NPC-0501 trial on the value of changing chemoradiotherapy sequence, replacing 5-fluorouracil with capecitabine, and altering fractionation for patients with advanced nasopharyngeal carcinoma.

BACKGROUND: A current recommendation for the treatment of patients with locoregionally advanced nasopharyngeal carcinoma (NPC) is conventional fractionated radiotherapy (RT) with concurrent cisplatin followed by adjuvant cisplatin and 5-fluorouracil (PF). This randomized NPC-0501 trial evaluated the therapeutic effect of changing to an induction-concurrent sequence or accelerated-fractionation sequence, and/or replacing 5-fluorouracil with capecitabine (X). METHODS: Patients with American Joint Committee on Cancer/International Union Against Cancer stage III to stage IVB NPC initially were randomly allocated to 1 of 6 treatment arms (6-arm full-randomization cohort). The protocol was amended in 2009 to permit centers to opt out of randomization regarding fractionation (3-arm chemotherapy cohort). RESULTS: A total of 803 patients were accrued (1 of whom was nonevaluable) from 2006 to 2012. Based on the overall comparisons, neither changing the chemotherapy sequence nor accelerated fractionation improved treatment outcome. However, secondary analyses demonstrated that when adjusted for RT parameters and other significant factors, the induction-concurrent sequence, especially the induction-PX regimen, achieved significant improvements in progression-free survival (PFS) and overall survival. Efficacy varied among different RT groups: although no impact was observed in the accelerated-fractionation group and the 3-arm chemotherapy cohort, a comparison of the induction-concurrent versus concurrent-adjuvant sequence in the conventional-fractionation group demonstrated a significant benefit in PFS (78% vs 62% at 5 years; P = .015) and a marginal benefit in overall survival (84% vs 72%; P = .042) after adjusting for multiple comparisons. Comparison of the induction-PX versus the adjuvant-PF regimen demonstrated better PFS (78% vs 62%; P = .027) without an increase in overall late toxicity. CONCLUSIONS: For patients irradiated using conventional fractionation, changing the chemotherapy sequence from a concurrent-adjuvant to an induction-concurrent sequence, particularly using induction cisplatin and capecitabine, potentially could improve efficacy without an adverse impact on late toxicity. However, further validation is needed for confirmation of these findings.

Analysis of Plasma Epstein-Barr Virus DNA in Nasopharyngeal Cancer After Chemoradiation to Identify High-Risk Patients for Adjuvant Chemotherapy: A Randomized Controlled Trial.

Purpose The contribution of adjuvant chemotherapy after chemoradiation therapy (CRT) in nasopharyngeal cancer (NPC) remains controversial. Plasma Epstein-Barr virus (EBV) DNA is a potential biomarker of subclinical residual disease in NPC. In this prospective, multicenter, randomized controlled trial, we used plasma EBV DNA to identify patients with NPC at a higher risk of relapse for adjuvant chemotherapy. Patients and Methods Eligible patients with histologically confirmed NPC of Union for International Cancer Control stage IIB to IVB, adequate organ function, and no locoregional disease or distant metastasis were screened by plasma EBV DNA at 6 to 8 weeks after radiotherapy (RT). Patients with undetectable plasma EBV DNA underwent standard surveillance. Patients with detectable plasma EBV DNA were randomly assigned to either adjuvant chemotherapy with cisplatin and gemcitabine for six cycles (arm 1) or observation (arm 2). Patients were stratified for primary treatment (RT v CRT) and stage (II/III v IV). The primary end point was relapse-free survival (RFS). Results Seven hundred eighty-nine patients underwent EBV DNA screening. Plasma EBV DNA was undetectable in 573 (72.6%) and detectable in 216 (27.4%); 104 (13.2%) with detectable EBV DNA were randomly assigned to arms 1 (n = 52) and 2 (n = 52). After a median follow-up of 6.6 years, no significant difference was found in 5-year RFS rate between arms 1 and 2 (49.3% v 54.7%; P = .75; hazard ratio for relapse or death, 1.09; 95% CI, 0.63 to 1.89). The level of post-RT plasma EBV DNA correlated significantly with the hazards of locoregional failure, distant metastasis, and death. Conclusion In patients with NPC with detectable post-RT plasma EBV DNA, adjuvant chemotherapy with cisplatin and gemcitabine did not improve RFS. Post-RT plasma EBV DNA level should be incorporated as the selection factor in future clinical trials of adjuvant therapy in NPC.

Concurrent-Adjuvant Chemoradiation Therapy for Stage III-IVB Nasopharyngeal Carcinoma-Exploration for Achieving Optimal 10-Year Therapeutic Ratio.

PURPOSE: This is an updated combined analysis of 2 randomized studies (NPC-9901 and NPC-9902 trials) to evaluate the 10-year outcome attributed to the addition of concurrent-adjuvant chemotherapy for advanced locoregional nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Eligible patients with stage III-IVB nonkeratinizing NPC were randomly assigned to radiation therapy alone (RT: 218 patients) or chemoradiation therapy (CRT: 223 patients) using 3 cycles of cisplatin (100 mg/m2) concurrent with RT, followed by 3 cycles of cisplatin (80 mg/m2) and fluorouracil (1000 mg/m2/day for 4 days). All of the patients were irradiated with conventional fractionation to ≥66 Gy. The median follow-up was 13.9 years. RESULTS: Intention-to-treat analysis confirmed that the CRT group achieved significant improvement in 10-year failure-free rate (FFR: 62% vs 52%, P = .016), progression-free survival rate (PFS: 56% vs 44%, P = .008), and overall survival rate (OS: 60% vs 50%, P = .044). There was no significant increase in overall late toxicity rate (51% vs 48%, P = .34) or noncancer deaths (19% vs 16%, P = .52). Exploratory studies showed no difference in disease control between 2 or 3 cycles of concurrent cisplatin; however, patients given 3 concurrent cycles had a significant increase in hearing impairment (40% vs 24%, P = .017). Only those who continued to receive 2 or more cycles of adjuvant cisplatin-fluorouracil achieved significant improvement in distant control (73% vs 65%, P = .037) and maximal survival gain. CONCLUSION: The addition of concurrent cisplatin plus adjuvant cisplatin-fluorouracil could significantly improve overall survival and disease control without incurring a significant increase in late toxicity or noncancer deaths. Exploratory analyses suggested that both the concurrent and the adjuvant phases contributed to tumor control. Furthermore, the number of concurrent cycles could be reduced from 3 to 2 cycles in order to achieve a similar survival benefit without incurring an excessive increase in hearing impairment. This is a useful hypothesis that warrants further validation.

Prospective, Multicenter, Phase 2 Trial of Induction Chemotherapy Followed by Bio-Chemoradiotherapy for Locally Advanced Recurrent Nasopharyngeal Carcinoma.

PURPOSE: To evaluate, in a phase 2 study, whether induction docetaxel, cisplatin, and fluorouracil (TPF) followed by weekly docetaxel and cetuximab in concurrence with intensity modulated radiation therapy can improve the treatment outcome for patients with advanced locally recurrent nasopharyngeal carcinoma (rNPC). METHODS AND MATERIALS: Thirty-three patients with rNPC (T3-T4, N0-N1, M0) were recruited. Of these, 19 patients (57.6%) had stage rT3 recurrence, and the rest had stage rT4. Eight patients also had rN1 at the time of relapse. Treatment outcomes and safety were evaluated. RESULTS: Among these 33 patients, 1 died after 1 cycle of TPF, 5 patients withdrew from the study during the induction period because of grade ≥3 toxicities; 27 patients completed the whole course of treatment, but 1 died before any assessment could be made. The median follow-up period was 28.5 months. The progression-free survival and overall survival at 3 years for the whole group were 35.7% and 63.8%, respectively. Among the 26 patients who could be assessed after treatment, the complete response rate was 30.8%, and the locoregional control rate at 3 years was 49.2%. Temporal lobe necrosis (TLN) developed in 8 cases. The rates of grade ≥3 hearing loss, soft tissue necrosis, dysphagia, and trismus were 30.8%, 15.4%, 11.5%, and 19.2%, respectively. Overall, 5 patients died owing to acute (1 after cycle 1 TPF and 1 after completion of bio-chemoradiotherapy) or late (2 epistaxis and 1 TLN) treatment-related complications. CONCLUSIONS: The proposed salvage treatment regimen for advanced locally recurrent NPC could achieve a better treatment outcome than seen in previous studies. However, poor tolerability of induction TPF and the high rate of TLN limit its applicability outside clinical trials.

Treatment outcomes of nasopharyngeal carcinoma in modern era after intensity modulated radiotherapy (IMRT) in Hong Kong: A report of 3328 patients (HKNPCSG 1301 study).

PURPOSE: To evaluate treatment outcomes, failure patterns and late toxicities in patients with nasopharyngeal carcinoma (NPC) treated by intensity modulated radiotherapy (IMRT) in 6 public hospitals in Hong Kong over a 10-year period from 2001 to 2010. MATERIAL AND METHODS: Eligible patients were identified through the Hong Kong Cancer Registry data base. Clinical information was retrieved and verified by oncologists working in the individual centers. Treatment details, survival outcomes and late toxicities were analyzed. RESULTS: A total of 3328 patients were recruited. The median follow-up time was 80.2 months. The 8-year actuarial overall survival (OS), local failure-free survival (LFFS), regional failure-free survival (RFFS), distant failure free survival (DFFS), progression-free survival (PFS) for the whole group was 68.5%, 85.8%, 91.5%, 81.5% and 62.6% respectively. Male gender, older age, advanced T and N stage were adverse prognostic factors for OS, DFFS and PFS, whereas use of chemotherapy in form of concurrent chemo-irradiation (CRT), neoadjuvant + CRT, or CRT + adjuvant chemotherapy were favorable prognostic factors for OS and PFS. The local control was adversely affected by advanced T stage. N stage remained as the single adverse prognostic factor for regional control. Distant metastasis was the commonest site of failure. CONCLUSION: IMRT is an effective treatment for NPC with excellent overall loco-regional control. Distant metastasis is the major site of failure. Concurrent chemotherapy with cisplatin has an established role in NPC patients treated by IMRT.

A multicenter, phase 3, randomized trial of concurrent chemoradiotherapy plus adjuvant chemotherapy versus radiotherapy alone in patients with regionally advanced nasopharyngeal carcinoma: 10-year outcomes for efficacy and toxicity.

BACKGROUND: Concurrent-adjuvant chemoradiotherapy (CRT) became a recommended treatment for locoregionally advanced nasopharyngeal carcinoma (NPC) with the first report of a significant survival benefit from the Intergroup 0099 study. However, data on late toxicities are lacking. Previous reports from the current NPC-9901 trial have raised concerns about a failure to improve overall survival (OS) because of an inadequate impact on distant control and increases in toxicities/noncancer deaths. Validation of the long-term therapeutic ratio is needed. METHODS: In this phase 3, randomized trial, patients with nonkeratinizing NPC (stage T1-4/N2-3/M0) were randomly assigned to radiotherapy alone (176 patients) or to CRT (172 patients) with concurrent cisplatin followed by adjuvant cisplatin plus fluorouracil. RESULTS: The early findings of significant improvements in tumor control were maintained: the CRT group achieved significantly higher 10-year overall failure-free (62% vs 50%; P = .01) and progression-free survival rates (56% vs 42%; P = .006) because of superior locoregional control (87% vs 74%; P = .003), whereas the impact on distant control remained insignificant (68% vs 65%; P = .24). The initial differences in toxicities diminished with longer follow-up: 52% versus 47% at 10 years for late toxicities (P = .20), 4.1% versus 2.8% for deaths due to treatment toxicity, and 15.1% versus 13.1% for deaths due to incidental/unknown causes. The OS rate for the CRT group reached statistical superiority at 10 years (62% vs 49%; P = .047). CONCLUSIONS: Long-term results have confirmed that CRT can significantly improve OS without excessive late toxicities for patients with regionally advanced NPC. However, more potent therapy is needed for improving distant control, especially for patients with stage IVA/B disease. Cancer 2017;123:4147-4157. © 2017 American Cancer Society.

A design of a DICOM-RT-based tool box for nonrigid 4D dose calculation.

The study was aimed to introduce a design of a DICOM-RT-based tool box to facilitate 4D dose calculation based on deformable voxel-dose registration. The computational structure and the calculation algorithm of the tool box were explicitly discussed in the study. The tool box was written in MATLAB in conjunction with CERR. It consists of five main functions which allow a) importation of DICOM-RT-based 3D dose plan, b) deformable image registration, c) tracking voxel doses along breathing cycle, d) presentation of temporal dose distribution at different time phase, and e) derivation of 4D dose. The efficacy of using the tool box for clinical application had been verified with nine clinical cases on retrospective-study basis. The logistic and the robustness of the tool box were tested with 27 applications and the results were shown successful with no computational errors encountered. In the study, the accumulated dose coverage as a function of planning CT taken at end-inhale, end-exhale, and mean tumor position were assessed. The results indicated that the majority of the cases (67%) achieved maximum target coverage, while the planning CT was taken at the temporal mean tumor position and 56% at the end-exhale position. The comparable results to the literature imply that the studied tool box can be reliable for 4D dose calculation. The authors suggest that, with proper application, 4D dose calculation using deformable registration can provide better dose evaluation for treatment with moving target.

Lipiodol versus diaphragm in 4D-CBCT-guided stereotactic radiotherapy of hepatocellular carcinomas.

PURPOSE: The purpose of this work was to investigate the potential of lipiodol as a direct tumor surrogate alternative to the diaphragm surrogate on four-dimensional cone-beam computed tomography (4D-CBCT) image guidance for stereotactic radiotherapy of hepatocellular carcinomas. METHODS: A total of 29 hepatocellular carcinomas (HCC) patients treated by stereotactic radiotherapy following transarterial chemoembolization (TACE) with homogeneous or partial defective lipiodol retention were included. In all, 4-7 pretreatment 4D-CBCT scans were selected for each patient. For each scan, either lipiodol or the diaphragm was used for 4D registration. Resulting lipiodol/diaphragm motion ranges and position errors relative to the reconstructed midventilation images were analyzed to obtain the motion variations, and group mean (ΔM), systematic (Σ), and random (σ) errors of the treatment setup. RESULTS: Of the lipiodolized tumors, 55 % qualified for direct localization on the 4D-CBCT. Significant correlations of lipiodol and diaphragm positions were found in the left-right (LR), craniocaudal (CC), and anteroposterior (AP) directions. ΔM and σ obtained with lipiodol and diaphragm were similar, agreed to within 0.5 mm in the LR and AP, and 0.3 mm in the CC directions, and Σ differed by 1.4 (LR), 1.1 (CC), and 0.6 (AP) mm. Variations of diaphragm motion range > 5 mm were not observed with lipiodol and in one patient with diaphragm. The margin required for the tumor prediction error using the diaphragm surrogate was 6.7 (LR), 11.7 (CC), and 4.1 (AP) mm. CONCLUSION: Image-guidance combining lipiodol with 4D-CBCT enabled accurate localization of HCC and thus margin reduction. A major limitation was the degraded lipiodol contrast on 4D-CBCT.

Clinical utility of plasma Epstein-Barr virus DNA and ERCC1 single nucleotide polymorphism in nasopharyngeal carcinoma.

BACKGROUND: Single nucleotide polymorphism (SNP) of the excision repair cross-complementing group 1 (ERCC1) gene has been linked with sensitivity to platinum and radiation. The authors hypothesized that the ERCC1 genotype for the SNPs cytosine-to-thymine substitution at codon 118 (C118T) and cytosine-to-adenine substitution at codon 8092 (C8092A) is prognostic in patients with nasopharyngeal carcinoma (NPC) who receive either radiotherapy (RT) or cisplatin plus RT. METHODS: The authors tested their hypothesis using biomarker screening samples from the Hong Kong NPC Study Group 0502 trial, which was a prospective, multicenter clinical trial that used post-RT plasma Epstein-Bar virus (EBV) DNA (pEBV) levels to screen patients with high-risk NPC for adjuvant chemotherapy. RESULTS: ERCC1 SNPs were analyzed in 576 consecutive patients who were screened by pEBV. In the total biomarker population, there was no significant association of ERCC1 C118T or C8092A genotype with relapse-free survival (RFS) or overall survival (OS). There also was no correlation between ERCC1 genotype and ERCC1 protein or messenger RNA expression in a subset of patients who had available paired biopsies. Post-RT pEBV status was the only independent prognosticator for RFS and OS in multivariate analyses. However, there was a significant interaction between ERCC1 C118T genotype and post-RT pEBV status (RFS, P = .0106; OS, P = .0067). The ERCC1 C118T genotype was significantly associated with both RFS (hazard ratio, 1.67; 95% confidence interval, 1.07-2.61; P = .024) and OS (hazard ratio, 2.31; 95% confidence interval, 1.22-4.40; P = .0106) in the post-RT pEBV-negative population, but not in the pEBV-positive population. CONCLUSIONS: The current results prospectively validate pEBV as the most significant prognostic biomarker in NPC that can be used to select high-risk patients for adjuvant therapy. The ERCC1 C118T genotype may help to identify a favorable subgroup (approximately 7%) of pEBV-negative patients with NPC who have an excellent prognosis and can be spared the toxicities of further therapy.

Epigenetic markers for noninvasive early detection of nasopharyngeal carcinoma by methylation-sensitive high resolution melting.

Nasopharyngeal carcinoma (NPC) is a human malignancy that is closely associated with Epstein-Barr Virus (EBV). Early diagnosis of NPC will greatly improve the overall survival. However, current EBV DNA marker detection still lacks the predictive value to perform well in high-risk populations for early detection of NPC. Since aberrant promoter hypermethylation of tumor suppressor genes (TSGs) is widely considered to be an important epigenetic change in early carcinogenesis, this study identified a panel of methylation markers for early detection of NPC and also assessed the clinical usefulness of these markers with noninvasive plasma specimens instead of biopsies. MS-HRM assays were carried out to assess the methylation status of a selected panel of four TSGs (RASSF1A, WIF1, DAPK1 and RARß2) in biopsies, NP brushings and cell-free plasma from NPC patients. High-risk and cancer-free groups were used as controls. DNA methylation panel showed higher sensitivity and specificity than EBV DNA marker in cell-free plasma from NPC patients at early Stages (I and II) and in addition to the EBV DNA marker, MS-HRM test for plasma and NP brushing DNA methylation significantly increased the detection rate at all NPC stages as well as local recurrence, using this selected four-gene panel (p<0.05). MS-HRM assay on a selected gene panel has great potential to become a noninvasive and complementary test for NPC early and recurrent detection in combination with the EBV DNA test to increase the sensitivity for NPC detection at an early stage.

Preliminary results of trial NPC-0501 evaluating the therapeutic gain by changing from concurrent-adjuvant to induction-concurrent chemoradiotherapy, changing from fluorouracil to capecitabine, and changing from conventional to accelerated radiotherapy fractionation in patients with locoregionally advanced nasopharyngeal carcinoma.

BACKGROUND: A current recommendation for locoregionally advanced nasopharyngeal carcinoma (NPC) is conventional fractionated radiotherapy with concurrent cisplatin plus adjuvant cisplatin and fluorouracil (PF). In this randomized trial, the authors evaluated the potential therapeutic benefit from changing to an induction-concurrent chemotherapy sequence, replacing fluorouracil with oral capecitabine, and/or using accelerated rather than conventional radiotherapy fractionation. METHODS: Patients with stage III through IVB, nonkeratinizing NPC were randomly allocated to 1 of 6 treatment arms. The protocol was amended in 2009 to permit confining randomization to the conventional fractionation arms. The primary endpoint was progression-free survival. Secondary endpoints included overall survival and safety. RESULTS: In total, 803 patients were accrued, and 706 patients were randomly allocated to all 6 treatment arms. Comparisons of induction PF versus adjuvant PF did not indicate a significant improvement. Unadjusted comparisons of induction cisplatin and capecitabine (PX) versus adjuvant PF indicated a favorable trend in progression-free survival for the conventional fractionation arm (P = .045); analyses that were adjusted for other significant factors and fractionation reflected a significant reduction in the hazards of disease progression (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.36-0.80) and death (HR, 0.42; 95% CI, 0.25-0.70). Unadjusted comparisons of induction sequences versus adjuvant sequences did not reach statistical significance, but adjusted comparisons indicated favorable improvements by induction sequence. Comparisons of induction PX versus induction PF revealed fewer toxicities (neutropenia and electrolyte disturbance), unadjusted comparisons of efficacy were statistically insignificant, but adjusted analyses indicated that induction PX had a lower hazard of death (HR, 0.57; 95% CI, 0.34-0.97). Changing the fractionation from conventional to accelerated did not achieve any benefit but incurred higher toxicities (acute mucositis and dehydration). CONCLUSIONS: Preliminary results indicate that the benefit of changing to an induction-concurrent sequence remains uncertain; replacing fluorouracil with oral capecitabine warrants further validation in view of its convenience, favorable toxicity profile, and favorable trends in efficacy; and accelerated fractionation is not recommended for patients with locoregionally advanced NPC who receive chemoradiotherapy.

The Functional Living Index-Cancer is a reliable and valid instrument in Chinese cancer patients.

PURPOSE: To evaluate the linguistic and psychometric properties of the Functional Living Index-Cancer (FLIC) in assessing the quality of life of Chinese cancer patients. METHODS: The English FLIC was translated into Traditional Chinese by the standard forward-backward procedure. After cognitive debriefing, a Traditional Chinese FLIC was administered to 500 cancer patients in a major public hospital in Hong Kong. Of which, 200 were invited to complete the questionnaire in 2 weeks. To identify a scale structure appropriate to Chinese, exploratory and confirmatory factor analyses were performed on two randomly split halves of the sample. RESULTS: We identified five scales of the Traditional Chinese FLIC which assess the physical, psychological, hardship, nausea and social aspects. These five scales and the overall scale demonstrated satisfactory fit and had the alpha coefficient ranged from 0.68 to 0.92. The intra-class correlation coefficient ranged from 0.67 to 0.88. In addition, all FLIC scales were negatively associated with the Eastern Cooperative Oncology Group performance status and, also except for the psychological scale, had lower scores in patients who were treated by chemotherapy. CONCLUSIONS: The Traditional Chinese FLIC is an appropriate health indicator for Chinese cancer patients.

Concurrent celecoxib with 5-fluorouracil/epirubicin/cyclophosphamide followed by docetaxel for stages II - III invasive breast cancer: the OOTR-N001 study.

OBJECTIVES: This prospective study aimed at investigating the efficacy and safety of the concurrent use of celecoxib (CXB) with 5-fluorouracil, epirubicin and cyclophosphamide (FEC), followed by docetaxel (T) in the neoadjuvant setting. PATIENTS AND METHODS: A total of 64 invasive breast cancer patients were recruited in the N001 Phase II, multicenter, open-label, single-arm study to receive four cycles of FEC (500, 100, 500 mg/m(2)) followed by four cycles of T (100 mg/m(2)) with concurrent CXB (200 mg b.i.d.) as neoadjuvant therapy (NAT). The combined chemotherapies were administered on day 1 of each cycle every 3 weeks. Primary endpoints were pathologic complete response (pCR) rate and objective response rate (ORR). Quasi-pCR (QpCR), pCR and near pCR (npCR) were discussed considering their similar survival outcomes. ORR included clinical complete response (cCR) and clinical partial response (cPR). Secondary endpoints included safety, breast conservation rate and disease-free survival. RESULTS: Between February 2006 and January 2010, 57 of 64 evaluable patients with luminal A (n = 35, 61.4%), luminal B (n = 12, 21.1%), HER-2 positive (n = 8, 14%) and triple-negative (n = 2, 3.5%) breast cancer completed NAT and surgery. QpCR rate was observed in 18 (31.6%) patients. Exclusive of triple-negative subtype, pCR (p = 0.761) did not differ compared to other subtypes, while npCR (p = 0.043) exhibited a difference. Patients with HER-2 overexpression had a significantly higher QpCR than those of the disease attribute (10/20 vs 8/37, p = 0.029). After NAT, 43 (75.4%) and 13 (22.8%) patients achieved cCR and cPR, respectively. Patients responding to FEC were more likely to achieve a better ORR after subsequent T (p = 0.004). Over 80% of all patients received breast-conserving therapy (BCT) after receiving NAT, and 11 of 14 (78.6%) patients with T3 tumor at diagnosis became eligible for BCT after NAT. A total of 60 patients completed ≥ 6 cycles of NAT, followed by surgery; at a median follow-up of 50 months, 80% of the patients are disease-free. Neither drug-induced life-threatening toxicity nor cardiotoxicity was observed. CONCLUSIONS: Neoadjuvant use of FEC-T with concurrent CXB is active and safe for treatment of operable invasive breast cancer. The ORR was higher, but QpCR was comparable to other studies. Most patients are still disease-free, and BCT became an option for the females. Further clinical and translational studies on the use of cyclooxygenase-2 inhibitors with neoadjuvant chemotherapy are warranted.

Clinical outcomes of 174 nasopharyngeal carcinoma patients with radiation-induced temporal lobe necrosis.

PURPOSE: To retrospectively study the clinical outcomes of nasopharyngeal carcinoma patients with radiation-induced temporal lobe necrosis (TLN) treated with steroids, surgery, or observation only. METHODS AND PATIENTS: We performed a retrospective analysis of 174 consecutive patients diagnosed with TLN between 1990 and 2008. Before 1998, symptomatic patients were treated with oral steroids, while asymptomatic patients were treated conservatively. After 1998, most symptomatic and asymptomatic patients with a large volume of necrosis were treated by intravenously pulsed-steroid therapy with a standardized protocol. We examined factors affecting grade 4 complication-free survival and overall survival. Outcomes of the three treatment groups, those receiving conservative treatment, those receiving oral steroid, and those receiving intravenous pulse steroid, were compared. RESULTS: The mean follow-up time was 115 months. Rates of grade 4 complication-free survival at 2 years and at 5 years after diagnosis of TLN were 72.2% and 54.1%, respectively. The 2-year and 5-year overall survival rates were 57.5% and 35.4%, respectively. Multivariate analysis revealed that being symptomatic at diagnosis (relative risk [RR], 4.5; p = 0.0001), re-irradiation of the nasopharynx (NP) (RR, 1.56; p = 0.008), salvage brachytherapy to the NP (RR, 1.75; p = 0.012), and a short latency period before the diagnosis of TLN (RR, 0.96, p < 0.0001) were independent prognosticators of poor grade 4 complication-free survival. Patients with all four factors had a 100% risk of developing grade 4 complications within 5 years; whereas if no factor was present, the risk was 12.5%. Intravenous pulse steroid therapy was associated with a higher clinical response rate compared with conventional steroid therapy (p < 0.0001); however, it did not affect complication-free survival in multivariate analysis. CONCLUSIONS: TLN patients with good prognosticators could be observed without active treatment. Although treatment with intravenously pulsed steroid was associated with better clinical response than conventional steroid delivery, it did not affect the complication-free survival rate of TLN patients.

A randomized trial on addition of concurrent-adjuvant chemotherapy and/or accelerated fractionation for locally-advanced nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE: To evaluate the therapeutic benefits by adding chemotherapy (+C) and/or accelerated-fractionation (AF) for patients with T3-4N0-1M0 nasopharyngeal carcinoma. MATERIALS AND METHODS: From 1999 to 2004, 189 eligible patients were randomized to one of four treatment groups (CF/CF+C/AF/AF+C). The number of fractions/week was 5 for the CF groups and 6 for the AF groups. Patients in the +C groups were given concurrent cisplatin plus adjuvant cisplatin and fluorouracil. RESULTS: The AF+C group achieved significantly higher failure-free rate (88% at 5-year) than the CF group (63%; p=0.013), the AF group (56%; p=0.001) and the CF+C group (65%; p=0.027). As compared with CF alone, the increase in late toxicity was statistically insignificant (36% vs. 20%; p=0.25). Deaths due to cancer progression decreased (7% vs. 33%; p=0.011) but deaths due to incidental causes increased (9% vs. 2%; p=0.62). Improvement in overall survival reached borderline significance (85% vs. 66%; p=0.058). CONCLUSIONS: Concurrent-adjuvant chemotherapy combined with AF significantly reduced failure and cancer-specific deaths. Although the increase in major late toxicity and incidental deaths were statistically insignificant, a subtle increase in non-cancer deaths narrowed the overall survival gain.

Factors contributing to the efficacy of concurrent-adjuvant chemotherapy for locoregionally advanced nasopharyngeal carcinoma: combined analyses of NPC-9901 and NPC-9902 Trials.

BACKGROUND: The current standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC) was conventional-fractionation radiotherapy plus concurrent-adjuvant chemotherapy as recommended by the Intergroup-0099 Study. This combined analysis of the NPC-9901 and the NPC-9902 Trials aims to provide more comprehensive data to evaluate the efficacy of the Intergroup-0099 regimen and the contributing factors. METHODS: Eligible patients with stage III-IVB non-keratinizing NPC were randomly assigned to radiotherapy-alone (RT(i) group: 218 patients) or chemoradiotherapy (CRT(i) group: 223 patients) using cisplatin (100mg/m(2)) for three cycles in concurrence with radiotherapy, followed by cisplatin (80 mg/m(2)) plus fluorouracil (1000 mg/m(2)/day for 4 days) for three cycles. The median follow-up was 6.1 years. FINDINGS: Comparison by intention-to-treat showed that the CRT(i) group achieved significant improvement in overall failure-free rate (FFR), locoregional-FFR and cancer-specific survival (p ≤ 0.019); but the improvements for distant-FFR and overall survival (OS) were statistically insignificant (p ≥ 0.14). Further exploratory studies based on actual treatment showed that an additional improvement achieved was a significant gain in OS (CRT(a) versus RT(a) group: 72% versus 63% at 5-year, p=0.037). Multivariate analyses showed that the dose of cisplatin during the concurrent phase had significant impact on locoregional-FFR and OS, while that of fluorouracil during the adjuvant phase was significant for distant-FFR. The 5-year locoregional-FFR for patients who received 0-1, 2 and 3 concurrent cycles were 79%, 88% and 88%, respectively; the corresponding distant-FFR by adjuvant cycles were 68%, 78% and 77%, respectively. INTERPRETATION: Our results support the current practice of adding concurrent cisplatin plus adjuvant cisplatin-fluorouracil to radiotherapy for treating patients with locoregionally advanced NPC. The concurrent phase is important for locoregional control and survival, cisplatin 200mg/m(2) in two concurrent cycles might be adequate. Additional chemotherapy using fluorouracil-containing combination contributed to improving distant control.

Real-time monitoring and control on deep inspiration breath-hold for lung cancer radiotherapy--combination of ABC and external marker tracking.

PURPOSE: In this article, the breath-hold and gating concepts were combined for application of lung cancer radiation treatment. The tumor movement was immobilized based on deep inspiration breath hold (DIBH), in which the breath-hold consistency and stability were monitored by infrared (IR) tracking and controlled by gating with a predefined threshold. The authors' goal is to derive the benefits from both techniques, namely, the minimized treatment margin and the known advantages of deep inspiration. The efficacy of the technique in terms of tumor immobility and treatment setup accuracy was evaluated in the study. METHODS: Fourteen patients who were diagnosed with non small cell lung cancer were included in this study. The control of tumor immobility was investigated interfractionally and intrafractionally. The intrabreath-hold tumor motion was devised based on the external marker movement, in which the tumor-marker correlation was studied. The margin of the planning target volume (PTV) was evaluated based on two factors: (1) The treatment setup error accounts for the patient setup and interbreath-hold variations and (2) the intrabreath-hold tumor motion in which the residual tumor motion during irradiation was studied. RESULTS: As the result of the study, the group systematic error and group random error of treatment setup measured at the isocenter were 0.2(R) +/- 1.6, 1.0(A) +/- 2.0, and 0.3(S) +/- 1.5 mm in the left-right (LR), anterior-posterior (AP), and caudal-cranial (CC) directions, respectively. The Pearson correlation coefficient were 0.81 (LR), 0.76 (AP), and 0.85 (CC) mm and suggest tendency in linear correlation of tumor and marker movement. The intrabreath-hold tumor was small in all directions. The group PTV margins of 3.8 (LR), 4.6 (AP), and 4.8 (CC) mm were evaluated to account for both setup errors and residual tumor motion during irradiation. CONCLUSIONS: The study applies the DIBH technique in conjunction with IR positional tracking for tumor immobilization and treatment setup localization. The technique not only proved to be reliable in terms of good tumor immobility and accurate treatment positioning but also to be potentially useful for dose escalation treatment as regarding of the substantially reduced PTV margin and minimizing radiation toxicity from the fully expanded lung volume.

Randomized trial of radiotherapy plus concurrent-adjuvant chemotherapy vs radiotherapy alone for regionally advanced nasopharyngeal carcinoma.

BACKGROUND: Current practice of adding concurrent-adjuvant chemotherapy to radiotherapy (CRT) for treating advanced nasopharyngeal carcinoma is based on the Intergroup-0099 Study published in 1998. However, the outcome for the radiotherapy-alone (RT) group in that trial was substantially poorer than those in other trials, and there were no data on late toxicities. Verification of the long-term therapeutic index of this regimen is needed. METHODS: Patients with nonkeratinizing nasopharyngeal carcinoma staged T1-4N2-3M0 were randomly assigned to RT (176 patients) or to CRT (172 patients) using cisplatin (100 mg/m(2)) every 3 weeks for three cycles in concurrence with radiotherapy, followed by cisplatin (80 mg/m(2)) plus fluorouracil (1000 mg per m(2) per day for 4 days) every 4 weeks for three cycles. Primary endpoints included overall failure-free rate (FFR) (the time to first failure at any site) and progression-free survival. Secondary endpoints included overall survival, locoregional FFR, distant FFR, and acute and late toxicity rates. All statistical tests were two-sided. RESULTS: The two treatment groups were well balanced in all patient characteristics, tumor factors, and radiotherapy parameters. Adding chemotherapy statistically significantly improved the 5-year FFR (CRT vs RT: 67% vs 55%; P = .014) and 5-year progression-free survival (CRT vs RT: 62% vs 53%; P = .035). Cumulative incidence of acute toxicity increased with chemotherapy by 30% (CRT vs RT: 83% vs 53%; P < .001), but the 5-year late toxicity rate did not increase statistically significantly (CRT vs RT: 30% vs 24%; P = .30). Deaths because of disease progression were reduced statistically significantly by 14% (CRT vs RT: 38% vs 24%; P = .008), but 5-year overall survival was similar (CRT vs RT: 68% vs 64%; P = .22; hazard ratio of CRT = 0.81, 95% confidence interval = 0.58 to 1.13) because deaths due to toxicity or incidental causes increased by 7% (CRT vs RT: 1.7% vs 0, and 8.1% vs 3.4%, respectively; P = .015). CONCLUSIONS: Adding concurrent-adjuvant chemotherapy statistically significantly reduced failure and cancer-specific deaths when compared with radiotherapy alone. Although there was no statistically significant increase in major late toxicity, increase in noncancer deaths narrowed the resultant gain in overall survival.

Risk of second primary malignancies following nasopharyngeal carcinoma in Hong Kong.

Nasopharyngeal carcinoma (NPC) is rare in most of the world but common among southeast Asians. Since NPC is usually diagnosed at relatively young ages and most patients now survive, the issue of second primary tumors (SPTs) has become important. Previous studies of SPTs among NPC survivors have given conflicting results. Data on patients with NPC diagnosed between 1996 and 2002 were abstracted from the medical records of two Hong Kong oncology centers. SPT incidence in these patients was compared to that of Hong Kong's general population using standardized incidence ratios (SIR). Eight-four patients were observed to have at least 1 SPT and 92 total additional cancers (SIR = 1.93, 95% CI = 1.55-2.37). The excess risk was greater for women and patients under 40 at diagnosis. Significant excesses were found for tongue, lung, nasal and middle ear, and brain cancers. The pattern of sites at which the greatest excess risk occurred is consistent with the hypothesis that much of the excess is due to treatment effects. The greater excess risk among patients diagnosed before 40 points to possible genetic influences. More research is needed to determine the reasons for greater excess risk among women.

Whole-field simultaneous integrated-boost intensity-modulated radiotherapy for patients with nasopharyngeal carcinoma.

PURPOSE: To retrospectively review the outcomes of our patients with newly diagnosed nondisseminated nasopharyngeal carcinoma treated with intensity-modulated radiotherapy using a whole-field simultaneous integrated-boost technique. METHODS AND MATERIALS: A total of 175 patients treated with WF-SIB between mid-2004 and 2005 were eligible for study inclusion. The distribution of disease by stage was Stage IA in 10.9%, Stage IIA in 2.3%, Stage IIB in 21.7%, Stage III in 41.1%, Stage IVA in 14.9%, and Stage IVB in 9.1%. Of the 175 patients, 2 (1.2%), 10 (5.7%), and 163 (93.1%) had World Health Organization type I, II, and III histologic features, respectively. We prescribed 70 Gy, 60 Gy, and 54 Gy delivered in 33 fractions within 6.5 weeks at the periphery of three planning target volumes (PTV; PTV70, PTV60, and PTV54, respectively). Of the 175 patients, 46 with early T-stage disease received a brachytherapy boost, and 127 with advanced local or regional disease received chemotherapy. RESULTS: The median follow-up period was 34 months. The overall 3-year local failure-free survival, regional failure-free survival, distant failure-free survival, and overall survival rate was 93.6%, 93.3%, 86.6%, and 87.2%, respectively. Cox regression analysis showed Stage N2-N3 disease (p = .029) and PTV (p = .024) to be independent factors predicting a greater risk of distant failure and poor overall survival, respectively. Grade 3 acute mucositis/pharyngitis occurred in 23.4% of patients, and Stage T4 disease was the only significant predictor of mucositis/pharyngitis (p = .021). CONCLUSION: Whole-field simultaneous integrated-boost intensity-modulated radiotherapy with a dose >70 Gy achieved excellent locoregional control, without an excess incidence of severe, acute mucositis/pharyngitis, in the present study. Strategies for using such highly conformal treatment for patients with a large tumor and late N-stage disease are potential areas of investigation for future studies.