Rozita Abdul Malik

Metformin synergizes 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) combination therapy through impairing intracellular ATP production and DNA repair in breast cancer stem cells

Metformin, an AMPK activator, has been reported to improve pathological response to chemotherapy in diabetic breast cancer patients. To date, its mechanism of action in cancer, especially in cancer stem cells (CSCs) have not been fully elucidated. In this study, we demonstrated that metformin, but not other AMPK activators (e.g. AICAR and A-769662), synergizes 5-fluouracil, epirubicin, and cyclophosphamide (FEC) combination chemotherapy in non-stem breast cancer cells and breast cancer stem cells. We show that this occurs through an AMPK-dependent mechanism in parental breast cancer cell lines. In contrast, the synergistic effects of metformin and FEC occurred in an AMPK-independent mechanism in breast CSCs. Further analyses revealed that metformin accelerated glucose consumption and lactate production more severely in the breast CSCs but the production of intracellular ATP was severely hampered, leading to a severe energy crisis and impairs the ability of CSCs to repair FEC-induced DNA damage. Indeed, addition of extracellular ATP completely abrogated the synergistic effects of metformin on FEC sensitivity in breast CSCs. In conclusion, our results suggest that metformin synergizes FEC sensitivity through distinct mechanism in parental breast cancer cell lines and CSCs, thus providing further evidence for the clinical relevance of metformin for the treatment of cancers.

CT Based 3-Dimensional Treatment Planning of Intracavitary Brachytherapy for Cancer of the Cervix : Comparison between Dose-Volume Histograms and ICRU Point Doses to the Rectum and Bladder

BACKGROUND CT based brachytherapy allows 3-dimensional (3D) assessment of organs at risk (OAR) doses with dose volume histograms (DVHs). The purpose of this study was to compare computed tomography (CT) based volumetric calculations and International Commission on Radiation Units and Measurements (ICRU) reference-point estimates of radiation doses to the bladder and rectum in patients with carcinoma of the cervix treated with high-dose-rate (HDR) intracavitary brachytherapy (ICBT). MATERIALS AND METHODS Between March 2011 and May 2012, 20 patients were treated with 55 fractions of brachytherapy using tandem and ovoids and underwent post-implant CT scans. The external beam radiotherapy (EBRT) dose was 48.6 Gy in 27 fractions. HDR brachytherapy was delivered to a dose of 21 Gy in three fractions. The ICRU bladder and rectum point doses along with 4 additional rectal points were recorded. The maximum dose (DMax) to rectum was the highest recorded dose at one of these five points. Using the HDR plus 2.6 brachytherapy treatment planning system, the bladder and rectum were retrospectively contoured on the 55 CT datasets. The DVHs for rectum and bladder were calculated and the minimum doses to the highest irradiated 2cc area of rectum and bladder were recorded (D2cc) for all individual fractions. The mean D2cc of rectum was compared to the means of ICRU rectal point and rectal DMax using the Students t-test. The mean D2cc of bladder was compared with the mean ICRU bladder point using the same statistical test .The total dose, combining EBRT and HDR brachytherapy, were biologically normalized to the conventional 2 Gy/fraction using the linear-quadratic model. (α/β value of 10 Gy for target, 3 Gy for organs at risk). RESULTS The total prescribed dose was 77.5 Gy α/β10. The mean dose to the rectum was 4.58 ± 1.22 Gy for D 2cc, 3.76 ± 0.65 Gy at D ICRU and 4.75 ± 1.01 Gy at DMax. The mean rectal D 2cc dose differed significantly from the mean dose calculated at the ICRU reference point (p<0.005); the mean difference was 0.82 Gy (0.48 -1.19 Gy). The mean EQD2 was 68.52 ± 7.24 Gy α/β3 for D 2cc, 61.71 ± 2.77 Gy α/β3 at D ICRU and 69.24 ± 6.02 Gy α/β3 at DMax. The mean ratio of D 2cc rectum to D ICRU rectum was 1.25 and the mean ratio of D 2cc rectum to DMax rectum was 0.98 for all individual fractions. The mean dose to the bladder was 6.00 ± 1.90 Gy for D 2cc and 5.10 ± 2.03 Gy at D ICRU. However, the mean D 2cc dose did not differ significantly from the mean dose calculated at the ICRU reference point (p=0.307); the mean difference was 0.90 Gy (0.49-1.25 Gy). The mean EQD2 was 81.85 ± 13.03 Gy α/β3 for D 2cc and 74.11 ± 19.39 Gy α/β3 at D ICRU. The mean ratio of D 2cc bladder to D ICRU bladder was 1.24. In the majority of applications, the maximum dose point was not the ICRU point. On average, the rectum received 77% and bladder received 92% of the prescribed dose. CONCLUSIONS OARs doses assessed by DVH criteria were higher than ICRU point doses. Our data suggest that the estimated dose to the ICRU bladder point may be a reasonable surrogate for the D 2cc and rectal DMax for D 2cc. However, the dose to the ICRU rectal point does not appear to be a reasonable surrogate for the D 2cc.

Intensity-modulated radiotherapy for nasopharyngeal carcinoma: Penang General Hospital experience.

PURPOSE To study the overall treatment time (OTT) and acute toxicity of intensity-modulated radiotherapy (IMRT) treatment for nasopharyngeal carcinoma (NPC). METHODS This retrospective study covered all NPC patients who underwent radical IMRT treatment at the Penang General Hospital from June 2011 to February 2012. Patients of any age and stage of disease with histologically proven diagnosis were included. Information was collected on patient demographics, clinical stage, treatment received, including any neoadjuvant and/or concurrent chemotherapy, acute toxity and completion of IMRT within the OTT. RESULTS A total of 26 NPC patients were treated with IMRT during the study period; 88.5% had stage III/IV disease. 45.2% received neo-adjuvant chemotherapy while 50.0% were given concurrent chemo-irradiation. All patients completed the treatment and 92.3% within the 7 weeks OTT. Xerostomia was present in all patients with 92.3% having grade 2. Severe grade III/IV acute toxicity occurred in 73.1% of patients, the commonest of which was oral mucositis (57.6%). This was followed by dysphagia which occurred in 53.8%, skin reactions in 42.3% and weight loss in 19.2%. However, haematological toxicity was mild with only one patient having leucopaenia. CONCLUSION IMRT treatment for NPC is feasible in our center. More importantly, it can be delivered within the 7 weeks OTT in the majority of patients. Severe grade 3/4 toxicity is very common (73.1%) and thus maximal nutritional and analgesic support is required throughout the treatment.

Health-related quality of life and psychological distress among cancer survivors in a middle-income country

Quality of life and psychological well‐being are important patient‐centered outcomes, which are useful in evaluation of cancer care delivery. However, evidence from low‐income and middle‐income countries remains scarce. We assessed health‐related quality of life (HRQoL) and prevalence of psychological distress (anxiety or depression), as well as their predictors, among cancer survivors in a middle‐income setting.

Abstract 5493: Metformin synergizes 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) sensitivity in breast cancer stem cells and non-stem breast cancer cells

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Incorporating cancer stem cells (CSCs)-targeting therapies into current therapies could prevent cancer progression, recurrence and metastasis. An anti-diabetic, AMPK-activating drug, metformin has been shown to kill CSCs and reduces cancer incidence and cancer related death. This study aimed to evaluate the combination treatment of metformin or other AMPK/mTOR-acting drugs with chemotherapy on breast CSCs and non-CSCs in the pre-clinical and clinical settings. We investigated the combination effect of metformin, AICAR, A-769662, or rapamycin with doxorubicin, cisplatin, paclitaxel, or FEC on breast CSCs (mammospheres) and non-CSCs in vitro. The study was extended clinically in a pilot study of ten non-diabetic locally advanced breast cancer patients treated with metformin and neoadjuvant FEC chemotherapy. Nine patients treated with FEC only were identified as historical controls. ESA+/CD44+/CD24-/low (CSCs) population of the tumor samples and tumor response were evaluated. In contrast to other drugs, metformin exhibited higher sensitivity in CSCs compared to attached cell lines. Metformin combined with FEC demonstrated a synergistic effect on breast CSCs and non-CSCs. Patients receiving metformin/FEC neoadjuvant therapy showed a significant reduction in CSCs proportion (P=0.008). Proportion of CSCs after treatment with metformin/FEC was significantly lower compared with the FEC-only neoadjuvant group (P=0.008). Five out of nine patients (56%) receiving metformin/FEC therapy showed a clinical response versus one out of eight (13%) patients in the FEC-only group. In conclusion, metformin synergizes FEC sensitivity in both CSCs and non-CSCs in breast cancer cell lines. Combination treatment of metformin and FEC reduces CSCs in primary tumor from non-diabetic locally advanced breast cancer patients. These results indicate that neoadjuvant metformin/FEC may be a potential treatment option for breast cancer patients and warrants further clinical investigations. Citation Format: Sian Siu Soo, Char Hong Ng, Rozita Abdul Malik, Yew Ching Teh, Boon Shing Tan, Gwo Fuang Ho, Mee Hoong See, Nur Aishah Mohd Taib, Cheng Har Yip, Soo Hwang Teo, Chee Onn Leong. Metformin synergizes 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) sensitivity in breast cancer stem cells and non-stem breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5493. doi:10.1158/1538-7445.AM2014-5493