Dose Planning Study of Target Volume Coverage with Intensity-Modulated Radiotherapy for Nasopharyngeal Carcinoma: Penang General Hospital Experience

Vincent Phua, Chee Ee,Tan, Boon Seang,Tan, Ai Lian,Eng, Kae Yann,Ng, Bong Seng,Ung, Ngie Min Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.4

Background: To compare the dosimetric coverage of target volumes and organs at risk in the radical treatment of nasopharyngeal carcinoma (NPC) between intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3DCRT). Materials and Methods: Data from 10 consecutive patients treated with IMRT from June-October 2011 in Penang General Hospital were collected retrospectively for analysis. For each patient, dose volume histograms were generated for both the IMRT and 3DCRT plans using a total dose of 70Gy. Comparison of the plans was accomplished by comparing the target volume coverage (5 measures) and sparing of organs at risk (17 organs) for each patient using both IMRT and 3DCRT. The means of each comparison target volume coverage measures and organs at risk measures were obtained and tested for statistical significance using the paired Student t-test. Results: All 5 measures for target volume coverage showed marked dosimetric superiority of IMRT over 3DCRT. V70 and V66.5 for PTV70 showed an absolute improvement of 39.3% and 24.1% respectively. V59.4 and V56.4 for PTV59.4 showed advantages of 18.4% and 16.4%. Moreover, the mean PTV70 dose revealed a 5.1 Gy higher dose with IMRT. Only 4 out of 17 organs at risk showed statistically significant difference in their means which were clinically meaningful between the IMRT and 3DCRT techniques. IMRT was superior in sparing the spinal cord (less 5.8Gy), V30 of right parotid (less 14.3%) and V30 of the left parotid (less 13.1%). The V55 of the left cochlea was lower with 3DCRT (less 44.3%). Conclusions: IMRT is superior to 3DCRT due to its dosimetric advantage in target volume coverage while delivering acceptable doses to organs at risk. A total dose of 70Gy with IMRT should be considered as a standard of care for radical treatment of NPC.

Capecitabine Pattern of Usage, Rate of Febrile Neutropaenia and Treatment Related Death in Asian Cancer Patients in Clinical Practice

Phua, Vincent Chee Ee,Wong, Wei Quan,Tan, Pei Lin,Bustam, Anita Zarina,Saad, Marniza,Alip, Adlinda,Ishak, Wan Zamaniah Wan Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.4

Background: Oral capecitabine is increasingly replacing intravenous 5-fluorouracil in many chemotherapy regimens. However, data on the risk of febrile neutropaenia (FN) and treatment related death (TRD) with the drug remain sparse outside of clinical trial settings despite its widespread usage. This study aimed to determine these rates in a large cohort of patients treated in the University of Malaya Medical Centre (UMMC). Materials and Methods: We reviewed the clinical notes of all patients prescribed with oral capecitabine chemotherapy for any tumour sites in University Malaya Medical Centre (UMMC) from $1^{st}$ January 2009 till $31^{st}$ June 2010. Information collected included patient demographics, histopathological features, treatment received including the different chemotherapy regimens and intent of treatment whether the chemotherapy was given for neoadjuvant, concurrent with radiation, adjuvant or palliative intent. The aim of this study is to establish the pattern of usage, FN and TRD rates with capecitabine in clinical practice outside of clinical trial setting. FN is defined as an oral temperature > $38.5^{\circ}C$ or two consecutive readings of > $38.0^{\circ}C$ for 2 hours and an absolute neutrophil count < $0.5{\times}10^9/L$, or expected to fall below $0.5{\times}10^9/L$ (de Naurois et al., 2010). Treatment related death was defined as death occurring during or within 30 days of last chemotherapy treatment. Results: Between $1^{st}$ January 2009 and $30^{th}$ June 2010, 274 patients were treated with capecitabine chemotherapy in UMMC. The mean age was 58 years (range 22 to 82 years). Capecitabine was used in 14 different tumour sites with the colorectal site predominating with a total of 128 cases (46.7%), followed by breast cancer (35.8%). Capecitabine was most commonly used in the palliative setting accounting for 63.9% of the cases, followed by the adjuvant setting (19.7%). The most common regimen was single agent capecitabine with 129 cases (47.1%). The other common regimens were XELOX (21.5%) and ECX (10.2%). The main result of this study showed an overall FN rate of 2.2% (6/274). The overall TRD rate was 5.1% (14/274). The FN rate for the single agent capecitabine regimen was 1.6% (2/129) and the TRD rate was 5.4% (7/129). All the TRDs were with single agent capecitabine regimen were used for palliative intent. Conclusions: Oral capecitabine is used widely in clinical practice in a myriad of tumour sites and bears a low risk of febrile neutropaenia. However, capecitabine like any other intravenous chemotherapeutic agent carries a significant risk of treatment related death.

Treatment Outcome for Nasopharyngeal Carcinoma in University Malaya Medical Centre from 2004-2008

Ee Phua, Vincent Chee,Loo, Wei Hoong,Yusof, Mastura Md,Ishak, Wan Zamaniah Wan,Tho, Lye Mun,Ung, Ngie Min Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.8

Background: Nasopharyngeal carcinoma (NPC) is the commonest radiocurable cancer in Malaysia. This study aimed to determine the treatment outcomes and late effects of radiotherapy for NPC patients treated in University Malaya Medical Centre (UMMC). Materials and Methods: All newly diagnosed patients with NPC referred for treatment to the Oncology unit at UMMC from 2004-2008 were retrospectively analyzed. Treatment outcomes were 5 years overall survival (OS), disease free survival (DFS), cause-specific survival (CSS), locoregional control (LRC) and radiotherapy-related late effects. The Kaplan-Meier method was used for survival analysis and differences in survival according to AJCC stage was compared using the log-rank test. Results: A total of 176 patients with newly diagnosed NPC were treated in UMMC during this period. Late presentation was common, with 33.5% presenting with T3-4 disease, 84.7% with N1-3 disease and 75.6% with AJCC stage 3-4 disease. Radical RT was given to 162 patients with 22.7% having RT alone and 69.3% having CCRT. The stipulated OTT was 7 weeks and 72.2% managed to complete their RT within this time period. Neoadjuvant chemotherapy was given to 14.8% while adjuvant chemotherapy was administered to 16.5%. The 5 years OS was 51.6% with a median follow up of 58 months. The 5 years OS according to stage were 81.8% for stage I, 77.9% for stage II, 47.4% for stage III and 25.9% for stage IV. The 5 years overall CSS, DFS and LRC were 54.4%, 48.4% and 70.6%, respectively. RT related late effects were documented in 80.2%. The commonest was xerostomia (66.7%). Other documented late effects were hearing deficit (17.3%), visual deficit (3.1%), neck stiffness (3.1%), dysphagia (3.4%), cranial nerve palsy (2.5%), pneumonitis (0.6%) and hypothyroidism (1.2%). Conclusions: The 5 years OS and LRC in this study are low compared to the latest studies especially those utilizing IMRT. Implementation of IMRT for NPC treatment should be strongly encouraged.

Carboplatin/5-fluorouracil as an Alternative to Cisplatin/5-Fluorouracil for Metastatic and Recurrent Head and Neck Squamous Cell Carcinoma and Nasopharyngeal Carcinoma

Kua, Voon Fong,Ismail, Fuad,Phua, Vincent Chee Ee,Aslan, Nik Muhd Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.2

Background: Palliative chemotherapy with cisplatin/5-fluorouracil (5FU) is the commonest regimen employed for metastatic and recurrent head and neck squamous cell carcinoma (SCCHN) and nasopharyngeal carcinoma (NPC). However, this regimen is cumbersome requiring 5 days of admission to hospital. Carboplatin/5FU may be an alternative regimen without compromising survival and response rates. This study aimed to compare the efficacy and toxicity of carboplatin/5FU regimen with the cisplatin/5FU regimen. Materials and Methods: This retrospective study looked at patients who had palliative chemotherapy with either cisplatin/5FU or carboplatin/5FU for metastatic and recurrent SCCHN and NPC. It included patients who were treated at UKMMC from $1^{st}$ January 2004 to $31^{st}$ December 2009 with either palliative IV cispaltin 75 $mg/m^2$ D1 only plus IV 5FU 750 $mg/m^2$ D1-5 infusion or IV Carboplatin AUC 5 D1 only plus IV 5FU 500 $mg/m^2$ D1-2 infusion plus IV 5FU 500 $mg/m^2$ D1-2 bolus. The specific objectives were to determine the efficacy of palliative chemotherapy in terms of overall response rate (ORR), median progression free survival (PFS) and median overall survival (OS) and to evaluate the toxicities of both regimens. Results: A total of 41 patients were eligible for this study. There were 17 in the cisplatin/5FU arm and 24 in the carboplatin/5FU arm. The ORR was 17.7 % for cisplatin/5FU arm and 37.5 % for carboplatin/5FU arm (p-value=0.304). The median PFS was 7 months for cisplatin/5FU and 9 months for carboplatin/5FU (p-value=1.015). The median OS was 10 months for cisplatin/5FU arm and 12 months for carboplatin/5FU arm (p-value=0.110). There were 6 treatment-related deaths (6/41=14.6%), four in the carboplatin/5FU arm (4/24=16.7%) and 2 in the cisplatin/5FU arm (2/17=11.8%). Grade 3 and 4 hematologic toxicity was also more common with carboplatin/5FU group, this difference being predominantly due to grade 3-4 granulocytopenia (41.6% vs. 0), grade 3-4 anemia (37.5% vs. 0) and grade 3-4 thrombocytopenia (16.6% vs. 0). Conclusions: Carboplatin/5FU is not inferior to cisplatin/5FU with regard to its efficacy. However, there was a high rate of treatment-related deaths with both regimens. A better alternative needs to be considered.

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

Tang, Weng Heng,Alip, Adlinda,Saad, Marniza,Phua, Vincent Chee Ee,Chandran, Hari,Tan, Yi Hang,Tan, Yan Yin,Kua, Voon Fong,Wahid, Mohamed Ibrahim,Tho, Lye Mun Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.5

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 (${\leq}2$ 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 $SRS/SRT{\pm}WBRT$ 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 ${\leq}2$, 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.

Treatment Outcome for Head and Neck Squamous Cell Carcinoma in a Developing Country: University Malaya Medical Centre, Malaysia from 2003-2010

Wong, Yoke Fui,Yusof, Mastura Md,Ishak, Wan Zamaniah Wan,Alip, Adlinda,Phua, Vincent Chee Ee Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.7

Background: Head and neck cancer (HNC) is the eighth most common cancer as estimated from worldwide data. The incidence of HNC in Peninsular Malaysia was reported as 8.5 per 100,000 population. This study was aimed to determine the treatment outcomes for HNC patients treated in the Oncology Unit of University Malaya Medical Centre (UMMC). Materials and Methods: All newly diagnosed patients with squamous cell carcinoma of head and neck (HNSCC) referred for treatment to the Oncology Unit at UMMC from 2003-2010 were retrospectively analyzed. Treatment outcomes were 5-year overall survival (OS), cause specific survival (CSS), loco-regional control (LRC) and radiotherapy (RT) related side effects. Kaplan-Meier and log rank analyses were used to determine survival outcomes, stratified according to American Joint Committee on Cancer (AJCC) stage. Results: A total of 130 cases were analysed. Most cases (81.5%) were at late stage (AJCC III-IVB) at presentation. The 5-year OS for the whole study population was 34.4% with a median follow up of 24 months. The 5-year OS according to AJCC stage was 100%, 48.2%, 41.4% and 22.0% for stage I, II, III and IVA-B, respectively. The 5-year overall CSS and LCR were 45.4% and 55.4%, respectively. Late effects of RT were documented in 41.4% of patients. The most common late effect was xerostomia. Conclusions: The treatment outcome of HNSCC at our centre is lagging behind those of developed nations. Efforts to increase the number of patients presenting in earlier stages, increase in the use of combined modality treatment, especially concurrent chemoradiotherapy and implementation of intensity modulated radiotherapy, may lead to better outcomes for our HNC patients.

Preoperative Long Course Chemoirradiation in a Developing Country for Rectal Carcinoma: Kuala Lumpur Hospital Experience

Lee, Wei Ching,Yusof, Mastura Md.,Lau, Fen Nee,Ee Phua, Vincent Chee Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.6

Background: The use of preoperative chemoirradiation is the commonest treatment strategy employed in Malaysia for locally advanced rectal cancer. We need to determine the local control and survival rates for comparison with established rates in the literature. Materials and Methods: This retrospective study analyzed all newly diagnosed patients with rectal adenocarcinoma who underwent long course preoperative radiotherapy (RT) at the Department of Radiotherapy and Oncology, Kuala Lumpur Hospital (HKL) between $1^{st}$ January 2004 and $31^{st}$ December 2010. The aim of the study was to determine the radiological response post radiotherapy, pathological response including circumferential resection margin (CRM) status, 3 years local control, 3 years overall survival (OS) and 3 years disease free survival (DFS). Statistical analysis was performed using the SPSS software. Kaplan-Meier and log rank analysis were used to determine survival outcomes. Results: A total of 507 patients with rectal cancer underwent RT at HKL. Sixty seven who underwent long course preoperative RT were eligible for this study. The median age at diagnosis was 60 years old with a range of 26-78 years. The median tumour location was 6 cm from the anal verge. Most patients had suspicion of mesorectum involvement (95.5%) while 28.4% of patients had enlarged pelvic nodes on staging CT scan. All patients underwent preoperative chemo-irradiation except for five who had preoperative RT alone. Only 38 patients underwent definitive surgery (56.7%). Five patients were deemed to be inoperable radiologically and 3 patients were found to have unresectable disease intraoperatively. The remaining 21 patients defaulted surgery (31.3%). The median time from completion of RT to surgery was 8 weeks (range 5.6 to 29.4 weeks). Fifteen patients (39.5%) had surgery more than 8 weeks after completion of RT. Complete pathological response was noted in 4 patients (10.5%). The pathological CRM positive rate after RT was 18.4%. With a median follow-up of 38.8 months, the 3 year local control rate was 67%. The 3 years rate for CRM positive (<2 mm), CRM clear (>2 mm) and pCR groups were 0%, 88.1% and 100% respectively (p-value of 0.007). The 3 year OS and DFS were 57.3% and 44.8% respectively. Conclusions: In conclusion, the approach of long course preoperative chemoirradiation for rectal cancer needs to be re-examined in our local setting. The high rate of local recurrence is worrying and is mainly due to patient defaulting post-preoperative chemoirradiation or delayed definitive surgery.

Treatment Outcome with Brachytherapy for Recurrent Nasopharyngeal Carcinoma

Cheah, Soon Keat,Lau, Fen Nee,Yusof, Mastura Md,Phua, Vincent Chee Ee Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.11

Background: To evaluate the treatment outcome and major late complications of all patients with recurrent nasopharyngeal carcinoma (NPC) treated with intracavitary brachytherapy (ICBT) in Hospital Kuala Lumpur. Materials and Methods: This retrospective study was conducted at the Department of Radiotherapy and Oncology, Hospital Kuala Lumpur, Malaysia. All patients with histologically confirmed recurrent NPC in the absence of distant metastasis treated in the period 1997-2010 were included in this study. These patients were treated with ICBT alone or in combination with external beam radiotherapy (EBRT). Treatment outcomes measured were local recurrence free survival (LRFS), disease free survival (DFS) and overall survival (OS). Results: Thirty three patients were eligible for this study. The median age at recurrence was 56 years with a median time to initial local recurrence of 27 months. Majority of patients were staged as rT1-2 (94%) or rN0 (82%). The proportion of patients categorised as stage III-IV at first local recurrence was only 9%. Twenty one patients received a combination of ICBT and external beam radiotherapy while 12 patients were treated with ICBT alone. Median interval of recurrence post re-irradiation was 32 months (range: 4-110 months). The median LRFS, DFS and OS were 30 months, 29 months and 36 months respectively. The 5 year LRFS, DFS and OS were 44.7%, 38.8% and 28.1% respectively. The N stage at recurrence was found to be a significant prognostic factor for LRFS and DFS after multivariate analysis. Major late complications occurred in 34.9% of our patients. Conclusions: Our study shows ICBT was associated with a reasonable long term outcome in salvaging recurrent NPC although major complications remained a significant problem. The N stage at recurrence was a significant prognostic factor for both LRFS and DFS.

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

Hashim, Natasha,Jamalludin, Zulaikha,Ung, Ngie Min,Ho, Gwo Fuang,Malik, Rozita Abdul,Ee Phua, Vincent Chee Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.13

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 48.6Gy 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 ($D_{Max}$) to rectum was the highest recorded dose at one of these five points. Using the HDRplus 2.6 brachyhtherapy 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 ($D_{2cc}$) for all individual fractions. The mean $D_{2cc}$ of rectum was compared to the means of ICRU rectal point and rectal $D_{Max}$ using the Student's t-test. The mean $D_{2cc}$ 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. (${\alpha}/{\beta}$ value of 10 Gy for target, 3 Gy for organs at risk). Results: The total prescribed dose was $77.5Gy{\alpha}/{\beta}10$. The mean dose to the rectum was $4.58{\pm}1.22Gy$ for $D_{2cc}$, $3.76{\pm}0.65Gy$ at $D_{ICRU}$ and $4.75{\pm}1.01Gy$ at $D_{Max}$. 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 (0.48-1.19Gy). The mean EQD2 was $68.52{\pm}7.24Gy_{{\alpha}/{\beta}3}$ for $D_{2cc}$, $61.71{\pm}2.77Gy_{{\alpha}/{\beta}3}$ at $D_{ICRU}$ and $69.24{\pm}6.02Gy_{{\alpha}/{\beta}3}$ at $D_{Max}$. The mean ratio of $D_{2cc}$ rectum to $D_{ICRU}$ rectum was 1.25 and the mean ratio of $D_{2cc}$ rectum to $D_{Max}$ rectum was 0.98 for all individual fractions. The mean dose to the bladder was $6.00{\pm}1.90Gy$ for $D_{2cc}$ and $5.10{\pm}2.03Gy$ 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 (0.49-1.25Gy). The mean EQD2 was $81.85{\pm}13.03Gy_{{\alpha}/{\beta}3}$ for $D_{2cc}$ and $74.11{\pm}19.39Gy_{{\alpha}/{\beta}3}$ 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 $D_{Max}$ for $D_{2cc}$. However, the dose to the ICRU rectal point does not appear to be a reasonable surrogate for the $D_{2cc}$.