown activity in metastatic colorectal cancer (mCRC) combined with conventional chemotherapy. The search for biomarkers to predict response to anti-angiogenic therapy in mCRC is of great interest. We investigated several potential predictive anti-angiogenic markers including circulating endothelial progenitor cells (EPC) in patients with mCRC receiving bevacizumab containing treatment within a randomised multicenter phase 2 study of the German AIO GI tumour study group. METHODS We collected sequential blood samples and tumour tissues from patients participating in a clinical trial for patients with mCRC. We performed flow cytometry of mononuclear cells isolated from peripheral blood to assess CD 133 + or CD 34 + /KDR + EPC before the first bevacizumab containing chemotherapy and after 21 days. Circulating VEGF blood levels before a bevacizumab containing chemotherapy regimen and after 21 days and VEGF expression in tumour tissue were examined. RESULTS Patients with mCRC and a partial remission after six months of immuno-chemotherapy containing bevacizumab showed a reduction of CD 34 negative KDR positive cells as early as 3 weeks after start of therapy. In contrast, no remarkable change in the number of CD 34 /KDR positive or CD 34 /CD133 positive cells was seen. Furthermore, there was no correlation between treatment response and VEGF expression within the tumour tissue. The mAb bevacizumab reduced serum-VEGF levels in patients independent of their treatment response to bevacizumab. DISCUSSION We examined circulating endothelial progenitor cells (EPC), serum-VEGF levels and the tumour tissue VEGF expression of patients with mCRC under a bevacizumab containing chemotherapy. The patients with a partial remission after six months of immuno-chemotherapy showed a reduction of CD 34 negative KDR positive cells as early as 3 weeks after start of therapy. Neither serum nor tissue markers were of significant predictive value in our pilot study. Furthermore, we review the current data on biomarkers for anti-angiogenic therapy of mCRC.

Induction Chemotherapy before Chemoradiotherapy and Surgery for Locally Advanced Rectal Cancer

Background:In the era of preoperative chemoradiotherapy (CRT) and total mesorectal excision (TME), the development of distant metastases is the predominant mode of failure in rectal cancer patients today. Integrating more effective systemic therapy into combined modality programs is the challenge. The question that needs to be addressed is how and when to apply systemic treatment with adequate dose and intensity.Material and Methods:This review article focuses on phase II–III trials designed to improve 5-fluorouracil (5-FU)-based combined modality treatment for rectal cancer patients through the inclusion of concurrent, adjuvant or, most recently, induction combination chemotherapy. Computerized bibliographic searches of PubMed were supplemented with hand searches of reference lists and abstracts of ASCO/ASTRO/ESTRO meetings.Results:After preoperative CRT and surgical resection, approximately one third of patients do not receive adjuvant chemotherapy, mainly due to surgical complications, patients’ refusal, or investigator’s discretion. In order to be able to apply chemotherapy with sufficient dose and intensity, an innovative approach is to deliver systemic therapy prior to preoperative CRT rather than adjuvant chemotherapy. Emerging evidence from several phase II trials and, recently, randomized phase II trials indicate that induction chemotherapy is feasible, does not compromise CRT or surgical resection, and enables the delivery of chemotherapy in adequate dose and intensity. Although this approach did not increase local efficacy in recent trials (e.g., pathological complete response rates, tumor regression, R0 resection rates, local control), it may help to improve control of distant disease.Conclusion:Whether this improvement in applicability and dose density of chemotherapy will ultimately translate into improved disease-free survival will have to be tested in a larger phase III trial.Hintergrund:Nach Einführung der präoperativen Radiochemotherapie (RCT) und der totalen mesoerektalen Excision manifestieren sich Rezidive beim Rektumkarzinom am häufigsten als Fernmetastasen. Daher ist die Integration einer systemisch effektiveren Therapie in das multimodale Behandlungskonzept derzeit die entscheidende Herausforderung. Die Frage ist, wann und wie diese Systemtherapie mit adäquater Dosis und Intensität verabreicht werden kann.Material und Methoden:Der Übersichtsartikel beschreibt Phase II–III Studien, deren Ziel es war, die allein 5-FU-basierte multimodale Behandlung durch Hinzunahme einer Kombinations-Chemotherapie, simultan zur Radiotherapie, adjuvant oder als Induktionstherapie, zu verbessern. Dazu diente eine Suchabfrage in Pubmed, in Referenzlisten publizierter Arbeiten sowie Abstrakts von ASCO/ASTRO/ESTRO-Konferenzen.Ergebnisse:Nach präoperativer RCT und Operation erhalten etwa ein Drittel aller Patienten wegen postoperativer Komplikationen, patientenseitiger Ablehnung oder Entscheidung des betreuenden Arztes keine adjuvante Chemotherapie. Ein innovativer Ansatz ist die Induktionschemotherapie vor präoperativer RCT und Operation, um die systemische Therapie in ausreichender Dosierung und Intensität durchführen zu können. Eine Vielzahl an Phase II-Studien, und zuletzt auch randomisierter Phase- II-Studien, zeigte, dass dieses Konzept durchführbar ist, die anschließende RCT und Operation nicht kompromittiert sowie die systemische Komponente in adäquater Dosis und Intensität applizierbar macht. Wenngleich dadurch die lokale Wirksamkeit (histopathologisch bestätigte Komplettremission, Tumorregression, R0-Resektionsrate, lokale Kontrolle) nicht verbessert wurde, könnte sich dieses Vorgehen positiv auf die systemische Tumorkontrolle auswirken.Schlussfolgerung:Eine Phase-III-Studie muss klären, ob die verbesserte Durchführbarkeit und Dosisdichte einer Induktionschemotherapie das krankheitsfreie Überleben verbessern kann.

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.

Methylated free-circulating HPP1 DNA is an early response marker in patients with metastatic colorectal cancer.

Detection of methylated free‐circulating DNA (mfcDNA) for hyperplastic polyposis 1 (HPP1) in blood is correlated with a poor prognosis for patients with metastatic colorectal cancers (mCRC). Here, we analyzed the plasma levels of HPP1 mfcDNA in mCRC patients treated with a combination therapy containing a fluoropyrimidine, oxaliplatin and bevacizumab to test whether HPP1 mfcDNA is a suitable prognostic and response biomarker. From 467 patients of the prospective clinical study AIO‐KRK‐0207, mfcDNA was isolated from plasma samples at different time points and bisulfite‐treated mfcDNA was quantified using methylation specific PCR. About 337 of 467 patients had detectable levels for HPP1 mfcDNA before start of treatment. The detection was significantly correlated with poorer overall survival (OS) (HR = 1.86; 95%CI 1.37–2.53). About 2–3 weeks after the first administration of combination chemotherapy, HPP1 mfcDNA was reduced to non‐detectable levels in 167 of 337 patients. These patients showed a better OS compared with patients with continued detection of HPP1 mfcDNA (HR HPP1(sample 1: pos/ sample 2: neg) vs. HPP1(neg/neg) = 1.41; 95%CI 1.00–2.01, HPP1(neg,pos/pos) vs. HPP1(neg/neg) = 2.60; 95%CI 1.86–3.64). Receiver operating characteristic analysis demonstrated that HPP1 mfcDNA discriminates well between patients who do (not) respond to therapy according to the radiological staging after 12 or 24 weeks (AUC = 0.77 or 0.71, respectively). Detection of HPP1 mfcDNA can be used as a prognostic marker and an early marker for response (as early as 3–4 weeks after start of treatment compared with radiological staging after 12 or 24 weeks) to identify patients who will likely benefit from a combination chemotherapy with bevacizumab.