Anthony T.C. Chan

Prospective Randomized Study of Intensity-Modulated Radiotherapy on Salivary Gland Function in Early-Stage Nasopharyngeal Carcinoma Patients

PURPOSE This randomized trial compared the rates of delayed xerostomia between two-dimensional radiation therapy (2DRT) and intensity-modulated radiation therapy (IMRT) in the treatment of early-stage nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS Between November 2001 and December 2003, 60 patients with T1-2bN0-1M0 NPC were randomly assigned to receive either IMRT or 2DRT. Primary end point was incidence of observer-rated severe xerostomia at 1 year after treatment based on Radiotherapy Oncology Group /European Organisation for the Research and Treatment of Cancer late radiation morbidity scoring criteria. Parallel assessment with patient-reported outcome, stimulated parotid flow rate (SPFR), and stimulated whole saliva flow rate (SWSFR) were also made. RESULTS At 1 year after treatment, patients in IMRT arm had lower incidence of observer-rated severe xerostomia than patients in the 2DRT arm (39.3% v 82.1%; P = .001), parallel with a higher fractional SPFR (0.90 v 0.05; P < .0001), and higher fractional SWSFR (0.41 v 0.20; P = .001). As for patients subjective feeling, although a trend of improvement in patient-reported outcome was observed after IMRT, recovery was incomplete and there was no significant difference in patient-reported outcome between the two arms. CONCLUSION IMRT is superior to 2DRT in preserving parotid function and results in less severe delayed xerostomia in the treatment of early-stage NPC. Incomplete improvement in patients subjective xerostomia with parotid-sparing IMRT reflects the need to enhance protection of other salivary glands.

Adjuvant intra-arterial lipiodol-iodine-131 for resectable hepatocellular carcinoma: a prospective randomised trial

Summary Background Resection of hepatocellular carcinoma is potentially curative, but local recurrence is common. In this prospective randomised trial, we aimed to find out if one dose of postoperative adjuvant intra-arterial iodine-131-labelled lipiodol could reduce the rate of local recurrence and increase disease-free and overall survival. Methods Patients who underwent curative resection for hepatocellular carcinoma and recovered within 6 weeks were randomly assigned one 1850 MBq dose of 131 I-lipiodol or no further treatment (controls). We compared rates of recurrence and disease-free and overall survival (the primary endpoints) between the two groups by intention to treat. We planned an interim analysis when 30 patients (both groups together) had been followed up for a median of 2 years, with the intention of stopping early if the between-group difference in disease-free survival was significant (p=0·029). Findings Between April, 1992, and August, 1997, we recruited 43 patients: 21 received intra-arterial 131 I-lipiodol and 22 received no adjuvant treatment. During a median follow-up of 34·6 (range 14·1–69·7) months, there were six (28·5%) recurrences among the 21 patients in the adjuvant treatment, compared with 13 (59%) in the controls (p=0·04). Median disease-free survival in the treatment and control groups was 57·2 (0·4–69·7) and 13·6 (2·1–68·3) months, respectively (p=0·037). 3-year overall survival in the treatment and control groups was 86·4% and 46·3%, respectively (p=0·039). The interim analysis showed a significant increase in disease-free survival in the treatment group compared with the controls (p=0·01), so we closed the trial early. 131 I-lipiodol had no significant toxic effects. Interpretation In patients with hepatocellular carcinoma, one 1850 MBq dose of intra-arterial 131 I-lipiodol given after curative resection significantly decreases the rate of recurrence and increases disease-free and overall survival.

Concurrent Chemotherapy-Radiotherapy Compared With Radiotherapy Alone in Locoregionally Advanced Nasopharyngeal Carcinoma: Progression-Free Survival Analysis of a Phase III Randomized Trial

PURPOSE Nasopharyngeal carcinoma (NPC) is highly sensitive to both radiotherapy (RT) and chemotherapy. This randomized phase III trial compared concurrent cisplatin-RT (CRT) with RT alone in patients with locoregionally advanced NPC. PATIENTS AND METHODS Patients with Hos N2 or N3 stage or N1 stage with nodal size > or = 4 cm were randomized to receive cisplatin 40 mg/m(2) weekly up to 8 weeks concurrently with radical RT (CRT) or RT alone. The primary end point was progression-free survival (PFS). RESULTS Three hundred fifty eligible patients were randomized. Baseline patient characteristics were comparable in both arms. There were significantly more toxicities, including mucositis, myelosuppression, and weight loss in the CRT arm. There were no treatment-related deaths in the CRT arm, and one patient died during treatment in the RT-alone arm. At a median follow-up of 2.71 years, the 2-year PFS was 76% in the CRT arm and 69% in the RT-alone arm (P =.10) with a hazards ratio of 1.367 (95% confidence interval [CI], 0.93 to 2.00). The treatment effect had a significant covariate interaction with tumor stage, and a subgroup analysis demonstrated a highly significant difference in favor of the CRT arm in Hos stage T3 (P =.0075) with a hazards ratio of 2.328 (95% CI, 1.26 to 4.28). For T3 stage, the time to first distant failure was statistically significantly different in favor of the CRT arm (P =.016). CONCLUSION Concurrent CRT is well tolerated in patients with advanced NPC in endemic areas. Although PFS was not significantly different between the concurrent CRT arm and the RT-alone arm in the overall comparison, PFS was significantly prolonged in patients with advanced tumor and node stages.

Randomized Phase II Trial of Concurrent Cisplatin-Radiotherapy With or Without Neoadjuvant Docetaxel and Cisplatin in Advanced Nasopharyngeal Carcinoma

PURPOSE To compare the toxicities, tumor control, survival, and quality of life of nasopharyngeal cancer (NPC) patients treated with sequential neoadjuvant chemotherapy followed by concurrent cisplatin-radiotherapy (CRT) or CRT alone. PATIENTS AND METHODS Previously untreated stage III to IVB NPC were randomly assigned to (1) neoadjuvant docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) every 3 weeks for two cycles, followed by cisplatin 40 mg/m(2)/wk concurrent with radiotherapy, or (2) CRT alone. Planned accrual was 30 patients per arm to detect 20% difference of toxicities based on 95% CIs. RESULTS From November 2002 to November 2004, 65 eligible patients were randomly assigned to neoadjuvant chemotherapy followed by CRT (n = 34) or CRT alone (n = 31). There was a high rate of grade 3/4 neutropenia (97%) but not neutropenic fever (12%) during neoadjuvant chemotherapy. No significant differences in rates of acute toxicities were observed between the two arms during CRT. Dose intensities of concurrent cisplatin, late RT toxicities and quality of life scores were comparable in both arms. The 3-year progression-free survival for neoadjuvant versus control arm was 88.2% and 59.5% (hazard ratio = 0.49; 95% CI, 0.20 to 1.19; P = .12). The 3-year overall survival for neoadjuvant versus control arm was 94.1% and 67.7% (hazard ratio = 0.24; 95% CI, 0.078 to 0.73; P = .012). CONCLUSION Neoadjuvant docetaxel-cisplatin followed by CRT was well tolerated with a manageable toxicity profile that allowed subsequent delivery of full-dose CRT. Preliminary results suggested a positive impact on survival. A phase III study to definitively test this neoadjuvant-concurrent strategy is warranted.

A prospective randomized study of chemotherapy adjunctive to definitive radiotherapy in advanced nasopharyngeal carcinoma

PURPOSE A prospective randomized trial was conducted to compare chemoradiotherapy against radiotherapy alone in the treatment of locoregionally advanced nasopharyngeal carcinoma. METHODS AND MATERIALS Eighty-two patients with histologically proven nasopharyngeal carcinoma who had either Hos N3 staging or any N stage with a nodal diameter of > or = 4 cm were entered. Seventy-seven patients were evaluated for tumor response and survival. The patients were randomized to receive two cycles of cisplatin 100 mg/m2 Day 1,5-fluorouracil 1000 mg/m2 24-h infusion Days 2, 3, and 4 before radical radiotherapy, and four cycles of postradiotherapy chemotherapy (37 patients) or radiotherapy alone (40 patients). All patients received radical radiotherapy to the nasopharynx and neck. The nasopharynx and upper neck were treated to 66 Gy by conventional fractionation and the lower neck to 58 Gy. Booster radiotherapy (7.5 Gy/two fractions/week) was given to any residual nodes after standard radiotherapy. RESULTS The patient characteristics, including staging, were similar in both arms. The overall response rate to neoadjuvant chemotherapy was 81% (19% complete response, 62% partial response). The rates of radiotherapy for boosting parapharyngeal disease or residual lymph nodes were not significantly different in the two arms. The overall complete response rate to chemoradiotherapy was 100%, and to radiotherapy alone, 95%. Toxicities in the chemoradiotherapy arm were mainly myelosuppression, nephrotoxicity, and nausea and vomiting. The degree of mucositis was not significantly different in the two arms. There was no treatment-related death. The median follow up was 28.5 months. The 2-year overall survival was 80% in the chemoradiotherapy arm and 80.5% in the radiotherapy arm. The 2-year disease-free survival was 68% in the chemoradiotherapy arm and 72% in the radiotherapy arm, without significant difference between the two arms. The locoregional relapse rate, distant metastatic rate, and median time to relapse were also not significantly different between the two arms. CONCLUSION Despite promising tumor response rates from Phase II trials, this prospective randomized trial has demonstrated no benefit from adjunctive chemotherapy to radiotherapy in the treatment of locoregionally advanced nasopharyngeal carcinoma.

Cancer Genome Scanning in Plasma: Detection of Tumor-Associated Copy Number Aberrations, Single-Nucleotide Variants, and Tumoral Heterogeneity by Massively Parallel Sequencing

BACKGROUND Tumor-derived DNA can be found in the plasma of cancer patients. In this study, we explored the use of shotgun massively parallel sequencing (MPS) of plasma DNA from cancer patients to scan a cancer genome noninvasively. METHODS Four hepatocellular carcinoma patients and a patient with synchronous breast and ovarian cancers were recruited. DNA was extracted from the tumor tissues, and the preoperative and postoperative plasma samples of these patients were analyzed with shotgun MPS. RESULTS We achieved the genomewide profiling of copy number aberrations and point mutations in the plasma of the cancer patients. By detecting and quantifying the genomewide aggregated allelic loss and point mutations, we determined the fractional concentrations of tumor-derived DNA in plasma and correlated these values with tumor size and surgical treatment. We also demonstrated the potential utility of this approach for the analysis of complex oncologic scenarios by studying the patient with 2 synchronous cancers. Through the use of multiregional sequencing of tumoral tissues and shotgun sequencing of plasma DNA, we have shown that plasma DNA sequencing is a valuable approach for studying tumoral heterogeneity. CONCLUSIONS Shotgun DNA sequencing of plasma is a potentially powerful tool for cancer detection, monitoring, and research.

Comprehensive Proteomic Profiling Identifies Serum Proteomic Signatures for Detection of Hepatocellular Carcinoma and Its Subtypes

BACKGROUND Detection of hepatocellular carcinoma (HCC) in patients with chronic liver disease (CLD) is difficult. We investigated the use of comprehensive proteomic profiling of sera to differentiate HCC from CLD. METHODS Proteomes in sera from 20 CLD patients with alpha-fetoprotein (AFP) <500 microg/L (control group) and 38 HCC patients (disease group) were profiled by anion-exchange fractionation (first dimension), two types (IMAC3 copper and WCX2) of ProteinChip Arrays (second dimension), and time-of-flight mass spectrometry (third dimension). Bioinformatic tests were used to identify tumor-specific proteomic features and to estimate the values of the tumor-specific proteomic features in the diagnosis of HCC. Cross-validation was performed, and we also validated the models with pooled sera from the control and disease groups, serum from a CLD patient with AFP >500 microg/L, and postoperative sera from two HCC patients. RESULTS Among 2384 common serum proteomic features, 250 were significantly different between the HCC and CLD cases. Two-way hierarchical clustering differentiated HCC and CLD cases. Most HCC cases with advanced disease were clustered together and formed two subgroups that contained significantly more cases with lymph node invasion or distant metastasis. For differentiation of HCC and CLD by an artificial network (ANN), the area under the ROC curve was 0.91 (95% confidence interval, 0.82-1.01; P <0.0005) for all cases and 0.954 (95% confidence interval, 0.881-1.027; P <0.0005) for cases with nondiagnostic serum AFP (<500 microg/L). At a specificity of 90%, the sensitivity was 92%. Both cluster analysis and ANN correctly classified the pooled serum samples, the CLD serum sample with increased AFP, and the HCC patient in complete remission. CONCLUSION Tumor-specific proteomic signatures may be useful for detection and classification of hepatocellular cancers.

Lamivudine for the Prevention of Hepatitis B Virus Reactivation in Hepatitis B s-Antigen Seropositive Cancer Patients Undergoing Cytotoxic Chemotherapy

PURPOSE For cancer patients receiving cytotoxic chemotherapy, hepatitis B virus (HBV) reactivation is a well described complication resulting in varying degrees of liver damage. The objectives of this study were to assess the efficacy of the antiviral agent lamivudine in reducing the incidence of HBV reactivation and diminishing morbidity and mortality of cancer patients with chronic HBV infection during chemotherapy. PATIENTS AND METHODS Two groups were compared in this nonrandomized study. The prophylactic lamivudine group consisted of 65 patients in a phase II study who were treated with lamivudine before and until 8 weeks after discontinuing chemotherapy. The historical controls consisted of 193 consecutive patients who underwent chemotherapy without prophylactic lamivudine. Significant prognosticators for the development of HBV reactivation were determined based on data from the controls. Potential confounding factors were identified between the two groups. The outcomes were compared. RESULTS In the controls, lymphoma and anthracycline usage were factors identified to be associated with reactivation. The two groups were comparable in most baseline characteristics, although in the prophylactic lamivudine group, there were significantly more patients with lymphoma and receiving anthracyclines. In the prophylactic lamivudine group, there was significantly less HBV reactivation (4.6% v 24.4% in the controls; P <.001), fewer incidences of hepatitis (17.5% v 44.6%; P <.0001) that were less severe (4.8% v 18.7%; P =.0005), and less disruption of chemotherapy (15.4% v 34.6%; P =.0029). The reduction in overall mortality was not statistically different. CONCLUSION Prophylactic lamivudine significantly reduced the incidence of HBV reactivation and the overall morbidity of cancer patients undergoing chemotherapy.

Clinical scoring system to predict hepatocellular carcinoma in chronic hepatitis B carriers

PURPOSE Hepatitis B virus (HBV) infection is an important etiology for hepatocellular carcinoma (HCC). We aim to develop a simple clinical score in predicting the risk of HCC among HBV carriers. PATIENTS AND METHODS We first evaluated 1,005 patients and found that the following five factors independently predicted HCC development: age, albumin, bilirubin, HBV DNA, and cirrhosis. These variables were used to construct a prediction score ranging from 0 to 44.5. The score was validated in another prospective cohort of 424 patients. RESULTS During a median follow-up of 10 years, 105 patients (10.%) in the training cohort and 45 patients (10.6%) in the validation cohort developed HCC. Cutoff values of 5 and 20 best discriminated HCC risk. By applying the cutoff value of 5, the score excluded future HCC development with high accuracy (negative predictive value = 97.8% and 97.3% in the training and validation cohorts, respectively). In the validation cohort, the 5-year HCC-free survival rates were 98.3%, 90.5%, and 78.9% in the low-, medium-, and high-risk groups, respectively. The hazard ratios for HCC in the medium- and high-risk groups were 12.8 and 14.6, respectively. CONCLUSION A simple prediction score constructed from routine clinical and laboratory parameters is accurate in predicting HCC development in HBV carriers. Future prospective validation is warranted.

Multicenter, Phase II Study of Cetuximab in Combination With Carboplatin in Patients With Recurrent or Metastatic Nasopharyngeal Carcinoma

PURPOSE To evaluate efficacy and toxicity of cetuximab plus carboplatin in recurrent or metastatic nasopharyngeal carcinoma (NPC) resistant to platinum treatment. PATIENTS AND METHODS A multicenter, open-label, single-arm, phase II study in patients with epidermal growth factor receptor-expressing NPC who progressed on or within 12 months after termination of platinum-based chemotherapy for recurrent or metastatic disease. Cetuximab was administered at an initial dose of 400 mg/m2 followed by weekly doses of 250 mg/m2. Carboplatin area under the curve 5 was administered every 3 weeks up to a maximum of eight cycles. RESULTS Sixty patients were enrolled (46 males, 14 females; median age, 44.5 years; range, 23 to 64 years), and all patients were included in the intent-to-treat and safety analyses. Of the 59 patients assessable for efficacy, there were seven partial responses (11.7%), 29 patients (48.3%) with stable disease, and 23 patients (38.3%) with progressive disease, giving an overall response rate of 11.7% (95% CI, 4.8% to 22.6%). The median time to progression was 81 days in all patients and was longest in the group of patients with a confirmed response (173 days). The median overall survival time was 233 days in all patients. Six patients (10%) experienced serious treatment-related adverse events. Grade 3 or 4 toxicities occurred in 31 patients (51.7%); of these patients, only 19 (31.7%) were considered to have toxicity related to cetuximab. CONCLUSION Cetuximab in combination with carboplatin demonstrates clinical activity and an acceptable safety profile in heavily pretreated patients with recurrent or metastatic NPC who had previously experienced treatment failure with platinum-based therapy.