7.1 Introduction
Pancreatic cancer is currently placed seventh in global cancer mortality [1]. In the United States of America, it is the fourth leading cause of cancer-related death. Because less than 10% of cases hold the potential of curative resections, systemic chemotherapy is the major treatment option. Patients with metastatic disease have a median untreated survival of 3-6 months. Due to tumor-related symptoms, such as pain, weight loss, nausea, and vomiting, quality of life (QoL) is impaired significantly.
Gemcitabine was the first drug that dem-onstrated a benefit in survival (4.4 versus 5.6 months), as well as an improvement in dis-ease-related symptoms in a randomized study [2]. Single-agent chemotherapy with gemcitabine is to date considered the standard of care for pa-tients with advanced pancreatic cancer [3] and it serves as reference in recently published tri¬als. Nevertheless, results for gemcitabine mono-therapy are poor and urgently deserve further improvement.
Recently, results for gemcitabine have been challenged by the combination of gemcitabine and erlotinib. One randomized trial demon¬strated a significant increase in median survival (6.4 versus 5.9 months; p = 0.03) for the combi¬nation of gemcitabine and erlotinib [4]. Whether this difference is clinically meaningful is a matter of discussion.
7.2 First-Line Chemotherapy
7.2.1 Locally Advanced Disease
Systemic therapy has been accepted as a stan-dard in locally advanced disease. Overall there is no significant benefit for patient treated with chemoradiation [5].
Chemoradiation may have a role as a con-solidation treatment for patients who do not have progressive disease during chemotherapy. This approach improved survival from 12 to 15 months in a retrospective analysis of data from phase II/III trials on stage III disease in the Groupe d'Etude et de Recherche en Cancreologie Onco-Radiotherapic (GERCOR) experience [6]. Otherwise we have to note that this overall sur-vival can also be reached with systemic chemo-therapeutic treatment without the side effects of radiation. Therefore, chemoradiation may have a marginal impact, only in the individual treat¬ment of patients with local advanced pancreatic cancer.
Last year preliminary results of an important randomized study were published comparing chemoradiation and chemotherapy for patients with locally advanced disease [7]. This trial seems to answer the final question about the impact of chemoradiation on this disease. A median over¬all survival of 8 months (after 16 months of ob¬servation) for patients with chemoradiation (cis-platin/5-FU/radiation) followed by gemcitabine versus 14.5 months for patients with gemcitabine standard therapy is a significant indicator for the use of gemcitabine standard therapy for this pa¬tient group.
There are also many other experimental treat-ment options such as chemoembolism/selected arterial perfusion and many others. None of them seems to be generally recommended for those patients, but the options often serve as a way to individualize treatment design.
7.2.2 Metastatic Disease
Until a decade ago, nihilistic behavior in the treatment of those patients prevailed. In the fore-ground was the main question about the general use of systemic chemotherapy at all [8, 9]. Two trials comparing chemotherapy with best sup-portive care suggested that chemotherapy may improve survival time and the quality of life [10, 11]. Further improvement was obtained by using of gemcitabine [2]. In spite of the lack of confirmatory trials and the use of a nonvalidated primary endpoint (clinical benefit), gemcitabine became a standard of care in advanced pancre-atic cancer. Gemcitabine achieves an objective response rate of 4%-26%, a median progression-free survival of 2.0-3.8 months, and a 1-year overall survival of 17%-28% [12-19]. The thera¬peutic activity of gemcitabine administered as a fixed dose rate infusion instead of the standard 30-min infusion did not significantly improve the outcome of patients with advanced pancre¬atic cancer [12]. The addition of a second cyto-toxic agent or other drugs to gemcitabine also did not improve treatment efficacy over single-agent gemcitabine [12-18, 20]. A metaanalysis sur¬mised that the addition of 5-fluorouracil (5-FU), cisplatin, or a platinum compound to gem-citabine may improve 1-year overall survival by 4% [21]. Completed randomized trials compar¬ing standard therapy gemcitabine and combina¬tion treatment such as gemcitabine/5-FU, gem-citabine/cisplatin or gemcitabine/capecitabine suggested a survival improvement for patients with good conditions [21]. The authors advise a combination therapy for those patients to get a maximum response. But these results are based only on subgroup analyses. A recent large ran¬domized trial (CONKO 004) will prospectively examine this point of interest [22].
After a cohort of unsuccessful trials, two gem-citabine-based doublets yielded a statistically significant outcome improvement over a single agent in phase III trials [4, 23]. However, the re¬sults of the gemcitabine/capecitabine combina¬tion could not be confirmed in another phase III trial [24]. Altogether, the advantage obtained by gemcitabine/capecitabine and by a gemcitabine/ erlotinib combination in overall survival was of marginal clinical significance, consisting of an absolute 7% improvement at 1 year (from 17%-19% with gemcitabine alone to 24%-26% with combined therapy) [4, 23]. Overall, from a clini¬cal perspective, these trials confirmed the lack of a significant impact of double-agent combina-tion therapy on the clinical course of pancreatic cancer.
7.3 Summary
Recapitulating the trials done to date, we have to notice that there is only a weak argument for combination therapy. In line with clinical consid-erations we have to recognize that the inclusion of new drugs into the therapy of advanced pan-creatic cancer does not result in a milestone for the outcome in this poorly served patient group.
Gemcitabine remains the standard drug in the therapy of pancreatic cancer, and only in a selected patient pool is the use of intensive ther-apy (combination with capecitabine or cisplatin) reasonable. The combination treatment of gem-citabine with erlotinib is useful for patients who display the cutaneous side effects of erlotinib within 6-8 weeks of treatment start, indicating the effective impact of this treatment schedule
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