L-Carnitine-supplementation in advanced pancreatic cancer (CARPAN) - a randomized multicentre trial

  • Matthias Kraft1Email author,

    Affiliated with

    • Kathleen Kraft1Email author,

      Affiliated with

      • Simone Gärtner1,

        Affiliated with

        • Julia Mayerle1,

          Affiliated with

          • Peter Simon1,

            Affiliated with

            • Eckhard Weber1,

              Affiliated with

              • Kerstin Schütte2,

                Affiliated with

                • Jens Stieler3,

                  Affiliated with

                  • Heide Koula-Jenik4,

                    Affiliated with

                    • Peter Holzhauer4,

                      Affiliated with

                      • Uwe Gröber5,

                        Affiliated with

                        • Georg Engel6,

                          Affiliated with

                          • Cornelia Müller7,

                            Affiliated with

                            • You-Shan Feng9,

                              Affiliated with

                              • Ali Aghdassi1,

                                Affiliated with

                                • Claudia Nitsche1,

                                  Affiliated with

                                  • Peter Malfertheiner2,

                                    Affiliated with

                                    • Maciej Patrzyk8,

                                      Affiliated with

                                      • Thomas Kohlmann9 and

                                        Affiliated with

                                        • Markus M Lerch1Email author

                                          Affiliated with

                                          Nutrition Journal201211:52

                                          DOI: 10.1186/1475-2891-11-52

                                          Received: 16 February 2012

                                          Accepted: 6 July 2012

                                          Published: 23 July 2012

                                          Abstract

                                          Background

                                          Cachexia, a >10% loss of body-weight, is one factor determining the poor prognosis of pancreatic cancer. Deficiency of L-Carnitine has been proposed to cause cancer cachexia.

                                          Findings

                                          We screened 152 and enrolled 72 patients suffering from advanced pancreatic cancer in a prospective, multi-centre, placebo-controlled, randomized and double-blinded trial to receive oral L-Carnitine (4 g) or placebo for 12 weeks. At entry patients reported a mean weight loss of 12 ± 2,5 (SEM) kg. During treatment body-mass-index increased by 3,4 ± 1,4% under L-Carnitine and decreased (−1,5 ± 1,4%) in controls (p < 0,05). Moreover, nutritional status (body cell mass, body fat) and quality-of-life parameters improved under L-Carnitine. There was a trend towards an increased overall survival in the L-Carnitine group (median 519 ± 50 d versus 399 ± 43 d, not significant) and towards a reduced hospital-stay (36 ± 4d versus 41 ± 9d,n.s.).

                                          Conclusion

                                          While these data are preliminary and need confirmation they indicate that patients with pancreatic cancer may have a clinically relevant benefit from the inexpensive and well tolerated oral supplementation of L-Carnitine.

                                          Keywords

                                          Pancreatic adenocarcinoma L-Carnitine Quality of life Survival Cancer cachexia Fatique syndrome

                                          Background

                                          Adenocarcinoma of the pancreas is highly resistant to chemo- or radiotherapy [1], has a 5-year survival rate of only 4% and ranks as fourth leading cause of cancer death [24]. One reason contributing to this high mortality is cancer cachexia, defined as an unintended weight loss of more than 10% in 6 months, which is present in more than 80% of pancreatic cancer patients [5]. Cancer cachexia is also a predictor for reduced quality of life, increased mortality, and poor response to therapy [610]. A deficiency of L-Carnitine has been proposed to be an underlying cause of cancer cachexia [11] and tumor associated fatigue [1214]. Although L-Carnitine can be generated via endogenous conversion from lysine and methionine, 75% of the required levels are provided from food sources. In vitro studies in human tumor cell lines have shown a positive effect of L-Carnitine regarding the inhibition of apoptosis and DNA-damage [15]. On the other hand, L-Carnitine is well known for its potential to modulate the inflammatory response mechanisms, which is known to play the predominant role in the generation of cancer cachexia, especially in pancreatic tumor patients [16]. We therefore conducted a multicentre trial to investigate the role of oral L-Carnitine supplementation on cancer cachexia in pancreatic cancer (CARPAN).

                                          Methods

                                          Patients from 4 participating tertiary referral centers were considered eligible for inclusion when they had histologically proven, advanced and irresectable adenocarcinoma of the pancreas (UICC Stage IV), had a Karnofsky performance status of >60 and declared their written informed consent to participate. The CARPAN protocol was approved by the ethics committee of Greifswald University (Reg.Nr.IIIUV73/05) and registered at clinical-trials.gov (NCT01330823) and under ISRCTN83465351. Patients were recruited regardless of concomitant or scheduled chemotherapy. Exclusion criteria were liver failure, a second malignancy, treatment with omega-3-fatty acids and the presence of a mental disorder precluding informed consent. From May 2006 until October 2009 a total of 152 patients were screened and 72 enrolled in the study (Figure 1). Reasons for non-enrollment were mostly due to poor performance status or withheld consent. Patients were randomized (sequential series of 4 per block, sealed envelopes, computer generated randomization code) to receive either an oral liquid formulation of L-Carnitine (4 g/d, obtained from Lonza, Basel, CH) or identically formulated placebo with follow up visits at 6 and 12 weeks after entry. Compliance was tested by determining serum L-Carnitine levels by Tandem-Mass-Spectrometry (normal range between 40–60 μmol/l) (ABI 2000, Perkin-Elmer, Turku, SF) [17]. L-Carnitine deficiency is generally believed to occur below 30 μmol/l, albeit data on functional relevance are controversially discussed [18]. At every study visit adverse events and body mass index (BMI) were recorded and bioelectrical impedance analysis (BIA-Nutrigard-M, Darmstadt, Germany) was used to determine body composition [19]. For evaluation of quality of life we used the EORTC-QLQ-C30 questionnaire with a pancreatic cancer specific module PAN26 [20] and for fatigue the Brief Fatigue Inventory (BFI) questionnaire [21]. Survival time in days was calculated from time of diagnosis to death. Sample size calculation was based on previous studies investigating the effect of L-Carnitine on inflammatory markers [22], with TNFα level differences as primary endpoint, and resulted in a recruitment goal of 90 patients (45 per treatment arm) for a statistical power of 90% with an error probability of <5%. After a prescheduled interim analysis for sample size recalculation of 72 blinded datasets showed a wide variation of the standard errors for inflammatory markers a recruitment of 554 patients (277 per group) would have been necessary. Since this goal was unattainable the study was closed after enrolment of 72 patients and the data were unblinded for statistical analysis.
                                          http://static-content.springer.com/image/art%3A10.1186%2F1475-2891-11-52/MediaObjects/12937_2012_509_Fig1_HTML.jpg
                                          Figure 1

                                          Flow chart of the trial.

                                          Data are presented as means ± SEM and 95% confidence intervals where appropriate. Statistical analysis for intention-to-treat and per-protocol analysis was done by Student’s t test and Pearson's chi-square test for parametric and Mann–Whitney-U-Test for non-parametric analysis. Quality of life data were analyzed using ANOVA. Results were considered significant when p was <0,05.

                                          Results

                                          Patient characteristics are given in Table 1 and showed no statistical difference between both groups at enrolment.
                                          Table 1

                                          Characteristics of the study population (n = 72) at baseline visit of the study (mean ± SEM)

                                          Parameter

                                          L-Carnitine (n = 38)

                                          Placebo (n = 34)

                                          gender

                                          male

                                          20 (52.6%)

                                          23 (67.6%)

                                          female

                                          18 (47.4%)

                                          11 (32.4%)

                                          mean age

                                          64.4 ± 1.67

                                          64.4 ± 1.65

                                          Karnofsky performance status

                                          76.8 ± 1.87

                                          80.0 ± 2.16

                                          Nutritional Status

                                          normal BMI (kg/m²)

                                          28.0 ± 1.01

                                          30.1 ± 0.84

                                          baseline visit BMI (kg/m²)

                                          24.7 ± 0.65

                                          24.9 ± 0.89

                                          Phase angle (°)

                                          4.4 ± 0.16

                                          4.4 ± 0.17

                                          Weight loss*

                                          present

                                          34 (89.5%)

                                          31 (91.2%)

                                          absent

                                          4 (10.5%)

                                          3 (8.8%)

                                          meanweight loss (kg)*

                                          11.4 ± 1.28

                                          12.3 ± 1.56

                                          Nutritional support

                                          none

                                          20 (52.6%)

                                          21 (61.8%)

                                          oral

                                          14 (36.8%)

                                          9 (26.5%)

                                           

                                          Parenteral nutrition

                                          4 (10.5%)

                                          4 (11.7%)

                                          ECM/BCM index **

                                          1.5 ± 0.11

                                          1.4 ± 0

                                          Cell percentage (%)

                                          41.8 ± 1.22

                                          42.70 ± 1.21

                                          chemotherapy (n) 35 (92%) 30 (88%)

                                          Laboratory values

                                          L-Carnitine level (μmol/l)

                                          25.3 ± 2.29

                                          24. 8 ± 2.11

                                          Albumine (g/l)

                                          33.8 ± 1.09

                                          33.7 ± 1.20

                                          CRP (mg/l)

                                          31.3 ± 6.55

                                          45.5 ± 10.39

                                          Leucocytes (Gpt/l)

                                          8.3 ± 0.83

                                          6.9 ± 0.46

                                          CA 19–9 (U/ml)

                                          14,095 ± 32,572

                                          18,345 ± 35,950

                                          No statistically significant differences were observed between L-Carnitine and placebo group.

                                          *weight loss during the last 6 month.

                                          **ECM/BCM-Index, Extra-Cellular-Mass/Body-Cell-Mass-Index.

                                          At entry 88% of patients in the placebo and 92% of patients in the L-Carnitine group received chemotherapy. There was no statistically significant difference between both groups (p < 0,05). 90% of the patients reported a weight loss of >10% during the previous 6 month. This observation is in line with previous reports on cancer cachexia [5]. 26 patients completed the entire follow up period and premature drop-out was due to death (n = 11), deteriorating health (n = 9), nausea (n = 8), excessive demand (n = 5), diarrhea (n = 2) or miscellaneous symptoms (n = 7). Drop out rates and reasons were not different between both treatment arms. Oral supplementation of L-Carnitine substantially increased L-Carnitine serum plasma levels up to 60% of the basic value at week 6 (p < 0,009) in the L-Carnitine group (Figure 2), while a constant decline of L-Carnitine plasma levels was evident during the observation period in the placebo group. This might be related to tumor effects and / or due to concomitant chemotherapy. L-Carnitine supplementation was well tolerated. Side effects did not differ significantly in comparison with placebo group (predominantly nausea, vomiting, and diarrhoea) and, whenever they occurred, may have been caused by concomitant chemotherapy.
                                          http://static-content.springer.com/image/art%3A10.1186%2F1475-2891-11-52/MediaObjects/12937_2012_509_Fig2_HTML.jpg
                                          Figure 2

                                          Reasons for discontinued convention of the study patients. Reasons for discontinued convention of the study patients.

                                          Patients on L-Carnitine treatment gained weight (BMI increase of 3.4% ± 1.35)whereas patients on placebo did not (BMI reduction of 1.5% ± 1.4, p < 0.018). After 12 weeks of therapy the difference amounted to 4.9% ± 1.9 (Figure 3) between groups. BIA revealed that this improvement was due to increases in body cell mass (BCM, p < 0,013) and body fat (BF, p < 0,041). CRP, albumin, leukocyte count and CA19-9 remained unaffected (data not shown). Regarding quality of life (EORTC-QLQ-C30/PAN26) the only significant changes were improvement in cognitive function (at enrolment 81,0 ± 21,5 in L-Carnitine group, 86,1 ± 17,2 in placebo group; after 6 -weeks L- Carnitine group 0,30 versus −0,13 in the placebo group, p < 0,034), improvement of global health s\tatus (at enrolment 53,6 ± 19,5 in L-Carnitine group, 65,3 ± 17,7 in placebo group; after 12 weeks L- Carnitine group 0,76 versus −0,32 in the placebo group, p < 0,041) and reduction in gastrointestinal symptoms (at enrolment 29,8 ± 32,1 in L-Carnitine group, 19,4 ± 24,5; in the placebo group; after 12 weeks L-Carnitine group −0,35 versus 0,78 in the placebo group; p < 0,033). Differences in fatigue (moderate/severe, >4 on BFI), present in 28,6% of L-Carnitine patients versus 41,7% in the placebogroup,were not statistically significant, nor was the survival benefit (Figure 2, median 519 ± 50d versus 399 ± 43d with placebo), and the reduction in length of hospital stay (36 ± 4d versus 41 ± 9d with placebo).
                                          http://static-content.springer.com/image/art%3A10.1186%2F1475-2891-11-52/MediaObjects/12937_2012_509_Fig3_HTML.jpg
                                          Figure 3

                                          Relevant nutritional parameters and survival. Relevant nutritional parameters (means ± SEM) and survival in days in the L-Carnitine treatment arm (black lines) and placebogroup (gray lines). Survival is given in days after diagnosis as Kaplan-Meier curve and body mass index (BMI), body fat, and body cell mass (BCM) aregiven as percent changes under respective treatment over 12 weeks. Asterisks indicate statistically significant differences (p < 0.05).

                                          Conclusion

                                          Cancer cachexia and malnutrition are associated with an increased risk of surgical complications and higher toxicity levels of chemotherapy. Quality of life and overall survival of colon cancer patients can improve under early nutritional intervention [23]. L-Carnitine is critical for energy generation by mitochondrial ß-oxidation and was found depleted under chemotherapy [2426]. Its oral supplementation can normalize nutritional L-Carnitine deficiency [27, 28] and reduce chemotherapy related side effects [29, 30]. We therefore tested whether oral L-Carnitine supplementation has a clinical benefit in patients with advanced pancreatic cancer and found that L-Carnitine can reduce malnutrition, increase bodyweight and improve body composition.

                                          When we planned and designed the study no persuasive data for clinical endpoints existed and we had to base the initial power calculations on inflammatory markers in humans under L-Carnitine treatment. While this study must be regarded as preliminary because inflammatory markers were found to be an unsuitable primary endpoint in our setting, the CARPAN trial provides the basis for a robust sample size calculation: a conclusive study of L-Carnitine benefits ought to enrol 148 patients in each arm to show a survival benefit with 90% power, and would need 157 patients in each arm to demonstrate an improvement in tumor fatigue. The presently available data show a benefit of L-Carnitine supplementation on body weight, body composition and some aspects of quality-of-life, even though it was underpowered to determine the statistical significance of other secondary endpoints. While the loss of significant changes in BCM at week 12 and a rapid increase in body fat between week 6 and 12 was an unexpected finding it might be explained by the underlying progressive tumor disease leading to changes in body composition, irrespective of gain of weight and due to reduced physical activity and progressive sarcopenia. Both are common findings in pancreatic tumors. In this context it is important to note, that the direct influence of L-Carnitine on tumor growth has not been measured in this study and is beyond the scope of this work. Future studies are needed to address this question as only recently L-Carnitine has been reported to modify apoptosis and DNA-damage in tumor cell lines of the brain via CPT-1 C [15].

                                          The CARPAN trial could suggest that the clinical benefit of an inexpensive and very well tolerated oral L-Carnitine supplementation may reach the clinical benefit level previously shown for palliative Gemcitabine chemotherapy [31] in pancreatic cancer patients.

                                          Abbreviations

                                          BIA: 

                                          Bioelectrical impedance analysis

                                          BF: 

                                          Body fat

                                          BFI: 

                                          Brief fatigue inventory

                                          BMI: 

                                          Body mass index

                                          BCM: 

                                          Body cell mass

                                          CPT: 

                                          Carnitine palmitoyltransferase

                                          CRP: 

                                          C-reactive protein

                                          ECM: 

                                          Extra cellular mass

                                          SEM: 

                                          Standard error of the mean

                                          TNFα: 

                                          Tumor nekrose faktor α.

                                          Declarations

                                          Acknowledgement

                                          This study was supported by the Alfried-Krupp-von-Bohlen-und-Hahlbach-Foundation (Graduate Schools Tumour Biology and Free Radical Biology), the Deutsche Krebshilfe/ Dr. Mildred-Scheel-Stiftung (109102), the Deutsche Forschungsgemeinschaft (DFGgRK840-E3/E4, MA 4115/1-2/3, NI 1297/1-1), the Federal Ministry of Education and Research (BMBFgANI-MED 03152061A and BMBF 0314107) and the European Union (EU-FP-7: EPC-TM and EU-FP7-REGPOT-2010-1). KK and SG both received a Gerhard-Domagk-Stipendium of Greifswald University Medicine made possible through unrestricted educational grants from Medinal GmbH, Greven, Germany, Fresenius Kabi Germany GmbH Bad Homburg, Germany and Nutricia GmbH, Erlangen, Germany. L-Carnitine bulk compound was kindly provided by Lonza Ltd., Basel, Switzerland.

                                          Authors’ Affiliations

                                          (1)
                                          Department of Medicine A, University Medicine Greifswald
                                          (2)
                                          Department for Gastroenterology, Hepatology and Infectious Diseases, Otto von Guericke University Magdeburg
                                          (3)
                                          Charité Universitaetsmedizin Berlin, Campus Virchow-Clinic, Medical Clinic Hematology/Oncology
                                          (4)
                                          Veramed Clinic
                                          (5)
                                          Academy of Micronutrient Medicine
                                          (6)
                                          University Pharmacy, University Medicine Greifswald
                                          (7)
                                          Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald
                                          (8)
                                          Department of Surgery, University Medicine Greifswald
                                          (9)
                                          Institute of Community Medicine, University Medicine of Greifswald

                                          References

                                          1. Rocha-Lima CM: New directions in the management of advanced pancreatic cancer: a review. Anticancer Drugs 2008, 19:435–446.View Article
                                          2. Greenlee RT, Hill-Harmon MB, Murray T, Thun M: Cancer statistics, 2001. CA Cancer J Clin 2001, 51:15–36.View Article
                                          3. DiMagno EP, Reber HA, Tempero MA: AGA technical review on the epidemiology, diagnosis, and treatment of pancreatic ductal adenocarcinoma. Americangastroenterological Association. gastroenterology 1999, 117:1464–1484.
                                          4. Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, et al.: Adjuvant chemotherapy with fluorouracil plus folinic acid vsgemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA 2010, 304:1073–1081.View Article
                                          5. Bachmann J, Ketterer K, Marsch C, Fechtner K, Krakowski-Roosen H, Büchler MW, Friess H, Martignoni ME: Pancreatic cancer related cachexia: influence on metabolism and correlation to weight loss and pulmonary function. BMC Cancer 2009, 9:255.View Article
                                          6. Pelzer U, Arnold D, Govercin M, Stieler J, Doerken B, Riess H, Oettle H: Parenteral nutrition support for patients with pancreatic cancer. Results of a phase II study. BMC Cancer 2010, 10:86.View Article
                                          7. Uomog , Gallucci F, Rabitti PG: Anorexia-cachexia syndrome in pancreatic cancer: recent development in research and management. JOP 2006, 7:157–162.
                                          8. Ockenga J, Valentini L: Review article: anorexia and cachexia in gastrointestinal cancer. Aliment Pharmacol Ther 2005, 22:583–594.View Article
                                          9. Bozzetti F: Screening the nutritional status in oncology: a preliminary report on 1,000 outpatients. Support Care Cancer 2009, 17:279–284.View Article
                                          10. Cohen SJ, Pinoverw H, Watson JC, Meropol NJ: Pancreatic cancer. Curr Treat Options Oncol 2000, 1:375–386.View Article
                                          11. Malaguarnera M, Risino C, Gargante MP, Tomasello AV, Costanzo M, Cannizzaro MA, Costanzo M, Cannizzaro MA: Decrease of serum carnitine levels in patients with or without gastrointestinal cancer cachexia. World Jgastroenterol 2006, 12:4541–4545.
                                          12. Graziano F, Bisonni R, Catalano V, Silva R, Rovidati S, Mencarini E, Ferraro B, Canestrari F, Baldelli AM, Deg A, et al.: Potential role of levocarnitine supplementation for the treatment of chemotherapy-induced fatigue in non-anaemic cancer patients. Br J Cancer 2002, 86:1854–1857.View Article
                                          13. Stone P, Richardson A, Ream E, Smith AG, Kerr DJ, Kearney N: Cancer-related fatigue: inevitable, unimportant and untreatable? Results of a multi-centre patient survey. Cancer Fatigue Forum. Ann Oncol 2000, 11:971–975.
                                          14. Schwartz AL, Nail LM, Chen S, Meek P, Barsevick AM, King ME, Jones LS: Fatigue patterns observed in patients receiving chemotherapy and radiotherapy. Cancer Invest 2000, 18:11–19.View Article
                                          15. Zaugg K, Yao Y, Reilly PT, Kannan K, Kiarash R, Mason J, Huang P, Sawyer SK, Fuerth B, Faubert B, et al.: Carnitine palmitoyltransferase 1 C promotes cell survival and tumorgrowth under conditions of metabolic stress. Genes Dev 2011, 25:1041–51.View Article
                                          16. Liu S, Zhang ZQ, Chen Q, Liu B, Wu JP, Zhu L: L-Carnitine ameliorates cancer cachexia in mice by regulating the expression and activity of carnitine palmityl transferase. Cancer Biol Ther 2011, 12:125–30.View Article
                                          17. Kodo N, Millington DS, Norwood DL, Roe CR: Quantitative assay of free and total carnitine using tandem mass spectrometry. Clin Chim Acta 1990, 186:383–390.View Article
                                          18. Rebouche CJ: Carnitine function and requirements during the life cycle. FASEB J 1992, 6:3379–3386.
                                          19. Bosy-Westphal A, Danielzik S, Dorhofer RP, Later W, Wiese S, Muller MJ: Phase angle from bioelectrical impedance analysis: population reference values by age, sex, and body mass index. JPEN J Parenter Enteral Nutr 2006, 30:309–316.View Article
                                          20. Fitzsimmons D, Johnson CD, George S, Payne S, Sandberg AA, Bassi C, Beger HG, Birk D, Buchler MW, Dervenis C, et al.: Development of a disease specific quality of life (QoL) questionnaire module to supplement the EORTC core cancer QoL questionnaire, the QLQ-C30 in patients with pancreatic cancer. EORTC Study group on Quality of Life. Eur J Cancer 1999, 35:939–941.View Article
                                          21. Radbruch L, Sabatowski R, Elsner F, Everts J, Mendoza T, Cleeland C: Validation of thegerman version of the brief fatigue inventory. J Pain Symptom Manage 2003, 25:449–458.View Article
                                          22. Grazig G, Meriggioli M: Can the treatment with L-carnitine improve the inflammation in chronic hemo dialysis patients? G Ital Nefrol 2004,21(Suppl 30):S204-S207.
                                          23. Nitenbergg , Raynard B: Nutritional support of the cancer patient: issues and dilemmas. Crit Rev Oncol Hematol 2000, 34:137–168.View Article
                                          24. Dodsonw L, Sachan DS, Krauss S, Hanna W: Alterations of serum and urinary carnitine profiles in cancer patients: hypothesis of possible significance. J Am Coll Nutr 1989, 8:133–142.
                                          25. Mancinelli A, D'Iddio S, Bisonni R, Graziano F, Lippe P, Calvani M: Urinary excretion of L-carnitine and its short-chain acetyl-L-carnitine in patients undergoing carboplatin treatment. Cancer Chemother Pharmacol 2007, 60:19–26.View Article
                                          26. Lancaster CS, Hu C, Franke RM, Filipski KK, Orwick SJ, Chen Z, Zuo Z, Loosw J, Sparreboom A: Cisplatin-induced down regulation of OCTN2 affects carnitine wasting. Clin Cancer Res 2010, 16:4789–4799.View Article
                                          27. Lebrun C, Alchaar H, Candito M, Bourg V, Chatel M: Levocarnitine administration in multiple sclerosis patients with immunosuppressive therapy-induced fatigue. Mult Scler 2006, 12:321–324.View Article
                                          28. Cruciani RA, Dvorkin E, Homel P, Culliney B, Malamud S, Lapin J, Portenoy RK, Esteban-Cruciani N: L-carnitine supplementation in patients with advanced cancer and carnitine deficiency: a double-blind, placebo-controlled study. J Pain Symptom Manage 2009, 37:622–631.View Article
                                          29. Pisano C, Vesci L, Milazzo FM, Guglielmi MB, Fodera R, Barbarino M, D'Incalci M, Zucchetti M, Petrangolini G, Tortoreto M, et al.: Metabolic approach to the enhancement of antitumor effect of chemotherapy: a key role of acetyl-L-carnitine. Clin Cancer Res 2010, 16:3944–3953.View Article
                                          30. Haschke M, Vitins T, Lude S, Todesco L, Novakova K, Herrmann R, Krahenbuhl S: Urinary excretion of carnitine as a marker of proximal tubular damage associated with platin-based anti neo plastic drugs. Nephrol Dial Transplant 2010, 25:426–433.View Article
                                          31. Burris HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, et al.: Improvements in survival and clinical benefit with gemcitabine as first line therapy for patients with advanced pancreas cancer a randomized trial. J Clin Oncol 1997, 15:2403–2413.

                                          Copyright

                                          © Kraft et al.; licensee BioMed Central Ltd. 2012

                                          This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                                          Advertisement