Katrine R. Schønnemann

Phase II study of short-time oxaliplatin, capecitabine and epirubicin (EXE) as first-line therapy in patients with non-resectable gastric cancer

Epirubicin, cisplatin and continuous infusion of 5-FU is a widely used palliative regimen in patients with gastric cancer. If cisplatin is substituted by oxaliplatin and 5-FU by capecitabine this regimen can be administered in the outpatient setting. Dose-limiting toxicity of oxaliplatin is peripheral sensory neuropathy and it is recommended to give oxaliplatin as a 120 min infusion. However, in patients with colorectal cancer a 30 min infusion of oxaliplatin can safely be administered without increasing neurotoxicity, standard infusion time is 30 min at our departments. In our phase I study the recommended doses of EXE was established (Dupont et al, 2006). Patients with non-resectable gastric adenocarcinoma were eligible. Patients received EXE (epirubicin 50 mg m−2 day 1; capecitabine 1000 mg m−2 day−1 continuously and oxaliplatin 130 mg m−2 day 1) as outpatient therapy every third week for a maximum of 8 cycles. From June 2004 to September 2005, we enroled 54 patients. Median age was 60 years (31–74 years) Median number of courses was 6 (1–8). Response rate was 45%. Median PFS was 6.8 (5.2–7.9) months and median survival was 10.1 (7.9–11.1) months. Most important grade 3 toxicities were as follows: nausea, vomiting, and diarrhoea (6%). Neurotoxicity grade 2 was seen in 36.5%. We therefore conclude, that EXE every third week is a convenient regimen that easily can be administrated in the outpatient setting but the regimen needs further evaluation in a phase III study.

Characteristics, therapy and outcome in an unselected and prospectively registered cohort of pancreatic cancer patients

PURPOSE Pancreatic cancer (PC) is associated with a dismal prognosis. Few studies have examined characteristics and outcome in an unselected population-based cohort of PC patients. Therefore, we investigated patient baseline characteristics, therapy choices and survival in a complete cohort of patients with PC. METHODS All cases diagnosed with PC between 2007 and 2009 in the Region of Southern Denmark (pop: 1,200,000) were prospectively registered. Patient characteristics including performance status, information about haematology, liver function and therapy were retrieved from patient charts, and used to compare differently treated and untreated groups. RESULTS Six-hundred-eighteen cases were registered as PC; 25 of which did not have adenocarcinomas. Patients were divided in 3 clinical groups based on initial therapy; group 1: resection (n=64), group 2: chemotherapy or chemo-radiotherapy (n=191), group 3: no tumour directed therapy (n=324). Median survival (mOS) (95% confidence interval (CI)) in the three groups was 25.7 months (18-30), 8.1 months (7.0-9.5) and 1.1 months (1.0-1.3) respectively. Three percent of patients participated in clinical trials. An evaluation of baseline factors prognostic value suggested that treated patients differed significantly from non-treated patients. CONCLUSION This study reports survival in treated groups comparable to results obtained from clinical trials with highly selected patients. However the majority of patients with PC do not receive cancer directed therapy. This group was significantly different in several baseline factors, which could suggest a different biology. Improving the outcome of PC patients calls for research into the large group of untreated patients, as only a minority of patients receive cancer directed therapy.

Long-term results of concurrent radiotherapy and UFT in patients with locally advanced pancreatic cancer.

BACKGROUND Definition and treatment options for locally advanced non-resectable pancreatic cancer (LAPC) vary. Treatment options range from palliative chemotherapy to chemoradiotherapy (CRT). Several studies have shown that a number of patients become resectable after complementary treatment prior to surgery. METHODS From 2001 to 2005, 63 consecutive patients with unresectable LAPC received CRT. CRT was given at a dose of 50 Gy/27 fractions, combined with UFT (300 mg/m(2)/day) and folinic acid. Re-evaluation of resectability was planned 4-6 weeks after completion of CRT. RESULTS Fifty-eight patients completed all 27 treatment fractions. Toxicity was generally mild, with 18 patients experiencing CTCAE grade 3 or worse acute reactions. One patient died following a treatment-related infection. Two patients developed grade 4 upper GI bleeding. Median survival was 10.6 (8-13) months. Eleven patients underwent resection, leading to a resection rate of 17%, and a median survival of 46 (23-nr) months. All 11 patients had a R0 resection. Median survival for the patients not resected was 8.8 (8-12) months. CONCLUSION CRT with 50 Gy combined with UFT, is a well-tolerated and effective treatment for patients with LAPC. R0 resection was possible in 17% leading to a long median survival of 46 months in resected patients.

Phase I study of docetaxel, oxaliplatin and capecitabine (TEX) as first line therapy to patients with advanced gastro-oesophageal cancer.

Abstract Background. ECF (epirubicin, cisplatin, 5-FU) has been a standard first-line regimen in patients with advanced gastro-esophageal cancer (GEC). If cisplatin is substituted by oxaliplatin (Eloxatin®) – E) and 5-FU by capecitabine (X – Xeloda®) this regimen is easily administered with at least comparable efficacy and lower toxicity. Recent studies indicate that efficacy can be improved by adding docetaxel (Taxotere® – T) to CF. We initiated a phase I trial of T, short-time infusion of E and continuously X (TEX) as first-line therapy in GEC to establish the recommended dose (RD) for further therapy. Materials and methods. Patients were enrolled in cohorts of three at five dose levels. Patients had histologically confirmed GEC adenocarcinoma. Therapy was administered day 1 with escalating doses of docetaxel (60 mg/m2 to 75 mg/m2 iv as a 60 minutes infusion), oxaliplatin (85 to 130 mg/m2 iv as a 30 minutes infusion) and oral capecitabine (1 000 to 1 250 mg/m2/day). TEX was repeated every third week for a maximum of eight cycles. Toxicity was evaluated according to CTCAE v3.0 and dose limiting toxicity (DLT) was evaluated after the first course of TEX. Results. From June 2007 to April 2009, 23 consecutive patients received TEX. At dose level V, two of four patients experienced DLT and therefore we included additional seven patients at dose level IV. Only one of seven experienced DLT but dose-intensity was reduced to 75% in four of seven patients after three courses of TEX. Therefore we defined dose level III as RD. Efficacy was promising with response rate 38%, PFS 9.4 months and OS 12.5 months. Conclusion. The recommended dose of TEX (docetaxel 60 mg/m2 iv day 1, oxaliplatin 115 mg/m2 iv day 1 and oral capecitabine 1250 mg/m2/day continuously) every three weeks is easily administered in an out-patient setting. Efficacy is promising and will be evaluated in a phase II study.

Phase II study of biweekly cetuximab in combination with irinotecan as second-line treatment in patients with platinum-resistant gastro-oesophageal cancer

BACKGROUND The purpose of this phase II trial was to evaluate the efficacy and safety of cetuximab and irinotecan as second-line treatment in patients with gastro-oesophageal adenocarcinoma. PATIENTS AND METHODS Patients with failure to first-line platinum-based chemotherapy received cetuximab 500 mg/m(2) and irinotecan 180 mg/m(2) every second week until disease progression. Toxicity was evaluated according to The Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v. 3.0. Antitumour activity was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) v. 1.0. RESULTS Sixty-three patients were enrolled, median age was 60 years, median performance status was 1 (0-1), 35 patients had two or more organs involved. The median number of courses was 5 (range 1-25). Response rate was 11% (6 partial response (PR)) and 37% had stable disease. Median progression free survival was 2.8 months and overall survival (OS) was 6.1 months. Grade 3-4 toxicity included: diarrhoea (6%), fatigue (5%), vomiting (5%) and neutropenia (16%). Two patients developed febrile neutropenia. Forty-six patients (73%) had developed grade 1-2 skin rash. Patients developing skin rash had a prolonged survival with an OS at 7.1 months. CONCLUSIONS The combination of cetuximab and irinotecan is active as second-line therapy in patients with gastro-oesophageal cancer. Cetuximab induced skin rash was associated with prolonged survival.

Characteristics, therapy and outcome in an unselected and prospectively registered cohort of patients with gastro-oesophageal cancer

Abstract Purpose. The purpose was to examine characteristics, treatment and outcome in an unselected, prospectively registered complete population of patients with gastro-oesophageal adenocarcinoma cancer (GEA). Methods. All cases diagnosed with GEA between 2008 and 2009 in the Region of Southern Denmark (pop: 1 200 000) were registered. Patient characteristics, including performance status, stage and therapy, were retrieved from patient charts and used to compare sub-groups of patients. Results. Three hundred and thirty patients were registered as having GEA. Patients were divided into three clinical subgroups based on initial treatment option: group 1: patients with resectable GEA (n = 113); group 2: patients receiving first-line therapy (n = 107); group 3: patients receiving no tumour-directed therapy (n = 110). Median overall survival (95% CI) in the three groups was 36 months (25–not reached), 7.1 months (7–9) and 2.4 months (2–3), respectively. Seven percent of patients participated in clinical trials. Conclusion. Among patients not amendable to resection, around 30% are candidates for three-drug combination chemotherapy. Age > 65 years was found not to be a poor prognostic factor for survival, giving the possibility of treating elderly patients in the future. Many patients (approx. 30%), however, never received cancer-directed therapy. In order to improve survival in the entire population, it is important that future trials also focus on this group of patients.

New recommendation of doses in an ongoing phase II study of docetaxel, oxaliplatin and capecitabine as first line therapy in advanced gastro-oesophageal cancer

Recently we reported our results from a phase I study of docetaxel, oxaliplatin and capecitabine (TEX) as fi rst line therapy to patients with advanced gastrooesophageal cancer [1]. To establish the recommended dose (RD) for further therapy, a total of 23 patients were enrolled in cohorts of three at fi ve different dose levels. The TEX regimen was investigated in order to fi nd an easily administered, well tolerated three weeks regimen in the out-patient setting, maintaining the effi cacy of DCF (docetaxel 75 mg/m 2 , cisplatin 75 mg/m 2 and 5-FU 750 mg/m 2 /d day 1 – 5 every three weeks) seen in the V-325 trial [2]. At dose level V, two of four patients experienced dose limited toxicity (DLT) and therefore we included additional seven patients at dose level IV. Only one of seven patients experienced DLT but because of hematologic toxicity dose-intensity was reduced to 75% in four of seven patients after three courses of TEX. Overall eight patients (35%) had febrile neutropenia. Probably, the use of granulocyte colony-stimulating factor (G-CSF) might have minimized these problems, but since it is not recommended routinely in the palliative setting in Denmark, we decided to use dose level III as the RD for the ongoing phase II study. Our phase I trial was not designed to evaluate effi cacy but we found a promising response rate (RR) of 35%, progression free survival (PFS) of 9.4 months and overall survival (OS) of 12.5 months indicating high effi cacy of this three-drug combination. Due to a case of febrile neutropenia grade 5 in phase II we evaluated toxicity in all six patients who

Trends in upper gastro-intestinal cancer among the elderly in Denmark, 1980–2012

Abstract Background Upper gastro-intestinal cancer (UGIC) includes malignancies in esophagus, stomach and small intestine, and represents some of the most frequent malignancies worldwide. The aim of the present analysis was to describe incidence, mortality and survival in UGIC patients in Denmark from 1980 to 2012 according to differences in age and time periods. Material and methods UGIC was defined as ICD-10 codes C15-C17. Data derived from the NORDCAN database with comparable data on cancer incidence mortality, prevalence and relative survival in the Nordic countries, where the Danish data were delivered from the Danish Cancer Registry and the Danish Cause of Death Registry with follow-up for death or emigration until the end of 2013. Results The proportion of male patients over the age of 70 years diagnosed with esophageal cancer was constant over time (around 42%) but increased in females to 49% in 2012. Incidence rates increased with time and continued to rise in all ages. Mortality rates were clearly separated by age groups with increasing mortality rates by increasing age group for both sexes. Relative survival increased slowly over time in all age groups. The proportion of older male and female patients with stomach cancer increased to 50% and 54%, respectively, in 2012. Incidence rates decreased steadily with time, especially from 1980 to 1990 but continued to decrease in all age groups. Mortality rates decreased considerably from 1980 to 90 and have been almost constant during the last decade for both women and men. Relative survival increased modest over time in both genders and all age groups. In 2012, only 1471 persons were alive after a diagnosis of stomach cancer. Conclusion There is a need for clinical trials focusing on patients over the age of 70 years with co-existing comorbidity.