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.
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/m2) every 3 weeks for three cycles in concurrence with radiotherapy, followed by cisplatin (80 mg/m2) plus fluorouracil (1000 mg per m2 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.
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 RARβ2) 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.
What's new?
Tests for Epstein‐Barr virus (EBV) DNA may help screen high‐risk populations for nasopharyngeal carcinoma (NPC), but these tests are not very sensitive. In this study, the authors developed a panel of biomarkers that instead tests for altered methylation of tumor‐suppressor genes. They found that, when plasma and swabs from early‐stage NPC patients were analyzed with the methylation panel, it detected the cancer with higher sensitivity and specificity than tests for EBV DNA. Combining the two tests may enhance noninvasive screening for NPC, thus enabling more timely and effective treatments.
•Treatment outcomes of 3328 NPC patient treated with IMRT in Hong Kong.•8 year local/regional control remained promising.•Confirmed benefits of concurrent chemotherapy with IMRT.•Additional ...chemotherapy onto backbone of concurrent chemo-irradiation warrants further investigation.•Various severe symptomatic complications after IMRT remained low.
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.
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.
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.
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.
This randomized study compared the results achieved by concurrent chemoradiotherapy (CRT) versus radiotherapy (RT) alone for nasopharyngeal carcinoma (NPC) with advanced nodal disease.
Patients with ...nonkeratinizing/undifferentiated NPC staged T1-4N2-3M0 were randomized to CRT or RT. Both arms were treated with the same RT technique and dose fractionation. The CRT patients were given cisplatin 100 mg/m2 on days 1, 22, and 43, followed by cisplatin 80 mg/m2 and fluorouracil 1,000 mg/m2/d for 96 hours starting on days 71, 99, and 127.
From 1999 to January 2004, 348 eligible patients were randomly assigned; the median follow-up was 2.3 years. The two arms were well-balanced in all prognostic factors and RT parameters. The CRT arm achieved significantly higher failure-free survival (72% v 62% at 3-year, P = .027), mostly as a result of an improvement in locoregional control (92% v 82%, P = .005). However, distant control did not improve significantly (76% v 73%, P = .47), and the overall survival rates were almost identical (78% v 78%, P = .97). In addition, the CRT arm had significantly more acute toxicities (84% v 53%, P < .001) and late toxicities (28% v 13% at 3-year, P = .024).
Preliminary results confirmed that CRT could significantly improve tumor control, particularly at locoregional sites. However, there was significant increase in the risk of toxicities and no early gain in overall survival. Longer follow-up is needed to confirm the ultimate therapeutic ratio.
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.
The 5‐year results from the NPC‐0501 trial demonstrate that conventional fractionation remains the standard recommendation for patients with locoregionally advanced nasopharyngeal carcinoma who are treated with chemoradiotherapy because acceleration does not appear to achieve any therapeutic benefit, and could affect the potential benefit of changing from concurrent‐adjuvant to induction‐concurrent chemotherapy. For patients who undergo irradiation with conventional fractionation, changing the chemotherapy sequence from concurrent‐adjuvant to induction‐concurrent, particularly using induction cisplatin and capecitabine, could improve efficacy without resulting in the development of late toxicities. However, further validation is needed for confirmation.
To retrospectively study the clinical outcomes of nasopharyngeal carcinoma patients with radiation-induced temporal lobe necrosis (TLN) treated with steroids, surgery, or observation only.
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.
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.
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.
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.
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.
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).
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.
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