Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: A phase III-study from the German CONKO-study group

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Abstract

Background

Gemcitabine usually given until progressive disease (PD) is the main first-line treatment option for patients with inoperable advanced pancreatic cancer (APC). Currently there is no accepted active regimen for second-line chemotherapy. Previous phase II studies suggest clinical relevant activity of oxaliplatin, folinic acid and 5-FU (OFF). We initiated a phase III multicentre study comparing OFF versus best supportive care (BSC) in patients with APC progressing while on gemcitabine therapy.

Methods

In this open randomized study, patients with CT and/or MRI confirmed progressive disease while on gemcitabine therapy were randomized 1:1 to OFF or BSC. Stratification included duration of first-line therapy (<3, 3 to 6 and >6 months), performance status (KPS 70–80%; 90–100%) and tumour stage (M1/M0). OFF consisted of folinic acid 200 mg/m2 followed by 5-fluorouracil 2 g/m2 (24 h) on d1, d8, d15, d22 and oxaliplatin 85 mg/m2 on days 8 and 22. After a rest of 3 weeks the next cycle was started on d43. A total of 165 patients were calculated to demonstrate a doubling of survival time after progression on first-line therapy.

Results

After inclusion of forty six patients the trial was terminated according to predefined protocol regulations due to insufficient accrual (lack of acceptance of BSC by patients and physicians. Patient characteristics were well balanced between both study arms. The OFF regimen was well tolerated with more patients with grade I/II paraesthesia and grade II/III nausea/emesis and diarrhoea. Median second-line survival was 4.82 [95% Confidence Interval; 4.29–5.35] months for OFF treatment and 2.30 [95% CI; 1.76–2.83] months with BSC alone (0.45 [95% CI: 0.24–0.83], p = 0.008). Median overall survival for the sequence GEM-OFF was 9.09 [95% CI: 6.97–11.21] and 7.90 [95% CI: 4.95–10.84] months for GEM-BSC (0.50 [95% CI: 0.27–0.95], p = 0.031) respectively.

Interpretation

Although stopped prematurely, this randomized trial provides at first time evidence for the benefit of second-line chemotherapy as compared to BSC alone for patients with APC. OFF significantly prolonged survival time compared to BSC alone after failure of first-line therapy with gemcitabine.

Introduction

Adenocarcinoma of the pancreas is a highly aggressive cancer, characterized by extensive local invasion, early regional and rapid systemic spread and a high degree of chemo-resistance. In spite of intensive research in the last decade, the 5 years survival rate in patients with advanced pancreatic cancer (APC) is still less than 5%.1 At present, pancreatic cancer is the fourth most frequent cause of death from solid tumours in the western world.2 In parallel with disease progression, patients with APC suffer from several symptoms such as abdominal pain, taste abnormalities, nausea and emesis, leading to inadequate nutrition intake, weight loss and fatigue. These symptoms contribute substantially to the deterioration in performance status and quality of life. Gemcitabine (GEM), the standard first-line chemotherapy for pancreatic cancer during the last decade, can lead to improvements of tumour-related symptoms and has shown modest survival advantage.3 Many multi-agent therapies have been tested but most of them failed to prove superiority over single-agent gemcitabine.4, 5, 6 At the time this trial was planned, best supportive care (BSC) was standard care for patients who progressed on first-line chemotherapy. However, patients with good performance status despite disease progression on gemcitabine therapy generally ask for further anti-cancer therapies. Indeed, several phase-II studies suggested second-line anticancer activity but there are no phase-III studies confirming the benefit of further chemotherapies after progression while on gemcitabine. 7, 8, 9 First-line therapy studies report the use of second-line chemotherapies in nearly 30% of patients.5, 6 This clearly underlines the clinical need for evidence based recommendations for patients progressing while on first-line therapy. Based on our phase-II results with the second-line regimen of oxaliplatin, 5-fluorouracil (24 h) and folinic acid (OFF),10 we initiated the CONKO-003 (CharitéONKOlogie) randomized phase-III trial aimed to investigate the role of OFF + BSC versus BSC alone in patients with APC following disease progression during gemcitabine treatment.

Section snippets

Eligibility criteria

Patients with histologically confirmed APC who had progressed during first-line gemcitabine therapy were eligible for this open randomized multicentre study. Other major inclusion criteria were: age ⩾18 years; Karnofsky performance status (KPS) > 60%; measurable reference lesion, adequate laboratory values for haematology (white blood cell [WBC] count >3.5 × 109/L, platelet count >100 × 109/L), renal (creatinine clearance >30 ml/min) and hepatic function (aspartate aminotransferase [AST] or alanine

Results

Recruitment started in December 2002. It was stopped in December 2003 by the protocol committee according to predefined protocol regulations (low recruitment). At that time 46 (OFF + BSC 23 pts/BSC 23 pts) patients from 12 study centres (average pt. recruitment 3) had been included. The major reason for low accrual was due to the diminishing acceptance of BSC alone by oncologists and patients after publishing the phase-II results of the OFF-regimen. Patient characteristics are well balanced

Discussion

Adenocarcinoma of the pancreas remains a malignancy with dismal prognosis. In addition to intensive ongoing research for more effective first-line protocols there is still an unmet need for evidence-based treatment options other than best supportive care for patients progressing while on gemcitabine therapy. Study results on second-line treatment in this disease are rare. We focused our attention on the combination of oxaliplatin, folinic acid and 5 fluorouracil (OFF) and demonstrated a median

Contributors

UP, IS, JSt, MA, JS, HR and HO contributed to patient enrolment, to the collection and assembly of the data. HR, HO and BD provided capacities for the trial. UP and HR drafted the article. HO, HR and UP were responsible for the study idea, study design, data analysis and interpretation. All authors provided final approval.

Previous presentation of preliminary data

H. Oettle, U. Pelzer et al. Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement): A4031.

Conflict of interest statement

None declared.

Acknowledgements

This study was supported by ‘Charité-Forschungsförderung’, ‘Arbeitsgemeinschaft internistischer Onkologie – AIO’, ‘Deutsche Krebsgesellschaft e.V.’ and Sanofi–Aventis GmbH (Frankfurt, Germany), medac GmbH (Wedel, Germany) who provided oxaliplatin, folinic acid and 5-fluorouracil free of charge.

We thank all patients for the participation and the study nurses and physicians for the support in this trial.

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