Elsevier

Cancer Treatment Reviews

Volume 38, Issue 7, November 2012, Pages 843-853
Cancer Treatment Reviews

Anti-Tumour Treatment
Systemic treatment of advanced pancreatic cancer

https://doi.org/10.1016/j.ctrv.2011.12.004Get rights and content

Abstract

Pancreatic cancer belongs to the most malignant gastrointestinal cancers and, in its advanced stage, remains a deadly disease for nearly all affected patients. Treatment of metastatic adenocarcinoma of the pancreas not only involves chemotherapy and targeted therapy, but also requires attention to accompanying comorbidities as well as frequently intensive supportive treatment and psychosocial support. Gemcitabine-based combinations with fluoropyrimidines and platin analogs have essentially failed to provide a substantial prolongation of survival and may constitute a treatment option only in patients with a good performance status. Among targeted therapies, only the EGFR tyrosine kinase inhibitor erlotinib has shown activity which is marginal in the overall population, but clinically relevant in patients developing skin rash. New avenues of polychemotherapy are presently explored since the gemcitabine-free FOLFIRINOX-regimen (infusional 5-fluorouracil/folinic acid plus irinotecan and oxaliplatin) was shown to be markedly superior to gemcitabine in selected good-performance patients. Pancreatic cancer is notably characterized as a hypovascular tumor rich in desmoplastic stromal tissue. An innovative approach to treatment therefore focuses on peritumoral fibroblasts and aims to induce a depletion of the stroma either by inhibition of the hedgehog pathway or by targeting SPARC (secreted protein acidic and rich in cysteine) via application of albumin-bound paclitaxel.

Introduction

Only a minority of pancreatic cancer (PC) patients (15–20%) present with resectable disease at first diagnosis. Patients with locally advanced, non-metastatic PC (LAPC) represent 15–20% of patients and have a median survival of 9–11 months. Metastatic disease, by comparison, is documented in 60–70% of patients and is associated with a much shorter survival of only 6–8 months in most studies. This observation has meanwhile led to a broad consensus that LAPC and metastatic PC should be viewed as prognostically (and possibly also biologically) different disease entities which require different treatment algorithms and accordingly should be investigated in separate clinical studies.1

The present review evaluates the available data on systemic treatment of advanced PC and specifically focuses on chemotherapy and biologically targeted therapy. In this context, it needs to be recognized that most of the randomized studies, even if they predominantly investigated metastatic PC, they also included varying, but smaller amounts of LAPC patients (Table 1, Table 2, Table 3, Table 4, Table 5). Only some of the more recent trials were rightfully limited to metastatic PC. The available evidence therefore regards advanced pancreatic cancer as a composite group in most studies. Since data were mostly derived from patients with metastatic PC, conclusions may have the greatest validity for this patient subgroup. Post hoc evaluations of treatment results obtained in LAPC were performed in some trials, but, due to the limited number of patients, did not allow formal conclusions. This smaller patient subgroup therefore needs to be addressed separately in properly designed trials.

The present review evaluates the available armamentarium of anticancer agents and aims to clarify the present treatment options. In view of the dismal prognosis of advanced disease, it also emphasizes the importance of adequate supportive therapy and early provision of psychosocial help.

Section snippets

Diagnosis

Once standard imaging procedures (CT or MRT) led to the classification of the tumor as non-resectable, the patho-histological or -cytological verification of neoplastic disease needs to be performed before oncological treatment can start. The clinical constellation of a typical mass in the pancreas combined with an elevated tumor marker (CA 19-9 or CEA) alone is not sufficient. Specifically, the interpretation of elevated CA 19-9 can be confounded by any affection of the biliary system

Psychosocial support

The sudden confrontation with a limitation of life expectancy to several months may cause substantial distress and poses problems most patients have not learned to cope with.

Clearly, reliable information on prognosis can only be provided to patients once the diagnostic work-up has been completed and once a final report on the stage of disease has been obtained. Only then, the oncologist may provide a realistic prognosis and may propose an adequate concept of cancer treatment.2 Importantly, this

Early access to palliative treatment

Patients are usually referred to palliative care in a late stage of their disease. Improved results with regard to quality and delivery may, however, be obtained when palliative care is offered early on and is further applied during the continuum of treatment. In this context, palliative care means control of symptoms, psychological support and assistance in decision making.4 That approach was previously shown to be beneficial in lung cancer, a comparably malignant and incurable illness. In a

Management of comorbidity

Pancreatic cancer is characterized by a number of comorbidities which often require increased attention and a close follow-up by the treating physician. Many patients suffer from pain as a primary disease-related symptom which requires appropriate medication or application of a celiac blockade.

Before antitumor treatment can be started in advanced disease, it is necessary to ensure optimal bile drainage and to apply biliary stents when hyperbilirubinemia due to bile duct obstruction is present.

Patient selection

Clearly, it needs to be asked to which extent clinical trials reflect patient reality since clinical trials tend to include younger patients and patients with a better socio-economic background. In a retrospective analysis, El-Rayes et al. demonstrated that patients treated within clinical trials at the Karmanos Cancer Institute had a median survival of 8.5 months as compared to patients treated at that institution outside clinical trials (5.0 months) or at non-institutional community centers (2.8

Chemotherapy is a standard of care in advanced pancreatic cancer

In a meta-analytical evaluation of 7 randomized controlled trials involving 432 patients with advanced PC, Sultana and coworkers demonstrated that chemotherapy improved survival compared to best supportive care with a hazard ratio (HR) of 0.64 (95% CI, 0.42–0.98). However, it was pointed out that there was a significant heterogeneity between studies (P = 0.0005) and that the upper limit of the confidence interval (CI) was quite close to 1.0.13

Activity of gemcitabine in 1st-line therapy

Since more than a decade, the antimetabolite gemcitabine (GEM) has been established as a chemotherapeutic standard in the treatment of advanced PC. Registration of GEM was based on a randomized trial which demonstrated the superiority of GEM over bolus 5-fluorouracil (5-FU) with regard to clinical benefit response (23.8% vs. 4.8%, P = 0.0022), and median overall survival (5.65 vs. 4.41 months, P = 0.0025).14 In addition, this study also indicated that GEM induced a marked improvement of 1-year

Gemcitabine-based chemotherapy doublets

While the introduction of GEM clearly improved therapeutic efficacy and 1-year survival, its impact on median overall survival remained modest. More intensive combination chemotherapies involving fluoropyrimidines, platinum analogs and other cytotoxic agents have been investigated in numerous phase II and III trials. Most of these failed, however, to show a statistically significant survival benefit compared to GEM alone.15 The true benefit gained from GEM-based combination chemotherapy

Meta-analytical evaluation of gemcitabine-based doublets

Since single studies were frequently criticized because of their underpowered statistical design, several meta-analyses were performed to allow more reliable conclusions based on larger patient numbers.13 Heinemann and coworkers reported a meta-analysis of fifteen trials comparing GEM versus GEM plus cyototoxic agent (GEM + X) which revealed a significant survival benefit for GEM + X with a pooled hazard ratio (HR) of 0.91, P = 0.004).15 An identical HR (0.91; 95% CI, 0.85–0.97) was also published by

Gemcitabine-based polychemotherapy regimens

Several studies investigated GEM-based polychemotherapy regimens involving 3–4 cytotoxic agents (Table 1). Reni and coworkers performed a small randomised trial (n = 99) testing the PEFG-regimen (cisplatin, epirubicin, fluorouracil, and GEM) versus GEM alone.19 Progression-free survival at 4 months was evaluated as a primary endpoint and was superior in the PEFG-arm (60% vs. 28%, HR = 0.46). While median overall survival was nearly identical in both treatment arms, the proportion of patients

5-Fluorouracil-based regimen

Since Burris and coworkers had demonstrated that 5-fluorouracil (5-FU) was significantly inferior to GEM, this agent appeared to have lost clinical relevance in the treatment of PC.14 It needs, however, to be mentioned that application of 5-FU as a bolus-regimen most probably represents the least effective way, this agent can be applied. Subsequently performed studies provide more insight into the topic of infusional 5-FU regimens. Ducreux and coworkers performed a randomized trial comparing

Capecitabine plus oxaliplatin (CapOx)

The first randomized study to evaluate the oral fluoropyrimidine capecitabine in combination with oxaliplatin (CapOx) as a palliative first-line treatment was a German AIO trial (Table 2). CapOx was compared to the combination of capecitabine plus GEM (Cap/Gem) or the combination of GEM plus oxaliplatin (mGemOx). Similar clinical efficacy was observed for the three drug combinations with regard to PFS (4.2, 5.7, 3.9 months) and overall survival (8.1, 9.0, 6.9 months). Expectedly, significant

Irinotecan-based chemotherapy

The evidence on the activity of irinotecan in PC is limited (Table 3). Among others, this may be due to two randomized trials demonstrating that the addition of irinotecan to GEM did not increase treatment efficacy compared to GEM alone.[32], [33] Due to the remarkable clinical activity of the FOLFIRINOX regimen the question arises to which extent irinotecan is responsible for this effect. Some evidence may come from a phase II study by Taieb and coworkers34 who investigated a modified FOLFIRI

FOLFIRINOX a new treatment standard

It is the merit of Conroy and coworkers to have introduced the FOLFIRINOX regimen, a combination of infusional 5-FU/folinic acid, irinotecan, and oxaliplatin, into the treatment of metastatic PC.23 In a randomized phase III trial, FOLFIRINOX was compared to single-agent GEM and demonstrated the clear superiority of FOLFIRINOX with regard to objective response rate (31.6% vs. 9.4%, P < 0.001), progression-free survival (6.4 months vs. 3.3 months; HR 0.47, P < 0.001) and overall survival (11.1 months

Inhibitors of the epidermal growth factor receptor (EGFR)

Inhibition of the EGFR has become an established treatment strategy in several solid tumors such as colorectal- or lung cancer. In PC both, the anti-EGFR directed antibody cetuximab and the oral EGFR tyrosine kinase inhibitor erlotinib were tested in several randomised trials. Only the combination of GEM with erlotinib proved to be effective and was registered for treatment of metastatic PC.

Gemcitabine plus erlotinib

Moore and coworkers performed a randomized trial to compare GEM plus erlotinib versus GEM alone.41 The addition of erlotinib to GEM induced a statistically significant improvement of progression-free- (HR = 0.77, P = 0.004) and overall survival (HR = 0.82, P = 0.038), while objective response rate was not significantly different between treatment arms. Since overall survival of LAPC patients was only marginally affected (HR = 0.94), registration of GEM plus erlotinib was limited to metastatic disease in

Treatment strategy: sequential application of drugs

The German AIO PK0104 trial compared first-line treatment with GEM plus erlotinib to capecitabine plus erlotinib.43 At disease progression, patients were scheduled to cross over to the respectively other chemotherapy, while treatment with erlotinib was stopped. This study indicated that both treatment strategies induced nearly identical survival times (6.6 months vs. 6.9 months). First-line treatment with GEM/erlotinib was, however, more effective that capecitabine/erlotinib when first time to

Gemcitabine plus cetuximab

The clinical efficacy of extracellular EGFR inhibition was tested in a randomized study performed in patients with advanced PC.44 When GEM plus cetuximab was compared to GEM, no significant difference was observed between the two arms of the study with regard to overall survival (6.3 vs. 5.9 months, HR = 1.06). Also progression-free survival (3.4 vs. 3.0 months, HR = 1.07) and overall response rates (12% vs. 14%) were similar in the GEM plus cetuximab- and the GEM arm, respectively. While median time

Inhibition of angiogenesis

The combination of angiogenesis inhibitors such as bevacizumab or axitinib with GEM-based regimens has essentially failed to improve survival in advanced PC patients[46], [47], [48], [49], [50], [51] (Table 6). Again, it became clear that promising data obtained at the phase II level did not necessarily translate into a statistically and clinically relevant survival benefit when tested in phase III studies.[50], [51]

It has been argued that PC in most cases represents a hypovascularized tumor

Targeting the stroma

Pancreatic cancer is characterized by hypovascularity and desmoplastic stroma which both may contribute to impaired drug delivery and subsequent resistance to chemotherapy.52 An innovative approach to deplete stromal tissue has been introduced by clinical application of nab-paclitaxel.53 This albumin-bound drug formulation was initially developed to avoid the toxicity associated with the polyethylated castor oil, used as a solvent for the drug.54

Preclinical evidence supports the assumption that

Second-line treatment

An evaluation of 2nd-line therapy in randomised trials indicates that 16–57% of PC patients did receive salvage chemotherapy after failure of 1st-line GEM.59 Median survival in GEM-resistant patients receiving best supportive care was 2.3 months in a small randomised trial.60 Meanwhile, several clinical studies (mainly phase II) support the clinical efficacy of 2nd-line treatment with overall survival times of 3–9 months (calculated from the start of second-line therapy) and PFST/TTP durations of

Prognostic and predictive factors

Prognostic factors are patient- and tumor related factors that predict patient outcome (mostly survival) independent of treatment. By contrast, predictive factors predict response of the tumor to treatment (measured in terms of tumor size or survival).62

Optimal management of metastatic PC includes the evaluation of these parameters for optimal guidance of therapy. The following analyses differentiate parameters determined before the start of treatment (baseline parameters) from those obtained

Pharmacodynamic parameters

GEM is a nucleoside analog which requires specific membrane transporter proteins for active uptake into the tumor cell. Among these, the human equilibrative nucleoside transporter 1 (hENT1) and, to a lesser degree, the human concentrative nucleoside transporter 3 (hCNT3) have been identified as important determinants of sensitivity to GEM.70 Accordingly, data obtained in vitro showed resistance to GEM in tumor cells lacking hENT1 expression. These results were supported by clinical analyses

Perspective for the design of future clinical trials

According to a consensus report of the National Cancer Institute of the United States, harmonization of clinical trials with respect to patient populations is sought to reduce heterogeneity between studies.81 Comparability between studies may markedly be improved given that the following recommendations are realized: 1) Patients with locally advanced and metastatic disease should be investigated in separate trials. 2) Patients with unfavorable ECOG performance status (ECOG PS ⩾ 2) should be

How to treat advanced pancreatic cancer in daily clinical practice (Fig. 1)?

At present time, only GEM and erlotinib are registered for treatment of advanced pancreatic cancer. According to the European registration, the use of erlotinib is limited to patients with metastatic PC. Given that erlotinib is not available in all European countries, single-agent GEM remains the standard reference treatment of advanced PC.

A treatment algorithm may be based on a primary evaluation of the performance status: (1) We recommend not to apply chemotherapy or at least to question its

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