Capecitabine monotherapy for recurrent and metastatic nasopharyngeal cancer.

BACKGROUND: Capecitabine monotherapy had activity in recurrent/metastatic nasopharyngeal carcinoma (NPC) as demonstrated previously in a small pilot study. We conducted a retrospective review of patients who received capecitabine for recurrent and metastatic NPC to further evaluate its clinical benefits. METHODS: Forty-nine patients with recurrent and metastatic NPC received capecitabine at a dose of 1-1.25 G/m(2) twice daily for 14 days in 3-week cycles. Disease sites were locoregional in 29%, distant in 45% and locoregional plus distant in 26%. All except one had prior platinum-based chemotherapy for relapse or as adjunctive treatment. Median follow-up was 10 months (range: 3-41). RESULTS: Treatment was generally well tolerated. Hand-foot syndrome was common and occurred in 86% (25% Grade 3). Grade 3 hematological toxicity occurred in 6%. Partial response rate was 31% (95% CI: 18%, 44%) and complete response rate was 6% (95% CI: 0%, 13%), for an overall response rate of 37% (95% CI: 23%, 50%). Median time-to-progression was 5 months and median survival was 14 months. One- and two-year survival rates were 54 and 26%, respectively. Significantly better survival was observed in patients treated for locoregional recurrence and those with severe hand-foot syndrome. CONCLUSIONS: Capecitabine has single agent activity in NPC and severe hand-foot syndrome predicts favorable outcome. Based on our experience, capecitabine monotherapy should be considered in patients with recurrent/metastatic NPC.

MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma.

CONTEXT: MicroRNAs have potential as diagnostic biomarkers and therapeutic targets in cancer. No study has evaluated the association between microRNA expression patterns and colon cancer prognosis or therapeutic outcome. OBJECTIVE: To identify microRNA expression patterns associated with colon adenocarcinomas, prognosis, or therapeutic outcome. DESIGN, SETTING, AND PATIENTS: MicroRNA microarray expression profiling of tumors and paired nontumorous tissues was performed on a US test cohort of 84 patients with incident colon adenocarcinoma, recruited between 1993 and 2002. We evaluated associations with tumor status, TNM staging, survival prognosis, and response to adjuvant chemotherapy. Associations were validated in a second, independent Chinese cohort of 113 patients recruited between 1991 and 2000, using quantitative reverse transcription polymerase chain reaction assays. The final date of follow-up was December 31, 2005, for the Maryland cohort and August 16, 2004, for the Hong Kong cohort. MAIN OUTCOME MEASURES: MicroRNAs that were differentially expressed in tumors and microRNA expression patterns associated with survival using cancer-specific death as the end point. RESULTS Thirty-seven microRNAs were differentially expressed in tumors from the test cohort. Selected for validation were miR-20a, miR-21, miR-106a, miR-181b, and miR-203, and all 5 were enriched in tumors from the validation cohort (P < .001). Higher miR-21 expression was present in adenomas (P = .006) and in tumors with more advanced TNM staging (P < .001). In situ hybridization demonstrated miR-21 to be expressed at high levels in colonic carcinoma cells. The 5-year cancer-specific survival rate was 57.5% for the Maryland cohort and was 49.5% for the Hong Kong cohort. High miR-21 expression was associated with poor survival in both the training (hazard ratio, 2.5; 95% confidence interval, 1.2-5.2) and validation cohorts (hazard ratio, 2.4; 95% confidence interval, 1.4-3.9), independent of clinical covariates, including TNM staging, and was associated with a poor therapeutic outcome. CONCLUSIONS: Expression patterns of microRNAs are systematically altered in colon adenocarcinomas. High miR-21 expression is associated with poor survival and poor therapeutic outcome.

Stereotactic radiosurgery versus gold grain implantation in salvaging local failures of nasopharyngeal carcinoma.

BACKGROUND: Limited local failure of nasopharyngeal carcinoma (NPC) can often be salvaged by reirradiation using different techniques. Both gold grain implantation (GGI) and stereotactic radiosurgery (SRS) have been used as salvage treatment of NPC but the relative efficacy of these two treatments is not known. METHODS AND MATERIALS: A total of 74 patients with local NPC failure were included in this retrospective analysis. Of these patients, 37 underwent SRS (median dose, 12.5 Gy) and 37 split-palatal GGI at a dose of 60 Gy. The two groups were individually matched for prognostic factors, except for tumor volume. The median follow-up was 42 months. RESULTS: Local control was better in the GGI group. The 3-year local failure-free rate was 77.9% for the GGI group compared with 68.3% for the SRS group. However, the difference was not statistically significant (p = 0.098). In the subgroup with a tumor volume of

Preliminary results of a randomized study on therapeutic gain by concurrent chemotherapy for regionally-advanced nasopharyngeal carcinoma: NPC-9901 Trial by the Hong Kong Nasopharyngeal Cancer Study Group.

PURPOSE: This randomized study compared the results achieved by concurrent chemoradiotherapy (CRT) versus radiotherapy (RT) alone for nasopharyngeal carcinoma (NPC) with advanced nodal disease. PATIENTS AND METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Predictive factors of tumor control and survival after radiosurgery for local failures of nasopharyngeal carcinoma.

BACKGROUND: Stereotactic radiosurgery has been employed as a salvage treatment of local failures of nasopharyngeal carcinoma (NPC). To identify patients that would benefit from radiosurgery, we reviewed our data with emphasis on factors that predicted treatment outcome. PATIENTS AND METHODS: A total of 48 patients with local failures of NPC were treated by stereotactic radiosurgery between March 1996 and February 2005. Radiosurgery was administered using a modified linear accelerator with single or multiple isocenters to deliver a median dose of 12.5 Gy to the target periphery. Median follow-up was 54 months. RESULTS: Five-year local failure-free probability after radiosurgery was 47.2% and 5-year overall survival rate was 46.9%. Neuroendocrine complications occurred in 27% of patients but there were no treatment-related deaths. Time interval from primary radiotherapy, retreatment T stage, prior local failures and tumor volume were significant predictive factors of local control and/or survival whereas age was of marginal significance in predicting survival. A radiosurgery prognostic scoring system was designed based on these predictive factors. Five-year local failure-free probabilities in patients with good, intermediate and poor prognostic scores were 100%, 42.5%, and 9.6%. The corresponding five-year overall survival rates were 100%, 51.1%, and 0%. CONCLUSION: Important factors that predicted tumor control and survival after radiosurgery were identified. Patients with good prognostic score should be treated by radiosurgery in view of the excellent results. Patients with intermediate prognostic score may also be treated by radiosurgery but those with poor prognostic score should receive other salvage treatments.

Preliminary results of radiation dose escalation for locally advanced nasopharyngeal carcinoma.

PURPOSE: To study the safety and efficacy of dose escalation in tumor for locally advanced nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: From September 2000 to June 2004, 50 patients with T3-T4 NPC were treated with intensity-modulated radiotherapy (IMRT). Fourteen patients had Stage III and 36 patients had Stage IVA-IVB disease. The prescribed dose was 76 Gy to gross tumor volume (GTV), 70 Gy to planning target volume (PTV), and 72 Gy to enlarged neck nodes (GTVn). All doses were given in 35 fractions over 7 weeks. Thirty-four patients also had concurrent cisplatin and induction or adjuvant PF (cisplatin and 5-fluorouracil). RESULTS: The average mean dose achieved in GTV, GTVn, and PTV were 79.5 Gy, 75.3 Gy, and 74.6 Gy, respectively. The median follow-up was 25 months, with 4 recurrences: 2 locoregional and 2 distant failures. All patients with recurrence had IMRT alone without chemotherapy. The 2-year locoregional control rate, distant metastases-free and disease-free survivals were 95.7%, 94.2%, and 93.1%, respectively. One treatment-related death caused by adjuvant chemotherapy occurred. The 2-year overall survival was 92.1%. CONCLUSIONS: Dose escalation to 76 Gy in tumor is feasible with T3-T4 NPC and can be combined with chemotherapy. Initial results showed good local control and survival.

Improvement of survival after addition of induction chemotherapy to radiotherapy in patients with early-stage nasopharyngeal carcinoma: Subgroup analysis of two Phase III trials.

PURPOSE: Induction chemotherapy has not been shown to improve survival in nasopharyngeal carcinoma (NPC) in Phase III trials. To evaluate the effect of induction chemotherapy in NPC further, we performed subgroup analysis of two Phase III trials according to the T and N stage. METHODS AND MATERIALS: Data from two phase III trials comparing cisplatin/epirubicin or cisplatin/bleomycin/5-fluorouracil followed by radiotherapy (RT) vs. RT alone in NPC were pooled together for analysis. Patients were stratified into four subgroups according to the 1997 American Joint Committee on Cancer T and N stage: T1-T2N0-N1, Group 1 (early-stage disease); T1-T2N2-N3, Group 2 (advanced N disease); T3-T4N0-N1, Group 3 (advanced T stage); and T3-T4N2-N3, Group 4 (advanced T and N disease). Group 1 consisted entirely of patients with Stage IIB disease. A total of 784 patients were included for analysis on an intent-to-treat basis. The median follow-up for the surviving patients was 67 months. RESULTS: No significant differences in overall survival, locoregional failure-free, or distant metastasis-free rates were observed between the combined and RT arms in Groups 2 to 4. Significant differences in the overall survival and distant metastasis-free rates were observed only in Group 1, favoring the combined chemotherapy and RT arm. The 5-year overall survival rate was 79% in the combined arm and 67% in the RT-alone arm (p = 0.048). The corresponding 5-year distant metastasis-free rates were 86% and 74% (p = 0.0053). CONCLUSIONS: Our results have shown that patients in Group 1, with early-stage NPC treated by RT alone, had relatively poor survival because of distant metastases. The observation of improved outcomes in this subgroup after the addition of induction chemotherapy has not been previously reported and warrants additional investigation.

Dose-response relationship of nasopharyngeal carcinoma above conventional tumoricidal level: a study by the Hong Kong nasopharyngeal carcinoma study group (HKNPCSG).

BACKGROUND AND PURPOSE: To define the dose-response relationship of nasopharyngeal carcinoma (NPC) above the conventional tumoricidal dose level of 66 Gy when the basic radiotherapy (RT) course was given by the 2D Ho's technique. PATIENTS AND METHODS: Data from all five regional cancer centers in Hong Kong were pooled for this retrospective study. All patients (n = 2426) were treated with curative-intent RT with or without chemotherapy between 1996 and 2000 with the basic RT course using the Ho's technique. The primary endpoint was local control. The prognostic significance of dose-escalation ('boost') after 66 Gy, T-stage, N-stage, use of chemotherapy, sex and age (< or =40 years vs >40 years) was studied. Both univariate and multivariate analyses were performed. RESULTS: On multivariate analysis, T-stage (P < 0.01; hazard ratio [HR], 1.58) and optimal boost (P = 0.01; HR, 0.34) were the only significant factors affecting local failure for the whole study population, and for the population of patients treated by radiotherapy alone, but not for patients who also received chemotherapy. The following were independent determinants of local failure for patient groups with different T-stages treated by radiotherapy alone: use of a boost in T1/T2a disease (P = 0.01; HR, 0.33); use of a boost (P < 0.01; HR, 0.60) and age (P = 0.01; HR, 1.02) in T3/T4 tumors. Among patients with T2b tumors treated by radiotherapy alone and given a boost, the use of a 20 Gy-boost gave a lower local failure rate than a 10 Gy-boost. There was no apparent excess mortality attributed to RT complications. CONCLUSIONS: Within the context of a multi-center retrospective study, dose-escalation above 66 Gy significantly improved local control for T1/T2a and T3/4 tumors when the primary RT course was based on the 2D Ho's technique without additional chemotherapy. 'Boosting' in NPC warrants further investigation. Caution should be taken when boosting is considered because of possible increase in radiation toxicity.

Concurrent and adjuvant chemotherapy for nasopharyngeal carcinoma: a factorial study.

PURPOSE: To study the efficacy of concurrent chemoradiotherapy (CRT) and adjuvant chemotherapy (AC) for nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Patients with Ho's stage T3 or N2/N3 NPC or neck node > or = 4 cm were eligible. Patients were randomly assigned to have radiotherapy (RT) or CRT with uracil and tegafur and to have AC or no AC after RT/CRT. AC comprised alternating cisplatin, fluorouracil, vincristine, bleomycin, and methotrexate for six cycles. There were four treatment groups: A, RT; B, CRT; C, RT and AC; D, CRT and AC. For CRT versus RT, groups B and D were compared with groups A and C. For AC versus no AC, groups C and D were compared with groups A and B. RESULTS: Three-year failure-free survival (FFS) and overall survival (OS) for CRT versus RT were 69.3% versus 57.8% and 86.5% versus 76.8%, respectively (P =.14 and.06; n = 110 v 109). Distant metastases rate (DMR) was significantly reduced with CRT (14.8% v 29.4%; P =.026). Locoregional failure rates (LRFR) were similar (20% v 27.6%; P =.39). Three-year FFS and OS for AC versus no AC were 62.5% versus 65% and 80.4% versus 83.1%, respectively (P =.83 and.69; n = 111 v 108). DMR and LRFR were not reduced with AC (P =.34 and.15, respectively). Cox model showed CRT to be a favorable prognostic factor for OS (hazard ratio, 0.42; P =.009). CONCLUSION: An improvement in OS with CRT was observed but did not achieve statistical significance. The improvement seemed to be associated with a significant reduction in DMR. AC did not improve outcome.

Re-irradiation of nasopharyngeal carcinoma with intensity-modulated radiotherapy.

BACKGROUND AND PURPOSE: To evaluate the treatment outcome in patients with locally recurrent nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). MATERIALS AND METHODS: Between October 2001 and May 2004, 31 patients with locally recurrent NPC received re-irradiation using IMRT. The rT classification distribution was 3 for rT1, 5 for rT2, 9 for rT3, and 14 for r T4. Median time from first course of radiotherapy to re-irradiation was 51 months. IMRT was performed using step-and-shoot method with nine 4-6 MV photon fields and median prescribed dose was 54 Gy (range: 50-60 Gy). Additional treatments included cisplatin-based induction chemotherapy in 68% and radiosurgery boost with a single dose which ranged from 8.5 to 12.5 Gy in 32%. Median follow-up time was 11 months. RESULTS: After re irradiation, 58% of patients had complete regression of primary tumor. One-year loco-regional progression-free, distant metastasis-free and overall survival rates were 56, 90, and 63%, respectively. Significantly better 1-year local progression-free rate was observed in rT1-3 than r T4 tumor (100 vs. 35%). Grade 3 late toxicities, mostly ototoxicity/cranial neuropathy, occurred in six patients (19%). One-year actuarial rates of late toxicities were 70% for all grades and 25% for Grade 3. CONCLUSION: Our preliminary results showed that good control of rT1-3 NPC can be achieved using IMRT with a dose between 50 and 60 Gy, whereas the outcome for r T4 tumor remained poor. Late toxicities were common but incidence of severe toxicities was relatively low.

A phase II study of docetaxel and cisplatin as first-line chemotherapy in patients with metastatic nasopharyngeal carcinoma.

To evaluate the efficacy and safety of docetaxel and cisplatin as first-line chemotherapy in patients with metastatic nasopharyngeal carcinoma (NPC). Nineteen previously untreated metastatic NPC patients received one to six cycles of docetaxel and cisplatin. Fifteen patients received at least three cycles. The starting dose was 75 mg/m2 every three weeks for both drugs in 15 patients, and 60 mg/m2 for both drugs in four patients. All patients were included in toxicity and survival analysis, and 16 patients were evaluable for response. Median follow-up time was 11.6 months. Hematological toxicity was severe with Grade 4 neutropenia in 78.9% patients and 51.3% cycles. Febrile neutropenia occurred in 42% patients and 12.5% cycles, with two septic deaths in the population treated with 75 mg/m2. Patients treated with a dose subsequently reduced to 60 mg/m2 had a lower incidence of Grade 4 neutropenia and no incidence of neutropenic fever/sepsis. Overall response rate was 62.5%, with a 95% confidence interval of 35-85%. Partial and complete response rates were 56.3% and 6.3%, respectively. Median time to progression was 5.6 months and median survival was 12.4 months. Three patients (15.6%) survived >2 years following chemotherapy. The combination of docetaxel and cisplatin is active in metastatic NPC. The dose of 60 mg/m2 for both drugs without colony-stimulating factor support should be further evaluated as a high incidence of febrile neutropenia was observed with 75 mg/m2 dose.

Prognostic value of epidermal growth factor receptor expression in patients with advanced stage nasopharyngeal carcinoma treated with induction chemotherapy and radiotherapy.

PURPOSE: A retrospective study was performed to correlate the expression of epidermal growth factor receptor (EGFR) with treatment outcome in advanced stage nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: The study population comprised 54 of 92 patients with American Joint Committee on Cancer Stage III-IV NPC with sufficient pretreatment tumor biopsy specimens for study. Immunohistochemical staining was performed to evaluate the extent and intensity of EGFR expression. All patients were treated by induction chemotherapy with two to three cycles of cisplatin 60 mg/m(2) and epirubicin 110 mg/m(2) every 3 weeks followed by radiotherapy. The median follow-up time was 52 months for all patients and 99 months for surviving patients. RESULTS: EGFR expression was present in 89% of cases. EGFR intensity was negative in 11%, weak in 43%, moderate in 13%, and strong in 33%. The EGFR extent was <5% in 15%, > or =5% but <25% in 13%, and > or =25% in 72%. No correlation was found between EGFR expression and T stage, N stage, stage group, nodal size, gender, and age. No statistically significant differences in chemotherapy response rates were found in patients with different EGFR intensity and extent. EGFR extent > or =25% was associated with a significantly poorer treatment outcome. The 5-year disease-specific survival, relapse-free survival, locoregional relapse-free, and distant metastasis-free rate in patients with EGFR extent > or =25% was 48%, 36%, 60%, and 55%, respectively. The corresponding rates in patients with EGFR extent <25% were 86%, 80%, 93%, and 86%. The differences were all statistically significant, except for distant metastasis. No statistically significant differences in relapse-free and disease-specific survival rates were found among patients with differing EGFR intensity. In multivariate analysis, EGFR extent was the only independent factor that predicted for disease relapse, locoregional failure, and cancer death. CONCLUSION: Our study results showed that EGFR expression was common in advanced stage NPC, and the expression did not correlate with tumor or nodal stage. Correlative analysis showed that EGFR extent was a strong, independent prognostic factor that determined locoregional control, relapse-free survival, and disease-specific survival in Stage III-IV NPC treated with induction chemotherapy and radiotherapy. Our findings suggest that EGFR expression status can identify a subgroup of patients within advanced stage disease that will have a poor outcome after induction chemotherapy and radiotherapy. Whether this patient subgroup will benefit from an alternate treatment strategy and anti-EGFR-targeted treatment requires additional studies.

Concomitant chemoirradiation for stage III-IV nasopharyngeal carcinoma in Chinese patients: results of a matched cohort analysis.

PURPOSE: To evaluate the toxicity and efficacy of concomitant chemoirradiation (CRT) followed by adjuvant chemotherapy compared with radiotherapy (RT) alone in Chinese patients with locoregionally advanced nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: Between March 1997 and September 2000, 47 Chinese patients with Stage III (n = 9, 19%) and IV (n = 38, 81%) NPC were treated with by CRT using cisplatin 100 mg/m(2) on Days 1, 22, and 43 of RT, plus adjuvant chemotherapy using cisplatin 80 mg/m(2) for 1 day and 5-fluorouracil 1 g/m(2) for 4 days on Days 71, 99, and 127. These patients were then compared with a cohort of 47 patients treated between 1990 and 1993 with RT alone, who were matched with respect to T stage, N stage, nodal bilaterality, nodal level, and nodal size. The RT techniques were similar in the two groups but different dose and fractionation schemes were used. The median biologic equivalent dose to 2 Gy per fraction delivered to the nasopharynx was 68 Gy in the CRT group and 65.3 Gy in the RT-alone group. RESULTS: The compliance rates were 62% for concomitant chemotherapy and 40% for adjuvant chemotherapy. No treatment-related deaths occurred. At the end of treatment, 96% of the CRT group and 79% of the RT-alone group achieved a complete response (p = 0.013). With a median follow-up of 26 months, the 3-year relapse-free survival, disease-specific survival, overall survival, local relapse-free survival, nodal relapse-free survival, and distant metastasis-free survival rate for the CRT group and the RT-alone group was 62% vs. 44% (p = 0.048), 67% vs. 71% (p = 0.88), 65% vs. 69% (p = 0.93), 87% vs. 75% (p = 0.059), 95% vs. 80% (p = 0.026), and 75% vs. 70% (p = 0.84), respectively. CONCLUSION: Our experience indicates that concomitant CRT improves locoregional control in Chinese patients with locoregionally advanced NPC, but our analyses failed to detect any impact on distant failure and survival. The failure to reduce distant metastasis and improve survival may have related in part to the more advanced disease stage in our patients and the relatively low compliance rate of adjuvant chemotherapy. Our findings suggest caution should be exercised in extrapolating the findings of the Intergroup Study 0099 to Chinese patients, and confirmatory results from prospective randomized studies in the endemic population are needed.

Tumor volume is not an independent prognostic factor in early-stage nasopharyngeal carcinoma treated by radiotherapy alone.

PURPOSE: To determine whether the tumor volume can predict the treatment outcome in early-stage nasopharyngeal carcinoma (NPC) treated by radiotherapy alone. METHODS AND MATERIALS: The pretreatment CT scans of 116 patients with American Joint Committee on Cancer Stage I-II NPC treated by radiotherapy alone were retrospectively reviewed. The clinician outlined the tumor extent. The primary tumor volume (PTV) and nodal volume (NV) were then calculated by a summation-of-areas technique. The PTV and NV were correlated with locoregional control, distant failure, and survival. The median follow-up time was 105 months. RESULTS: Patients with Stage I disease had a 5-year locoregional control rate of 95% and a disease-specific survival (DSS) rate of 97%; for Stage II disease, the corresponding rates were 81% and 79%. The PTV ranged from 1.3 to 75.5 cm3 (median, 12.6 cm3), with substantial overlap between T1 and T2 disease. The NV ranged from 0 to 35.4 cm(3). Patients with a PTV >15 cm3 had significantly worse local control (5-year control rate, 82% vs. 93%; p = 0.033), but no statistically significant difference was noted in survival (5-year DSS rate, 83% vs. 89%; p = 0.30). The difference in local control was mainly seen in those with T2 disease. Patients with NV >4 cm3 had a greater distant failure rate (5-year distant metastasis-free rate, 72% vs. 90%; p = 0.011) and worse survival (5-year DSS rate, 76% vs. 94%; p = 0.0038). Nodal control was excellent with no difference between a NV of < or =4 cm3 and a NV of >4 cm3 (5-year control rate, 97% vs. 100%). The survival rate was worst in patients with a PTV >15 cm3 and a NV >4 cm3 (5-year DSS rate, 68%) and best in those with a PTV of < or =15 cm3 and a NV of < or =4 cm3 (5-year DSS rate, 92%). Multivariate analysis, however, showed that only parapharyngeal extension (T2b) and N1 stage were independent factors that predicted locoregional control and survival, and N1 stage was the only factor that predicted distant failure. CONCLUSION: The pretreatment tumor volume has a limited prognostic value in early-stage NPC compared with the usual T and N classification, with Stage T2b and N1 as independent factors that predicted treatment outcome. Within T2 disease, the estimation of tumor volume may identify a subgroup of patients with a greater risk of local failure that warrants more aggressive treatment.

A phase II study of capecitabine in patients with recurrent and metastatic nasopharyngeal carcinoma pretreated with platinum-based chemotherapy.

To evaluate the efficacy and toxicity of capecitabine as a salvage chemotherapy regimen in Chinese patients with recurrent or metastatic nasopharyngeal carcinoma (NPC) previously treated with platinum-based chemotherapy, 17 patients with recurrent or metastatic NPC previously treated with platinum-based chemotherapy as adjuvant or palliative treatments received oral capecitabine at a dose of 1.25 G/m(2) twice daily in 3-week cycles consisting of 2 weeks of treatment followed by rest period of 1 week. Seven patients had local recurrence, seven had distant metastases, one had loco-regional recurrence, and two had both local/regional recurrence and distant metastases. Patients received a median number of three cycles of capecitabine (range: 1-6). The median follow-up was 7.5 months (range: 3-25.3). All patients were included in the efficacy and adverse events analysis. Three patients (17.6%) achieved partial response and one patient (5.9%) achieved complete response, with an overall response rate of 23.5% (95% confidence interval, 7-50%). The duration of response's were 4.2, 5, 6+, and 23.1+ months. Nine patients (52.9%) had stable disease whereas four (23.5%) had progressive disease. The median time to progression was 4.9 months. The median survival was 7.6 months. Five patients are still alive with an estimated 1-year survival rate of 35%. Treatment-related adverse events were generally mild except hand-foot syndrome which occurred in 58.8% of patients. Capecitabine is an effective salvage regimen in patients with recurrent and metastatic NPC. Capecitabine as a single agent or in combination with other chemotherapeutic agents or treatment modalities should be further studied in NPC.

Dosimetric predictors of radiation-induced acute nausea and vomiting in IMRT for nasopharyngeal cancer.

PURPOSE: We wanted to investigate dosimetric parameters that would predict radiation-induced acute nausea and vomiting in intensity-modulated radiation therapy (IMRT) for undifferentiated carcinoma of the nasopharynx (NPC). METHODS AND MATERIALS: Forty-nine consecutive patients with newly diagnosed NPC were treated with IMRT alone in this prospective study. Patients receiving any form of chemotherapy were excluded. The dorsal vagal complex (DVC) as well as the left and right vestibules (VB-L and VB-R, respectively) were contoured on planning computed tomography images. A structure combining both the VB-L and the VB-R, named VB-T, was also generated. All structures were labeled organs at risk (OAR). A 3-mm three-dimensional margin was added to these structures and labeled DVC+3 mm, VB-L+3 mm, VB-R+3 mm, and VB-T+3 mm to account for physiological body motion and setup error. No weightings were given to these structures during optimization in treatment planning. Dosimetric parameters were recorded from dose-volume histograms. Statistical analysis of parameters' association with nausea and vomiting was performed using univariate and multivariate logistic regression. RESULTS: Six patients (12.2%) reported Grade 1 nausea, and 8 patients (16.3%) reported Grade 2 nausea. Also, 4 patients (8.2%) complained of Grade 1 vomiting, and 4 patients (8.2%) experienced Grade 2 vomiting. No patients developed protracted nausea and vomiting after completion of IMRT. For radiation-induced acute nausea, V40 (percentage volume receiving at least 40Gy) to the VB-T and V40>=80% to the VB-T were predictors, using univariate analysis. On multivariate analysis, V40>=80% to the VB-T was the only predictor. There were no predictors of radiation-induced acute vomiting, as the number of events was too small for analysis. CONCLUSIONS: This is the first study demonstrating that a V40 to the VB-T is predictive of radiation-induced acute nausea. The vestibules should be labeled as sensitive OARs, and weightings should be considered for dose sparing during optimization in the treatment planning of IMRT.

Comparative analysis of dosimetric parameters of three different radiation techniques for patients with Graves' ophthalmopathy treated with retro-orbital irradiation.

BACKGROUND: We would like to investigate the if IMRT produced better target coverage and dose sparing to adjacent normal structures as compared with 3-dimensional conformal radiotherapy (3DCRT) and lateral opposing fields (LOF) for patients with Graves' ophthalmopathy treated with retro-orbital irradiation. METHODS: Ten consecutive patients diagnosed with Graves' ophthalmopathy were prospectively recruited into this study. An individual IMRT, 3DCRT and LOF plan was created for each patient. Conformity index (CI), homogeneity index (HI) and other dosimetric parameters of the targets and organs-at-risk (OAR) generated by IMRT were compared with the other two techniques. RESULTS: Mann-Whitney U test demonstrated that CI generated by IMRT was superior to that produced by 3DCRT and LOF (p=0.005 for both respectively). Similarly HI with IMRT was proven better than 3DCRT (p=0.007) and LOF (p=0.005). IMRT gave rise to better dose sparing to some OARs including globes, lenses and optic nerves as compared with 3DCRT but not with LOF. CONCLUSIONS: IMRT, as compared with 3DCRT and LOF, was found to have a better target coverage, conformity and homogeneity and dose sparing to some surrounding structures, despite a slight increase but clinically negligible dose to other structures. Dosimetrically it might be a preferred treatment technique and a longer follow up is warranted to establish its role in routine clinical use.

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.

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.