Marniza Saad

Risk of Treatment Related Death and Febrile Neutropaenia with Taxane-Based Adjuvant Chemotherapy for Breast Cancer in a Middle Income Country Outside a Clinical Trial Setting

BACKGROUND The risk of treatment-related death (TRD) and febrile neutropaenia (FN) with adjuvant taxane- based chemotherapy for early breast cancer is unknown in Malaysia despite its widespread usage in recent years. This study aims to determine these rates in patients treated in University Malaya Medical Centre (UMMC). PATIENTS AND METHODS Patients who were treated with adjuvant taxane-based chemotherapy for early breast cancer stages I, II or III from 2007-2011 in UMMC were identified from our UMMC Breast Cancer Registry. The TRD and FN rates were then determined retrospectively from medical records. TRD was defined as death occurring during or within 30 days of completing chemotherapy as a consequence of the chemotherapy treatment. FN was defined as an oral temperature >38.5°C or two consecutive readings of >38.0°C for 2 hours and an absolute neutrophil count <0.5x109/L, or expected to fall below 0.5x109/L. RESULTS A total of 622 patients received adjuvant chemotherapy during this period. Of these patients 209 (33.6%) received taxane-based chemotherapy. 4 taxane-based regimens were used namely the FEC-D, TC, TAC and AC-PCX regimens. The commonest regimen employed was the FEC-D regimen accounting for 79.9% of the patients. The FN rate was 10% and there was no TRD. CONCLUSION Adjuvant taxane-based chemotherapy in UMMC for early breast cancer has a FN rate of 10%. Primary prophylactic G-CSF should be considered for patients with any additional risk factor for FN.

Which is the best method of sterilization for recycled bone autograft in limb salvage surgery: a radiological, biomechanical and histopathological study in rabbit.

BackgroundLimb salvage surgery is a treatment of choice for sarcomas of the extremities. One of the options in skeletal reconstruction after tumour resection is by using a recycled bone autograft. The present accepted methods of recycling bone autografts include autoclaving, pasteurization and irradiation. At the moment there is lack of studies that compare the effectiveness of various sterilization methods used for recycling bone autografts and their effects in terms of bone incorporation. This study was performed to determine the effects of different methods of sterilization on bone autografts in rabbit by radiological, biomechanical and histopathological evaluations.MethodsFresh rabbit cortical bone is harvested from the tibial diaphysis and sterilized extracorporeally by pasteurization (n = 6), autoclaving (n = 6), irradiation (n = 6) and normal saline as control group (n = 6). The cortical bones were immediately reimplanted after the sterilization process. The subsequent process of graft incorporation was examined over a period of 12 weeks by serial radiographs, biomechanical and histopathological evaluations. Statistical analysis (ANOVA) was performed on these results. Significance level (α) and power (β) were set to 0.05 and 0.90, respectively.ResultsRadiographic analysis showed that irradiation group has higher score in bony union compared to other sterilization groups (p = 0.041). ANOVA analysis of ‘failure stress’, ‘modulus’ and ‘strain to failure’ demonstrated no significant differences (p = 0.389) between treated and untreated specimens under mechanical loading. In macroscopic histopathological analysis, the irradiated group has the highest percentage of bony union (91.7 percent). However in microscopic analysis of union, the pasteurization group has significantly higher score (p = 0.041) in callus formation, osteocytes percentage and bone marrow cellularity at the end of the study indicating good union potential.ConclusionsThis experimental study shown that both irradiation and pasteurization techniques have more favourable outcome in terms of bony union based on radiographic and histopathological evaluations. Autoclaving has the worst outcome. These results indicate that extracorporeal irradiation or pasteurization of bone autografts, are viable option for recycling bone autografts. However, pasteurization has the best overall outcomes because of its osteocytes preservation and bone marrow cellularity.

Prognostic Factors in Patients with Non-small Cell Lung Carcinoma and Brain Metastases: a Malaysian Perspective

BACKGROUND Brain metastases occur in about 20-40% of patients with non-small-cell lung carcinoma (NSCLC), and are usually associated with a poor outcome. Whole brain radiotherapy (WBRT) is widely used but increasingly, more aggressive local treatments such as surgery or stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT) are being employed. In our study we aimed to describe the various factors affecting outcomes in NSCLC patients receiving local therapy for brain metastases. MATERIALS AND METHODS The case records of 125 patients with NSCLC and brain metastases consecutively treated with radiotherapy at two tertiary centres from January 2006 to June 2012 were analysed for patient, tumour and treatment-related prognostic factors. Patients receiving SRS/SRT were treated using Cyberknife. Variables were examined in univariate and multivariate testing. RESULTS Overall median survival was 3.4 months (95%CI: 1.7-5.1). Median survival for patients with multiple metastases receiving WBRT was 1.5 months, 1-3 metastases receiving WBRT was 3.6 months and 1-3 metastases receiving surgery or SRS/SRT was 8.9 months. ECOG score (≤2 vs >2, p=0.001), presence of seizure (yes versus no, p=0.031), treatment modality according to number of brain metastases (1-3 metastases+surgery or SRS/SRT±WBRT vs 1-3 metastases+WBRT only vs multiple metastases+WBRT only, p=0.007) and the use of post-therapy systemic treatment (yes versus no, p=0.001) emerged as significant on univariate analysis. All four factors remained statistically significant on multivariate analysis. CONCLUSIONS ECOG ≤2, presence of seizures, oligometastatic disease treated with aggressive local therapy (surgery or SRS/SRT) and the use of post-therapy systemic treatment are favourable prognostic factors in NSCLC patients with brain metastases.

Risk of treatment related death (TRD) with adjuvant chemotherapy for breast cancer: A study in University Malaya Medical Centre (UMMC)

Background: The risk of TRD with adjuvant chemotherapy for early breast cancer is unknown in Malaysia despite its widespread usage. This study aims to determine this rate in a large cohort of patients treated in UMMC. Patients & Methods: Patients who were treated with neoadjuvant or adjuvant chemotherapy for early breast cancer stages I, II or III from 2000-2007 in UMMC were identified from our UMMC Breast Cancer Registry. The TRD rate and 5 years overall survival (OS) were determined. TRD is defined as death occurring during or within 30 days of completing chemotherapy as a consequence of the chemotherapy treatment. OS was defined as death from any cause from the date of diagnosis to the date of death. OS was determined using the Kaplan-Meier method and differences between AJCC stages were compared by log-rank test. Results: A total of 1317 were identified for analysis. The median age at diagnosis was 49 years with a range of 24 to 74 years. The rate of TRD was 0.1%. The 5 years OS rate was 77.3% with a median follow up of 62 months. The 5 years OS according to AJCC stage were 90.7% for stage I, 83.9% for stage II and 62.2% for stage III disease. The commonest chemotherapy regimen used was the FEC (5-Fluorouracil, Epirubicin, Cyclophosphamide) regimen accounting for approximately 90% of the cases. Conclusion: Adjuvant chemotherapy for early breast cancer with the FEC regimen is safe with a TRD rate of 0.1% in our centre. Background The role of chemotherapy in cancer treatment is highly misunderstood not just in the public domain but also amongst medical practitioners. The fact that chemotherapy only plays a minor role as a definitive modality of cancer treatment is not well understood and it is mainly limited to haematological malignancies and germ cell tumours. Chemotherapys role in the treatment of solid tumours is mainly confined to neoadjuvant, adjuvant and palliative settings. As such, it is of utmost importance to be cognizant to the rate of TRDs with chemotherapy other than being aware of its potential benefits when used in these settings. Informing patients that this risk is negligible or less than one percent which is the figure often quoted by clinicians may be inadequate as this gives the impression that it is extremely rare. Moreover less than 1% can mean anywhere between 1 in 1001, 1 in 10000, 1 in 100000, 1 in 1000000 and so forth. Patients deserve to fully understand the real risk of TRDs and equally important is the need for clinicians to realize that TRDs are much commoner than perceived. There are various definitions of TRD used in the literature. For the purpose of this study the TRD was defined as deaths that occurred less than or equal to 30 days after the last cycle of chemotherapy, death of which was due to the chemotherapy itself. This definition was chosen as it was commonly used in many reported phase 3 trials and it is the least ambiguous amongst all definitions encountered in the literature. One major drawback is the fact that it does not take into account deaths that may be related to the long term side effects of chemotherapy for example deaths due to cardiac events which is especially relevant for anthracycline drugs commonly used for breast cancer treatment. Having said that, it is very difficult to prove that these deaths are directly due to the effect of chemotherapy alone as there are frequently many other confounding factors. Breast cancer is the commonest cancer treated with adjuvant chemotherapy in Malaysia. A commonly used regimen is the FAC regime (5 Fluorouracil, Adriamycin, Cyclophosphamide). In a trial involving 1491 patients in node positive breast cancer patients post definitive surgery, 745 patients received adjuvant TAC (Docetaxel, Adriamycin, Cyclophosphamide) and 746 patients received FAC. The TRDs for the TAC group and FAC group was similar at 0.3%. (1). The commonest regime used in our center is the FEC regime (5 Fluorouracil, Epirubicin, Cyclophosphamide). A pivotal phase 3 study, PACS 01 trial compared the FEC regime for 6 cycles with the FEC-D regime (FEC3-Docetaxel3) involving 996 patients in the FEC arm and 1003 patients in the FEC-D arm. Although significant high rates of febrile neutropaenia at 8.4% and 11.2% were reported in the FEC and FEC-D arms respectively, there were no early TRDs. However, there was one delayed cardiac death in each

Monte Carlo skin dose simulation in intraoperative radiotherapy of breast cancer using spherical applicators

The relatively new treatment modality electronic intraoperative radiotherapy (IORT) is gaining popularity, irradiation being obtained within a surgically produced cavity being delivered via a low-energy x-ray source and spherical applicators, primarily for early stage breast cancer. Due to the spatially dramatic dose-rate fall off with radial distance from the source and effects related to changes in the beam quality of the low keV photon spectra, dosimetric account of the Intrabeam system is rather complex. Skin dose monitoring in IORT is important due to the high dose prescription per treatment fraction. In this study, modeling of the x-ray source and related applicators were performed using the Monte Carlo N-Particle transport code. The dosimetric characteristics of the model were validated against measured data obtained using an ionization chamber and EBT3 film as dosimeters. By using a simulated breast phantom, absorbed doses to the skin for different combinations of applicator size (1.5-5 cm) and treatment depth (0.5-3 cm) were calculated. Simulation results showed overdosing of the skin (>30% of prescribed dose) at a treatment depth of 0.5 cm using applicator sizes larger than 1.5 cm. Skin doses were significantly increased with applicator size, insofar as delivering 12 Gy (60% of the prescribed dose) to skin for the largest sized applicator (5 cm diameter) and treatment depth of 0.5 cm. It is concluded that the recommended 0.5-1 cm distance between the skin and applicator surface does not guarantee skin safety and skin dose is generally more significant in cases with the larger applicators. HIGHLIGHTS • Intrabeam x-ray source and spherical applicators were simulated and skin dose was calculated. • Skin dose for constant skin to applicator distance strongly depends on applicator size. • Use of larger applicators generally results in higher skin dose. • The recommended 0.5-1 cm skin to applicator distance does not guarantee skin safety.

Efficacy, safety, and prognostic indicators of first-line sunitinib in patients with metastatic renal cell carcinoma: A single center experience

Background: We assessed the efficacy and safety of sunitinib as the first-line treatment in metastatic renal cell carcinoma (mRCC) patients. The predictors of survival and efficacy in mRCC as identified from previous studies, including the Memorial Sloan Kettering Cancer Center (MSKCC) and the International Metastatic RCC Database Consortium (IMDC) factors, were also evaluated. Patients and Methods: Data from 56 patients with mRCC, treated with sunitinib at our institute (2006–2014), were analyzed retrospectively. Prognostic factors for overall survival (OS) and progression-free survival (PFS) were evaluated using univariate and multivariate analyses performed by log-rank test and Cox regression. Results: Fifty-one (91.1%) patients received starting dose of sunitinib of 50 mg/day in 4/2 schedule. The median PFS was 12.7 months (95% confidence interval [CI], 4.5–20.9 months) and the median OS was 16.9 months (95% CI, 3.8–29.9 months). The objective response rate was 27.5%. Dose interruption and reduction due to toxicities were required in 37.5% and 60.7% of patients, respectively. The most common Grades 3–4 toxicities were hand-foot syndrome (HFS) (23.2%), thrombocytopenia (16.1%), and hypertension (14.3%). The Eastern Cooperative Oncology Group performance status ≥2, hemoglobin < lower limit of normal, neutrophil > upper limit of normal (ULN), platelet > ULN, no prior nephrectomy, metastatic sites >:1, liver metastases, lymph node metastases, and development of HFS were independent prognostic factors. Conclusions: Sunitinib treatment has acceptable efficacy and safety profile in Malaysian mRCC patients. The MSKCC and IMDC factors are relevant for predicting survival in our patient cohort while HFS is a promising prognostic predictor which warrants further investigation.

Management of patients with advanced prostate cancer in the Asia Pacific region: ‘real-world’ consideration of results from the Advanced Prostate Cancer Consensus Conference (APCCC) 2017

The Asia Pacific Advanced Prostate Cancer Consensus Conference (APAC APCCC 2018) brought together 20 experts from 15 APAC countries to discuss the real‐world application of consensus statements from the second APCCC held in St Gallen in 2017 (APCCC 2017).

Single vs multiple fraction palliative radiotherapy for uncomplicated painful bone metastases treated at University of Malaya Medical Centre: A single institutional Malaysian experience

This study was conducted to compare pain response between single and multiple fraction palliative radiotherapy and to describe prognostic factors affecting treatment response in University of Malaya Medical Centre (UMMC).

Impact of adjuvant chemotherapy on survival of women with T1N0M0, hormone receptor negative breast cancer

BACKGROUND The benefit of adjuvant chemotherapy in women with T1N0M0 breast cancers is unclear. While gene expression-based prognostic assays may aid management of women with early estrogen receptor (ER) positive tumors, therapeutic decision-making in women with early stage ER negative tumors remains fraught with difficulties. We investigated the association between adjuvant chemotherapy and overall survival in women with T1N0M0, hormone receptor negative breast cancers. METHOD All newly diagnosed breast cancer patients with node-negative and hormone receptor negative tumors measuring≤2cm at the University Malaya Medical Centre (Malaysia) from 1993 to 2013 were included. Mortality of patients with and without adjuvant chemotherapy were compared and adjusted for possible confounders using propensity score. RESULTS Of 6732 breast cancer patients, 341 (5.1%) had small (≤2cm), node-negative and hormone receptor negative tumors at diagnosis. Among them, only 214 (62.8%) received adjuvant chemotherapy. Five-year overall survival was 88.1% (95% confidence interval (CI): 82.0%-94.2%) for patients receiving chemotherapy and 89.6% (95% CI: 85.1%-94.1%) for patients without chemotherapy. Chemotherapy was not associated with survival following adjustment for age, ethnicity, tumor size, tumor grade, HER2 status, lympho-vascular invasion, type of surgery and radiotherapy administration. However, chemotherapy was associated with a significant survival advantage (adjusted hazard ratio: 0.35, 95%CI: 0.14-0.91) in a subgroup of women with high-grade tumors. CONCLUSION Adjuvant chemotherapy does not appear to be associated with a survival benefit in women with T1N0M0, hormone receptor negative breast cancer except in those with high-grade tumors.

Efficacy and safety of pazopanib in advanced renal cell carcinoma treated at University Malaya Medical Centre (UMMC)

Background: Pazopanib is a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) that was approved as first line treatment for advanced renal cell carcinoma (aRCC). The pivotal trial showed significant increase in median progression free survival (mPFS) of 9.2 months versus 4.0 months with placebo and objective response rate of 30%. Median overall survival (mOS) was 28.4 months with pazopanib. Local data on efficacy and safety of pazopanib is lacking. This study reviewed the efficacy and safety of pazopanib in aRCC in University Malaya Medical Centre (UMMC). Methods: We retrospectively reviewed outcome of patients with advanced renal cell carcinoma who received pazopanib from January 2012 to March 2017. Analysis was done in July 2017. Results: Twenty-one patients were enrolled – 16 (76.2%) were males and five (23.8%) were females. The mean age at diagnosis was 61.9 years old. Majority of the patients were of Chinese ethnicity, ( n = 13, 61.9%). Fourteen patients (67%) were diagnosed as metastatic disease at presentation and all had cytoreductive nephrectomy. Eighteen patients (86%) had clear cell histology. The most common metastatic site was lung (66.7%) followed by bone and liver. Except for one, all patients were treated with pazopanib in the first line setting. Majority of the patients (76.2%) was started on pazopanib within a year after diagnosis. Fourteen patients (66%) were started on 800 mg daily as the initial dose. From the analysis, the best tumour response is partial response ( n = 8, 38%) followed stable disease ( n = 4, 19%). Six patients (28.6%) had progressive disease while three other patients were not assessable. The mPFS was 9 months (95% CI: 7.2 – 10.8) and mOS was 24 months. For toxicity analysis, only 17 patients had side-effects documented in our database. The most common side effects were hypertension (19%) and hand-foot syndrome (19%) followed by diarrheoa (14.3%). Conclusions: In general, pazopanib is well tolerated and demonstrated good PFS and OS in our study population, comparable to previous studies and real-world data.