Herman Wong

An Intensive Surveillance Program Detected a High Incidence of Hepatocellular Carcinoma Among Hepatitis B Virus Carriers With Abnormal Alpha-Fetoprotein Levels or Abdominal Ultrasonography Results

PURPOSE To study the incidence and treatment outcomes of hepatocellular carcinoma (HCC) detected in an intensive surveillance program (ISP) of hepatitis B virus (HBV) carriers. PATIENTS AND METHODS We screened 1,018 HBV carriers by serum alpha-fetoprotein (AFP) measurement and abdominal ultrasonography (AUS). Patients with an abnormal AFP level or AUS result were enrolled in an ISP that included Lipiodol computed tomography followed by AFP measurement/AUS every 3 months for 2 years and then every 6 months thereafter. The rest were on routine surveillance for 2 years. RESULTS A total of 9,849 serum AFP measurements and 3,053 AUSs were performed. After a median follow-up of 4.12 years, we diagnosed 24 HCCs among 78 patients with abnormal screening test results at enrollment (group A); 23 HCCs among 93 patients with only abnormal surveillance test results during follow-up (group B); and nine HCCs among 847 patients with 2 years of normal surveillance (group C). Annual incidence of HCC in the ISP was 760.2 (95% CI, 538.4 to 1,073.7) per 100,000. Mean tumor sizes were 3.02, 2.91, and 4.82 cm in groups A, B, and C, respectively (P = .01). Tumor resection rate of the ISP was 36.2%, although another 29.8% of the patients were eligible for locoregional ablative therapy. CONCLUSION This study illustrated that a high incidence of relatively small HCCs may be detected by using intensive surveillance of high-risk HBV carriers. However, the surgical resection rate was low, and we were not able to demonstrate clinical benefit with the early detection. Future surveillance studies should consider incorporation of therapy aimed at long-term control of small-sized tumors.

Sequence variations of precore/core and precore promoter regions of hepatitis B virus in patients with or without viral reactivation during cytotoxic chemotherapy.

Reactivation of the hepatitis B virus (HBV) is a well‐described complication among cancer patients undergoing cytotoxic chemotherapy. Mutations in the preC/C and the preC promoter regions of HBV have been reported in some patients who developed this condition. A G‐to‐A mutation at nt 1896 in the preC/C region (HBeAg negative/anti‐HBe positive) has been associated with more severe liver disease than that caused by wild type virus. In addition, it has been suggested that patients with these mutations may be more likely to reactivate than those with the wild type virus. Whether or not such mutations were present before the commencement of or developed during the course of cytotoxic chemotherapy is not known. In this study, 28 cancer patients (consisting of 14 consecutive patients who developed HBV reactivation and another 14 who had no reactivation during cytotoxic chemotherapy) are reported. The objectives were firstly, to determine the prechemotherapy HBeAg status and nucleotide sequences of the preC/C and preC promoter regions of HBV in order to determine if these parameters affected the rate of reactivation, and secondly, for those who developed reactivation, to determine whether the mutations were present before chemotherapy or developed during, possibly as a result of, cytotoxic chemotherapy. HBV DNA was amplified by PCR and nucleotide sequencing performed on samples taken prior to chemotherapy and at the time of reactivation. Results revealed that 16 of the 28 patients were HBeAg negative/anti‐HBe positive. Of these 16, four (57%) of the seven patients who had nt 1896 mutation, but only one (17%) of the six who had the wild type HBV genome, developed reactivation. Three had no detectable HBV DNA. In the majority of cases, the type of virus, i.e. wild/mutant at preC/C, that was detected during the reactivation was identical to that detected in the pretreatment samples. With respect to the preC promoter region, the two commonest mutations detected were at nt 1762 (A to T) and nt 1764 (G to A). When this region was translated into amino acid sequences, stop codons leading to truncated X protein at carboxyl terminus were found in four patients, three of whom developed HBV reactivation. We conclude that chronic HBV carriers who are HBeAg negative/anti‐HBe positive with nt 1896 mutation (G to A) may be more likely to develop HBV reactivation during cytotoxic chemotherapy than those with the wild type virus. Cytotoxic chemotherapy does not appear to select out mutant HBV, or to be consistently mutagenic in patients who develop HBV reactivation. The occurrence of stop codons in the amino acid sequences of the X protein in three patients who developed HBV reactivation, including one who was detected only at the time of reactivation, is of particular interest, as such mutant viruses remain replication competent.

A Phase I-II study of sequential administration of topotecan and oral etoposide (toposiomerase I and II inhibitors) in the treatment of patients with small cell lung carcinoma.

Topotecan (9‐dimethylaminomethyl‐10‐hydroxycampthothecin) is a new topoisomerase I inhibitor with promising efficacy in the treatment of patients with small cell lung carcinoma (SCLC). Combination with a topoisomerase II inhibitor may potentate the therapeutic effect of topotecan, although there has been conflicting preclinical information on the combination. The objectives of this study were to establish the maximum tolerated dose and to determine the efficacy of the sequential combination of intravenous topotecan and oral etoposide in the treatment of patients with SCLC.

Transarterial Ethanol Ablation of Hepatocellular Carcinoma with Lipiodol-Ethanol Mixture: Phase II Study

PURPOSE This prospective trial aimed to evaluate the safety and effectiveness of transarterial ethanol ablation (TEA) of intrahepatic lesions of hepatocellular carcinoma (HCC) with a Lipiodol-ethanol mixture. MATERIALS AND METHODS Seventy-seven patients were recruited and 164 lesions (mean size, 5.2 cm +/- 3.0) were treated. Inclusion criteria included histologic proof of HCC, refusal of (n = 9) or contraindication to (n = 68) surgical resection, Eastern Cooperative Oncology Group performance status no greater than 2, and intrahepatic disease without vascular invasion. The mixture consisted of 33% ethanol by volume, with the total dose of Lipiodol-ethanol mixture limited to 60 mL for each treatment session. The primary endpoint was patient survival. Secondary endpoints were tumor response, adverse effects of treatment, and progression-free survival. Median follow-up time for the whole cohort was 2.3 years. RESULTS Median overall survival was 2.2 years. Overall survival and progression-free survival rates at 1 year and 2 years were 77.9% and 50.1% and 63.6% and 46.3%, respectively. Complete ablation according to radiologic criteria was achieved in 61 patients (79.2%) and 86% of the 164 treated lesions. Mean tumor volume reduction was 65.22%. Patient survival was significantly better in patients with tumors no larger than 5 cm (Cox proportional-hazards regression, P = .0074). Treatment response was significantly better for patients with tumors no greater than 7 cm (chi2 test, P = .0462; Fisher exact test, P = .0326). Adverse effects included irreversible hepatic decompensation (0.6% of procedures), pain (4.8%), and fever (13.8%). CONCLUSIONS TEA is a safe and effective means to establish local control of unresectable and resectable intrahepatic lesions of HCC.

Phase II Randomized Study Comparing the Toxicity Profile of Gemcitabine plus Cisplatin with Gemcitabine plus Oral Etoposide in the Treatment of Advanced Non-Small Cell Lung Cancer

Objective: This is a randomized phase II study designed to compare the toxicity profile of a non-platinum-based with a platinum-based regimen in the treatment of advanced non-small cell lung cancer. Methods: Eighty-nine chemotherapy-naïve patients were randomized either to gemcitabine (1,000 mg/m2, 30-min infusion on days 1, 8 and 15) and oral etoposide (50 mg, days 1–14; GE group) or gemcitabine at the same schedule and cisplatin (75 mg/m2 on day 15; GP group). The primary endpoint is toxicity, and secondary endpoints include response rate, survival outcome and quality of life (QOL). Results: The incidence of WHO grade 3 or 4 anemia, neutropenia and thrombocytopenia was 29, 44 and 22% (GE group), and 28, 49 and 23% (GP group), respectively (p = 0.75, 0.95 and 0.87, respectively). The rate of grade 2 or above nausea was numerically higher in the GP arm, but the difference was not statistically significant (GE 15.5%, GP 27.7%, p = 0.20). The rate of vomiting in the GE and GP arms was 20.0 and 20.5%, respectively (p = 0.96). However, subjective changes in QOL scores on nausea and vomiting were significantly higher in the GP arm (p = 0.001). Other symptoms including sore mouth and hair loss were significantly higher in the GE arm (p = 0.003 and 0.007, respectively). There were also significant differences observed in emotional (p = 0.014), cognitive (p = 0.028) and social functioning (p = 0.034) in favor of GP. The differences in tumor response (35.5 and 46.5% for GE and GP, respectively) were not significantly different. Median time to disease progression (33.8 and 40.7 weeks, respectively) and overall survival (41.4 and 57.3 weeks, respectively) were of borderline significance in favor of the GP arm (p = 0.055). Conclusion: This toxicity profile of GE is similar to GP, but the apparent inferior efficacy may discourage further investigation.

A phase I safety and pharmacokinetic study of OGT 719 in patients with liver cancer.

OGT 719 (Oxford GlycoSciences, Abingdon, UK) is a novel nucleoside analogue with a galactose molecule attached to a fluorinated pyrimidine. OGT 719 has the capacity selectively to bind to asialoglycoprotein receptors that are found exclusively on hepatocytes and hepatocellular carcinoma (HCC) cells. The aim of this study was to establish the safety and to examine the pharmacokinetics of this novel compound in patients with liver cancer. Fourteen patients received a total of 37 cycles of OGT 719 at four dose levels ([500 mg/m2 first cycle, 1 000 mg/m2 subsequent cycles], 1000 mg/m2, 3 300 mg/m2 and 7500mg/m2). OGT 719 was administered as a 3-h intravenous infusion in a 250 ml saline solution, daily for 5 days every 4 weeks. Pharmacokinetic parameters were studied during the first cycle of dose levels 1 and 2 (500 mg/m2, and 1 000 mg/m2, respectively). The maximum plasma concentration was attained within 5 min of completing the infusion and almost doubled, dose dependently, with a doubling of the infused dose. The plasma level declined rapidly in a monophasic manner with an elimination half-life of 2.1 and 2.5 h for dose level 1 and 2, respectively. The mean area under the curve (AUCo−t, area under the curve to 24 h; AUCo−∞, area under the curve to infinity) doubled at the higher dose level. None of the patients had a significant tumor response. Elimination half-life of OGT 719 by 3-h intravenous infusion is short and monophasic. Toxicity was minimal at the highest dose level.

Sequential chemotherapy with combination irinotecan and cisplatin followed by docetaxel for treatment-naïve patients with advanced non-small cell lung cancer

Background: Sequential administration of platinum-based doublet therapy and then a taxane may reduce the risk of drug resistance and, therefore, improve treatment outcome. This study was designed to evaluate the efficacy and tolerability of sequential administration of irinotecan and cisplatin and then docetaxel in patients with advanced non-small cell lung cancer (NSCLC). Methods: Eligible patients received irinotecan in 60-mg/m2 infusions for 30 to 60 minutes on days 1, 8, and 15, and cisplatin in 75-mg/m2 infusions for 60 minutes on day 1 every 28 days for four cycles (IC). Regardless of the response, patients received up to four cycles of sequential docetaxel in 75-mg/m2 infusions for 60 minutes. Results: Forty-six patients with histologically confirmed chemotherapy-naïve stage IIIB or IV NSCLC were enrolled, of whom 42 were evaluable. The response rate at completion of chemotherapy with IC was 45.2% (95% confidence interval [CI]: 30.2%–60.3%). Five patients had improvement of disease status during sequential docetaxel, and seven patients had disease progression. Progression-free survival was 8.0 months (95% CI: 5.4–9.9 months), and the overall median survival was 14.6 months (95% CI: 9.8–17.9 months). The 1-, 2-, and 3-year survival rates were 54.3%, 22.6%, and 12.1%, respectively. The incidence of severe (≥CTC V2 grade 3) neutropenia during IC was 23.9% compared with 95.7% for sequential docetaxel (p < 0.0001). Conclusion: Sequential administration of IC and then docetaxel is feasible and is associated with a prolonged progression-free survival, but the current data do not confirm an improvement in treatment outcome by the sequential approach.