Paclitaxel-carboplatin combination chemotherapy in advanced breast cancer: accumulating evidence for synergy, efficacy, and safety.

Patients with metastatic breast cancer receive multiple lines of cytotoxic chemotherapy, with taxane and anthracycline-based regimens being the most active. Anthracyclines carry the risk of significant cardiotoxicity at high cumulative doses and when combined with trastuzumab, an anti-HER2 antibody. Carboplatin has shown promising single-agent activity in advanced breast cancer, is not a P-glycoprotein substrate, and is conveniently administered on an outpatient basis. Preclinical experiments demonstrated schedule-dependent synergistic cytotoxic effects of the paclitaxel first/carboplatin last (PC) combination. Pharmacokinetic parameters of paclitaxel and carboplatin were studied by Hellenic Cooperative Oncology Group (HECOG) and no significant interaction or correlation with clinical parameters were found. We assessed PC both as salvage as well as first-line treatment of advanced breast cancer patients in phase II studies which disclosed 40-60% response rates and median survival times of 12-20 mo with manageable toxicity. These results were confirmed by other groups and prompted us to the first randomized phase III trial comparing PC to the standard of epirubicin/paclitaxel (EP), a trial that showed equivalent efficacy and tolerable toxicity for PC. Registry retrospective analysis identified factors prognostic for improved outcome: good performance status, low tumor burden, lack of anthracycline exposure and of hormonal maintenance therapy. PC combinations with HER1 or HER2 modulators are being evaluated both by HECOG and by international groups. Paclitaxel coupled with carboplatin provides an alternative therapeutic option for anthracycline-exposed patients and warrants further clinical research in the direction of anthracycline-free management of metastatic breast cancer.

Fetal tachycardia: is digitalis still the first-line therapy?

Medical treatment of fetal tachycardias has substantially improved neonatal outcome over the past years. Digitalis has been often used as first-line therapy in these cases, and more recently the use of several newer agents have been reported. We present four cases of fetal tachycardia with a favorable neonatal outcome after successful treatment with digitalis. Rapid transplacental digitalization appears to be an effective and reliable treatment option for fetal tachycardia, particularly in non-hydropic fetuses. In hydropic fetuses, however, digitalis alone appears to be less effective and administration of a second drug is usually needed.

Morphological-histochemical study of intestinal carcinoids and K-ras mutation analysis in appendiceal carcinoids.

Intestinal carcinoids are potentially malignant neoplasms. Their histogenesis and pathogenesis are currently uncertain. The morphological and histochemical characteristics of twenty intestinal carcinoids are studied. The primary sites of three mucin-producing tumors were examined by electron microscope. Furthermore 11 appendiceal carcinoids were analysed by the polymerase chain reaction (PCR) for the detection of ras and p53 point mutations. Microscopically all carcinoids were of mixed type. Focal mucin production was evident in three carcinoids that metastasised to regional lymph nodes. HID-Alcian blue staining proved that mucin in both primary and secondary foci did not belong to the sulphated group. The secretory granules and mucin droplets found in a single neoplastic cell suggest that carcinoids of the small intestine and some of the appendix arise from the endoderm. Neither ras nor p53 mutations were detected. It seems that ras oncogenes are probably not involved in the pathogenesis of appendiceal carcinoids.

A randomized comparative study of antiemetic prophylaxis with ondansentron in a single 32-mg loading dose versus 8 mg every 6 h in patients undergoing cisplatin-based chemotherapy.

In several studies a single dose of 32 mg was compared to an ondansentron (OND) administration schedule of every 6 h, yielding no differences in overall efficacy. The aim of this randomized comparative study was to identify differences of these two schedules on an hour-to-hour control of nausea and vomiting, during the first 24 h in patients receiving cisplatin (CDDP)-based chemotherapy. One hundred ten patients were randomly assigned to two groups (A and B); all received combination chemotherapy with CDDP at a dose of 100 mg/m2. OND was administered as follows: group A: 8 mg, 30 min before the infusion of CDDP, and repeated every 6 h after the first dose (totally 4 doses) in the first 24 h, and group B: 32 mg before CDDP, as a loading dose and this was the total dose for the first 24 h. No overall difference was noticed during the first 24 h, as well as the next 3 days from the infusion of CDDP in the intensity of vomits, vomits without gastric content (retches), and nausea. In a more detailed monitoring of the distribution of emetic episodes during the first 24 h, there were important differences between these two antiemetic schedules: for group A an increased vomiting with or without gastric content between midnight and 6 p.m. was observed, and for group B between 6 p.m. and midnight (vomits with p 0.03, and without gastric content p 0.02). Preloading with the total 24-hour dose of OND 32 mg exhibits a more potent antiemetic activity during the initial 18 h, becoming weaker over the last 5 h of the first day, whereas the every-6-hour schedule leaves periods of poor emesis control between dosing intervals.

Tropisetron in the prevention of acute nausea and vomiting in patients treated with high dose epirubicin.

Tropisetron is a novel selective antagonist of the type-3 serotonin (5-HT3) receptor, with proven efficacy in the control of emesis related to cancer treatment. Epirubicin in doses of > 100 mg/m2 has a high emetogenic potential. This study was designed to determine whether a single intravenous administration of tropisetron could prevent acute nausea and vomiting in patients treated with high dose epirubicin. Forty chemotherapy naive breast cancer patients treated with epirubicin at a dose of 110 mg/m2 on an outpatient basis were enrolled in the study. Tropisetron 5 mg i.v. was used as antiemetic prophylaxis. "On demand" treatment with tropisetron 5 mg p.os was used for the rescue of patients who failed on the initial i.v. dose. Complete control of acute nausea and vomiting had 62.5% (95% C.I. 47.2-77.8), partial control 15% (95% C.I. 3.8-26.2) and 22.5% (95% C.I. 9.3-35.7) insufficient control or failure. Headache was the most common adverse event reported in 3 patients (7.5%) and constipation in 2 patients (5%). Interestingly, patients with a negative experience of nausea and vomiting during pregnancy and those treated for metastatic disease, had a better control of chemotherapy-induced nausea and vomiting. In conclusion, a single 5 mg i.v. dose of tropisetron is safe and effective in preventing acute emesis in patients treated with high dose epirubicin.

Paclitaxel with carboplatin versus paclitaxel with carboplatin alternating with cisplatin as first-line chemotherapy in advanced epithelial ovarian cancer: preliminary results of a Hellenic Cooperative Oncology Group study.

Ninety previously untreated patients with advanced epithelial ovarian cancer (International Federation of Gynecology and Obstetrics stages IIC, III, and IV) were randomized, after initial cytoreductive surgery, to receive paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) 175 mg/m2 as a 3-hour infusion with either carboplatin at an area under the concentration-time curve of 7 (group A) or carboplatin at an area under the concentration-time curve of 7 on courses 1, 3, and 5, alternating with cisplatin 75 mg/m2 on courses 2, 4, and 6 (group B). Treatment was given every 3 weeks, up to a total of six courses. Sixty-one patients (33 and 28 patients in groups A and B, respectively) had residual disease after the initial cytoreductive surgery. Patients with measurable or evaluable disease had a high overall response (82% v 57%). A 52% and 39% complete response rate for groups A and B, respectively, with no statistically significant difference between the groups was also observed. With a median follow-up of 12 months (range, 0.33 to 24 months), 29 patients have progressed (18 and 11 in groups A and B, respectively), and 13 have died (seven and six, respectively). Median time to progression was 20.36 months (range, 0.20 to 23.54 months) for group A, whereas this has not yet been reached for group B. Median survival has not yet been reached, but there is no significant difference between the two groups (P = .6972). Treatment was generally well tolerated. Grade 3 and 4 neutropenia was 20% and 32% for groups A and B, respectively, while grade 3 and 4 thrombocytopenia was 4% and 7%, respectively, with no significant difference between the two groups. In conclusion, both combinations seem very active for the treatment of advanced epithelial ovarian cancer and are associated with acceptable toxicity.

Paclitaxel (175 mg/m2) plus carboplatin versus paclitaxel (225 mg/m2) plus carboplatin in non-small cell lung cancer: a randomized study.

A recent phase II study by our group documented a response rate of 27% with the combination paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) 175 mg/m2 plus carboplatin dosed to a target area under the concentration-time curve of 7 in patients with advanced non-small cell lung cancer. In an effort to evaluate the dose-response relationship of paclitaxel with quality of life, we initiated a phase III prospective trial. Patients with inoperable non-small cell lung cancer were randomized into two groups. Group A received paclitaxel 175 mg/m2 plus carboplatin dosed to an area under the concentration-time curve of 6 every 3 weeks. Group B received the same regimen, with paclitaxel increased to 225 mg/m2. Since July 1996, 49 patients have entered the study, 29 in group A and 20 in group B. Patient and tumor characteristics were well distributed between both groups. In group A, 16 patients were evaluable, with one complete response, six partial responses, three stable disease, and six progressive disease. In group B, 12 patients were evaluable, with two partial responses, four stable disease, and six progressive disease. Treatment was well tolerated in both groups. More neurotoxicity and neutropenia were noticed with high-dose paclitaxel. There were no drug-related deaths. It is too early to draw definite conclusions regarding response and survival, but regarding toxicity, it seems that paclitaxel 225 mg/m2 plus carboplatin dosed to an area under the concentration-time curve of 6 is well tolerated without the use of growth factors. Although the results are premature, quality of life does not seem to be affected by the increased paclitaxel dose.

Accelerated bifractionated radiation with concurrent cisplatin administration in locally advanced head and neck cancer: a feasibility study.

AIMS AND BACKGROUND: To test the feasibility of accelerated interrupted twice-daily radiation and concurrent cisplatin administration in patients with locally advanced head and neck cancer. PATIENTS AND METHODS: Nineteen patients with locally advanced head and neck cancer were treated with accelerated bifractionated radiation with concurrent administration of cisplatin. There were 18 men and 1 female with a median age of 60 years (range, 17-71) and median performance status of 90 (range, 80-100). Sixteen patients (85%) presented with stage IV disease. Primary site included the nasopharynx (n = 7), oropharynx (n = 5), hypopharynx (n = 1) and larynx (n = 6). Radiation consisted of two fractions of 1.6 Gy each daily, five times weekly to a total dose of 64 Gy. Cisplatin was administered at a dose of 100 mg/m2 on days 2 and 28 of the treatment period. RESULTS: Nine patients achieved a complete response (47%; 95% Cl, 25%-70%) and 5 a partial response (26%; 95% Cl, 7%-46%). Grade III-IV toxicity included leukopenia (16%), mucositis (26%), dry mouth (5%), weight loss (16%) and infection (5%). After a median follow-up of 27.11 months (range, 1-33 +), 9 patients have died. Median time to progression was 11 months (range, 1-32 +) and median survival 25 months (range, 1-32 +). CONCLUSIONS: Accelerated twice-daily radiation with concurrent cisplatin is effective in locally advanced head and neck cancer and can be safely given with manageable toxicity.

Genomic organization and chromosomal mapping of the murine alpha 1,2-mannosidase IB involved in N-glycan maturation.

alpha 1,2-Mannosidases are a family of enzymes with similar amino acid sequences that are required for the formation of complex and hybrid N-linked oligosaccharides in mammalian cells. We are reporting the first genomic structure of a member of this enzyme family, the murine alpha 1,2-mannosidase IB gene. Two BALB/c cosmid genomic clones (Cos.31.1 and Cos.25.1) and three overlapping 129/su P1 genomic clones were isolated. Analysis of Cos.31.1 and the P1 clones showed that the alpha 1,2-mannosidase IB gene spans > or = 80 kb of the genome and consists of 13 exons representing the complete open reading frame of the enzyme. Fluorescence in situ hybridization with alpha 1,2-mannosidase IB genomic DNA (Cos.31.1) localized the gene to mouse chromosome 3F2. Sequence analysis of the Cos.25.1 cosmid clone provided evidence for the existence of another related gene or pseudogene. Fluorescence in situ hybridization with Cos.25.1 localized this sequence to mouse chromosome 4A13.

Intensified carboplatin regimen with GM-CSF support in non-small cell lung cancer (NSCLC). A Hellenic Co-operative Oncology Group Study (HeCOG).

This is a continuation of a HeCOG previous trial utilizing carboplatin and vindesine in conventional doses as a non-toxic regimen provided easily on an outpatient basis in NSCLC. In the present study we investigated whether an intensified dose-carboplatin could yield a better response. Carboplatin at a dose of 450 mg/m2 dose in combination with vindesine 3 mg/m2 every three weeks and GM-CSF support was used in a phase II study to treat 44 patients with non-small cell lung cancer (NSCLC). As compared to our previous study carboplatin dose intensity was increased from 75 mg/m2/wk to 150 mg/m2/wk. Six patients (13.6%) responded to treatment and all were partial responders. The median duration of response was 5 months (range 1.5-9 month). After a retrospective analysis a dose response effect was not evident at different carboplatin AUC doses. Twenty patients (45.45%) experienced thrombocytopenia and seventeen patients (38.6%) anemia as major toxicities. This study shows that in NSCLC a dose-response effect does not exist between carboplatin dose intensification and response rate cannot be traced.

Paclitaxel and carboplatin in recurrent or metastatic head and neck cancer: a phase II study.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) appears to be one of the most active drugs in the treatment of advanced head and neck cancer. The maximum tolerated dose of paclitaxel in combination with carboplatin is currently being evaluated in phase I/II studies. We designed a phase II study to evaluate the activity and acute and cumulative toxicity of this combination in patients with recurrent or metastatic cancer of the head and neck. Chemotherapy consisted of paclitaxel 200 mg/m2, given as a 3-hour infusion, and carboplatin dosed to an area under the concentration-time curve of 7 mg x min/mL, administered every 28 days. Granulocyte colony-stimulating factor (5 microg/kg) also was given on days 2 to 12 of each cycle. At the time of this report, 41 patients had entered this study. Primary sites included the nasopharynx (10 patients), larynx (18), oral cavity (three), oropharynx (six), hypopharynx (three), and unknown (one). Among 25 evaluable patients with non-nasopharyngeal cancer, there were two complete responses and three partial responses, for an overall response rate of 20% (95% confidence interval, 4% to 36%). Among eight evaluable patients with nasopharyngeal cancer, four achieved a complete response and two a partial response. Grade 3 to 4 toxicities included anemia (2.5%), leukopenia (7.5%), thrombocytopenia (5%), vomiting (5%), stomatitis (2.5%), and infection (5%). These preliminary data indicate that the combination of paclitaxel and carboplatin is active against advanced head and neck cancer, particularly when used in the treatment of nasopharyngeal cancer.

Paclitaxel by 3-h infusion and carboplatin in anthracycline-resistant advanced breast cancer. A phase II study conducted by the Hellenic Cooperative Oncology Group.

37 patients with advanced breast cancer resistant to anthracyclines were treated with paclitaxel 200 mg/m2 by 3-h infusion and carboplatin at an area under the curve of 7 mg.min/ml every 4 weeks with G-CSF support. There were 5 (14%, 95% CI 3-25%) complete and 11 (30%, 95% CI 15-45%) partial responders. Median duration of response was 11.5 months (range 5.2-16.8+), median time to progression 8 months (range 0.26-16.8+) and median survival 12 months (range 0.5-19.6+). Grade 3-4 leucopenia (27%), thrombocytopenia (10%) and diarrhoea (5%) were noted. In conclusion, the combination of paclitaxel and carboplatin is active and well tolerated in patients with advanced breast cancer resistant to anthracyclines.

Phase II study of 5-fluorouracil and interferon-gamma in patients with metastatic colorectal cancer. A Hellenic Cooperative Oncology Group Study.

Preclinical data have shown a synergism between 5-fluorouracil and interferon-gamma against human colon carcinoma cell lines. We conducted a phase II trial of this combination in 34 patients with metastatic colorectal cancer. 5-Fluorouracil was administered as an intravenous bolus of 500 mg/m2 weekly and interferon-gamma subcutaneous injection at a dose of 200 micrograms (6 x 10(6) IU) 3 times a week. Thirty-two patients were evaluable for response. There was one complete and two partial responses (response rate 9.0%, 95% CI 1.98-25.02%). Eleven patients (34%) had stable disease. Common toxicities included fever 81%, nausea/vomiting 19%, diarrhea 16%, flu-like syndrome 16%, malaise 12.5% and leukopenia 12.5%. These results indicate that the above combination of 5-fluorouracil and interferon-gamma has an unimpressive activity in patients with advanced colorectal carcinoma. Toxicity was very tolerable.

Soluble interleukin-2 receptors in patients with advanced colorectal carcinoma.

The levels of soluble interleukin-2 receptors (sIL-2R) were measured in the serum of 52 patients with advanced colorectal carcinoma and compared to CEA and CA 19-9 levels. Twenty-five normal, age and sex-matched individuals served as controls. Seventy-five per cent of the patients had increased mean serum levels of sIL-2R (1539 +/- 155 U/ml), while normal controls had mean levels of 555 +/- 31 U/ml (p < 0.001). The relationship with hepatic or lymph nodal metastases showed no statistically significant difference (p = 0.34 and p = 0.47, respectively). Serum sIL-2R levels showed a linear correlation with CEA (p < 0.05). Patients with lower pretreatment sIL-2R levels (less than 1.200 U/ml) had a longer survival than patients with higher initial levels (more than 1.200 U/ml) (p = 0.0049). In conclusion, the present work shows that the serum levels of sIL-2R: a) are elevated in patients with advanced colorectal cancer, b) have no relationship with the type of metastases, c) correlate with serum CEA and d) have a prognostic value for survival.

The nucleotide sequence of TTP1, a gene encoding a predicted type II membrane protein.

The DNA sequence of a 2967 bp fragment located near the centromere of chromosome II, between the CEN2 and FUR4 genes, was determined. The segment contains a new open reading frame of 1794 bp. The product encoded by the gene, designated TTP1, is a predicted type II membrane protein of 597 amino acid residues with a short cytoplasmic NH2-terminus, a membrane-spanning region and a large COOH-terminal region containing three potential N-glycosylation sites. Gene disruption indicated that TTP1 is not essential for cell growth.

Isolation of a mouse Golgi mannosidase cDNA, a member of a gene family conserved from yeast to mammals.

The amino acid sequence of the specific alpha-mannosidase involved in N-oligosaccharide processing in Saccharomyces cerevisiae was found to have a high degree of similarity to the deduced amino acid sequence of a rabbit liver alpha-mannosidase partial cDNA, demonstrating that processing mannosidases have been conserved through eukaryotic evolution. Regions of sequence identity were chosen to design degenerate oligonucleotide primers that can be used to prepare probes using the polymerase chain reaction (PCR) for cloning processing mannosidases from other eukaryotes. Using these primers for PCR with mouse liver cDNA as template, two related but distinct PCR products were obtained. The amino acid sequences of PCR1 and PCR2 were 88 and 65% identical with the corresponding sequence of the rabbit enzyme, respectively. Southern blot analysis of mouse genomic DNA using PCR1 and PCR2 as probes revealed that they are derived from two different genes, indicating the existence of a mammalian mannosidase gene family with at least two members. Using PCR2 as a probe, a novel mouse cDNA was isolated from a 3T3 cDNA library. It contains an open reading frame which encodes a type II membrane protein of 73 kDa with a cytoplasmic region of about 35 amino acids, a Ca2+ binding consensus sequence, and a single N-glycosylation site. Northern blot analysis of mouse tissues and L cells revealed tissue-specific expression of multiple transcripts, ranging in size from 4.2 to 8.5 kilobases, that suggests a complex pattern of gene regulation. Transient expression of the influenza hemagglutinin epitope-tagged cDNA in COS cells followed by indirect immunofluorescence with monoclonal antibody 12CA5 showed that the cloned mannosidase is primarily localized in a juxtanuclear position corresponding to the Golgi. The C-terminal domain lacking the putative transmembrane region was shown to have alpha-mannosidase activity when expressed in COS cells as a secreted Protein A fusion product.

The relationship between acute inflammatory lesions of the preterm placenta and amniotic fluid microbiology.

OBJECTIVE: Our objective was to determine the relationship between microbial invasion of the amniotic cavity and the presence and severity of acute inflammatory lesions in the placenta. STUDY DESIGN: Placental histologic and amniotic fluid microbiologic studies were performed in 92 consecutive patients who were admitted with preterm labor and intact membranes and delivered within 48 hours after amniocentesis. RESULTS: The prevalence of a positive amniotic fluid culture was 38% (35 of 92). There was a strong association between the presence and severity of inflammation in the amnion, chorion-decidua, umbilical cord, and chorionic plate and the results of the amniotic fluid culture (p less than 0.0001 for each tissue section). Three patterns of inflammation of the chorion-decidua were identified: marginating, nonmarginating, and a mixed pattern. The marginating and the mixed patterns of inflammation were strongly associated with the presence of a positive amniotic fluid culture. Acute inflammation of the chorionic plate was the most sensitive indicator of a microbial invasion of the amniotic cavity (sensitivity 96.6%), and funisitis and umbilical vasculitis had the highest specificity (85.7%). CONCLUSION: The presence of acute inflammatory lesions of the chorioamniotic membranes can serve as a marker of microbial invasion of the amniotic cavity.

Meconium-stained amniotic fluid: a risk factor for microbial invasion of the amniotic cavity.

The purpose of this study was to determine whether meconium-stained amniotic fluid is a marker for microbial invasion of the amniotic cavity. Amniocentesis was performed on 707 patients presenting with preterm labor and intact membranes. Meconium-stained amniotic fluid was present in 4.2% (30/707) of patients with preterm labor. The prevalence of positive amniotic fluid cultures was significantly higher in women with meconium-stained amniotic fluid than in women with clear fluid (33% [10/30] vs 11% [75/677]; p = 0.001; odds ratio = 4.01; 95% confidence interval = 1.6 to 9.4). Patients with meconium-stained amniotic fluid were also more likely to have failed tocolysis and delivered a preterm neonate more frequently than patients with clear fluid (83% [25/30] vs 38% (258/677); p = 0.0001; odds ratio = 8.1; 95% confidence interval = 2.9 to 24.4). We conclude that meconium-stained amniotic fluid is a risk factor for microbial invasion of the amniotic cavity and preterm delivery in women with preterm labor and intact membranes.

Preterm delivery: a risk factor for retained placenta.

The purpose of this study was to determine whether preterm delivery, with and without intraamniotic infection, is a risk factor for retained placenta. This complication occurred more frequently in women with preterm vaginal delivery than in women with term vaginal delivery (9.1% [21/231] vs 1.1% [6/561]; p less than 0.00001; odds ratio = 9.25). There was no significant difference in the prevalence of retained placenta between women with preterm labor and intact membranes and those with preterm premature rupture of membranes (8% [10/125] vs 10.4% [11/106]; p greater than or equal to 0.05). A positive amniotic fluid culture or clinical chorioamnionitis was not associated with a higher incidence of retained placenta. This study indicates that preterm delivery is associated with an increased risk of complications of the third stage of labor.

Amniotic fluid interleukin-1 in spontaneous labor at term.

The regulatory signals responsible for the increased biosynthesis of prostaglandins during parturition have not been established. Interleukin-1 (IL-1) is capable of stimulating prostaglandin production by intrauterine tissues and is an inflammation mediator. It has been postulated as a signal for the onset of labor in the setting of intrauterine infection. A study was designed to determine if spontaneous labor at term was associated with changes in IL-1 activity in amniotic fluid. Such fluid was retrieved from 41 women in labor and from 39 women who were not in labor at term. Immunodetectable IL-1 beta was present in 22 of the 41 women in labor but in only 8 of the 39 women without labor. IL-1-like bioactivity was not different between the two groups at a dilution of 1:4, but at dilutions of 1:12, 1:36 and 1:108, amniotic fluid from women in labor had significantly higher bioactivity than that from women not in labor. A significant correlation was found between the bioassay and immunoassay results. Our data show that inhibitors of IL-1 bioactivity are present in amniotic fluid and suggest that in a subset of laboring women at term, an inflammatory reaction may play a role in triggering the onset of parturition.