Dietary exposure to chloropropanols of secondary school students in Hong Kong.

This paper reports levels of 3-monochloropropan-1,2-diol (3-MCPD) and 1,3-dichloro-2-propanol (1,3-DCP) in a wide range of food items and estimates their dietary exposure for secondary school students in Hong Kong. Dietary exposure to chloropropanols was estimated using local food consumption data obtained from secondary school students in 2000 and the concentrations of 3-MCPD and 1,3-DCP in food samples taken from the local market. The dietary exposure to 3-MCPD for an average secondary school student consumer was estimated to be 0.063-0.150 µg kg(-1) body weight (bw) day(-1), whilst that for the high consumer was 0.152-0.300 µg kg(-1) bw day(-1). Both estimates fell below the provisional maximum tolerable daily intake of 2 µg kg(-1) bw established by the Joint Expert Committee on Food Additives (JECFA) and amounted to less than 20% of this safety reference value. The dietary exposure to 1,3-DCP for an average secondary school student consumer was estimated to be 0.003-0.019 µg kg(-1) bw day(-1), whilst that for the high consumer was 0.009-0.040 µg kg(-1) bw day(-1). The resulting margins of exposures were of low concern for human health. It could be concluded that both the average and high secondary school student consumers were unlikely to experience major toxicological effects of 3-MCPD and 1,3-DCP.

Functional status is well maintained in older women during adjuvant chemotherapy for breast cancer.

BACKGROUND: While adjuvant chemotherapy is known to improve survival in older women with breast cancer, there is little information about its effects on physical function and health-related quality of life. PATIENTS AND METHODS: 'Young' (<65 years of age) and 'older' (> or = 65 years of age) postmenopausal women completed the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core Module (QLQ-C30) and BR23 questionnaires and other measures prior to, during and at the completion of anthracycline-based adjuvant chemotherapy, and then 6 and 12 months later. RESULTS: Physical, role and social function decreased during chemotherapy and emotional function improved (all P <0.01). The decline in physical function was more marked in young (age range 31-64 years; n = 45) than in older women (65-80 years; n = 20) (P <0.05), despite similar baseline values and drug dose intensities. Physical and role function had recovered at 6 months post-chemotherapy. Older patients had consistently better emotional function (P <0.01). CONCLUSIONS: Physical function and other functional domains are impaired in postmenopausal women during adjuvant chemotherapy for breast cancer, but recover subsequently. Physical function appeared to be better maintained in the older women, who tolerated adjuvant chemotherapy well overall. A knowledge of these effects is important for clinical decision-making and when defining social support needs during adjuvant chemotherapy.

A pilot study of low dose hydroxyurea as a novel resistance modulator in metastatic renal cell cancer.

Mechanisms of chemoresistance in renal cell carcinoma include P-glycoprotein, overexpression of multidrug resistance-1 (mdr1) gene, and unstable chromosomal aberrations. In vitro exposure of resistant tumor cells to low dose hydroxyurea causes loss of chromosomal aberrations, decrease in the mdr1 gene copies, and increased sensitivity to vinblastine. Patients received continuous hydroxyurea 500 mg every Monday, Wednesday and Friday. Vinblastine 5 mg/m2 was given intravenously on days 1 and 8 every 21 days. Seventeen patients with a median age of 63 (range 40-80) received a median of 3 courses of vinblastine (range 1-14). Toxicities included: > or = grade 3 non-hematologic toxicity (1) and febrile neutropenia (2). No treatment related mortality occurred. Three patients (17.6%) had partial responses. The median survival was 38.0 weeks (95% CI = 26.9-49.1 weeks). The addition of hydroxyurea given at the dose of 500 mg orally three times weekly had no major impact on the expected antitumor effect of vinblastine.

A phase III study of high-dose intensification without hematopoietic progenitor cells support for patients with high-risk primary breast carcinoma.

Patients with more than nine ipsilateral lymph node involvement or inflammatory breast cancer have a 5-year survival rate of approximately 50%. We studied the efficacy of high-dose intensification, comparing it with the standard dose chemotherapy for patients with high-risk primary breast cancer. Patients with inflammatory breast cancer or more than nine ipsilateral lymph node involvement without evidence of distant metastasis were randomized to receive either standard dose 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) every 3 weeks for nine courses (control) or six courses of FAC followed by two courses of cyclophosphamide (5.25 g/m2), etoposide (1,500 mg/m2), and cisplatin (165 mg/m2) (HDCVP). The study was terminated in 1998 because of slow accrual of patients. Forty-six patients were entered in the study. At 4 years, the overall survival was 72.8% (SE 11.9%) and 61.7% (SE 12.4%), and disease-free survival were 45.5% (SE 12.3%) and 33.7% (SE 11.9%) for the control and HDCVP groups, respectively (p = 0.757 and 0.720). With the small number of patients in our study, a small overall survival benefit of high-dose intensification compared with the standard therapy cannot be excluded. However, any substantial benefit is unlikely.

Combination of epirubicin and cisplatin in hormone-refractory metastatic prostate cancer.

Anthracyclines and cisplatin have been shown separately to have modest activity in prostate cancer. The synergism between anthracyclines and cisplatin, with the lack of overlapping toxicities, led to the conduct of this phase II trial of the combination of epirubicin and cisplatin in hormone-refractory metastatic prostate cancer. Twenty-one evaluable patients with hormone-refractory metastatic prostate cancer received epirubicin 100 mg/m2 followed by cisplatin 80 mg/m2 with prehydration and mannitol diuresis. Epirubicin and cisplatin produced a biochemical response (>50% decrease in tumor marker) in 32% of patients, symptomatic improvement in 38%, and a response in measurable and evaluable disease sites in 14%. Toxicities were mainly hematologic, with 77% and 41% >grade 2 neutropenia and thrombocytopenia, respectively. Greater than grade 2 toxicities were: cardiac (three), renal secondary to sepsis (one), nausea and vomiting (two), weakness (one), mucositis (one), and diarrhea (one). The combination of epirubicin and cisplatin was associated with manageable toxicities in this elderly population; however, antitumor activity was marginal in this disease. Participation in clinical trials should continue to be offered to patients with hormone-refractory metastatic prostate cancer.

Mitoxantrone, prednimustine, and vincristine for elderly patients with aggressive non-Hodgkin's lymphoma.

Elderly patients with intermediate- or high-grade non-Hodgkin's lymphoma have a worse outcome than those who are younger than 60 years. It has been shown that aggressive combination chemotherapy is poorly tolerated in older patients resulting in a subsequent decrease in dose intensity. A phase II trial was conducted with mitoxantrone, prednimustine, and vincristine (NSO) in this group of patients. NSO consists of mitoxantrone 12 mg/M2 intravenously on day one, vincristine 1.4 mg/M2 intravenously on day 1 (maximum dose of two mg), and prednimustine 100 mg/M2 orally once a day for four days. NSO was repeated every 21 days. Thirty-six patients were able to be evaluated. There were 18 males and 18 females with the median age of 71 (range 60-85). NSO was well tolerated and nonhematological toxicities were uncommon. More than 80% of the patients received 90% or greater of the intended dose. The complete response rate was 60.6% and partial response was 21.8%. At 60 months the Kaplan-Meier estimate of progression-free survival was 47.9% (standard error 8.6%) and actual survival was 40.6% (standard error 8.8%). There were no differences in outcome between those with performance status (PS) of zero or one and those with PS > 1. NSO is well tolerated by elderly patients including those with PS > 1. These results compare favorably with other combinations in elderly patients with aggressive non-Hodgkin's lymphoma.

Expression of transmembrane 4 superfamily member, CD9, is related to improved progression-free survival in patients with diffuse non-Hodgkin's lymphoma.

Decreased expression of the transmembrane 4 superfamily member, CD9, is associated with poor prognosis in patients with breast or non-small cell lung cancer. The expression of CD9 in lymphoma was examined in this study. Fifty-one sections with diffuse lymphomas were examined. Thirty-seven had low expression and 14 high expression of CD9. At 5 years the progression-free survival rates were 83.3+/-10.8% and 32.8+/-9.2% (p=0.018), and the actual survival were 83.3+/-10.8% and 56.8+/-8.9% (p=0.256) for those with high and low CD9 expression respectively. Decreased expression of CD9 appears to be a prognostic factor for poor survival in patients with diffuse lymphomas.

Pleurodesis with iodized talc for malignant effusions using pigtail catheters.

OBJECTIVE: To assess the efficacy of using an iodized talc slurry as a sclerosing agent instilled into the pleural space via a 12-French pigtail catheter for controlling malignant pleural effusions. DESIGN: A prospective study in which patients were followed until their death. SETTING: A university-affiliated tertiary-care teaching hospital. PATIENTS: Medical oncology patients admitted with symptomatic malignant pleural effusions were considered for iodized talc pleurodesis. MAIN OUTCOME MEASURES: The control of pleural effusion. Treatment failure was defined as any reaccumulation of fluid in the pleural space. RESULTS: Fifteen patients were treated for a total of 17 instillations. The median follow-up on all patients until death was 6 months (range 1-20). The most frequent adverse effect in the study group was pleuritic chest pain (60%). The probability of control of effusion, as determined by the method of Kaplan-Meier, was 81% (SEM 9.7%). The cost of preparing 5 g of iodized talc was $4.32 (US). CONCLUSIONS: Iodized talc slurry instilled through a small-bore pigtail catheter is a safe, economical, and effective treatment for malignant pleural effusion.

Antiandrogen withdrawal syndrome with nilutamide.

Antiandrogens are combined with medical or surgical castration to achieve total androgen blockade in metastatic prostate cancer. Discontinuation of antiandrogens at disease progression has been associated with prostate-specific antigen (PSA) decrease, symptom improvement, and occasionally objective tumor regression. Two cases of metastatic prostate cancer demonstrating decrease in PSA of 92% and 56% on discontinuation of nilutamide therapy are reported. Improvement in urinary symptoms, bone pain and, in one, disappearance of para-aortic lymphadenopathy paralleled the PSA decrease. The duration of the withdrawal response of 6 months was comparable to those reported with discontinuation of flutamide.

Hydroxyurea did not enhance the clinical response to vinblastine in patients with anthracycline-resistant metastatic breast cancer.

BACKGROUND: Vinblastine is commonly used in metastatic breast cancer after anthracycline failure. The response rate to vinblastine is approximately 20%, with short duration of response. In vitro studies have shown that the addition of hydroxyurea resulted in increased accumulation of vinblastine in tumor cells and in loss of double minutes. We evaluated the combination of vinblastine and hydroxyurea in patients with anthracycline-resistant metastatic breast cancer. PATIENTS AND METHODS: Fourteen assessable patients with metastatic breast cancer were entered in the study. All patients had progressed on anthracyclines or progressed within 8 months of stopping anthracyclines. Patients received hydroxyurea (500 mg orally) every Monday, Wednesday and Friday starting one week before the first course of chemotherapy and continuing throughout treatment until disease progression. Vinblastine (6 mg/m2) was given intravenously every 21 days, RESULTS: The median number of courses for vinblastine was 3.5 (range, 1-6). Three patients had partial responses in soft tissue metastases (21%). Four patients had stable disease. Four patients had > grade 2 neutropenia, and 1 patient had grade 4 thrombocytopenia. There were 2 cases of grade 3 constipation, 2 of grade 3 nausea, and 1 each of grade 2 neuropathy and myalgia. There was no treatment-related mortality. CONCLUSIONS: Low-dose hydroxyurea in combination with vinblastine has a 21% response rate in metastatic breast cancer after anthracycline failure. Toxicity was mild and generally reversible. At the adopted dose schedule of hydroxyurea, the antitumor activity of vinblastine in anthracycline-resistant metastatic breast cancer did not appear to be enhanced.

Randomized placebo-controlled trial of granulocyte-macrophage colony-stimulating-factor support for dose-intensive cyclophosphamide, etoposide, and cisplatin.

This is a double-blind randomized placebo-controlled trial to evaluate the efficacy and safety of granulocyte-macrophage colony-stimulating-factor (GM-CSF) after dose-intensive cyclophosphamide, etoposide, and cisplatin (DICEP). Fifty-six patients with lymphoma or breast carcinoma were randomized to receive GM-CSF 250 microg/m2 or placebo subcutaneously (SC) every 12 hr after each course of DICEP until recovery of absolute neutrophil count (ANC) of 1.5 x 10(9)/L. Each patient was to receive three courses of DICEP. There were 28 patients in each group. The median duration of ANC below 0.5 x 10(9)/L was 10 versus 12 days for Course 1 (P = 0.010), 10 versus 12 days for Course 2 (P = 0.248), and 16.5 versus 15 days for Course 3 (P = 0.126); platelet counts below 20 x 10(9)/L was 4 versus 4 days for Course 1 (P = 0.586), 8.5 versus 7 days for Course 2 (P = 0.013), and 23.5 versus 10.5 days for Course 3 (P = 0.104); hospitalization for patients readmitted with cytopenic fever were 4 versus 8 days for Course 1 (P = 0.035); 7 versus 6 days for Course 2 (P = 0.692); and 8 versus 12 days for Course 3 (P = 0.884) in the GM-CSF and placebo group, respectively. GM-CSF significantly shortens the duration of neutropenia and readmission only during the first course of DICEP. There was a delay in platelet recovery and an increase in transfusion requirement during subsequent courses in the GM-CSF group. The result cautions the routine use of lineage specific hematopoietic growth factors in supporting repeated cycles of dose-intensive chemotherapy.

Allogeneic bone marrow transplantation for leukemia following piperazinedione and fractionated total body irradiation.

Between 1980 and 1988, 126 patients with leukemia were treated with piperazinedione and fractionated total body irradiation (TBI) followed by allogeneic bone marrow transplantation from HLA matched siblings. Sixty-one patients had acute myelogenous leukemia, 46 acute lymphoblastic leukemia, and 19 chronic myelogenous leukemia. Patients with acute leukemia in first complete remission were transplanted only if perceived to have a low probability of remaining in remission with conventional therapy. The toxicity from the preparative regimen was similar to that of cyclophosphamide and TBI except that none of the patients in the study had hemorrhagic cystitis or veno-occlusive disease. After a median follow up of 114 months, 29 patients (23%) are still alive without relapse. The survival of patients with acute myelogenous or lymphoblastic leukemia transplanted in their first remission were 35% and 43%, respectively. The survival of patients transplanted in their first chronic phase of chronic myelogenous leukemia was 60%. The results of this preparative regimen are comparable to those of cyclophosphamide and TBI.

Duration of intravenous antibiotics for patients with neutropenic fever.

BACKGROUND: Standard therapy for febrile neutropenia after chemotherapy has consisted of intravenous antibiotic until resolution of both fever and neutropenia. We attempted to shorten the hospital stay by discontinuing intravenous antibiotics in blood culture negative patients who remained clinically stable and afebrile for 48 hours. PATIENTS AND METHODS: Febrile neutropenic admissions of non-leukemic patients were reviewed. They were divided by three consecutive six month intervals into Group 1 (prior to initiation of the policy), Group 2 (after the policy was instituted), and Group 3 (to monitor the implementation of the policy after the initial six months). RESULTS: There were 134 admissions for neutropenic fever. Median duration of intravenous antibiotic for Group 1 was 7 days (95% Confidence Interval 6-9). It was significantly decreased to 5 days (4-6) and 4 days (3-5) for Groups 2 and 3 respectively (p = 0.004 and p < 0.001). Median duration of hospital stay for Group 1 was 10 days (7-13). It was also significantly decreased to 7 (5-8) and 6 days (5-7) for Groups 2 and 3 respectively (p = 0.04 and p = 0.002). CONCLUSION: Early discontinuation of intravenous antibiotics in patients with negative blood culture who remain afebrile and clinically stable for 48 hours results in shorter duration of hospital stay with potential for reduction in hospital costs.

Factors predicting long-term survival for metastatic breast cancer patients treated with high-dose chemotherapy and bone marrow support.

BACKGROUND: Poor prognosis of Stage IV breast cancer patients have at best a 10% 3-year survival rate with conventional chemotherapy. Dose-intensive chemotherapy improved survival rates for some of these patients. METHODS: All patients were Stage IV estrogen receptor-negative or estrogen receptor-positive hormonal refractory and received conventional chemotherapy (induction phase) to the point of achieving maximal response; if disease was stable or the patients responded, they entered high-dose chemotherapy (intensive phase). Seventy-six percent of the patients received two high-dose treatments with cyclophosphamide (4.5-6.0 g/m2), etoposide (750-1500 mg/m2), and cisplatin (120-180 mg/m2). Patients were randomized to receive or not receive autologous marrow. To identify prognostic factors for survival, univariate statistical analysis and multivariate models were applied to patient subsets. RESULTS: Univariate analysis identified a number of factors whose presence indicates improvement in overall survival rates. These include: (1) absence of liver relapse (P = 0.001); (2) absence of soft tissue relapse (P = 0.001); (3) a smaller number of metastatic sites at the time of detecting Stage IV disease (P = 0.026); and (4) disease-free interval greater than 1 year from initial diagnosis to Stage IV disease (P = 0.011). Multivariate models were fitted to the data, and three variables were identified as independent negative predictors for overall survival: (1) liver site (P = 0.001); (2) soft tissue site (P = 0.039); and (3) prior adjuvant chemotherapy (P = 0.028). CONCLUSIONS: Shorter survival after high-dose chemotherapy is predicted independently by patients pretreated with adjuvant chemotherapy, by disease distributed to the liver or the soft tissue.

Allogeneic bone marrow transplantation for hematological malignancies following etoposide, cyclophosphamide, and fractionated total body irradiation.

Forty-three patients received etoposide, cyclophosphamide, and fractionated total body irradiation before allogeneic marrow transplantation. Fifteen patients had chronic myelogenous leukemia in chronic phase or acute leukemia in first remission (standard risk) and twenty-eight patients with more advanced disease (high risk). All patients received etoposide 1,500 mg/m2 intravenously on day -8, cyclophosphamide 60 mg/kg/day intravenously on days -7 and -6, and total body irradiation at 170 cGy twice a day on days -3, -2, and -1. During the first 100 days 12 high risk patients (43%) died from causes unrelated to relapse while none of the standard risk patients died. Renal and hepatic dysfunction were also significantly increased during the first 14 days in the high risk group. The addition of 1,500 mg/m2 of etoposide to the cyclophosphamide and total body irradiation was well tolerated for patients with standard risk. However, the regimen was poorly tolerated with high mortality in patients with more advanced disease.

Influence of mobilized peripheral blood cells on the hematopoietic recovery by autologous marrow and recombinant human granulocyte-macrophage colony-stimulating factor after high-dose cyclophosphamide, etoposide, and cisplatin.

Peripheral blood cells (PBC) can hasten hematopoietic recovery after high-dose chemotherapy. To determine if PBC apheresed after mobilization further enhance hematopoietic recovery over that achieved with autologous bone marrow (ABM) and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF), 14 patients with metastatic solid tumors were supported by ABM and rhGM-CSF during the first course of high doses of cyclophosphamide, etoposide, and cisplatin (CVP) and 11 of these 14 patients by mobilized PBC with ABM and rhGM-CSF during the second CVP. Each patient served as his or her own control. Identical doses of CVP were administered in both courses: cyclophosphamide 5.25 g/m2, etoposide 1,200 mg/m2, and cisplatin 165 to 180 mg/m2. PBC were collected on day 10 after mobilization with cyclophosphamide (3 g/m2) intravenously (IV) on day 1, doxorubicin (50 mg/m2) as a continuous IV infusion over 48 hours starting day 2, and rhGM-CSF as a daily 4-hour IV infusion starting day 4 at 0.6 mg/m2 for 14 days. Comparing recovery in the 11 patients to receive two cycles of therapy, the median days to an absolute neutrophil count of 0.1 x 10(9)/L and 0.5 x 10(9)/L were not statistically significant between the two courses; neither was there a difference in the incidence of fever and bacteremia. The median number of days to platelet count of 0.02 x 10(12)/L unmaintained by platelet transfusion was 20 from marrow infusion for course 1 and 16 for course 2 (P = .059). The median number of days to a platelet count of 0.05 x 10(12)/L was significantly shortened: 24 and 19 days for courses 1 and 2, respectively (P = .045). Patients who received PBC required fewer number of platelet transfusions. Extramedullary toxicities were not different between the groups. Our finding of enhanced early recovery of platelets and reduced platelet transfusion requirement is in concordance with other studies.

Pharmacokinetics of cyclosporine in bone marrow transplantation: longitudinal characterization of drug in lipoprotein fractions.

The pharmacokinetics of cyclosporine (CSA; 2 mg/kg given iv over a period of 2 h every 12 h) in whole blood, plasma, high-density lipoproteins (HDL), and low-density lipoproteins (LDL) were studied after single (n = 10) and multiple (31 days; n = 6) doses in patients receiving allogeneic bone marrow transplants. Whereas HDL-cholesterol levels decreased significantly, LDL-cholesterol levels increased from day 1 to day 31 of CSA dosing. The mean area under the concentration-time curve and half-life values of CSA in whole blood or total plasma did not differ after single or multiple doses. Greater amounts of CSA were contained in the HDL relative to the LDL fraction over the 24-h period after a single dose; the reverse was found after multiple dosing. Cyclosporine was not detectable in the very LDL fractions. The percentage of total plasma CSA contained in each lipoprotein fraction was independent of the concentration of CSA in total plasma or whole blood. The pharmacokinetics of CSA in the various biologic matrices were not associated with measurements of kidney and liver function. Taken together, the variability of CSA pharmacokinetics previously reported in whole blood or total plasma was also found in lipoprotein fractions. The relative changes in CSA content of lipoproteins may offer an explanation for differences in drug effect with multiple dosing.

Second bone marrow transplants for relapsed leukemia.

Seventeen patients who had a relapse at a median of 9 months after marrow transplant (14 allogeneic and three syngeneic) received second transplants. Eight patients were in remission when transplanted. Of the nine patients with active disease at the time of transplant, six had complete remissions, and one converted from blastic to chronic phase of chronic myelogenous leukemia. The median survival was 9 months (95% confidence interval, 4 to 17 months). Four patients died within 100 days of transplantation, and three were disease-free. Ten patients died after 100 days, all except two of disease relapse. Five patients had remissions that were greater than 12 months and longer than the remission after their first transplant (inversions). Three patients remain alive and disease-free at 37+, 55+, and 61+ months, the former two despite remissions of less than 1 year after their first transplant. Second transplants with a different cytoreductive regimen can eradicate disease resistant to prior myeloablative treatment; some patients may benefit from second transplants, even if the first transplant only achieves a short remission.

An effective acute graft-vs.-host disease prophylaxis with minidose methotrexate, cyclosporine, and single-dose methylprednisolone.

Cyclosporine and methotrexate at standard doses (15 mg/m2 on day 1 and 10 mg/m2 on days 3, 6, and 11, total 45 mg/m2) are effective in the prophylaxis of acute graft-vs.-host disease. However, the combination has significant early toxicities with delayed engraftment, increased mucositis, and hepatotoxicity. We modified the combination by adding single-dose methylprednisolone and lowered the total dose of methotrexate to 35 mg/m2 (5 mg/m2 on days 1, 3, and 6, and then 10 mg/m2 on days 11 and 18) and then to 20 mg/m2 (5 mg/m2 on days 1, 3, 6, and 11) in an attempt to decrease these side effects in two sequential consecutive groups of patients. We demonstrated that the modified regimens maintained the efficacy with reduced toxicities. The rate of engraftment was comparable to cyclosporine alone and the hepatotoxicity was reduced with reduced doses of methotrexate. Factors such as early immunosuppression of the host, intravenous immunoglobulin, the timing of steroid administration, nucleotide free diet and germ free environment may contribute to the effectiveness of the combination and permit reduction of methotrexate dose.

Prophylaxis of cytomegalovirus infection with ganciclovir in allogeneic marrow transplantation.

Cytomegalovirus (CMV) infection is one of the most common causes of morbidity and mortality after allogeneic marrow transplantation. We studied 14 consecutive CMV-seropositive patients adding ganciclovir (2.5 mg/kg i.v. every 8 hours for 7 days prior to transplant and 6 mg/kg three times a week after neutrophils became greater than 0.5 x 10(9)/l and the patients were platelet transfusion-independent until d 70) to our previous prophylaxis regimen which consisted of intravenous immunoglobulin and acyclovir. The result was compared with 30 consecutive patients whom we studied with our previous regimen. The addition of ganciclovir did not cause any extra toxicities. The incidence of interstitial pneumonitis and cumulative probability of CMV excretion in the first 100 d post-transplantation was significantly reduced (p = 0.038 and p = 0.035 respectively). The result shows that addition of ganciclovir significantly decreased the incidence of CMV infection in the early post-transplantation period.