Wing K. Chan

Phase II and pharmacokinetic study of paclitaxel therapy for unresectable hepatocellular carcinoma patients.

Hepatocellular carcinoma (HCC) is a common lethal disease in Asia and there is no effective chemotherapy. Identification of new effective drugs in the treatment of inoperable HCC is urgently need. This is a phase II clinical study to investigate the efficacy, toxicity and pharmacokinetics of paclitaxel in HCC patients. Twenty patients with measurable, unresectable HCC, normal serum bilirubin, normal bone marrow and renal functions were studied. Paclitaxel 175 mg m(-2) was given intravenously over 3 h every 3 weeks. No complete or partial responses were observed. Five patients had stable disease. Major treatment toxicities (grade 3-4) were neutropenia (25%), thrombocytopenia (15%), infection (10%) and allergy (10%). Treatment-related deaths occurred in two patients. The median survival was 12 weeks (range 1-36). Paclitaxel is metabolized by the liver and the pharmacokinetics of paclitaxel in cancer patients with liver involvement or impairment may be important clinically. Pharmacokinetic study was completed in 13 HCC patients. The paclitaxel area under the curve was significantly increased (P < 0.02), clearance decreased (P < 0.02) and treatment-related deaths increased (P = 0.03) in patients with hepatic impairment. In conclusion, paclitaxel in this dose and schedule has no significant anti-cancer effect in HCC patients. Paclitaxel should be used with caution in cancer patients with liver impairment.

Phase II study of flutamide in the treatment of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a male predominant disease and may be an androgen‐dependent or androgen‐responsive tumor. This Phase II study was designed to investigate the clinical activity and toxicity of flutamide in the treatment of patients with advanced HCC.

Phase II study of mitoxantrone in unresectable primary hepatocellular carcinoma following hepatitis B infection

SummaryA total of 20 patients with histologically proven primary hepatocellular carcinoma (PHC) received mitoxantrone IV at a dose of 10–16 mg/m2 every 3 weeks. All patients had previous hepatitis B infection. None underwent remission after treatment; 2 had stable disease and 18 progressive disease. The median overall survival was 13 weeks (range, 1–59 weeks). There was no evidence of significant antitumor activity for mitoxantrone in our patients with PHC. Hematotoxicity occurred in 100% of the patients with grades 2–4 leukopenia, 89% of those with grades 1–4 anemia, and 26% of those with grades 2–3 thrombocytopenia. Cardiotoxicity occurred in 20% of the patients after 14–30 mg/m2 mitoxantrone; these included complete heart block with fatal outcome in one case, decreased ventricular ejection fraction in one, and sinus tachycardia in two. Nausea, vomiting, fever, diarrhea, and alopecia were mild and occurred in 15%–45% of the patients (Table 3). Therefore, patients with PHC following hepatitis B infection may be less tolerant to mitoxantrone, resulting in the apparent increase in toxicities.

Phase II Trial of Systemic Recombinant Interleukin-2 in the Treatment of Refractory Nasopharyngeal Carcinoma

Background: Interleukin-2 (IL-2) is a cytokine produced by activated T cells, which has shown powerful immunostimulatory and antineoplastic properties. Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated cancer with abundant lymphocyte infiltration histologically. The activity of IL-2 in the treatment of NPC patients is currently unknown. A phase II study was, therefore, initiated to evaluate the efficacy, toxicity and immunological consequences of intravenous bolus IL-2 in patients with recurrent/metastatic NPC. Methods: Between November 1996 and April 1997, 14 patients with recurrent/metastatic NPC were entered into the study. Recombinant IL-2 (Proleukin, Chiron) was injected by intravenous bolus every 8 h at 72,000 IU/kg for a maximum of 15 doses. After 7 days, patients were retreated with a second identical cycle of therapy. Those patients who were stable or responding to treatment 5–6 weeks later went on to receive another course (two cycles) of therapy. All patients received prophylactic antibiotics and antipyretic medicine. Response and toxicities were evaluated. Serial plasma level of TNF-α, IL-6, soluble IL-2 receptor, IL-10 and soluble CD8 were determined. Results: Fourteen patients received a total of 34 cycles of therapy. No response was observed. Fifty percent had stable disease, 50% had progressive disease after a median of two cycles of therapy. There was one treatment-related death from acute myocardial infarction. Body weight increase (>5%) occurred in 80% of cycles, and hypotension (BP <80 mm Hg systolic) occurred in 53%. Serum creatinine increase (>2 mg%) occurred in 24% of cycles, and SGOT/SGPT increase (>3×) in 10% of cycles. Symptoms of somnolence, general malaise, nausea and vomiting, pruritus, xerostomia, desquamation were generally mild to moderate but rapidly reversible. Conclusion: The single modality of intravenous bolus IL-2 at the dose level of 72,000 IU/kg is clinically ineffective in NPC patients. Potential mechanisms of the ineffectiveness of IL-2 therapy on NPC patients are discussed.

Phase II study of megestrol acetate in the treatment of hepatocellular carcinoma

This is a report of a phase II study of megestrol acetate (160mg/day, orally) in the treatment of hepatocellular carcinoma (HCC). Forty‐six patients with advanced HCC were studied and tumour response, changes in appetite, bodyweight, a feeling of well‐being, survival and toxicity were evaluated. Thirty‐two patients were able to be evaluated for response; there were no complete responders or partial responders. Twelve patients (38%) had stable disease and seven of these patients had a minor response with a median size reduction in the tumour of 18%. Twenty patients (62%) had progressive disease. Five of 24 (21%) patients had a median reduction in α‐fetoprotein levels of 59ng/mL. The overall median survival was 4 months (range 1 week to 27 months). Twenty of 32 (62%) patients had an increased appetite and feeling of well‐being. Fourteen of 22 (64%) patients had a median lean bodyweight gain of 5 kg (range 1–14 kg). Toxicities were minimal. Tests for glucocorticoid receptors were performed in 10 patients. Four of five patients who were positive for glucocorticoid receptors in the tumour had a stable disease and all five patients who were negative for glucocorticoid receptors had progressive disease. Megestrol acetate had no significant effect on the tumour in HCC patients. However, megestrol acetate is useful in the palliative management of HCC patients, with improvements in appetite, bodyweight and a feeling of well‐being with minimal side effects. Some patients had stable disease, a minor reduction of tumour size and a prolonged survival after megestrol acetate treatment and this response may be related to the presence of glucocorticoid receptors in the HCC tumour.

Weekly etoposide, epirubicin, cisplatin, 5-fluorouracil and leucovorin: an effective chemotherapy in advanced gastric cancer.

In order to optimize the therapeutic index of combining etoposide, epirubicin, cisplatin, 5-fluorouracil (5-FU), leucovorin (EEPFL) chemotherapy in the treatment of advanced gastric cancer, a trial of a novel schedule of weekly administration was conducted. Weekly EEPFL treatment consisted of a concomitant boost of etoposide 40 mg m(-2) i.v. over 30 min, epirubicin 10 mg m(-2) i.v. over 5 min to a backbone regimen, weekly PFL chemotherapy with cisplatin 25 mg m(-2), 5-FU 2200 mg m(-2), leucovorin 120 mg m(-2) given simultaneously by 24-h i.v. infusion. Response, survival and toxicity were evaluated. Forty-two patients were studied. Median age was 69 (range 31-84) years. Twenty-six per cent of patients showed complete response and 45% partial response. The overall response rate was 71% (95% confidence interval 58-84%). For a total of 507 weekly EEPFL cycles delivered, the incidence of grade 4 leucopenia was 1% of cycles. One patient died of neutropenia septicaemia. There was no other grade 4 toxicity. Grade 3 and 2 leucopenia occurred in 7% and 14% of cycles. The incidence of grade 3 and 2 mucositis was 1% and 3% of cycles. Grade 3 and 2 diarrhoea occurred in 0.4% and 1.6% of cycles. Overall median survival was 10 months (range 3-41+ months). Weekly EEPFL chemotherapy is an effective regimen with tolerable toxicities in the treatment of advanced gastric cancer. A randomized controlled clinical trial to formally assess the efficacy and benefit of EEPFL chemotherapy is under way.

A Phase II Study of Carboplatin in Nasopharyngeal Carcinoma

This is a phase II study to evaluate the efficacy and toxicity of short-course carboplatin in advanced-stage nasopharyngeal carcinoma (NPC). Thirty-three previously untreated stage III-IV NPC patients were studied. Carboplatin was given as a rapid intravenous injection every 3 weeks. The dose of carboplatin was calculated according to the individual patients creatinine clearance and desired platelet nadir of 75,000/microliter according to the Egorin formula. Response and toxicity were evaluated. Thirty-two patients were evaluated for response. The median age was 54 years, range 30-70 years. Twenty-four patients had local regional disease and 8 patients had metastatic disease. The median dose of carboplatin given was 415 mg/m2 (range 91-791 mg/m2). Fourteen (44%) patients had a partial response with a 95% confidence interval of 26-62%. Fifteen (47%) patients had stable disease and 3 (9%) progressive disease. The overall median survival rate was not reached at 43 months. Overall toxicity was tolerable. Grade III-IV myelosuppression occurred in 4 (12%) patients. There were no other major toxicity- or treatment-related deaths. We conclude that carboplatin has a significant anticancer effect in advanced NPC. Thus carboplatin combination chemotherapy for the treatment of NPC is worthy of future clinical investigations.

A Pilot Study of Cisplatin, 5-Fluorouracil and High Dose Leucovorin in Chinese Patients with Head and Neck Cancer

Background: Cisplatin, 5-fluorouracil and high dose leucovorin PFL (HDLV) chemotherapy has been reported to be highly active in treatment of head and neck cancer patients. However overall toxicity was high. Before considering PFL (HDLV) chemotherapy for a phase III study in Taiwan, a pilot study of PFL (H DLV) chemotherapy is necessary. Methods: Patients with histologically proven squamous cell carcinoma of head and neck, American Journal Committee on Cancer (AJCC) stage TV, previouly untreated, were eligible for study. Cisplatin 20mg/m^2, 5-fluorouracil (5-FU) 800mg/m^2, leucovorin (LV) 500mg/m^2 were given as a continuous intravenous infusion over 96 hours and the cycle repeated every 28 days. Patients were evaluated for the response and toxicity. Results: Fourteen patients were studied. There were 1 CR (7%) and 8 PR (57%) with a overall response rate (CR+PR) of 64%. The major toxicities were mucositis and myelosuppression. Grade III to IV mucositis occurred in 35% of patients. No treatment related death occurred. Conclusion: Although PFL (HDLV) is an active chemotherapy regiment in head and neck cancer, but its toxicity appears to be excessive. Other PFL regimens that may be equally active but much less toxic should be considered for further evaluation in future studies.