ASCO Update – Pancreatic cancer
memo (2008) Vol. 1: 259–262 DOI 10.1007/s12254-008-0070-x Printed in Austria © Springer-Verlag 2008
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magazine of european medical oncology
Pancreatic cancer G. Pall Department for General Internal Medicine/Oncology, University Hospital for Internal Medicine, District/University Hospital Innsbruck, Innsbruck, Austria Received 15 August 2008; accepted 29 September 2008
Every year oncologists from all over the world present cutting edge research at the annual meeting of the American Society of Clinical Oncology (ASCO). Pancreatic cancer definitely represents a tumour where basic and clinical research is urgently warranted, as the prognosis for patients suffering from this illness is still very poor and only minor advances have been achieved during the last decade. This article is intended to inform the reader about some of the most important abstracts concerning pancreatic cancer presented at this year’s ASCO-Annual Meeting at Chicago, covering the areas of early, locally advanced and metastatic disease. Keywords: Pancreatic cancer, chemotherapy, chemoradiotherapy
Introduction Pancreatic cancer remains one of the most devastating tumour entities. This is due to several reasons: 1) High biological aggressiveness with tendency to early systemic spread. 2) Low chemotherapy sensitivity. 3) Missing tools for early detection. Accordingly, there is an urgent need for therapeutic improvements both in the early stages of disease and in the locally advanced/metastatic setting. The aim of this article is to summarize the most important abstracts relating to the field of pancreatic cancer presented as this year’s ASCO-Annual Meeting and to put these new data into clinical context.
Adjuvant therapy Due to an initially often asymptomatic or at least oligosymptomatic clinical course, early detection of pancreatic cancer and the resulting opportunity for surgical resection remain a rare scenario. Moreover, despite resection with microscopically free margins, prognosis, even for patients with very early Correspondence: Georg Pall, Department for General Internal Medicine/Oncology, University Hospital for Internal Medicine, District/University Hospital Innsbruck, Anichstr. 35, 6020 Innsbruck, Austria. E-mail:
[email protected]
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disease, remains poor, with 5–20% long-term survival [1]. These data point towards the importance of establishing effective adjuvant and/or neoadjuvant treatment strategies. Unfortunately, little progress has been made during the past 20 years. Based on the results of a small study (43 patients were enrolled) published in 1985, adjuvant chemoradiotherapy with 5-Fluorouracil (5-FU) followed by 5-FU-monotherapy for 2 years was adopted as a standard procedure in the USA, as in this trial a significant survival benefit in comparison with observation alone could be observed [2]. This study has been criticised for several reasons (low patient number, high drop-out rates, unclear relative contribution of chemoradiotherapy/chemotherapy) and adjuvant treatment was often not implemented in daily practice outside the USA. Furthermore, an European Organization for Research and Treatment of Cancer-(EORTC-)study comparing adjuvant chemoradiotherapy with 5-FU versus observation failed to show a significant survival advantage but revealed remarkable toxicity [3]. With the publication of the ESPAC-1-trial new interest was raised concerning the value of adjuvant chemotherapy alone [4]. In this study, patients receiving a 5-FU/Folinic Acid (FA)-bolus regime seemed to experience a better outcome than patients receiving adjuvant chemoradiotherapy. However, interpretation of the results was hampered by the complex 2 × 2 factorial design and the lack of radiotherapy quality control. Finally, in 2005 a metaanalysis of published trials concerning adjuvant therapy in pancreatic cancer suggested a survival benefit for chemotherapy but not for chemoradiotherapy [5]. At this years ASCO-Annual Meeting the final results of the CONKO-001 study were presented [6]. In this trial patients with pancreatic adenocarcinoma were randomized between observation alone and adjuvant chemotherapy consisting of 6 cycles gemcitabine (see Fig. 1 for protocol details) after surgical resection with curative intent. Three hundred and sixty-eight patients with a median age of 62 years were included, CA 19-9 and CEA-levels after surgery were not allowed to exceed 2.5 the upper limit normal. According to the protocol, chemotherapy had to be started within 6 weeks from surgery. Of note, patients could be included irrespective of their resection status (R0, R1) and tumour stage (T1-4, N0-1). Disease free survival was defined as the primary study endpoint. Overall survival and toxicity were the secondary endpoints. Pancreatic cancer 4/2008
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Gemcitabine
Surgery
Gemcitabine
Gemcitabine
Gemcitabine
Gemcitabine
Gemcitabine
1000 mg/m2 d1,8,15; q 4 weeks
R
Observation Fig. 1: Design of the CONKO-001-study
Tab. 1: Survival results of CONKO-001 Observation Gemcitabine DF5 (median)
6.9 months
13.4 months
HR 0.66; p < O.001
OS (median)
20.2 months
22.8 months
HR 0.72; p = 0.005
In their presentation at Chicago the authors were able to confirm the already published results of the first interim-analysis concerning the primary endpoint disease free survival. Adjuvant gemcitabine led to an improvement in median DFS from 6.9 months to 13.4 months (HR 0.66; p < 0.001). This benefit was consistent in all the prespecified subgroups (R0 vs. R1, N0 vs. N1, T1 + 2 vs. T3 + 4). The final analysis concerning overall survival also favours adjuvant gemcitabine (Tab. 1). With a HR of 0.72 and a prolongation of the median overall survival from 20.2 months to 22.8 months the level of statistical significance was reached (HR 0.72; p = 0.005). This resulted in an absolute survival benefit of 17% and 12% after 3 and 5 years, respectively. Again all the supgroups evaluated seemed to show the same trend of benefit from adjuvant chemotherapy. Reported toxicity was mild and definitely within the range one would have expected considering the chemotherapy regimen used. In summary, CONKO-001 adds further evidence to support the value of adjuvant chemotherapy in pancreatic cancer. In contrast to the ESPAC-1-trial the design of CONKO-001 was straight forward and such the results of this study seem reliable and probably reflect the true effectiveness of adjuvant chemotherapy. Doing so, CONKO-001 now seems to define a new, generally acceptable, standard for the adjuvant treatment of pancreatic cancer. Nevertheless, despite the observed survival benefit, there remains much room for improvement. Questions to be answered in the future relate to the possible role of gemcitabine-based combination-therapies, which, at least in patients with good performance status, improve outcome in the set-
ting of locally advanced/metastatic disease [7]. As a possible tool to better select patients who will benefit from adjuvant gemcitabine pharmacogenetic markers like the ribonucleotide reductase M1 gene (RRM-1) might be of importance [8]. Neoadjuvant therapeutic concepts for patients considered primary resectable have been evaluated in phase II studies, with the aim to earlier select patients who are going to benefit from chemotherapy and to avoid surgery for those who progress rapidly despite immediate systemic therapy. Longterm results of these trials are comparable to the outcome of published trials for adjuvant therapy and a randomized comparison of these two concepts might be of interest [9, 10]. Finally, as the rate of local recurrence in the gemcitabine arm of CONKO-001 still was as high as 35% every effort should be undertaken to try to incorporate chemoradiotherapy approaches into the adjuvant treatment plan based on the fundament of gemcitabine chemotherapy.
Locally advanced disease Another important publication at this year’s ASCO-Annual Meeting referred to the clinical problem of locally advanced pancreatic cancer not amenable to surgery but without radiologic evidence for distant metastases. Like in the adjuvant setting there is controversy about the value of chemoradiotherapy as an adjunct to palliative chemotherapy. Early studies in the 1980s reported conflicting results [11, 12]. The most recent and largest randomized trial was reported by the Federation Francophon de Cancerologie Digestive (FFCD) [13]. Patients in the control arm of this study received gemcitabine chemotherapy alone and experienced superior survival in comparison with patients randomized to the experimental arm consisting of initial chemoradiotherapy with cisplatin/5FU followed by gemcitabine. Eastern Cooperative Oncology Group (ECOG) 4201, presented at the ASCO-Annual Meeting this year [14], was planned as a randomized phase III trial comparing gemcitab-
Gemcitabine
Locally advanced Pancreatic cancer
R
1000 mg/m2 d1,8,15,22,29,36
Gemcitabine
Gemcitabine
Gemcitabine
1000 mg/m2 d1,8,15; q 4 weeks
Radiotherapy (50.4 Gy) Gemcitabine
600 mg/m2 d1,8,15,22,29,36
Gemcitabine
Gemcitabine
Gemcitabine
1000 mg/m2 d1,8,15; q 4 weeks
Fig. 2: Design of the E4201-study
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chemotherapy until progression or unacceptable toxicity remains a validated option, too.
Tab. 2: Major toxicity differences in the E4201-study Gemcitabine/ XRT
Gemcitabine
Gastrointestinal (G3/4)
38%
14%
p < 0.03
Fatigue (G3/4)
32%
6%
p < 0.006
Palliative chemotherapy
ine monotherapy with the concept of initial chemoradiotherapy with gemcitabine followed by gemcitabine monotherapy using the same schedule as in the control arm (see Fig. 2). Defining overall survival as the primary endpoint, the number of patients planned to recrute was 316. Unfortunately, due to poor accrual, the study had to be closed prematurely when only 74 patients were randomized. Bearing the limitation of the lack of sufficient power in mind, the treatment arm incorporating chemoradiotherapy nevertheless led to a modest improvement in overall survival (HR 0.574, p = 0.34, median 9.3 mo. vs. 11 mo.) albeit at the cost of increased toxicity (especially gastrointestinal symptoms, fatigue and myelosuppression; see Tab. 2). Concerning the secondary endpoints response rate and progression free survival no significant differences could be observed. The integration of chemoradiotherapy led to a provocative reduction in the rates of local recurrence (41% vs. 23%). Unfortunately, due to the low patient numbers, the presented results do not provide a clear answer to the question initially raised. Nevertheless, they represent another hint that chemoradiotherapy may be of importance to reach optimal treatment results in locally advanced pancreatic cancer. Based on the preliminary results of the Groupe Cooperateur Multdisciplinaire en Oncologie (GERCOR) [15], at this timepoint it seems reasonable to offer chemoradiotherapy to those patients who at least do not progress during an initial phase of palliative chemotherapy alone. Preferably, this should be done in the setting of a clinical trial. Clearly, continuing
PD during Gemcitabine
Current guidelines for the use of systemic therapies for the palliative treatment of patients with pancreatic cancer cover the options for first-line therapy only, as, until recently, no randomized controlled trials regarding the benefits of second-line treatment had been conducted. At the ASCO-Annual Meeting 2008 a German Study Group presented the final results of their CONKO-003-study dealing with patients who progressed during gemcitabine first-line therapy [16]. Initially planned as the comparison of a combination chemotherapy consisting of oxaliplatin and 5-FU/FA (OFF) with best supportive care, the protocol had to be amended as the patients were not willing to accept best supportive care as the only treatment. Therefore the investigators chose to compare the OFF-regimen with the use of 5-FU/FA (FF) alone (see Fig. 3). Patients with progressive disease during gemcitabine therapy were randomized between the two treatment arms and treatment was continued until progression or unacceptable toxicity. Overall survival was determined as the primary study endpoint, disease-free survival and toxicity were evaluated as secondary endpoints. 168 patients were included, with a median age of 60 years. The majority of patients were diagnosed with distant metastases, and the numbers of patients with good, intermediate and missing initial response to gemcitabine during first-line therapy were equally distributed between the study arms. Concerning the primary endpoint of overall survival the OFF-arm showed statistically significant superior results in comparison with FF (see Tab. 3). PFS also favoured OFF. Toxicities were comparable between the two arms, most importantly there was only a low percentage of high-grade neurotoxicity in the OFF-arm caused by oxaliplatin, probably due to the relatively short treatment duration and the lower oxaliplatin dose-intensity comparing OFF with the FOLFOX-
FF
FF
FF
FF
OFF
OFF
OFF
OFF
R
FF
5-FU 2 g/m2 (24 hr) Folinic acid 200 mg/m2
d1,8,15,22
q 6 weeks 2
5-FU 2 g/m (24 hr) OFF
Folinic acid 200 mg/m2 Oxaliplatin 85 mg/qm
d1,8,15,22 d8,22
Fig. 3: Design of the CONKO-003-study
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Tab. 3: Survival results of CONKO-003 FF
OFF
OS (median)
13 weeks
26 weeks
p = 0.014
PFS (median)
9 weeks
13 weeks
p = 0.012
protocol often used in colorectal cancer (Grad 3/4 neurotoxicity in OFF-arm: 3%). Clearly the authors have to be congratulated for conducting this study and as such, for the first time, providing evidence for the efficacy of second-line treatment in pancreatic cancer in the setting of a randomized trial. Without doubt, a comparison of either of the two study arms with best supportive care alone would have been of great interest, but on the other hand patients’ wish in refusing the bestsupportive-care option has to be accepted. One important information from the CONKO-003-study is the feasibility of second-line treatment, and based on the results the OFFprotocol should be the first choice for patients able to tolerate further chemotherapy after progression on gemcitabine. With the widespread adoption of gemcitabine therapy in the adjuvant setting, OFF also seems a reasonable treatment option for patients with a short progression-free interval after completing or progressing during the adjuvant treatment period. Data regarding quality of life would be desirable, as is always the case if certain therapies offer relatively short survival benefits. Whether OFF or FF is also of value after first-line therapy with gemcitabine-based combinations (i.e., gemcitabine/oxaliplatin = GEMOX; gemcitabine/ capecitabine = GEMCAP) cannot be concluded from the present data.
Conclusion Treatment of pancreatic cancer is often considered a field without any progress and without doubt the prognosis for patients suffering from this kind of cancer still is one of the worst within the spectrum of solid tumours. Nevertheless, the recent publications at this year’s ASCO-Annual Meeting, addressed by this article, represent important steps forward as we begin to answer some of the most burning questions concerning the value of conventional cytostatic therapy, radiation therapy and multimodality treatments. Hopefully, these studies can build the basis for further improvements most likely to come from the introduction of molecular targeted agents into clinical practice.
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