Increasing tamoxifen dose in breast cancer patients based on CYP2D6 genotypes and endoxifen levels: effect on active metabolite isomers and the antiestrogenic activity score.

Tamoxifen (Tam), the major drug for estrogen receptor (ER)-positive breast cancer, is converted to its active metabolites, Z- and Z'-endoxifen and 4-OH-Tam isomers, primarily by cytochrome P450 CYP2D6. In 117 patients taking 20 mg/day of Tam, we determined CYP2D6 genotypes and measured the plasma levels of Tam metabolites. The Z-endoxifen levels increased while Z'-endoxifen levels decreased with increasing metabolizer phenotype activity (MPA) score (P ≤ 0.0004). The dosage in patients with endoxifen <40 nmol/l and/or CYP2D6 MPA scores of 0 was increased to 30 mg/day and their metabolite isomers were monitored for up to 90 days. Of the 24 patients on the increased dose, 90% showed an increase in active isomers by day 60; the rate of increase correlated with the MPA score. Notably, their antiestrogenic activity scores (AASs), which estimate total isomer biologic activity, increased from a baseline median of 17 to 26 at day 60. Further studies involving increasing/decreasing the Tam dosage based on the AAS may determine whether dose adjustment can optimize treatment and improve long-term survival.

Pulmonary involvement in patients with early rheumatoid arthritis.

OBJECTIVES: To assess the pleuropulmonary changes in patients with early rheumatoid arthritis (RA), using high-resolution computed tomography (HRCT). METHODS: Forty-three non-smoking patients with early RA were included. The disease duration was<1 year, without previous treatment. Disease activity was assessed using the 28-joint indices score (DAS28). Hand and wrist X-rays were evaluated using Larsen's criteria. Pulmonary functional tests (PFTs) were performed in 32 patients. The patients and 18 non-smokers healthy individuals were assessed by plain chest X-ray (CXR) and HRCT of the lungs. RESULTS: HRCT revealed air trapping in 69% (25/36), bronchiectasis in 58% (25/43), bronchial wall thickening in 52% (22/43) and ground glass opacities (GGOs) in 35% (15/43) of the patients. Pleural thickening and effusion were observed in 11% (5/43). CXR was abnormal in one patient revealing a single pulmonary nodule. GGOs were the only HRCT sign observed exclusively in RA patients. All the other abnormalities were depicted in the control group at the same frequency as in the patients. However, the extent (as expressed by the HRCT score) of air trapping, bronchiectasis and bronchial wall thickening was significantly greater in the patients than in the control group (p<0.05). The PFTs were within normal values. DAS28, PFTs, and the Larsen score did not show any significant correlation with either each HRCT sign score separately or the total score. CONCLUSIONS: Lung abnormalities are frequently observed in patients with early RA on HRCT, even when CXR and PFTs are normal. Limited areas of GGOs were the abnormalities depicted exclusively in patients.

Tumor size is of prognostic value in surgically treated FIGO stage II cervical cancer.

OBJECTIVES: Tumor size is a well recognized prognostic factor in early stage cervical carcinoma (CX). However, limited knowledge exists about the value of tumor size in surgically treated CX with extrauterine extension. METHODS: 245 cases of local advanced CX (FIGO stage IIA and IIB) who received upfront surgery were evaluated regarding tumor size, regarding the prediction of pelvic lymph node involvement and recurrence free and overall survival during a median follow-up time of 54 months (95% CI 45.4-62.6 months). Tumors larger than 4 cm were defined as bulky stage disease. RESULTS: Bulky disease was seen in 46.1% (113/245). 60.2% of these patients showed pelvic lymph node involvement, compared to 42.4% (56/132) in non-bulky tumors (p=0.006; odds ratio: 2.2 [95% CI: 1.3-3.6]). Patients with bulky tumors showed an increase of recurrent disease (40.2% vs. 28.0%; p=0.045). The relative risk for recurrent disease was 1.97 (95% CI: 1.3-3.0). The 5-year overall survival rate was significantly lower (67.7% [95% CI: 58.2-74.8] vs. 49.5% [95% CI: 36.8-59.1]; p=0.0015). In multivariate analysis, tumor stage, pelvic lymph node involvement and maximal tumor size were independent prognostic factors. CONCLUSIONS: The results suggest that tumor size, defining bulky disease as tumors larger than 4 cm, is of prognostic impact also in FIGO stage II cervical carcinomas. A revised FIGO/TNM classification system similar to the subgrouping of stage IB CX is recommended for stage II using a cut-off value of 4 cm as discriminator: stage IIA1 and stage IIB1 for tumors with 4 cm (i.e. bulky disease).

Pattern of invasion is of prognostic value in surgically treated cervical cancer patients.

OBJECTIVES: Different patterns of invasion (representing different grades of tumor cell dissociation) are associated with prognostic outcome in cancer. We evaluated the prognostic value of different patterns of invasion (PI) in cervical carcinomas (CX). METHODS: Six hundred eleven surgically treated CX (FIGO IB to IIB) were re-evaluated histologically regarding the PI, using a three-level scoring system. Closed PI was defined as cohesive growth with well-delineated (pushing) borders. In finger-like PI the tumor grows in solid cords/trabecles. Highly dissociative growth in small groups or single cells was defined as spray-like PI. Types of PI were correlated to tumor stage, histo-morphologic factors and prognostic outcome. RESULTS: Sixty percent of the tumors showed a spray-like PI, 30% a finger-like PI and only 7.4% were of the closed type. Spray-like PI showed a significant correlation with advanced stage disease, lymphovascular space involvement, poorly differentiated tumors and pelvic lymph node metastases. Spray-like PI was accompanied by a reduced 5-year overall survival when compared to the finger-like and closed PI (68.7% vs. 80.9% vs. 88.5%; P=0.0004). The prognostic impact of the PI disappeared in node-positive patients (P=0.06) but persisted in patients without pelvic lymph node disease (P=0.03). In multivariate analysis, using COX regression model, the PI represented as independent prognostic factor. CONCLUSIONS: Spray-like PI (i.e., highest degree of tumor cell dissociation) is associated with advanced tumor stages, increased rate of recurrency and a reduced overall survival. In separate analysis of patients with and without lymph node metastases, the impact of PI persisted only in node-negative cases as a prognostic factor.

CD44-v6 concentrations in carcinoma of the uterine cervix: lack of prognostic significance.

Several kinds of cellular adhesion molecules, like different splicing variants of CD 44, have gained important as prognostic or markers for metastatic disease. Fresh frozen samples from 64 cervical carcinoma (CX) were stored in liquid nitrogen and examined using ELISA-technique, testing the prognostic impact. Normal cervical tissue served as control. CD 44-v6 concentration, was significant elevated in tumor tissue, when compared to the controls (P=0.04). There was no correlation to tumor stage (P=0.61), lymphovascular space involvement (P=0.075) or pelvic lymph node involvement (P=0.81). The CD 44-v6 concentration was not informative regarding recurrence-free and overall survival. Contrary to immunohistochemistry, the quantification of CD 44-v6 using ELISA-technique does not provide any further information.

Clinical relevance of urokinase-type plasminogen activator and its inhibitor type 1 (PAI-1) in squamous cell carcinoma of the uterine cervix.

OBJECTIVE: The expression of uPA and PAI-1 as parameters of tumour-associated proteolysis has been implicated in the process of tumour cell invasion and the metastatic process. However, there is limited information on the impact of these parameters in cervical carcinoma. METHODS: Quantitative levels for uPA (n = 114) and PAI-1 (n = 103) were researched in operatively treated, surgically staged squamous cell cancer of the uterine cervix, using an ELISA-technique. Results were assessed regarding their impact in predicting pelvic lymph nodes metastases, tumour recurrence rate and recurrence free survival (RFS) using uni- and multivariate analysis. RESULTS: Median levels of both parameters were significantly higher in tumour tissue than in normal cervical tissue (p < 0.001). Detection of uPA gave no useful prognostic information. PAI-1 concentration showed a positive correlation with advanced tumour stage (p = 0.008), but no significant correlation with nodal status (pN0: 2.6 vs. pN1: 4.0 ng/mg protein; p = 0.092). Using a cut-off level of 2.4 ng/mg protein, patients with elevated PAI-1 levels demonstrated reduced RFS (45.9 versus 52.9 months; p = 0.1). Multivariate analysis, including nodal status, tumour stage, lymphovascular space involvement and grading failed to demonstrate any prognostic impact of uPA and PAI-1. CONCLUSIONS: The results indicate, that PAI-1 expression is of some prognostic impact in cervical cancer, indicating an association of elevated PAI levels with local tumour progression and reduced recurrence-free survival.

p53 in surgically treated and pathologically staged cervical cancer: correlation with local tumor progression, but not with lymphatic spread.

There is only limited information about the prognostic value of p53 immunostaining in cervical cancer. The purpose of this study was to assess the clinical significance of p53 and prognosis in operatively treated cervical carcinoma. A hundred and fourteen primary surgically treated cervical carcinomas (CX) were obtained from the so called Wertheim Archive in the Department of Obstetrics and Gynecology at the University of Leipzig. These included 105 squamous cell cancer (SCC) and nine adenocarcinomas (AC). No cases received neoadjuvant therapy. For immunohistochemical analysis, the cases were tested with the monoclonal antibody DO-7 (DAKO Diagnostics, Denmark). Two hundred tumor cell nuclei were counted for positive nuclear immunostaining, regardless of staining intensity. Cases were stated as positive when a minimum of 10% nuclei showed positive staining. Fresh frozen tissue was available from 21 CX for p53-mutation analysis (exons 4-9) using PCR-based amplification and SSCP-analysis. Of the squamous cell cancers (SCC), 63.8% showed positive nuclear p53-immunostaining; adenocarcinomas (AC) were completely negative (P = 0.0000, Chi2-test). Stage-by-stage analysis revealed no differences in p53-expression. However, combining pT1b- and pT2-cases, the difference in positive immunostaining reached statistical significance (44.4% vs. 71.7%; P = 0.007). There were no differences in p53-reactivity regarding the presence of pelvic lymph node metastases, tumor grading, relapse-free survival and tumor recurrence. In addition, only 5% of CX with positive p53-immunostaining showed genomic alterations in mutational analysis. p53-immunoreactivity showed significant correlation with local tumor progression but not with lymphatic spread, lacking any prognostic impact in surgically treated cervical cancer. There is no correlation of p53-immunostaining with the occurrence of p53-gene mutations in cervical cancer.

[Significance of family anamnesis in cervix carcinoma]. / Bedeutung der Familienanamnese beim Zervixkarzinom.

OBJECTIVE: Except for certain types of familiar cancer, the impact and contribution of familial factors to the development of sporadic cancer is thought to be relatively minor. Some earlier case reports had been suspected genetic background in cervical cancer (CX). MATERIAL AND METHODS: The literature was screened and cervical cancer patients from the Department of Obstetrics and Gynecology of the University Hospital of Leipzig were searched for familiar history of malignant tumors at any sites to establish familial risk for CX. RESULTS: Analysis showed, that 15 to 20% of cervical cancer represented at least one first-degree relative with malignant disease any site. The familial relative risk for in situ or invasive CX was reported to range between 1.8 to 2.0 and the heretability was between 0.11 and 0.15 for in situ and 0.22 and 0.33 for the invasive form. In some families a clustering, i.e. two or more female first-degree sibs were affected by CX, was observed, the frequency ranged between 1.7 and 7%. Analyses of risk by age of onset are rarely done and the results are controversy. Two large studies reported an aggregation of tobacco-related and HPV-associated malignancies, like oro-pharyngeal, lung and anorectal sites, in cervical cancer families. Moreover, it has been shown, that both mothers and daughters, who had invasive CX as the first primary cancer, had an excess of lung cancer as a second tumor site. CONCLUSIONS: The correlation of HPV-associated neoplasms in affected families suggest a role of mild or moderate hereditary immunosuppression in explaining a part of familial predisposition to cervical cancer are biologically founded. Consequently, this would not imply germ line mutations in oncogenes or tumor suppressor genes but in genes modulating immune response and perhaps causing susceptibility to a variety of viral infections.

[Epidemiology and pathogenesis of cervical cancer]. / Epidemiologie und formale Pathogenese des Zervixkarzinoms.

The majority of the estimated incidence of 471,000 new cases for invasive cervical cancer (CX) and 215,000 cancer deaths occurs in the developing countries. For Germany the CX accounts at 8th position of all cancers in women in 1997 with 5,800 newly diagnosed cases. But, every fourth woman between 25th- and 35th-year of life has been affected by CX. This counts at the upper third of the incidence in the European Union (EU). The estimated loss of live-years for women affected by CX is about nine years. The lethality for all stages of invasive cervical cancer is about 30%. For the last two decades stagnation of the reduction of mortality by CX has been reported for EU and the USA, especially affecting woman up to 35th-year of life. The percentage of this age group of all primary operative treated CX at the Leipzig University Hospital between 1979 and 1999 was 26.2%, with a mean age of 43.4 +/- 11.1 years. Improved screening for CX in the western countries and a change in environmental factors have been caused an increase of cervical precancerous (CIN-) lesions. The frequency of CIN-lesions has been estimated to be 100-times higher than the incidence of invasive cancer (21.1) in Germany. The pathogenesis of CX is multistage and CIN I and II represent highly regressive lesions, whereas CIN III requires therapeutic intervention, caused by high progression rate. The Bethesda-classification of low und high grade squamous intraepithelial lesions (SIL) cannot be recommended for biopsies or conisation specimens. Dsyplastic lesions of endocervical columnar epithelium should not be graded, the only general accepted lesion represents the adenocarcinoma in situ (ACIS). Both, CIN and ACIS represents proliferative active lesions, caused by infection with HPV. But the detection of morphologic alterations, associated with HPV, like koilocytes, are inverse correlated with the grade of the CIN-lesion.

A pilot study of interpersonal psychotherapy by telephone with cancer patients and their partners.

A single-arm pilot study explored the feasibility of adapting in Interpersonal Psychotherapy (IPT) by telephone to reduce psychological distress and to enhance coping during cancer treatment. Therapy focuses on role transitions, interpersonal conflicts, and grief precipitated by cancer. Breast cancer patients receiving high-dose chemotherapy received weekly sessions with a psychologist throughout chemotherapy and for 1 month afterwards. Patients could invite one 'partner' to receive individual telephone IPT. Psychosocial functioning was assessed using standardized measures at study entry, after chemotherapy, and following telephone IPT. Accrual and participation supplied evidence of feasibility: 14 patients and 10 partners were recruited, 82.5% of those eligible. Patients had a mean of 16 sessions; partners had a mean of 11. Participants rated their satisfaction with the program between 'good' and 'excellent'. A test of the efficacy of telephone IPT requires a larger, randomized trial. In order to standardize the intervention, a treatment manual was developed. This study indicated the importance of outreach to family members as well as to cancer patients, intensive patient education about oncology treatment and the medical care setting, and psychosocial services that continue after cancer treatment has been completed.

5-year results of dose-intensive sequential adjuvant chemotherapy for women with high-risk node-positive breast cancer: A phase II study.

PURPOSE: We conducted a phase II pilot study of dose-intensive adjuvant chemotherapy with doxorubicin followed sequentially by high-dose cyclophosphamide to determine the safety and feasibility of this dose-dense treatment and to estimate the disease-free and overall survival in breast cancer patients with four or more involved axillary lymph nodes. PATIENTS AND METHODS: Seventy-three patients received adjuvant treatment with four cycles of doxorubicin 75 mg/m(2) as an intravenous bolus every 21 days, followed by three cycles of cyclophosphamide 3,000 mg/m(2) every 14 days with granulocyte colony-stimulating factor support. RESULTS: Seventy-one patients were assessable, and all but two completed all planned chemotherapy. There was no treatment-related mortality. The most common toxicity was neutropenic fever, which occurred in 39% of patients. Median disease-free survival is 66 months (95% confidence interval, 34 to 98 months), and median overall survival has not yet been reached. At 5 years of follow-up, the disease-free survival is 51.7%, and overall survival is 60.0%. There is no long-term treatment-related toxicity, and no cases of acute myelogenous leukemia or myelodysplastic syndrome have been observed. CONCLUSION: Our pilot study of doxorubicin followed by cyclophosphamide demonstrates the safety and feasibility of the sequential dose-dense plan. Long-term follow-up, although noncomparative, is promising. However, this regimen is associated with a higher incidence of toxicity (and also higher costs) than the standard dose and schedule of doxorubicin and cyclophosphamide, and therefore it should not be used as conventional therapy in the absence of demonstrated improvement of outcome. Randomized trials testing the dose-dense approach have been completed but not yet reported. Because the sequential plan can decrease overlapping toxicities, it is an appropriate platform for the addition of newer active agents, such as taxanes or monoclonal antibodies.

Sequential dose-dense doxorubicin, paclitaxel, and cyclophosphamide for resectable high-risk breast cancer: feasibility and efficacy.

PURPOSE: Dose-dense chemotherapy is predicted to be a superior treatment plan. Therefore, we studied dose-dense doxorubicin, paclitaxel, and cyclophosphamide (A-->T-->C) as adjuvant therapy. METHODS: Patients with resected breast cancer involving four or more ipsilateral axillary lymph nodes were treated with nine cycles of chemotherapy, using 14-day intertreatment intervals. Doses were as follows: doxorubicin 90 mg/m2 x 3, then paclitaxel 250 mg/m2/24 hours x 3, and then cyclophosphamide 3.0 g/m2 x 3; all doses were given with subcutaneous injections of 5 microg/kg granulocyte colony-stimulating factor on days 3 through 10. Amenorrheic patients with hormone receptor-positive tumors received tamoxifen 20 mg/day for 5 years. Patients treated with breast conservation, those with 10 or more positive nodes, and those with tumors larger than 5 cm received radiotherapy. RESULTS: Between March 1993 and June 1994, we enrolled 42 patients. The median age was 46 years (range, 29 to 63 years), the median number of positive lymph nodes was eight (range, four to 25), and the median tumor size was 3.0 cm (range, 0 to 11.0 cm). The median intertreatment interval was 14 days (range, 13 to 36 days), and the median delivered dose-intensity exceeded 92% of the planned dose-intensity for all three drugs. Hospital admission was required for 29 patients (69%), and 28 patients (67%) required blood product transfusion. No treatment-related deaths or cardiac toxicities occurred. Doxorubicin was dose-reduced in four patients (10%) and paclitaxel was reduced in eight (20%). At a median follow-up from surgery of 48 months (range, 3 to 57 months), nine patients (19%) had relapsed, the actuarial disease-free survival rate was 78% (95% confidence interval, 66% to 92%), and four patients (10%) had died of metastatic disease. CONCLUSION: Dose-dense sequential adjuvant chemotherapy with doxorubicin, paclitaxel, and cyclophosphamide (A-->T-->C) is feasible and promising. Several ongoing phase III trials are evaluating this approach.

Phase I study of escalating doses of edatrexate in combination with paclitaxel in patients with metastatic breast cancer.

Motivated by the observation of preclinical synergy, a Phase I dose escalation study of edatrexate in combination with a 3-h paclitaxel infusion was performed in patients with advanced breast cancer to determine the maximum tolerated dose (MTD) of edatrexate and the toxicities associated with this combination and to report preliminary observations of efficacy with this novel combination. Thirty-six patients were enrolled in this Phase I trial. Thirty-five eligible patients were treated every 21 days in cohorts of at least three patients and were assessable for toxicity. One patient was ineligible due to hyperbilirubinemia. Stepwise dose escalations of edatrexate were administered until grade >3 nonhematological dose-limiting toxicities were reported. The initial dose level of edatrexate was 180 mg/m2; subsequent cohorts were treated with escalating doses of edatrexate (210, 240, 270, 300, 350, and 400 mg/m2). Edatrexate was administered by i.v. infusion over 1 h. Paclitaxel was administered 24 h later at a fixed dose of 175 mg/m2 as a 3-h infusion with standard dexamethasone, diphenhydramine, and cimetidine premedication. The MTD of edatrexate was reached at the 350 mg/m2 level in this study. Grade 3 diarrhea was seen in one patient at the 300 and 400 mg/m2 dose levels, requiring dose reductions. Two patients experienced grade 4 stomatitis at the 400 mg/m2 dose level and also required dose reduction, establishing the MTD as 350 mg/m2. Grade 3 nausea and vomiting were noted in two of three patients at the highest dose level. Of 35 patients, 4 patients reported grade 3 myalgias and 1 patient reported grade 3 neurosensory complaints, which were seen mostly at the 350 and 400 mg/m2 dose levels; however, 1 patient reported grade 3 myalgias at 180 mg/m2. No cumulative neurotoxicity was observed, and no patient experienced an allergic reaction to paclitaxel. In 23 patients with bidimensionally measurable disease, there were four complete (17%) and seven partial responses, with an overall response rate of 48% (95% confidence interval, 27-69%). All of the responses were seen in patients who had not received prior chemotherapy for stage IV disease. The median duration of response was not assessable because many responding patients went on to receive high-dose chemotherapy treatment with stem cell support. The combination of edatrexate and paclitaxel for treatment of metastatic breast cancer is a feasible and safe regimen. The MTD of edatrexate was 350 mg/m2 when combined with a 3-h infusion of paclitaxel (175 mg/m2) given 24 h later. Activity was noted even among patients who had relapsed shortly after receiving methotrexate- and/or doxorubicin-containing adjuvant regimens. Additional studies evaluating the sequences and dosing schema for this combination are warranted to improve the response proportion and define the duration of the response.

Paclitaxel for breast cancer: the Memorial Sloan-Kettering Cancer Center experience.

The proven safety profile and antitumor activity of paclitaxel (Taxol) in the treatment of metastatic breast cancer led investigators at Memorial Sloan-Kettering Cancer Center (MSKCC) to further examine the agent's potential in the treatment of advanced breast cancer. Efficacy and tolerability studies of paclitaxel as single-agent therapy were undertaken, along with parallel investigations of quality-of-life parameters. The studies examined the effects of 96-hour infusion schedules of paclitaxel and are currently assessing the feasibility of a weekly 1-hour infusion schedule. Researchers at MSKCC also compared the results of a variety of two- and three-drug paclitaxel-containing regimens to determine possible synergism and better define safety profiles. They examined the combination of paclitaxel and edatrexate, as well as a promising combination of paclitaxel and a monoclonal antibody directed at growth factor receptors. The latter ongoing trial will include both laboratory studies that examine possible cellular mechanisms for the combination's observed synergy and a clinical trial that combines paclitaxel with a monoclonal antibody directed against the epidermal growth factor. In conclusion, the investigators discuss the optimal integration of paclitaxel into doxorubicin/cyclophosphamide (Cytoxan, Neosar)-based adjuvant therapy for node-positive stage II-III resectable breast cancer.

Phase II study of semisynthetic paclitaxel in metastatic breast cancer.

The aim of this phase II study was to characterise the efficacy and toxicity of semisynthetic paclitaxel in patients with metastatic breast cancer. Eligible patients had measurable disease and had been treated with one prior chemotherapy regimen either as adjuvant or for metastatic disease. Semisynthetic paclitaxel was given at a dose of 175 mg/m2 over 3 h every 21 days with dexamethasone, cimetidine and diphenhydramine premedications. 31 patients were entered. All were evaluable for toxicity. 30 patients were evaluable for response because 1 patient was lost to follow-up after receiving one cycle. One patient achieved a complete response and 10 patients achieved partial responses for an overall response rate (CR + PR) of 37% (95% confidence interval 20-56%). 17 patients (55%) experienced at least one episode of grade 3 or 4 neutropenia. There were two episodes of febrile neutropenia complicating 155 cycles of therapy. One of these resulted in a treatment-related death in a patient with pulmonary metastasis. 3 patients required dose reductions for grade 3 sensory neuropathy. Our study shows that the antitumour activity and toxic effects of semisynthetic paclitaxel appear to be identical to the naturally occurring product.

Metabolic effects of successful intraportal islet transplantation in insulin-dependent diabetes mellitus.

The intraportal injection of human pancreatic islets has been indicated as a possible alternative to the pancreas transplant in insulin-dependent diabetic patients. Aim of the present work was to study the effect of intraportal injection of purified human islets on: (a) the basal hepatic glucose production; (b) the whole body glucose homeostasis and insulin action; and (c) the regulation of insulin secretion in insulin-dependent diabetes mellitus patients bearing a kidney transplant. 15 recipients of purified islets from cadaver donors (intraportal injection) were studied by means of the infusion of labeled glucose to quantify the hepatic glucose production. Islet transplanted patients were subdivided in two groups based on graft function and underwent: (a) a 120-min euglycemic insulin infusion (1 mU/kg/min) to assess insulin action; (b) a 120-min glucose infusion (+75 mg/di) to study the pattern of insulin secretion. Seven patients with chronic uveitis on the same immunosuppressive therapy as grafted patients, twelve healthy volunteers, and seven insulin-dependent diabetic patients with combined pancreas and kidney transplantation were also studied as control groups. Islet transplanted patients have: (a) a higher basal hepatic glucose production (HGP: 5.1 +/- 1.4 mg/kg/ min; P < 0.05 with respect to all other groups) if without graft function, and a normal HGP (2.4 +/- 0.2 mg/kg/min) with a functioning graft; (b) a defective tissue glucose disposal (3.9 +/- 0.5 mg/kg/min in patients without islet function and 5.3 +/- 0.4 mg/kg/min in patients with islet function) with respect to normals (P < 0.01 for both comparisons); (c) a blunted first phase insulin peak and a similar second phase secretion with respect to controls. In conclusion, in spite of the persistence of an abnormal pattern of insulin secretion, successful intraportal islet graft normalizes the basal HGP and improves total tissue glucose disposal in insulin-dependent diabetes mellitus.

Sequential adjuvant therapy: the Memorial Sloan-Kettering Cancer Center experience.

Adjuvant chemotherapy has a real but modest impact on the disease-free and overall survival of patients with breast cancer. Recent attempts to improve its effectiveness have focused on dose intensity and new agents. Sequential therapy maximized dose intensity while limiting overlapping toxicity. Sequential therapy using doxorubicin followed by cyclophosphamide/methotrexate/5-fluorouracil (CMF) has been found superior in patients with high-risk resectable breast cancer. The novel chemotherapy agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is now known to be highly active in advanced breast cancer and appears to be clinically non-cross-resistant with doxorubicin. Therefore, this drug is being studied as a component of the next generation of adjuvant chemotherapy regimens. The most appropriate way to incorporate paclitaxel has not yet been defined, but its concurrent administration with other agents has, in some cases, been troublesome. Based on the demonstrated advantage of the sequential plan for doxorubicin and CMF, we conducted a series of pilot trials testing sequential high-dose therapy. Initially, we studied multiple cycles of doxorubicin followed by cyclophosphamide; we later added paclitaxel to this regimen. These phase II studies demonstrate the feasibility of sequential therapy with doxorubicin, paclitaxel, and cyclophosphamide, and early disease-free survival results are promising. Cooperative group projects are under way or planned to further define the activity of these regimens.

Pilot study of 5-azacytidine (5-AZA) and carboplatin (CBDCA) in patients with relapsed/refractory leukemia.

5-azacytidine (5-AZA) and carboplatin (CBDCA) are two agents which have demonstrated antileukemic activity in a number of phase I-II trials. Their mechanisms of action and pharmacology related to cell resistance suggested suitability for combination therapy. The aim of this pilot was to evaluate the effects of this combination in the treatment of patients with relapsed/refractory acute leukemia. A total of 21 patients was enrolled. 5-azacytidine, at doses ranging from 50-150 mg/m2/day, was administered as a 2-hr infusion for 5 consecutive days. On day 3, patients began a 5-day course of CBDCA given as a 24-hr continuous intravenous infusion of 250 mg/m2/day. There were no complete remissions with this regimen. Although there were three partial responses, these were generally of short duration. Nonhematologic toxicities were mild. No correlation was seen between response and serum platinum levels. These results demonstrate that the 5-AZA/CBDCA combination is ineffective therapy for heavily pretreated patients with acute leukemia.

Phase II and pharmacologic study of docetaxel as initial chemotherapy for metastatic breast cancer.

PURPOSE: Because docetaxel (Taxotere, RP 56976; Rhone-Poulenc Rorer, Antony, France) appeared to be active against breast cancer in phase I trials, we performed this phase II study. PATIENTS AND METHODS: Thirty-seven patients with measurable disease were enrolled. Only prior hormone therapy was allowed, as was adjuvant chemotherapy completed > or = 12 months earlier. Docetaxel 100 mg/m2 was administered over 1 hour every 21 days. Diphenhydramine hydrochloride and/or corticosteroid premedication was added after hypersensitivity-like reactions (HSRs) were seen in two of the first six patients. Pharmacokinetic studies were performed during cycle 1 for correlation with toxicity. RESULTS: Thirty-seven patients were assessable. Nineteen (51%) required dose reductions, usually for neutropenic fever. The median nadir WBC count was 1.4 x 10(3)/microL. HSRs were noted in 20 patients (54%). At a median cumulative dose of 297 mg/m2 (range, 99.6 to 424.5 mg/m2), 30 patients (81%) developed fluid retention, for which 11 (30%) subsequently stopped treatment. The first-cycle plasma area under the concentration-time curve (AUC) did not correlate with toxicity, although an ineligible patient with hepatic metastases (pretreatment bilirubin level 1.8 mg/dL) had an elevated AUC and died of toxicity. Responses were seen at all sites. On an intent-to-treat basis, there were two (5%) complete responses (CRs) and 18 (49%) partial responses (PRs). The overall response proportion (CRs plus PRs) was 54% (95% confidence interval, 37% to 71%). The median time to response was 12 weeks (range, 3 to 15) and the median duration was 26 weeks (range, 10 to 58+). CONCLUSION: Docetaxel is active for metastatic breast cancer. Neutropenia and fluid retention are dose-limiting. The AUC did not predict toxicity, but caution is warranted when treating patients with liver dysfunction. An understanding of the pathophysiology of the fluid retention may facilitate prevention. Frequent HSR may warrant prophylactic premedication.