Medical Oncology

, Volume 27, Issue 2, pp 430–433

Gemcitabine and lenalidomide combination in a patient with metastatic pancreatic cancer: a case study

Authors

    • Department of Oncology, Division of Cellular and Molecular MedicineSt. George’s University of London
  • Shiyam Nizar
    • Department of Oncology, Division of Cellular and Molecular MedicineSt. George’s University of London
    • Department of Oncology, Division of Cellular and Molecular MedicineSt. George’s University of London
Original Paper

DOI: 10.1007/s12032-009-9228-6

Cite this article as:
Liu, W.M., Nizar, S. & Dalgleish, A.G. Med Oncol (2010) 27: 430. doi:10.1007/s12032-009-9228-6

Abstract

The proportion of people surviving pancreatic cancer is extremely low, with just 10% of patients diagnosed with any stage of the disease living beyond 1 year and a 5-year relative survival rate of <5%. The lack of effective therapy is one the main reason for such a bleak outlook. Herein, we report on a patient with pancreatic adenocarcinoma and metastatic disease treated with a combination regimen of gemcitabine and lenalidomide, without major complications. We also present in vitro data that highlight a hyper-additive effect of the two drugs when used in combination. To date, 33 months after diagnosis, the patient remains well and continues in full-time employment.

Keywords

Pancreatic cancerDrug combination therapyGemcitabineLenalidomide

Introduction

Current statistics place pancreatic cancer as the fourth most common cause of cancer related death in the world today, after lung, colon and breast [1]. This cancer is remarkable in that it has a death rate that almost equals the incidence rate [2]. The proportion of people surviving pancreatic cancer is extremely low, with just 10% of patients diagnosed with any stage of the disease living beyond 1 year, and a 5-year relative survival rate of <5% [13]. In addition to difficulties in diagnosis, one reason for the high mortality associated with pancreatic cancer is a lack of effective therapy, as the disease possesses multiple molecular aberrations that result in the disease being intrinsically resistant to chemotherapy [4]. The optimum treatment for pancreatic disease has not been fully established, which currently involves modulation of disease using gemcitabine. However, although it is the leading treatment, it only offers modest survival benefits, and the survival rate at 12 months is just 18% [5, 6]. Here, we report on a patient with pancreatic adenocarcinoma and metastatic disease treated with a combination regimen of gemcitabine and lenalidomide, without major complications, and compared the response with a crude in vitro model of drug combination.

Case report

A 70-year-old woman presented in June 2006 with an incidental liver lesion on computer axial tomography (CT) undertaken for a gynaecological complaint, which after biopsy was found to be adenocarcinoma of the pancreas. The CT-scan of her abdomen also suggested splenic involvement (Fig. 1). Treatment commenced in September 2006 with weekly gemcitabine (1,000 mG/m2). There was an initial and dramatic decrease in the pancreatic tumour marker carbohydrate antigen (CA) 19-9, from a peak prior to chemotherapeutic intervention of 7,340–1,770 U/mL at 2 months post initiation of treatment (Fig. 2). However, there was a marked clinical deterioration after 2-months with weight loss and increasing of malaise and tiredness. These symptoms were associated with an increase in CA 19-9. The decision was made and with informed patient consent to support gemcitabine with daily lenalidomide at 20 mG, which was introduced in November 2006 and administered in combination with the gemcitabine given every other week. The idea was to enhance drug activity via the synergistic immunological activities of both drugs as single treatment with lenalidomide in previous phase-II studies gave an immediate but transient response in three pancreatic cancer patients in a phase 1/2 study [7]. There was a continued fall in CA 19-9, which would be maintained at low levels even during gemcitabine holidays. Parenthetically, temporary cessation of treatment in responses to intercurrent infections, or dose-reductions caused an increase in tumour markers, which was corrected by resumption of both agents. There were no major complications such as marrow depression associated with the treatment regimen. To date, 33 months after initial diagnosis and disease management by this combination therapy the disease is stable, with no changes in splenic metastases and no further liver lesions, and the patient remains well and continues in full time employment.
https://static-content.springer.com/image/art%3A10.1007%2Fs12032-009-9228-6/MediaObjects/12032_2009_9228_Fig1_HTML.jpg
Fig. 1

Effect on tumour and metastases. CT scans showing the mass in the pancreas (arrow), the liver (L) and the dense areas within the spleen (S) indicating metastases. There was a reduction in tumour size, from 28.7 mm to 18.8 mm after treating for 24 months, and a loss of dense areas within the spleen

https://static-content.springer.com/image/art%3A10.1007%2Fs12032-009-9228-6/MediaObjects/12032_2009_9228_Fig2_HTML.gif
Fig. 2

Effect on carbohydrate antigen 19-9 levels. The levels of the tumour marker CA 19-9 was reduced upon treatment with gemcitabine and lenalidomide. These low levels were maintained by continued treatment. The shaded box focuses in on the dates after treatment, and highlights the maintained low levels of CA 19-9

Discussion

Currently, the standard treatment for patients with pancreatic cancer is gemcitabine. It produces significant improvements to treatment strategies compared to the previous gold standard of treatment in 5-flurouracil. However, although gemcitabine is the leading treatment, it only offers modest survival benefits, and the survival rate at 12 months is just 18% [5].

Combinational therapeutic approaches have shown great benefit, and indeed, have been shown to singly enhance the efficacy of novel agents, which alone have minimal effect [8]. In particular, combination approaches with gemcitabine and chemotherapy such as irinotecan, capecitabine and gefitinib have proved successful, [4], and studies have reported small improvements and prolongation of life; however, they have been associated with marked increase in toxicities.

At the commencement of administration in this patient, there were no reports of combinations with gemcitabine and lenalidomide. Reasons for potential synergy were considered to be indirect effects such as enhancement of immunological responses, as well as direct ones (e.g. suppression of angiogenesis). More importantly, an accumulation of myeloid suppressive T-cells has been attributed to decreased immune function in patients through inhibition of antigen-presenting functionality [9, 10]. It has thus been suggested that elimination of these myeloid suppressor cells, which is possible through the administration of gemcitabine [11], may improve the effects of cancer immunotherapies such as those related to thalidomide [7, 12].

The use of gemcitabine with lenalidomide reported here that lead to dramatic falls in a marker for pancreatic cancer and disease stabilisation is further highlighted when the patient had to be taken off treatment when unwell. In particular, during the last quarter of 2008, the patient developed a pulmonary infection that brought about a suspension of medication. Her CA 19-9 rose during this break, which on resumption of treatment, started to fall again. Interestingly, the disease management became similar to that of a chronic nature in that rather than using chemotherapy as a way of induction remission, it is now used to maintain a stable-disease state and in doing so, extend life.

Considering this lack of information on gemcitabine and lenalidomide combination, and as a consequence of the degree of response seen in this patient, we also explored the value of combining gemcitabine with lenalidomide in vitro. This could then be used as a marker of the effect seen clinically. We used a simple comparison analysis [8] to assess the interactions between these two agents in a pancreatic cancer cell line (Panc1). Results indicated a potential hyper-additive effect of combining these two agents at sub-optimal concentrations (Fig. 3). We plan to use these data to initiate a formal clinical trial to assess specifically, the efficacy of gemcitabine and lenalidomide therapy combination. Indeed, our experience in other patients support this notion.
https://static-content.springer.com/image/art%3A10.1007%2Fs12032-009-9228-6/MediaObjects/12032_2009_9228_Fig3_HTML.gif
Fig. 3

Effect of combination therapy in vitro. The pancreatic cancer cell line Panc-1 was cultured with gemcitabine (gen: 30 and 100 nM) and lenalidomide (len: 1 and 10 μM) for 3 days. Cell numbers were assessed by trypan blue exclusion analysis, and were significantly reduced in combination treatment compared to single agent therapies. A total of 1 μM lenalidomide is achievable in the plasma of patients treated with 20 mG. Data points represent the means and SDs of three separate experiments

In conclusion, we describe a patient with metastatic pancreatic cancer who would not have been expected to survive more than 6 months, but has now survived over 33-months. Her disease management was a combination of gemcitabine and lenalidomide, neither of which can be stopped without biochemical and clinical deterioration.

Copyright information

© Humana Press Inc. 2009