Comparison of Clinical Outcomes Between Low- and High-Risk Groups of Early Breast Cancer Patients Treated with Intraoperative Radiotherapy in Addition to External Beam Radiation: A Multi-Centre Prospective Study.

BACKGROUND: There is a paucity of data on the use of intraoperative radiotherapy (IORT) with low-energy X-rays in Malaysian women with early breast cancer. The aim of this study is to evaluate the clinical, cosmetic, and patient-reported outcomes in low- and high-risk early breast cancer patients treated with breast conserving surgery (BCS) and IORT. METHODOLOGY: Patients suitable for BCS who were treated with IORT between January 2016 and June 2019 from three centres were analysed. They were divided into low-risk and high-risk groups based on the risk of recurrence according to the TARGeted Intraoperative radioTherapy (TARGIT) A and B study criteria. Outcomes of interest included local recurrence, wound complications, and radiation toxicity, with a subset analysed for cosmetic and patient-reported outcomes. RESULTS: Within a median follow-up of 31 months, there were 104 and 211 patients in the low- and high-risk groups, respectively. No significant difference was observed in local recurrence rates (low-risk, 1.0% vs. high-risk, 1.4%; p = 1.000). Both cohorts exhibited low frequencies of severe wound complications ranging between 1.4 and 1.9%. No major radiation toxicities were reported in either group. In the subgroup analysis, low-risk patients had significantly better mean scores in the subscales of inframammary fold and scar. Based on the BREAST-Q patient-reported outcomes questionnaire, seven out of nine parameters were scored similarly between both groups with no significant difference. CONCLUSION: This study showed that the use of IORT in both low- and high-risk early breast cancers is efficacious and safe with low recurrence rates and an acceptable toxicity profile.

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

OBJECTIVES: 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. METHODS: Through the Association of Southeast Asian Nations Costs in Oncology study, 1490 newly diagnosed cancer patients were followed-up in Malaysia for 1 year. Health-related quality of life was assessed by using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EuroQol-5 (EQ-5D) dimension questionnaires at baseline, 3 and 12 months. Psychological distress was assessed by using Hospital Anxiety and Depression Scale. Data were modeled by using general linear and logistic regressions analyses. RESULTS: One year after diagnosis, the mean EORTC QLQ-C30 Global Health score of the cancer survivors remained low at 53.0 over 100 (SD 21.4). Fifty-four percent of survivors reported at least moderate levels of anxiety, while 27% had at least moderate levels of depression. Late stage at diagnosis was the strongest predictor of low HRQoL. Increasing age, being married, high-income status, hospital type, presence of comorbidities, and chemotherapy administration were also associated with worse HRQoL. The significant predictors of psychological distress were cancer stage and hospital type. CONCLUSION: Cancer survivors in this middle-income setting have persistently impaired HRQoL and high levels of psychological distress. Development of a holistic cancer survivorship program addressing wider aspects of well-being is urgently needed in our settings.

The efficacy and tolerability of scalp cooling in preventing chemotherapy-induced alopecia in patients with breast cancer receiving anthracycline and taxane-based chemotherapy in an Asian setting.

BACKGROUND: Scalp cooling has been shown in several studies to be an effective method in preventing chemotherapy-induced alopecia (CIA). Data on the use of scalp cooling in Asian countries are limited, and evidence for its use and efficacy among our patients are not available. OBJECTIVE: The aim of this study was to assess the effectiveness and tolerability of scalp cooling among breast cancer patients in our study population. METHODS: Consecutive breast cancer patients receiving FE75C, FE100C, FE100C-D, docetaxel75 or docetaxel, and cyclophosphamide (TC) at our treatment center were recruited and allocated to the treatment (scalp cooling, DigniCapTM system) or control group in this prospective nonrandomized controlled study. The assessment of alopecia was carried out using the World Health Organization grading system and clinical photographs. RESULTS: Seventy patients were recruited, but only 25 completed the study and were evaluable for analysis. Five of 12 patients (42%) in the scalp cooling group managed to preserve hair. Two of three patients who received FE75C and TC regimens had minimal hair loss. All patients treated with FE100C had severe hair loss. Half of all patients who received scalp cooling throughout chemotherapy rated the treatment as reasonably well tolerated. The most common reason for discontinuing scalp cooling was intolerance to its side effects. CONCLUSION: Scalp cooling is potentially effective in reducing CIA caused by docetaxel, TC, and FE75C chemotherapy regimen. However, it was not well tolerated by our study population. The dropout rate was high, and this needs to be taken into consideration when pursuing further trials in a similar setting.

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 Student's 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/ß value of 10 Gy for target, 3 Gy for organs at risk). RESULTS: The total prescribed dose was 77.5 Gy α/ß10. 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/ß3 for D 2cc, 61.71 ± 2.77 Gy α/ß3 at D ICRU and 69.24 ± 6.02 Gy α/ß3 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/ß3 for D 2cc and 74.11 ± 19.39 Gy α/ß3 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.