Deniz Gencer

Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial

BACKGROUND Fluorouracil-based chemoradiotherapy is regarded as a standard perioperative treatment in locally advanced rectal cancer. We investigated the efficacy and safety of substituting fluorouracil with the oral prodrug capecitabine. METHODS This randomised, open-label, multicentre, non-inferiority, phase 3 trial began in March, 2002, as an adjuvant trial comparing capecitabine-based chemoradiotherapy with fluorouracil-based chemoradiotherapy, in patients aged 18 years or older with pathological stage II-III locally advanced rectal cancer from 35 German institutions. Patients in the capecitabine group were scheduled to receive two cycles of capecitabine (2500 mg/m(2) days 1-14, repeated day 22), followed by chemoradiotherapy (50·4 Gy plus capecitabine 1650 mg/m(2) days 1-38), then three cycles of capecitabine. Patients in the fluorouracil group received two cycles of bolus fluorouracil (500 mg/m(2) days 1-5, repeated day 29), followed by chemoradiotherapy (50·4 Gy plus infusional fluorouracil 225 mg/m(2) daily), then two cycles of bolus fluorouracil. The protocol was amended in March, 2005, to allow a neoadjuvant cohort in which patients in the capecitabine group received chemoradiotherapy (50·4 Gy plus capecitabine 1650 mg/m(2) daily) followed by radical surgery and five cycles of capecitabine (2500 mg/m(2) per day for 14 days) and patients in the fluorouracil group received chemoradiotherapy (50·4 Gy plus infusional fluorouracil 1000 mg/m(2) days 1-5 and 29-33) followed by radical surgery and four cycles of bolus fluorouracil (500 mg/m(2) for 5 days). Patients were randomly assigned to treatment group in a 1:1 ratio using permuted blocks, with stratification by centre and tumour stage. The primary endpoint was overall survival; analyses were done based on all patients with post-randomisation data. Non-inferiority of capecitabine in terms of 5-year overall survival was tested with a 12·5% margin. This trial is registered with ClinicalTrials.gov, number NCT01500993. FINDINGS Between March, 2002, and December, 2007, 401 patients were randomly allocated; 392 patients were evaluable (197 in the capecitabine group, 195 in the fluorouracil group), with a median follow-up of 52 months (IQR 41-72). 5-year overall survival in the capecitabine group was non-inferior to that in the fluorouracil group (76% [95% CI 67-82] vs 67% [58-74]; p=0·0004; post-hoc test for superiority p=0·05). 3-year disease-free survival was 75% (95% CI 68-81) in the capecitabine group and 67% (59-73) in the fluorouracil group (p=0·07). Similar numbers of patients had local recurrences in each group (12 [6%] in the capecitabine group vs 14 [7%] in the fluorouracil group, p=0·67), but fewer patients developed distant metastases in the capecitabine group (37 [19%] vs 54 [28%]; p=0·04). Diarrhoea was the most common adverse event in both groups (any grade: 104 [53%] patients in the capecitabine group vs 85 [44%] in the fluorouracil group; grade 3-4: 17 [9%] vs four [2%]). Patients in the capecitabine group had more hand-foot skin reactions (62 [31%] any grade, four [2%] grade 3-4 vs three [2%] any grade, no grade 3-4), fatigue (55 [28%] any grade, no grade 3-4 vs 29 [15%], two [1%] grade 3-4), and proctitis (31 [16%] any grade, one [<1%] grade 3-4 vs ten [5%], one [<1%] grade 3-4) than did those in the fluorouracil group, whereas leucopenia was more frequent with fluorouracil than with capecitabine (68 [35%] any grade, 16 [8%] grade 3-4 vs 50 [25%] any grade, three [2%] grade 3-4). INTERPRETATION Capecitabine could replace fluorouracil in adjuvant or neoadjuvant chemoradiotherapy regimens for patients with locally advanced rectal cancer. FUNDING Roche Pharma AG (Grenzach-Wyhlen, Germany).

Expression of Transketolase like gene 1 (TKTL1) predicts disease-free survival in patients with locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy

BackgroundFor patients with locally advanced rectal cancer (LARC) neoadjuvant chemoradiotherapy is recommended as standard therapy. So far, no predictive or prognostic molecular factors for patients undergoing multimodal treatment are established. Increased angiogenesis and altered tumour metabolism as adaption to hypoxic conditions in cancers play an important role in tumour progression and metastasis. Enhanced expression of Vascular-endothelial-growth-factor-receptor (VEGF-R) and Transketolase-like-1 (TKTL1) are related to hypoxic conditions in tumours. In search for potential prognostic molecular markers we investigated the expression of VEGFR-1, VEGFR-2 and TKTL1 in patients with LARC treated with neoadjuvant chemoradiotherapy and cetuximab.MethodsTumour and corresponding normal tissue from pre-therapeutic biopsies of 33 patients (m: 23, f: 10; median age: 61 years) with LARC treated in phase-I and II trials with neoadjuvant chemoradiotherapy (cetuximab, irinotecan, capecitabine in combination with radiotherapy) were analysed by quantitative PCR.ResultsSignificantly higher expression of VEGFR-1/2 was found in tumour tissue in pre-treatment biopsies as well as in resected specimen after neoadjuvant chemoradiotherapy compared to corresponding normal tissue. High TKTL1 expression significantly correlated with disease free survival. None of the markers had influence on early response parameters such as tumour regression grading. There was no correlation of gene expression between the investigated markers.ConclusionHigh TKTL-1 expression correlates with poor prognosis in terms of 3 year disease-free survival in patients with LARC treated with intensified neoadjuvant chemoradiotherapy and may therefore serve as a molecular prognostic marker which should be further evaluated in randomised clinical trials.

Capecitabine-associated hand–foot–skin reaction is an independent clinical predictor of improved survival in patients with colorectal cancer

Background:Hand–foot–skin reaction (HFSR) is an adverse event frequently observed during treatment with capecitabine (cape). In the present analysis, we sought to evaluate the potential association of HFSR and survival in German patients with metastatic colorectal cancer and locally advanced rectal cancer treated with cape in clinical trials.Methods:Patients of the Arbeitsgemeinschaft für Internistische Onkologie (AIO) KRK-0104 and the Mannheim rectal cancer trial were evaluated. HFSR was graded according to NCI-CTC criteria in both trials. Time to first occurrence of HFSR was described per cycle and HFSR developing during cycles 1 and 2 was defined as ‘early HFSR’. Baseline characteristics between the patient groups with or without HFSR were compared using Mann–Whitney-U, Fisher’s exact or χ2-test, as appropriate. Haematological and non-haematological toxicities observed in both groups were compared using Fisher’s exact test. Progression-free (PFS) or disease-free (DFS) as well as overall survival (OS) data from both trials were pooled and the HFSR group was compared with the non-HFSR using Kaplan–Meier analysis.Results:A total of 374 patients were included, of whom 29.3% developed any HFSR. Of these, 51% had early HFSR. Baseline characteristics were comparable between both HFSR groups concerning age, gender, ECOG performance status and UICC stage. On multivariate analysis none of these factors had influence on the occurrence of HFSR. The percentage of all-grade (and grade 3–4) haematological toxicities did not differ between both the groups. By contrast, patients exhibiting HFSR had a significantly higher rate of all-grade (but not grade 3–4) diarrhoea, stomatitis/mucositis and fatigue (P<0.01, respectively). Patients with HFSR had improved PFS/DFS (29.0 vs 11.4 months; P=0.015, HR 0.69) and OS (75.8 vs 41.0 months; P=0.001, HR=0.56). Within the HFSR group, PFS/DFS and OS were comparable between patients with early vs late HFSR.Interpretation:The present analysis provides evidence for the association of HFSR and survival in patients with colorectal cancer. Baseline characteristics, with the exception of UICC stage, older age and ECOG performance status, and the time of occurrence of HFSR had no impact on survival. Patients with HFSR had a higher probability of developing any-grade gastrointestinal toxicity and fatigue while no correlation with haematological toxicity was found.

Mapisal Versus Urea Cream as Prophylaxis for Capecitabine-Associated Hand-Foot Syndrome: A Randomized Phase III Trial of the AIO Quality of Life Working Group

PURPOSE Hand-foot syndrome (HFS) is a frequently occurring adverse event associated with anticancer drugs. This study compares a newly introduced ointment containing several antioxidants and exhibiting high radical protection factor, which has been available on the German market since 2011, with urea cream for prevention of HFS in patients treated with capecitabine. PATIENTS AND METHODS Patients with GI tumors or breast cancer treated with capecitabine were included in this randomized phase III study. The primary end point was prevention of HFS of any grade within 6 weeks of treatment as indicated by a standardized patient diary. The study had 80% power to show a 20% reduction of the incidence of HFS with the new ointment. Secondary end points included time to development of HFS greater than grade 1, evaluation of capecitabine dose intensity, and quality of life analyses. RESULTS A total of 152 patients were evaluable. In total, 47 of 152 patients experienced HFS (30.9%), 39.5% with the new ointment and 22.4% in the urea arm (stratified odds ratio, 2.37; P = .02). Time to HFS greater than grade 1 was comparable, but time to any-grade HFS was significantly longer in the urea group (P = .03). Capecitabine dose intensity, time under study, and percentage of days with correct administration of study medication were identical, as were adverse events except for HFS. Skin-related quality of life was significantly worse in the group treated with the new ointment at the end of study treatment. CONCLUSION This trial demonstrated that 10% urea cream was superior to the new ointment at preventing HFS over the first 6 weeks of treatment with capecitabine.

Presentation, Treatment, and Analysis of Prognostic Factors of Terminally ill Patients with Gastrointestinal Tumors

Background: Few data have been published about terminally ill patients with gastrointestinal tumors treated in palliative care units. Patients and Methods: We analyzed the data of 737 admissions of 435 patients that were treated in a palliative care unit, and tried to identify prognostic factors for survival. Results: Most frequent diagnoses at admission were colorectal, gastric, esophageal, and pancreatic cancer. Major clinical symptoms were pain (66.9%), anorexia (60.8%), weight loss (39.2%), and nausea/vomiting (36.6%). In 71.6% of the patients, morphine derivatives were administered. In 33.0% of cases, red blood cell transfusions were applied, parenteral nutrition was given in 31.3%. Median survival, calculated from the day of first hospitalization, was 35 days. On univariate analysis, several clinical and laboratory parameters were identified as prognostically important factors. In the multivariate Cox regression analysis, 5 parameters were significant: ascites and anorexia, elevated leukocyte count and lactate dehydrogenase activity, as well as decreased albumine levels. Using these parameters, patients were divided into 3 risk groups: low-risk (presence of 0–1 factors), intermediaterisk (2–3 factors), and poor-risk patients (4–5 factors). Median survival for poor-risk patients was 18 days, intermediate- and low-risk patients survived 43 and 136 days, respectively (p < 0.0001). Conclusion: In multivariate analysis, 5 prognostic factors were identified, and 3 patient groups were defined. After multicenter validation, these factors may help to guide treatment decisions in terminally ill patients with gastrointestinal tumors.

Quality of Life and Symptom Evaluation in Daily Oncology Practice: A Survey of 150 Patients with Advanced Gastrointestinal Tumours Receiving Palliative Chemotherapy

Background: Quality of life (QoL) is frequently investigated as a secondary endpoint in clinical trials but is rarely evaluated in clinical practice. The present survey sought to assess the QoL of patients with advanced gastrointestinal tumours receiving palliative chemotherapy. Furthermore, we wanted to compare the results of subscales of the generic EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire, version 3.0) using assessment tools with an emphasis on pain and depression. Patients and Methods: 150 patients with gastrointestinal tumours undergoing palliative chemotherapy completed 3 questionnaires. QoL was assessed using the EORTC QLQ-C30, Beck depression inventory (BDI) was utilised to measure the severity of patients’ depression and a visual analogue scale (VAS) was applied to measure patient’s pain intensity. Correlations between these assessments were calculated. Results: The survey revealed that treatment of pain and depression appeared to be inadequate in the present cohort of patients with metastatic gastrointestinal cancer. Good correlations between EORTC QLQ-C30 subscales and the VAS (r = 0.86), as well as the BDI (r = 0.63) were found. Conclusion: The present analysis indicates the need for better symptom control regarding the examples ‘pain’ and ‘depression’. In view of the good correlation between the EORTC QLQ-C30 and the BDI and VAS, further studies on the implementation of the EORTC QLQ-C30 as a screening tool, or for follow-up measurements in daily practice are warranted.

Characteristics, Treatment and Prognostic Factors of Patients with Gynaecological Malignancies Treated in a Palliative Care Unit at a University Hospital

Background: Limited clinical data have been published on patients suffering from advanced gynaecological malignancies treated in palliative care units, and little is known about prognostic factors. Methods: In a retrospective study, the data of 225 patients with breast, ovarian and cervical cancer treated in the palliative care unit of a university hospital between 1998 and 2009 were assembled. Clinical aspects and baseline symptoms, laboratory parameters, the clinical course, and outcome were evaluated. Results: 225 patients (497 cases; cancer diagnoses: breast 79%, ovarian 13%, and cervix 8%) were included in the analysis. The main symptoms were weakness/fatigue (71%), pain (65%), anorexia/nausea (62%), and dyspnea (46%). Pain control was achieved in 85% of all cases, satisfying control of other symptoms in 80%. The median overall survival (OS) was 59 days. 53% of the patients died at the palliative care unit. In the Cox proportional hazards model, 8 parameters indicated an unfavourable outcome: anorexia/nausea, disordered mental status, elevated lactate dehydrogenase, γ-glutamyltransferase, leukocyte count, hypoalbuminaemia, anaemia and hypercalcaemia. Based on these parameters 3 risk groups were defined: low risk (0-2 factors), intermediate risk (3-5 factors), and high risk (6-8 factors). Median survival for high-risk group was 13 days, for intermediate group 61 days, and for low-risk patients 554 days (p < 0.0001). Conclusion: Weakness/fatigue, pain and anorexia were the main symptoms leading to the hospitalisation of patients with gynaecological malignancies. Symptom and pain control was accomplished in 80% of cases. 8 parameters were identified as indicating a poor outcome, and patients showing at least 6 or more of these factors had a very limited prognosis. Although studied retrospectively, these results may be helpful for individual treatment decisions in patients with advanced gynaecological malignancies. Prospective data and the introduction of documentation systems could help to gain more powerful knowledge about the quality of palliative care.

Pharma News / PharmaTicker

Mit Aflibercept wurde eine innovative antiangiogene Substanz entwickelt, die sich vor allem durch ihren 3-fachen Wirkansatz von bisherigen Angiogenesehemmern unterscheidet. Im Unterschied zu Anti-VEGFR-Antikörpern oder sogenannten Small-MoleculesVEGFR-Tyrosinkinase-Inhibitoren agiert das aus löslichen VEGF-R1 und VEGF-R2 zusammengesetzte Fusionsprotein wie eine Falle. Es fängt zirkulierende VEGF-A, VEGF-B und zudem PlGF, verhindert so die Kompensation der untereinander interagierenden Wachstumsfaktoren und blockiert die Tumorangiogenese nicht nur umfassender, sondern zudem vergleichsweise rasch und teilweise 1000fach stärker als z.B. Bevacizumab [1–3]. Signifikant verbesserte Ansprechrate und Überlebenszeit Dass Aflibercept bei Patienten mit metastasiertem kolorektalen Karzinom hochwirksam ist – unabhängig davon, ob sie bereits antiangiogen vorbehandelt sind oder nicht –, zeigen die Ergebnisse der VELOUR-Studie auf [4]. In dieser großen multinationalen randomisierten Phase-III-Studie waren 1226 Patienten nach Versagen einer Oxaliplatin-basierten Therapie mit Aflibercept versus Placebo in Kombination mit FOLFIRI behandelt worden – ein Drittel nach Vorbehandlung mit Bevacizumab. Die zusätzliche Behandlung mit Aflibercept zur Chemotherapie erbrachte einen signifikanten Überlebensvorteil bzw. senkte das Sterberisiko um knapp 20% (HR 0,817; p = 0,0032) [4]. Die effektive antiangiogene Wirkung des Fusionsproteins bilde sich insbesondere in der vergleichsweise hohen und gegenüber dem Kontrollarm signifikant erhöhten Ansprechrate (19,8 vs. 11,1%; p = 0,0001) ab. Mit der therapieinduzierten Reduktion des Tumorvolumens gingen tumorbedingte Beschwerden zurück. Auch im Hinblick auf die Verträglichkeit schnitt Aflibercept gut ab [4].

Strategies for Prevention and Treatment of Chemotherapy-Induced Hand-Foot-Skin-Reaction (HFSR)

Hand-foot-skin-reaction (HFSR), also known as palmoplantar erythrodysesthesia, is a frequently occurring side effect of many antineoplastic therapies. Interruption, dose reduction or even discontinuation of anti-tumor therapy due to missing strategies in prevention or treatment of HFSR can be the consequence. According to severity grade of HFSR restrictions in activities of daily life can occur, which can lead to an impairment of quality of life (QOL). Especially skin-related QOL, which actually can be assessed by a variety of different questionnaires, often decreases when HFSR occurs, which can be underlined by some lately published investigations. Nardone and coworkers used the skindex-16 questionnaire to measure the skin-related QOL of patients treated with sunitinib and sorafenib. Patients with higher grades of HFSR showed lower results in the symptoms and emotions scores of the skindex-16 [1]. Chan et al. report in a lately published review that CTCAE grading of HFSR seems to correlate well with skin-related QOL, irrespective of the available questionnaires used for assessment [2].

Neue Entwicklungen in der perioperativen (Radio-)Chemotherapie des lokal fortgeschrittenen Rektumkarzinoms

5-fluorouracil-based chemoradiotherapy represents a standard neoadjuvant treatment for patients with locally advanced rectal cancer. This review discusses recent data on the modification and intensification of 5-fluorouracil based chemoradiotherapy. Moreover, the role of induction chemotherapy as well as the role of adjuvant chemotherapy after neoadjuvant chemoradiotherapy and tumor resection is critically discussed.