Michael C.H. Lee

Clinical Outcomes and Patterns of Failure After Intensity-Modulated Radiotherapy for Nasopharyngeal Carcinoma

PURPOSE To study and report the clinical outcomes and patterns of failure after intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS The treatment outcomes of NPC patients treated with IMRT at Pamela Youde Nethersole Eastern Hospital between 2005 and 2007 were reviewed. The location and extent of locoregional failures were transferred to the pretreatment planning computed tomography for dosimetry analysis. Statistical analyses were performed on dose coverage and locoregional failures. RESULTS A total of 193 NPC patients were analyzed; 93% had Stage III/IV disease. Median follow-up was 30 months. Overall disease failure (at any site) developed in 35 patients. Among these, there were 23 distant metastases, 16 local failures, and 9 regional failures. Four of the locoregional failures were marginal. Dose conformity with IMRT was excellent. Patients with at least 66.5 Gy to their target volumes had significantly less locoregional failure. The 2-year local progression-free, regional progression-free, distant metastasis-free, and overall survival rates were 95%, 96%, 90%, and 92%, respectively. CONCLUSIONS Intensity-modulated radiotherapy provides excellent locoregional control for NPC. Distant metastasis remains the most difficult challenge, and more effective systemic agents should be explored for patients presenting with advanced locoregional diseases.

MAJOR LATE TOXICITIES AFTER CONFORMAL RADIOTHERAPY FOR NASOPHARYNGEAL CARCINOMA-PATIENT-AND TREATMENT-RELATED RISK FACTORS

PURPOSE To retrospectively analyze the factors affecting late toxicity for nasopharyngeal carcinoma. METHODS AND MATERIALS Between 1998 and 2003, 422 patients were treated with a conformal technique with 2-Gy daily fractions to a total dose of 70 Gy. Conventional fractionation (5 fractions weekly) was used in 232 patients and accelerated fractionation (6 fractions weekly) in 190 patients. One hundred seventy-one patients were treated with the basic radiotherapy course alone (Group 1), 55 patients had an additional boost of 5 Gy in 2 fractions (Group 2), and 196 patients underwent concurrent cisplatin-based chemotherapy (Group 3). RESULTS The 5-year overall toxicity rate was significantly greater in Group 3 than in Group 1 (37% vs. 27%, p = 0.009). Although the overall rate in Group 2 was not elevated (28% vs. 27%, p = 0.697), a significant increase in temporal lobe necrosis was observed (4.8% vs. 0%, p = 0.015). Multivariate analyses showed that age and concurrent chemotherapy were significant factors. The hazard ratio of overall toxicity attributed to chemotherapy was 1.99 (95% confidence interval, 1.32-2.99, p = 0.001). The mean radiation dose to the cochlea was another significant factor affecting deafness, with a hazard ratio of 1.03 (95% confidence interval, 1.01-1.05, p = 0.005) per 1-Gy increase. The cochlea that received >50 Gy had a significantly greater deaf rate (Group 1, 18% vs. 7%; and Group 3, 22% vs. 14%). CONCLUSION The therapeutic margin for nasopharyngeal carcinoma is extremely narrow, and a significant increase in brain necrosis could result from dose escalation. The significant factors affecting the risk of deafness included age, concurrent chemoradiotherapy, and greater radiation dose to the cochlea.

Sensorineural Hearing Loss After Treatment of Nasopharyngeal Carcinoma: A Longitudinal Analysis

PURPOSE To analyze the effects of radiotherapy (RT) and chemotherapy in relation to sensorineural hearing loss (SNHL) after contemporary treatment of nasopharyngeal carcinoma. METHODS AND MATERIALS A total of 87 nasopharyngeal carcinoma patients were treated with RT or chemoradiotherapy using either three-dimensional conformal RT or intensity-modulated RT between 2004 and 2005. Tympanometry and pure-tone audiogram assessments were performed before treatment and then serially at 6-month intervals. The dose-volume data of the cochlea were analyzed. The effects of cisplatin administered in concurrent and nonconcurrent phases was explored. RESULTS Of the 170 eligible ears, RT (n = 30) and chemoradiotherapy (n = 140) resulted in 40% (n = 12) and 56.4% (n = 79) persistent SNHL (> or = 15 dB loss), respectively, after a median follow-up of 2 years. SNHL at a high frequency was more frequent statistically in the chemoradiotherapy group than in the RT-alone group (55% vs. 33.3%, p < 0.01), but not at a low frequency (7.9% vs. 16.7%, p = 0.14). Within the chemoradiotherapy group, the mean cochlea dose and concurrent cisplatin dose were important determinants of high-frequency SNHL, with an odds ratio of 1.07/Gy increase (p = 0.01) and an odds ratio of 1.008/mg/m(2) increase (p < 0.01), respectively. Age, gender, and nonconcurrent cisplatin dose were not statistically significant factors. A mean radiation dose to the cochlea of <47 Gy would result in <15% of patients developing severe (> or = 30 dB) high-frequency SNHL. CONCLUSION The results of our study have shown that high-frequency SNHL is significantly related to the mean cochlea dose and the concurrent cisplatin dose. A mean dose constraint of 47 Gy to the cochlea is recommended to minimize SNHL after chemoradiotherapy.

Potential improvement of tumor control probability by induction chemotherapy for advanced nasopharyngeal carcinoma

PURPOSE To assess the reduction of tumor bulk and improvement of tumor control probability (TCP) by using induction chemotherapy for advanced nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS From February to December 2005, 20 patients with Stage III-IVB NPC were treated with induction-concurrent chemotherapy and intensity-modulated radiotherapy with accelerated fractionation. Combination of cisplatin and 5-fluorouracil was used in the induction phase and single agent Cisplatin in the concurrent phase. All patients were irradiated at 2Gy per fraction, 6 daily fractions per week, to a total dose of 70Gy. RESULTS Nineteen (95%) patients completed all 3 cycles of induction chemotherapy and 90% had 2 cycles of concurrent chemotherapy. Induction chemotherapy achieved significant down-staging of T-category in 35% of patients (p=0.016) and reduction of gross tumor volume (GTV_P) from 55.6 to 22.9cc (mean 61.4%, p<0.001). Although the mean radiation dose did not show any substantial change, the volume within GTV_P that failed to reach 70Gy was reduced from 10.2% to 3.8% (p=0.017). The estimated local TCP increased from 0.83 to 0.89 (p=0.002). CONCLUSIONS Induction chemotherapy using cisplatin-5-fluorouracil could significantly reduce tumor bulk leading to potential improvement in tumor control.

The superiority of hybrid-volumetric arc therapy (VMAT) technique over double arcs VMAT and 3D-conformal technique in the treatment of locally advanced non-small cell lung cancer – A planning study

PURPOSE To compare the dosimetric performance of three different treatment techniques - conformal radiotherapy (CRT), double arcs volumetric modulated arc therapy (RapidArc, RA) and Hybrid-RapidArc (H-RA) for locally-advanced non-small cell lung cancer (NSCLC). MATERIAL AND METHODS CRT, RA and H-RA plans were optimized for 24 stage III NSCLC patients. The target prescription dose was 60Gy. CRT consisted of 5-7 coplanar fields, while RA comprised of two 204(o) arcs. H-RA referred to two 204(o) arcs plus 2 static fields, which accounted for approximately half of the total dose. The plans were optimized to fulfill the departmental plan acceptance criteria. RESULTS RA and H-RA yielded a 20% better conformity compared with CRT. Lung volume receiving >20Gy (V20) and mean lung dose (MLD) were the lowest in H-RA (V20 1.7% and 2.1% lower, MLD 0.59Gy and 0.41Gy lower than CRT & RA respectively) without jeopardizing the low-dose lung volume (V5). H-RA plans gave the lowest mean maximum spinal cord dose (34.4Gy, 3.9Gy<CRT and 2.2Gy<RA plans) and NTCP of lung. Higher average MU per fraction (addition 52.4MU) was observed with a reduced treatment time compared with CRT plans. CONCLUSION The H-RA technique was superior in dosimetric outcomes for treating locally-advanced NSCLC compared to CRT and RA.

RapidArc radiotherapy planning for prostate cancer: Single-arc and double-arc techniques vs. intensity-modulated radiotherapy

RapidArc is a novel technique using arc radiotherapy aiming to achieve intensity-modulated radiotherapy (IMRT)-quality radiotherapy plans with shorter treatment time. This study compared the dosimetric quality and treatment efficiency of single-arc (SA) vs. double-arc (DA) and IMRT in the treatment of prostate cancer. Fourteen patients were included in the analysis. The planning target volume (PTV), which contained the prostate gland and proximal seminal vesicles, received 76 Gy in 38 fractions. Seven-field IMRT, SA, and DA plans were generated for each patient. Dosimetric quality in terms of the minimum PTV dose, PTV hotspot, inhomogeneity, and conformity index; and sparing of rectum, bladder, and femoral heads as measured by V70, V-40, and V20 (% of volume receiving >70 Gy, 40 Gy, and 20 Gy, respectively), treatment efficiency as assessed by monitor units (MU) and treatment time were compared. All plan objectives were met satisfactorily by all techniques. DA achieved the best dosimetric quality with the highest minimum PTV dose, lowest hotspot, and the best homogeneity and conformity. It was also more efficient than IMRT. SA achieved the highest treatment efficiency with the lowest MU and shortest treatment time. The mean treatment time for a 2-Gy fraction was 4.80 min, 2.78 min, and 1.30 min for IMRT, DA, and SA, respectively. However, SA also resulted in the highest rectal dose. DA could improve target volume coverage and reduce treatment time and MU while maintaining equivalent normal tissue sparing when compared with IMRT. SA achieved the greatest treatment efficiency but with the highest rectal dose, which was nonetheless within tolerable limits. For busy units with high patient throughput, SA could be an acceptable option.

Parapharyngeal Extension of Nasopharyngeal Carcinoma: Still a Significant Factor in Era of Modern Radiotherapy?

PURPOSE To retrospectively analyze the prognostic value of parapharyngeal space (PPS) extension after conformal radiotherapy for nasopharyngeal carcinoma. PATIENTS AND METHODS Between 1998 and 2005, 700 patients were treated with conformal radiotherapy at 2 Gy/fraction daily to a total of 70 Gy. All patients underwent staging with magnetic resonance imaging. The incidence of PPS was determined, and the extent of involvement was further subclassified regarding the presence or absence of carotid space (CS) involvement. The prognostic parameters, including age, gender, stage, chemotherapy, additional boosting, and extent of PPS involvement, were analyzed by univariate and multivariate analyses. RESULTS The median duration of follow-up was 51 months, and the 5-year overall survival rate for the whole group was 73%. The overall incidence of PPS extension was high (74%), and 29% had additional extension to the CS. Multivariate analysis showed age, gender, chemotherapy, T stage, and N stage to be significant prognostic factors, but not PPS involvement with or without CS extension. In the subgroup of patients with Stage T2 disease (n = 242), the presence of PPS involvement alone or PPS plus CS extension had no statistically significant effect in terms of local control (p = 0.68), distant metastases (p = 0.34), or overall survival (p = 0.24) compared with those without PPS involvement (Stage T2a). CONCLUSIONS With better tumor delineation by magnetic resonance imaging and improved coverage using modern radiotherapy techniques, PPS extension per se no longer predicts for disease outcome. Hence, subcategorizing Stage T2 disease is no longer important in future International Union Against Cancer/American Joint Committee on Cancer classifications.

Treatment of primary liver cancer using highly-conformal radiotherapy with kv-image guidance and respiratory control

PURPOSE To implement a reliable, practical and reproducible treatment procedure, based on in-room kV-image guidance and respiratory control, for liver cancer patients treated with high dose conformal radiotherapy using a commercially available treatment system. MATERIALS AND METHODS CT stimulation was conducted under voluntary breath hold or gating using the Varian Real-time Position Management™ (RPM) System. Treatments were delivered daily under kV image guidance to verify the diaphragmatic or lipiodol-defined tumor position. RESULTS Thirty-three patients with liver confined hepatocellular carcinoma were treated between May 2006 and Dec 2009. After a median follow-up period of 16.5 months (range: 3.5-40.7), all but 2 patients demonstrated radiological tumor regression. Eight patients (24%) achieved complete remission. The median tumor shrinkage was 42% (27-100%). Subsequent in-field tumor progression was observed in only three patients (10%). For the 23 patients with abnormal alpha fetoprotein level, 22 of them showed biochemical response with a median AFP level drop of 78%. The treatment was well tolerated: Grade 3 toxicities occurred in 5 patients (1 leucopenia, 1 elevated liver enzyme and 3 elevated bilirubin level) but there was no grade 4 toxicity or treatment related death. The 1 year overall survival rate is 71.7% and median survival time is 17.2 months (3.5-40.7 months). CONCLUSIONS Excellent treatment results with minimal toxicities could be achieved in a clinical environment with a commercially available highly sophisticated radiotherapy system.

The impact of dosimetric inadequacy on treatment outcome of nasopharyngeal carcinoma with IMRT

BACKGROUND AND PURPOSE This study aims to address the relationship between tumor size and dosimetric inadequacy in treating nasopharyngeal carcinoma (NPC), and how it subsequently affects the local control. MATERIAL AND METHODS 444 NPC patients treated with IMRT from 2005 to 2010 were included in the study. The planning aim was to deliver at least 66.5 Gy (i.e. 95% of 70 Gy) to 95% of the primary gross tumor volume (GTV_P) while keeping all the critical neurological organs at risk (OAR) within dose tolerance. Treatment outcome were analyzed according to T stage, GTV_P volume and the degree of under-dosing. RESULTS Disease outcome was related to T stage, GTV_P volume and the degree of under-dosing. The 5-year local failure free survival (LFFS), disease free survival (DFS) and overall survival (OS) for T4 disease were 74%, 50.4% and 63.6% respectively. 48 cm(3) was identified as the critical cut-off GTV_P volume, the large volume group (GTV_P ≥ 48 cm(3)) had lower 5-year DFS (50.4% vs. 76.6%) and OS (65.2% vs. 86.3%, p < 0.001). Most T4 diseases (and some T3) were under-dosed (<66.5 Gy) and an under-dosed GTV_P volume of 3.4 cm(3) was found to be prognostically important. Multivariate analyses showed that the effect of GTV_P volume on LFFR and DFS was outweighed by the degree of under-dosing. CONCLUSIONS Treatment outcome of locally advanced NPC was significantly affected by the volume of under-dosed (<66.5 Gy) GTV_P due to the neighboring neurological structures. A new set of OAR dose constraint and specification is proposed.

Should all nasopharyngeal carcinoma with masticator space involvement be staged as T4

INTRODUCTION The prognostic significance of the involvement of anatomical masticator space (MS) in nasopharyngeal carcinoma (NPC) was retrospectively reviewed. MATERIAL AND METHODS 1104 Patients with non-metastatic NPC treated with radical radiotherapy between 1998 and 2010 were re-staged according to the 7th edition of the American Joint Committee on Cancer (AJCC) staging system; tumors with medial pterygoid muscle (MP) and/or lateral pterygoid muscle (LP) involvement but did not fulfill the criteria for T3 or T4 were staged as TX. The tumor volume data, dosimetric data and survival endpoints of different T stage diseases were analyzed and compared to study the significance of MS involvement. RESULTS The overall MS involvement rate was 61.0%. The median volumes of the primary gross tumor volume were 9.6ml, 15.2ml, 19.9ml, 32.6ml and 77.3ml for T1, T2, TX, T3 and T4, respectively (p<0.001). T1, T2 and TX tumors received higher minimum dose to the gross tumor volume and planning target volume than T3 and T4. Multivariate analysis showed that age, gender, T-/N-classification and the use of chemotherapy were significant prognostic factors for various survival end-points. Patients with TX disease had similar survival rates as with T1-T2; and had a significantly better 5-year overall survival rate (86.6% vs. 76.6%; p=0.013) and a trend of higher 5-year distant failure-free survival rate (91.5% vs. 81.3%; p=0.09) than patients with T3 disease. CONCLUSION NPC with the involvement of MP and/or LP alone should be classified as T2 disease.