Frankie Mo

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.

Hepatitis B Virus Reactivation in Lymphoma Patients With Prior Resolved Hepatitis B Undergoing Anticancer Therapy With or Without Rituximab

PURPOSE Reactivation of hepatitis B virus (HBV) infection is a well-recognized complication in cancer patients with chronic HBV (hepatitis B surface antigen [HBsAg] positive) undergoing cytotoxic chemotherapy. In patients who have resolved HBV (HBsAg negative and antibody to hepatitis B core antigen [anti-HBc] +/- antibody to hepatitis B surface antigen [anti-HBs] positive), such incidence has been much less common until recent use of rituximab. In this study on HBsAg-negative/anti-HBc-positive lymphoma patients, the objectives were to determine the HBV reactivation rate in patients treated with rituximab-containing chemotherapy and to compare it with the rate in patients treated without rituximab. PATIENTS AND METHODS Between January 2003 and December 2006, all patients diagnosed with CD20(+) diffuse large B-cell lymphoma (DLBCL) had HBsAg determined before anticancer therapy. They were treated with either cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) alone or rituximab plus CHOP (R-CHOP). HBsAg-negative patients had anti-HBc determined; serum was stored for anti-HBs and HBV DNA. All patients were observed for HBV reactivation, which was defined as detectable HBV DNA with ALT elevation during and for 6 months after anticancer therapy. RESULTS Among 104 CD20(+) DLBCL patients, 80 were HBsAg negative. Of the latter, 46 patients (44.2%) were HBsAg negative/anti-HBc positive; 25 of these patients were treated with CHOP, and none had HBV reactivation. In contrast, among the 21 patients treated with R-CHOP, five developed HBV reactivation, including one patient who died of hepatic failure (P = .0148). Exploratory analysis identified male sex, absence of anti-HBs, and use of rituximab to be predictive of HBV reactivation. CONCLUSION Among HBsAg-negative/anti-HBc-positive DLBCL patients treated with R-CHOP, 25% developed HBV reactivation. Close monitoring until at least 6 months after anticancer therapy is required, with an alternative approach of prophylactic antiviral therapy to prevent this potentially fatal condition.

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.

Assessment of Liver Function in Patients With Hepatocellular Carcinoma: A New Evidence-Based Approach—The ALBI Grade

PURPOSE Most patients with hepatocellular carcinoma (HCC) have associated chronic liver disease, the severity of which is currently assessed by the Child-Pugh (C-P) grade. In this international collaboration, we identify objective measures of liver function/dysfunction that independently influence survival in patients with HCC and then combine these into a model that could be compared with the conventional C-P grade. PATIENTS AND METHODS We developed a simple model to assess liver function, based on 1,313 patients with HCC of all stages from Japan, that involved only serum bilirubin and albumin levels. We then tested the model using similar cohorts from other geographical regions (n = 5,097) and other clinical situations (patients undergoing resection [n = 525] or sorafenib treatment for advanced HCC [n = 1,132]). The specificity of the model for liver (dys)function was tested in patients with chronic liver disease but without HCC (n = 501). RESULTS The model, the Albumin-Bilirubin (ALBI) grade, performed at least as well as the C-P grade in all geographic regions. The majority of patients with HCC had C-P grade A disease at presentation, and within this C-P grade, ALBI revealed two classes with clearly different prognoses. Its utility in patients with chronic liver disease alone supported the contention that the ALBI grade was indeed an index of liver (dys)function. CONCLUSION The ALBI grade offers a simple, evidence-based, objective, and discriminatory method of assessing liver function in HCC that has been extensively tested in an international setting. This new model eliminates the need for subjective variables such as ascites and encephalopathy, a requirement in the conventional C-P grade.

High Viral Load and Hepatitis B Virus Subgenotype Ce Are Associated With Increased Risk of Hepatocellular Carcinoma

PURPOSE We aimed to investigate the impact of hepatitis B virus (HBV) DNA and HBV genotypes/subgenotypes on the risk of hepatocellular carcinoma (HCC). PATIENTS AND METHODS A prospective cohort of patients infected with chronic HBV in a surveillance program for HCC since 1997 was studied. Ultrasound and alpha-fetoprotein evaluation were regularly performed to detect HCC. Risk factors for HCC and the relationship between HBV DNA and HBV genotypes were determined. RESULTS Among 1,006 patients with a median follow-up of 7.7 years, 86 patients (8.5%) developed HCC. With reference to the low HBV DNA stratum (log HBV DNA </= 4.5 copies/mL), the hazard ratio for HCC of the intermediate HBV DNA stratum (log HBV DNA > 4.5 to 6.5 copies/mL) was 1.62 (95% CI, 1.05 to 2.48; P = .027) and that of the high HBV DNA stratum (log HBV DNA > 6.5 copies/mL) was 2.73 (95% CI, 1.76 to 4.25; P < .001). Among patients with genotyping results, 330 patients had HBV genotype B and 439 patients had HBV genotype C (94 subgenotype Ce and 345 subgenotype Cs). With reference to HBV genotype B, HBV subgenotype Ce has the highest risk of HCC (hazard ratio = 2.75; 95% CI, 1.66 to 4.56; P < .0001) and HBV subgenotype Cs has intermediate risk (hazard ratio = 1.70; 95% CI, 1.09 to 2.64; P = .020). On multivariate analysis, HBV DNA, HBV genotypes, liver cirrhosis, male sex, older age, and lower serum albumin were independent risk factors of HCC. CONCLUSION High HBV DNA level and HBV genotype C, particularly subgenotype Ce, increased the risk of HCC in chronic hepatitis B.

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.

Plasma Epstein-Barr Viral Deoxyribonucleic Acid Quantitation Complements Tumor-Node-Metastasis Staging Prognostication in Nasopharyngeal Carcinoma

PURPOSE To evaluate the effect of combining circulating Epstein-Barr viral (EBV) DNA load data with TNM staging data in pretherapy prognostication of nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS Three hundred seventy-six patients with all stages of NPC were studied. Pretreatment plasma/serum EBV DNA concentrations were quantified by a polymerase chain reaction assay. Determinants of overall survival were assessed by multivariate analysis. Survival probabilities of patient groups, segregated by clinical stage (I, II, III, or IV) alone and also according to EBV DNA load (low or high), were compared. RESULTS Pretherapy circulating EBV DNA load is an independent prognostic factor for overall survival in NPC. Patients with early-stage disease were segregated by EBV DNA levels into a poor-risk subgroup with survival similar to that of stage III disease and a good-risk subgroup with survival similar to stage I disease. CONCLUSION Pretherapy circulating EBV DNA load is an independent prognostic factor to International Union Against Cancer (UICC) staging in NPC. Combined interpretation of EBV DNA data with UICC staging data leads to alteration of risk definition of patient subsets, with improved risk discrimination in early-stage disease. Validation studies are awaited.

New Utility of an Old Marker: Serial α-Fetoprotein Measurement in Predicting Radiologic Response and Survival of Patients With Hepatocellular Carcinoma Undergoing Systemic Chemotherapy

PURPOSE There are limitations in using radiologic evaluation to assess the treatment outcome of patients with hepatocellular carcinoma (HCC). The use of serial alpha-fetoprotein (AFP) in monitoring response has not been rigorously evaluated. We aimed to study the clinical value of AFP trend in an attempt to validate AFP as a surrogate serologic end point. PATIENTS AND METHODS Participants from a phase III randomized trial of systemic chemotherapy in HCC were studied. Serum AFP was prospectively collected in parallel with clinical and radiologic outcome. AFP response was defined as a decrease in AFP of more than 20% after a minimum of two cycles of chemotherapy. We studied the relationship between AFP response and treatment outcome in terms of radiologic response and overall survival. RESULTS Of 188 patients, 117 patients with elevated serum AFP (> 20 microg/L) and documented radiologic evaluation had received at least two cycles of chemotherapy. A total of 47 AFP responders were identified. AFP responders had better survival than nonresponders (13.5 v 5.6 months, respectively; P < .0001), and AFP response was strongly associated with radiologic response (P < .0001). Multivariate analysis suggested that AFP response was significantly associated with survival (hazard ratio, 0.413; 95% CI, 0.273 to 0.626; P < .0001). AFP responses were frequently observed in patients with radiologically stable disease (SD) and tended to identify a subgroup of SD patients with better survival. CONCLUSION Serial AFP measurement is useful in prognostication and monitoring treatment response in HCC patients undergoing systemic chemotherapy. Incorporation of AFP response into the criteria evaluating treatment outcome should be considered in clinical practice and clinical trials of novel agents in HCC.

Prognostic significance of tumor angiogenesis, Ki 67, p53 oncoprotein, epidermal growth factor receptor and HER2 receptor protein expression in undifferentiated nasopharyngeal carcinoma—a prospective study†

This study prospectively examines the prognostic role of p53 oncoprotein (p53), Ki67‐antigen (Ki67), tumor angiogenesis (MVD), epidermal growth factor receptor (EGFR), and HER2 receptor protein (HER2) expression in Chinese with undifferentiated nasopharyngeal carcinoma (NPC).

Epigenetic Therapy Using Belinostat for Patients With Unresectable Hepatocellular Carcinoma: A Multicenter Phase I/II Study With Biomarker and Pharmacokinetic Analysis of Tumors From Patients in the Mayo Phase II Consortium and the Cancer Therapeutics Research Group

PURPOSE Epigenetic aberrations have been reported in hepatocellular carcinoma (HCC). In this study of patients with unresectable HCC and chronic liver disease, epigenetic therapy with the histone deacetylase inhibitor belinostat was assessed. The objectives were to determine dose-limiting toxicity and maximum-tolerated dose (MTD), to assess pharmacokinetics in phase I, and to assess activity of and explore potential biomarkers for response in phase II. PATIENTS AND METHODS Major eligibility criteria included histologically confirmed unresectable HCC, European Cooperative Oncology Group performance score ≤ 2, and adequate organ function. Phase I consisted of 18 patients; belinostat was given intravenously once per day on days 1 to 5 every 3 weeks; dose levels were 600 mg/m(2) per day (level 1), 900 mg/m(2) per day (level 2), 1,200 mg/m(2) per day (level 3), and 1,400 mg/m(2) per day (level 4). Phase II consisted of 42 patients. The primary end point was progression-free survival (PFS), and the main secondary end points were response according to Response Evaluation Criteria in Solid Tumors (RECIST) and overall survival (OS). Exploratory analysis was conducted on pretreatment tumor tissues to determine whether HR23B expression is a potential biomarker for response. RESULTS Belinostat pharmacokinetics were linear from 600 to 1,400 mg/m(2) without significant accumulation. The MTD was not reached at the maximum dose administered. Dose level 4 was used in phase II. The median number of cycles was two (range, one to 12). The partial response (PR) and stable disease (SD) rates were 2.4% and 45.2%, respectively. The median PFS and OS were 2.64 and 6.60 months, respectively. Exploratory analysis revealed that disease stabilization rate (complete response plus PR plus SD) in tumors having high and low HR23B histoscores were 58% and 14%, respectively (P = .036). CONCLUSION Epigenetic therapy with belinostat demonstrates tumor stabilization and is generally well-tolerated. HR23B expression was associated with disease stabilization.