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Neurology India, Vol. 58, No. 1, January-February, 2010, pp. 20-23 Original Article Lycopene in treatment of high-grade gliomas: A pilot study Tarun Puri, Shikha Goyal, Pramod K. Julka, Omana Nair, Daya N. Sharma, Goura K. Rath Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi - 110 029, India Correspondence Address: Dr. Tarun Puri, Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi - 110 029, India, tpuri90@gmail.com Date of Acceptance: 02-Jul-2009
Code Number: ni10005 DOI: 10.4103/0028-3886.60389 Abstract Background : The therapeutic benefit of lycopene is well established for carcinoma prostate in various clinical trials and has been proposed for other malignancies including high-grade gliomas. Keywords: Chemotherapy, high-grade glioma, lycopene, radiotherapy Introduction The role of oxidative stress in the genesis of various cancers is well described. [1] In vitro and animal studies have shown that antioxidants may slow or prevent the development of cancer. [2] Brain is considered abnormally sensitive to oxidative damage as brain tissue has a high rate of oxygen consumption, high lipid content and relatively low antioxidant defenses, compared to other tissues. [3],[4] Significantly reduced serum levels of antioxidants, β-carotene and β-tocopherol have been reported in patients with brain tumor compared to controls. The protective effect of β-carotene and β-tocopherol is primarily due to their antioxidant properties. [5] Additionally, other mechanisms such as enhancement of immune response, inhibitory mutagenesis, reduction of induced nuclear damage, anti-inflammatory effects and effects on gene regulation have been described. [6] Micronutrients (vitamins, minerals and other agents found in foods, such as flavanoids) have potential therapeutic effects in cell cultures and animal models of peripheral cancers. [7] The therapeutic benefit of lycopene is well established for carcinoma of prostate in various clinical trials. [8],[9] Animal models have demonstrated benefit in carcinoma lung, breast and colon. Carotenoids have been shown to inhibit DNA synthesis in vitro in C-6 glioma cells inoculated in rats, without significant toxicity. [10],[11] However, the actual benefit of adding supplemental micronutrients such as lycopene to adjuvant management of gliomas has never been investigated. We undertook a pilot study in 50 patients to study the effect of adding a carotenoid, lycopene, to radiotherapy and chemotherapy in the adjuvant treatment of high-grade gliomas. Materials and Methods The study was conducted at the Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi. Patients with high-grade gliomas (anaplastic astrocytoma or glioblastoma multiforme) were included in the study from November 2002 to November 2003. A convenient sample size of 50 patients was chosen as a suitable number for this pilot study for this uncommon malignancy. All patients underwent surgery followed by adjuvant radiotherapy 60 Gray over six weeks, initially 50 Gray in 25 fractions over five weeks followed by boost 10 Gray in five fractions over one week. Concurrent chemotherapy with paclitaxel at a dose of 60 mg/m 2 i/v weekly was given to all patients (as a radiosensitiser). Patients were randomized into two groups: Group A received oral lycopene supplementation (8 mg daily) with radiotherapy, starting on Day 1 of radiotherapy, while Group B received placebo. Pre-and post-radiotherapy plasma lycopene levels were measured using high-precision liquid chromatography (HPLC). Patients were followed up at three-monthly interval with clinical examinations. McDonald′s criteria were used for response assessment. Magnetic resonance imaging (MRI) brain and brain Single Photon Emission Computed Tomography (SPECT) were done three-monthly for two visits and six-monthly thereafter. The primary endpoint was response at six months following completion of radiotherapy. Time to progression was also determined. The data was analyzed using SPSS Software v10.0 (SPSS corporation Chicago IL) by applying Student′s t-test, ANOVA F test, Chi-square test and Karl Pearson Correlation Coefficient. Results The distribution of patients and disease characteristics were well balanced in the two groups [Table - 1]. Baseline lycopene levels were higher in the Group A, but the difference between the two groups was not statistically significant. Post radiotherapy, the lycopene levels were higher in both study arms compared to baseline, but the lycopene-supplemented group had significantly higher levels than the placebo group (P = 0.009) [Table - 2]. All patients were alive at six months. The response seen at six months was similar in the two study groups, although greater number of patients in Group A achieved a complete response (10 vs. 5). Of the 50 patients recruited in the study, imaging for response assessment was not available for six patients. The lycopene-supplemented group showed a significant higher median follow-up compared to the placebo group (66.29 weeks vs. 38.71 weeks, P = 0.05) [Table - 3]. Time to progression was also longer in the lycopene-supplemented group although the difference between the two groups was not statistically significant (40.83 weeks vs. 26.74 weeks; P = 0.089). Discussion Increasing knowledge of the biology of gliomas has triggered development of innovative treatment strategies that can combat diffuse local invasion associated with these malignancies and are effective against both dividing and migrating cells. Several micronutrients including citrus flavonoids, selenium, and carotenoids such as lycopene may cross the blood-brain barrier and have potential pro-apoptotic and anti-invasion activity. [7] Lycopene is the most potent antioxidant among the commonly known carotenoids and shows synergism with other carotenoids when present in a mixture. [12] Its anti-proliferative and pro-apoptotic activity is mediated through several mechanisms including reduction in expression of cell cycle regulatory proteins such as cyclin D1 leading to inhibition of cell cycle progression from G0/G1 to S phase and differentiation in cancer cells, inhibition of IGF-1-mediated stimulation of tumor growth, upregulation of gap-junctional gene connexion 43 thus increasing intercellular communication and modulation of carcinogen-metabolizing enzymes. [13],[14] Other mechanisms include IL-6 inhibition, 5-lipoxygenase inhibition, prevention of oxidative DNA damage, modulation of immune function and modulation of transcription through a direct interaction with ligand-activated nuclear receptors or indirectly through changes in status of cellular redox reactions. Lycopene is lipophilic and concentrates in various body tissues (adrenal, liver, testes, prostate) though the serum or tissue levels do not correlate well with the amount of supplemented carotenoid. [15] Apart from being a chemopreventive agent, lycopene has shown promising anti-proliferative activity in human and animal cancer cell lines in lung, breast and colon cancers. Lycopene supplementation in advanced prostate cancer has improved survival compared with orchidectomy alone, in addition to subjective and objective tumor responses. [9] Doses of 15 mg twice daily given three weeks before radical prostatectomy in newly diagnosed carcinoma prostate have shown reduction in tumor volumes, sterilization of surgical margins and extraprostatic disease and decreased serum prostate-specific antigen (PSA) levels. [8] Carotenoids including lycopene have shown inhibitory activity against rat C-6 glioma cells in culture consequent to inhibition of DNA synthesis. [10] In vivo studies on rats inoculated with transplantable C-6 glioma cells have shown a growth inhibition of 30-55% with carotenoids, with no significant hepatotoxic effect. Enhancement of anti-tumor immunity in vivo was proposed to be an additional mechanism of tumor inhibition. [11] Rao et al. conducted a randomized crossover study on 12 healthy subjects to investigate the dose-response relationship of lycopene on the absorption and in vivo antioxidant properties at low level of intake (5, 10, 20 mg). Lycopene supplementation was given in the form of ketchup or oleoresin capsules. It was observed that serum lycopene levels showed a significant increase at all doses. However, serum levels plateaued at doses beyond 8-10 mg. [16] Another report suggested that 80% of the people administered lycopene absorbed less than 6 mg of lycopene, suggesting a possible saturation of absorptive mechanisms. [17],[18] Based on these reports and lack of prior experience with lycopene in gliomas, a dose of 8 mg was selected for our study. Patients were recruited for the present study in the period 2002-03, when temozolomide was still not the standard of care for adjuvant management of glioblastomas. Paclitaxel was used as a radiosensitizing agent consequent to prior Phase 2 data and our experience with paclitaxel given concurrent with radiotherapy in high-grade gliomas. [19],[20] The patients were followed up as a part of the study for a planned duration of six months post radiotherapy. Subsequent to this, patients were followed up during routine hospital visits. On account of a significant dropout of patients, overall survival data are not available (not intended for collection as a part of study design). We do not currently have a system of active follow-up of patients who do not attend outpatient clinics and mortality is not accounted for unless reported by the patient′s family. The follow-up duration may serve as a surrogate for survival based on the assumption that survivors or healthy patients would be expected to follow up for a longer period compared with the deceased or sick, though we understand that this assumption may be associated with considerable bias, and may not be statistically sound. The encouraging results obtained in our study and evidence from recent reviews on the incorporation of nutritional agents in cancer management have potentially opened new vistas in cancer management. It would be interesting and worthwhile to conduct larger, preferably multicentre studies incorporating currently recommended chemotherapeutics (temozolomide) to obtain more conclusive evidence. [21],[22] References
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