Combining A Platinum-Based Drug With Gemcitabine Could Extend Survival For Patients With Pancreatic Cancer

Main Category: Pancreatic Cancer
Also Included In: GastroIntestinal / Gastroenterology
Article Date: 19 Nov 2007 - 11:00 PDT

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Administering a platinum-based chemotherapeutic agent with gemcitabine, the main drug used to treat pancreatic cancer, could help extend the lives of some patients with this cancer, according to a pooled analysis of previous data from clinical trials. However, patients who are extremely sick should still be treated with gemcitabine alone, the analysis suggests.

Prognosis in pancreatic cancer remains dismal, since most patients are diagnosed late in their disease and already have metastases when they first present to a physician. Without treatment, median survival is just 3-4 months. The standard of care for this tumour type is chemotherapy with gemcitabine---whose chemical structure resembles a nucleoside, enabling it to block DNA replication by becoming incorporated into strings of natural nucleosides--- and efforts to combine this drug with other agents have so far produced no significant extension of survival time. However, there is limited evidence from some underpowered trials suggesting that platinum-based drugs might enhance the effect of gemcitabine.

There is also a scientific rationale for exploring these combinations. Preclinical studies indicate that gemcitabine not only increases the number of cross-links in DNA formed by cisplatin (whose mechanism of action is to stop DNA replication by introducing these so-called cross-link mutations into the helix structure), but it also effectively prevents the cell from repairing the damage. Conversely, cisplatin also seems to enhance the number of gemcitabine molecules incorporated into DNA in cancer cells, thereby boosting the rate of cell death in tumours. Clinical work in phase 2 and 3 studies has suggested that the combination of gemcitabine and cisplatin is particularly active in pancreatic cancer.

To further analyse the results of already-completed trials of combination therapy, and to address the problem of lack of statistical power in published papers, Dr Volker Heinemann and colleagues did a pooled analysis in which they used individual-patient data from the two largest European trials. The focus of their analysis was to evaluate the therapeutic efficacy of a combined treatment with gemcitabine plus either cisplatin or oxaliplatin (both platinum-based drugs) compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer.

The two trials selected for the analysis were the GERCOR/GISCAD French/Italian intergroup study and a German multicentre study. The first compared gemcitabine and oxaliplatin to gemcitabine alone and included 326 patients. The second involved treatment with gemcitabine plus cisplatin or gemcitabine alone and included 195 patients. Both trials focused on patients with histologically proven, unresectable, locally advanced or metastatic pancreatic cancer.

For the purposes of the pooled analysis, the total patient population consisted of 503 analysable patients from both trials, who were evenly distributed between the treatment regimens with respect to age, gender, performance status, and stage of disease. Although the results of the trials were individually non-significant, in the pooled analysis overall response rates were significantly improved by platinum-based combination therapy as compared to single-agent gemcitabine (22% versus 14%).

The median progression-free survival in the total group of 503 patients amounted to 18 weeks, and there was an overall positive effect of combination treatment on this endpoint. However, the treatment effect varied between subgroups. In those with locally advanced disease only performance status was significantly related to outcome, indicating a clearly greater benefit from combination chemotherapy in patients with a good performance status (33 versus 14 weeks).

Median overall survival was 33 weeks. But in a further subgroup analysis, there was strong evidence for the existence of an unfavourable subgroup, defined as patients with an Eastern Cooperative Oncology Group performance status of 1-2, who do not benefit from the more aggressive combination chemotherapy. Dividing up the results by which trial the patients were initially enrolled in showed that the French/Italian trial produced a slightly better prognosis in both overall and progression free survival, which corresponded to these patients' more favourable baseline profile.

Since individual patient data could not be obtained from the two other randomised controlled trials of platinum-based regimens, the authors caution that their results should be considered as purely hypothesis generating "since the totality of evidence could not be utilized". What is more, they say, the results obtained in the pooled analysis need to be seen in the context of a growing number of randomised trials combining gemcitabine with other cytotoxic agents. So far, only one trial, with 533 patients, showed that a combination of gemcitabine with capecitabine induced a significantly longer survival compared to gemcitabine alone.

However, the authors comment that, overall, "it may be concluded that patients with good performance status should be candidates for the more intensive combination therapy, while patients with a compromised performance status should rather be offered cytotoxic treatment with gemcitabine alone."

Increased survival using platinum analog combined with gemcitabine as compared to single-agent gemcitabine in advanced pancreatic cancer: pooled analysis of two randomized trials, the GERCOR/GISCAD intergroup study and a German multicenter study.
Heinemann V, Labianca R, Hinke A, Louvet C.
Annals Oncol 2007; 18: 1652-59

This summary is provided by the Cancer Media Service which is operated by The European School of Oncology.

http://www.cancerworld.org/mediaservice