Neural correlates of an injury-free model of central sensitization induced by opioid withdrawal in humans.

Preclinical evidence suggests that opioid withdrawal induces central sensitization (CS) that is maintained by supraspinal contributions from the descending pain modulatory system (DPMS). Here, in healthy human subjects we use functional magnetic resonance imaging to study the supraspinal activity during the withdrawal period of the opioid remifentanil. We used a crossover design and thermal stimuli on uninjured skin to demonstrate opioid withdrawal-induced hyperalgesia (OIH) without a CS-inducing peripheral stimulus. Saline was used in the control arm to account for effects of time. OIH in this injury-free model was observed in a subset of the healthy subjects (responders). Only in these subjects did opioid infusion and withdrawal induce a rise in activity in the mesencephalic-pontine reticular formation (MPRF), an area of the DPMS that has been previously shown to be involved in states of CS in humans, which became significant during the withdrawal phase compared with nonresponders. Paradoxically, this opioid withdrawal-induced rise in MPRF activity shows a significant negative correlation with the behavioral OIH score indicating a predominant inhibitory role of the MPRF in the responders. These data illustrate that in susceptible individuals central mechanisms appear to regulate the expression of OIH in humans in the absence of tissue injury, which might have relevance for functional pain syndromes where a peripheral origin for the pain is difficult to identify.

Stereotactic ablative radiotherapy for medically inoperable early stage lung cancer: early outcomes.

OBJECTIVE. To evaluate the clinical outcome and safety of stereotactic ablative radiotherapy for medically inoperable stage I non-small-cell lung carcinoma. DESIGN. Retrospective case series. SETTING. Pamela Youde Nethersole Eastern Hospital, Hong Kong. PATIENTS. All patients with medically inoperable stage I non-small-cell lung carcinoma receiving stereotactic ablative radiotherapy since its establishment in 2008. MAIN OUTCOME MEASURES. Disease control rate, overall survival, and treatment toxicities. RESULTS. Sixteen stage I non-small-cell lung carcinoma patients underwent the procedure from June 2008 to November 2011. The median patient age was 82 years and the majority (81%) had moderate-to-severe co-morbidity based on the Adult Comorbidity Evaluation 27 index. With a median follow-up of 22 months, the 2-year primary tumour control rate, disease-free survival and overall survival rates were 91%, 71% and 87%, respectively. No grade 3 (National Cancer Institute Common Terminology Criteria for Adverse Events) or higher treatment-related complications were reported. CONCLUSION. Stereotactic ablative radiotherapy can achieve a high degree of local control safely in medically inoperable patients with early lung cancer.

Adjuvant chemoradiation for resected gastric cancer: a 10-year experience.

BACKGROUND: The Intergroup 0116 study demonstrated that concurrent chemoradiation improved overall survival (OS) in resected gastric cancer. However, there are few reports focusing on late toxicity and factors governing prognosis. This study aimed to determine these two important aspects for employing this regimen. METHODS: Patients with resected gastric cancer stage IB to IV (M0) disease, treated between July 1998 and December 2007, were analyzed. The majority of the patients were treated using 5 cycles of 5-fluorouracil (5FU)/leucovorin chemotherapy with 45 Gy/25 fractions radiotherapy concurrent with cycles 2 and 3, as per the Intergroup 0116 study. RESULTS: We treated 120 patients (107 standard protocol, 13 with concurrent 5FU alone), and 14% had a close or positive margin. Median age was 59 years (35-79 years). Acute toxicity ≥ grade 3 was seen in 66% of all patients (hematological 61%, stomatitis 3%, diarrhea 6%, vomiting 2%). Median follow-up was 33 months (range 6-125 months). Five-year OS and relapse-free survival were 51 and 54%, respectively. On multivariate analysis, surgical margin status, stage of the disease, and radiotherapy with computed tomography (CT) planning were important prognostic factors. Anemia and gastritis were the two most frequently occurring late complications, though they were usually mild and asymptomatic. Clinically significant renal impairment was uncommon. Other rare complications included intestinal obstruction, malabsorption, hypertension, and secondary malignancy. CONCLUSIONS: Postoperative chemoradiation is safe and late toxicity is usually mild in extent. Results were comparable to the Intergroup 0116 study. R0 resection is of utmost importance and radiotherapy should best be delivered by conformal techniques.

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.

Reirradiation with intensity-modulated radiotherapy for locally recurrent T3 to T4 nasopharyngeal carcinoma.

BACKGROUND: The purpose of this study was to assess the efficacy and toxicities of reirradiation using intensity-modulated radiotherapy (IMRT) in patients with locally advanced recurrent nasopharyngeal carcinoma (NPC). METHODS: Thirty-eight patients with consecutive rT3 to rT4 NPC treated between 2005 and 2013 were retrospectively analyzed. RESULTS: The 3-year overall survival (OS), progression-free survival (PFS), and local control rate were 47.2%, 17.5%, and 44.3%, respectively. Gross target volume (GTV) D95 , GTV D50 , and age were all important prognostic factors for OS and PFS, but only GTV D95 was an important determinant for local control. A total of 73.7% patients experienced ≥1 grade 3 late toxicities and 3 patients died of massive epistaxis. Temporal lobe necrosis (TLN) developed sooner with a higher total biological equivalent dose. CONCLUSION: Adequate tumor dose coverage was important for treating rT3 to rT4 NPC. Although late complications were common, treatment-related mortality was solely vascular in nature. Dose constraints of neurologic structures for reirradiation should be revised with the latest information on late toxicities. © 2016 Wiley Periodicals, Inc. Head Neck 39: 533-540, 2017.

Comparison of Planning Quality and Efficiency Between Conventional and Knowledge-based Algorithms in Nasopharyngeal Cancer Patients Using Intensity Modulated Radiation Therapy.

PURPOSE: Intensity modulated radiation therapy (IMRT) is widely used to achieve a highly conformal dose and improve treatment outcome. However, plan quality and planning time are institute and planner dependent, and no standardized tool exists to recognize an optimal plan. RapidPlan, a knowledge-based algorithm, can generate constraints to assist optimization and produce high-quality IMRT plans. This report evaluated the quality and efficiency of using RapidPlan in nasopharyngeal carcinoma (NPC) IMRT planning. METHODS AND MATERIALS: RapidPlan was configured using 79 radical IMRT plans for NPC; 20 consecutive NPC patients indicated for radical radiation therapy between October 2014 and May 2015 were then recruited to assess its performance. The ability of RapidPlan to produce acceptable plans was evaluated. For plans that could not achieve clinical acceptance, manual touch-up was performed. The IMRT plans produced without RapidPlan (manual plans) and with RapidPlan (RP-2 plans, including those with manual touch-up) were compared in terms of dosimetric quality and planning efficiency. RESULTS: RapidPlan by itself could produce clinically acceptable plans for 9 of the 20 patients; manual touch-up increased the number of acceptable plans (RP-2 plans) to 19. The target dose coverage and conformity were very similar. No difference was found in the maximum dose to the brainstem and optic chiasm. RP-2 plans delivered a higher maximum dose to the spinal cord (46.4 Gy vs 43.9 Gy, P=.002) but a lower dose to the parotid (mean dose to right parotid, 37.3 Gy vs 45.4 Gy; left, 34.4 Gy vs 43.1 Gy; P<.001) and the right cochlea (mean dose, 48.6 Gy vs 52.6 Gy; P=.02). The total planning time for RP-2 plans was significantly less than that for manual plans (64 minutes vs 295 minutes, P<.001). CONCLUSIONS: This study shows that RapidPlan can significantly improve planning efficiency and produce quality IMRT plans for NPC patients.

Primary tumor volume of nasopharyngeal carcinoma: prognostic significance for local control.

PURPOSE: To study the prognostic significance of primary tumor volume on local control of nasopharyngeal carcinoma. METHODS AND MATERIALS: Between 1998 and 2001, 308 consecutive patients with nasopharyngeal carcinoma treated with radical intent were staged with MRI. On the basis of the extent of tumor infiltration outlined by a diagnostic radiologist, the gross tumor volume of the primary and involved retropharyngeal nodes (GTV-P) was delineated by a radiation oncologist for three-dimensional conformal radiotherapy to the nasopharyngeal region using the Helax-TMS Planning System. All patients were treated with 2 Gy daily to a total dose of 70 Gy in 6-7 weeks. Additionally, chemotherapy was given to 128 patients (42%). RESULTS: The median GTV-P for the whole series was 22 cm(3) (range, 1.4-218 cm(3)). Although the GTV-P varied substantially within each T stage, the overall correlation between these two parameters was strongly significant (p <0.01), with the median GTV-P 2.7 cm(3) for T1, 13.2 cm(3) for T2, 28.1 cm(3) for T3, and 65.5 cm(3) for T4. With a median follow-up of 1.9 years (range, 0.1-3.9 years), the 3-year local failure-free rate was 87%. The 3-year local failure-free rate was 97% for patients with a GTV-P <15 cm(3) compared with 82% for those with a GTV-P > or =15 cm(3) (p <0.01). On multivariate analysis (with T stage as a covariate), GTV-P remained an independent prognostic factor for the local failure-free rate (hazard ratio, 1.01; 95% confidence interval, 1.00-1.02; p <0.01). CONCLUSION: Our data suggested that GTV-P is a strongly significant factor for predicting local control of nasopharyngeal carcinoma. The risk of local failure was estimated to increase by 1% for every 1 cm(3) increase in primary tumor volume.

Case Report: Neuropathic pain in a patient with congenital insensitivity to pain.

We report a unique case of a woman with Channelopathy-associated Insensitivity to Pain (CIP) Syndrome, who developed features of neuropathic pain after sustaining pelvic fractures and an epidural hematoma that impinged on the right fifth lumbar (L5) nerve root. Her pelvic injuries were sustained during painless labor, which culminated in a Cesarean section. She had been diagnosed with CIP as child, which was later confirmed when she was found to have a null mutation of the SCN9a gene that encodes the voltage-gated sodium channel Nav1.7. She now complains of troubling continuous buzzing in both legs and a vice-like squeezing in the pelvis on walking. Quantitative sensory testing showed that sensory thresholds to mechanical stimulation of the dorsum of both feet had increased more than 10-fold on both sides compared with tests performed before her pregnancy. These findings fulfill the diagnostic criteria for neuropathic pain. Notably, she only experiences the negative symptoms (such as numbness and tingling) and she has not reported sharp, burning or electric shock sensations, although the value of verbal descriptors is somewhat limited in a person who has never felt pain before. However, her case strongly suggests that at least some of the symptoms of neuropathic pain can persist despite the absence of the Nav1.7 channel. Pain is a subjective experience and this case sheds light on the transmission of neuropathic pain in humans that cannot be learned from knockout mice.

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.

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.

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.

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.

An analysis of the efficacy of serial screening for familial nasopharyngeal carcinoma based on Markov chain models.

Treatment of nasopharyngeal carcinoma (NPC) can be improved by early detection of the disease as treatment outcome worsens with disease's progression. This can be achieved with a mass screening program using Epstein Barr virus (EBV) serology and nasopharyngoscopy. The efficacy of any screening strategy should be evaluated before putting it into practice. Such evaluation is ideally performed with simulation as time and cost often preclude the evaluation by randomized trial. This study simulated and compared the outcomes of 4 screening strategies over a period of 12 years: (A) Annual screening, (B) biennial screening, (C) triennial screening, and (D) triennial screening for participants tested EBV negative and annual screening once the participants are tested EBV positive. Progression of the disease was divided into 4 phases and calculated by applying Markov chain model. Parameters of the transition matrix and probabilities were estimated using data from previous screening results of 1,072 family members of NPC patients. The early detection rates with strategies A, B, C and D are 88, 79, 71 and 87% respectively. The 5-year overall survival with screening is 10-12% higher than that without and is the highest with strategies A and D. Strategy D, however, requires only 64% screening tests compared with strategy A and has almost identical resultant disease stage distribution to strategy A. We concluded that strategy D offered the highest efficacy for NPC screening of family members of NPC patients among the four strategies studied.

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.

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

Outcomes of nasopharyngeal carcinoma screening for high risk family members in Hong Kong.

We undertook a large retrospective study to evaluate the impact of screening family members of NPC patients with Epstein Barr Virus (EBV) serology. 1,199 asymptomatic family members of NPC patients were entered into the annual screening program with EBV serology and nasopharyngoscopy between 1994 and 2005. Eighteen participants of our screening program developed NPC; 17 of them were treated in our institute, of whom 16 were detected in screening. The sensitivity and specificity of EBV serology were 83.3 and 87.0%, respectively, and for the program they were 88.9 and 87.0%, respectively. Stage distributions and survival outcomes of the 17 cases were compared with that of 1,185 consecutive symptomatic patients diagnosed in the same period through general referral. It was found that the screening program resulted in early detection of cancer, with 59% presenting at early stage (stage I: 41%, stage II: 18%) compared to 24% (stage I: < 1%, stage II: 23%) of symptomatic cancers (P < 0.001), and a significant improvement in disease-free survival (P = 0.04). The cancer specific survival and overall survival rate at 5-year are also higher (92 vs. 77% and 92 vs. 70%, respectively), though they fail to reach statistical significance. In conclusion, screening asymptomatic family members of NPC patients annually leads to earlier detection of NPC and clinically valuable survival advantage among these family members. A larger sample size is needed to confirm its full potential in survival benefit.

Familial nasopharyngeal carcinoma in Hong Kong: epidemiology and implication in screening.

The pathogenetic mechanism of nasopharyngeal carcinoma (NPC) is still unclear. Its familial aggregation, on the other hand, has been well documented by many epidemiological studies. The objective of this study was to evaluate the clinical characteristics of familial NPC in an endemic region. Between March 1994 and November 2005, 1,202 consecutive patients were treated at our institution. Patients were divided into 2 groups according to their family history: group 1 had at least one first-degree relative with NPC at the time of diagnosis, and group 2 did not. There were 125(10.4%) patients in group 1, 66% of them had diseased siblings, 44% had diseased parents and 2% had diseased offspring. The patients in group 1 were on average about 2 years younger than group 2 at diagnosis (47.9 vs. 49.8, P = 0.04). There were also more stage I-II patients in group 1 (38 [corrected] vs. 23%, P < 0.01). Although the 5 year overall survival was also higher with group 1 (79 vs. 69%, P < 0.01), only age, sex, T classification and N classification were found to be significant independent factors but not family history per se (P = 0.10). Similar findings were observed after excluding screen-detected patients from group 1. The high incidence of familial clustering and improved outcomes from early detection highlight the importance of screening among these high risk family members.

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.

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.

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.