Management of advanced stage uterine sarcomas: a bone of contention.

Uterine sarcomas constitute a rare group of neoplasms characterized by an aggressive clinical course and poor prognosis. It is this rarity that has resulted in clinical-trial reports and literature reviews including a broad range of histological subtypes of sarcoma. This has a detrimental effect on interpretation and application of the results; the pathological subtype demands a tailored approach. Surgical resection remains the mainstay of treatment for non metastatic uterine sarcomas. Although adjuvant radiation therapy has reportedly been of little survival value, it appears to improve local control and may delay recurrence. The role of adjuvant chemotherapy has yet to be established; however, bearing in mind the limitations and assumptions in the pooling of data the therapeutic options should be based on the pathological subtype. Considering the poor overall survival in uterine sarcomas, the need for new therapeutic agents is critical. New drugs with possible activity in uterine sarcomas include trabectedin, temozolomide, liposomal doxorubicin and gemcitabine.

Postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel and CMF in patients with high-risk breast cancer: safety analysis of the Hellenic Cooperative Oncology Group randomized phase III trial HE 10/00.

BACKGROUND: A randomized phase III trial in high-risk breast cancer patients was conducted, to further explore the impact of dose-density in the adjuvant treatment for breast cancer. The safety analysis is presented. PATIENTS AND METHODS: From October 2000 until June 2005, 1121 node-positive patients were randomized to sequential dose-dense epirubicin 110 mg/m(2) and paclitaxel (Taxol, Bristol Myers-Squibb, Princeton, New Jersey, USA) 250 mg/m(2) (group A), or concurrent epirubicin 83 mg/m(2) and paclitaxel 187 mg/m(2) (group B), both followed by three cycles of 'intensified' combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil (CMF). Granulocyte colony-stimulating factor was given prophylactically with the dose-dense treatments. RESULTS: Median dose intensity of epirubicin and paclitaxel was double in group A, as designed, with significantly less cycles administered at full dose (P < 0.001). Median cumulative dose of all drugs and total treatment duration, however, were identical between groups. Severe taxane-related toxic effects were more frequent in group A, while severe thrombocytopenia was low and present only in group A. There were no differences in the rates of other hematological toxic effects, including febrile neutropenia. The rates of secondary malignancies were low. CONCLUSION: Both regimens as used in the present study are well tolerated and safe. The rates of severe taxane-related toxic effects and thrombocytopenia, although low overall, are significantly increased with the dose-dense sequential regimen.

Combination chemotherapy with paclitaxel and gemcitabine followed by concurrent chemoradiotherapy in non-operable localized non-small cell lung cancer. A hellenic cooperative oncology group (HeCOG) phase II study.

UNLABELLED: Concurrent chemoradiotherapy has become a standard therapy for locoregionally advanced inoperable nonsmall cell lung cancer (NSCLC). The purpose of this phase II trial was to evaluate the efficacy and toxicity of concurrent chemoradiotherapy following induction with non-platinum chemotherapy in patients with inoperable locally advanced NSCLC. PATIENTS AND METHODS: All patients with locally advanced inoperable NSCLC ECOG performance status (PS): 0-1 following staging received paclitaxel 200 mg/m2 in a 3-h infusion on day 1 and gemcitabine 1000 mg/m2 on days 1 and 8 every 21 days for two cycles. The patients with a response or stable disease (SD) continued to receive paclitaxel 60 mg/m2 weekly and radiotherapy 63 Gy given at 1.8 Gy once a day for 7 weeks. RESULTS: Forty-three eligible patients entered the study. The median age was 63 years (range 42-76), male 93%, IIIB 63% and IIIA 37%. Following induction 15 (36.5%) of the patients responded: complete response (CR), 2%; partial response (PR), 33%; and 19 (46.5%) SD. From those with SD, 7 (37%) improved to a PR following concurrent chemoradiotherapy. With a median follow-up of 44 months (95% CI: range 36-53) the median survival was 20.8 months (95% CI: range 15.4-26.3) and time-to-progression 8.4 months (95% CI: range 6.2-10.6). The median survival of those who had improved response from SD to PR was 31.4 months (95% CI: range 18.7-44.1) versus 20.8 months (95% CI: range 5.5-11.3) for those who had no improvement (p=0.20). The commonest grade 3/4 toxicity in induction was neutropenia 12% with 2 febrile neutropenic patients whereas in the concurrent chemoradiotherapy neutropenia, neurotoxicity and oesophagitis were observed in 6% of the patients. CONCLUSION: Concurrent chemoradiotherapy following induction chemotherapy in patients with stage III NSCLC is feasible with reasonable efficacy and acceptable toxicity.

Postoperative dose-dense sequential chemotherapy with epirubicin, followed by CMF with or without paclitaxel, in patients with high-risk operable breast cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group.

PURPOSE: The aim of this study was to explore the effect of dose-dense sequential chemotherapy with or without paclitaxel primarily on disease-free survival (DFS) and secondarily on overall survival (OS) in patients with high-risk operable breast cancer. PATIENTS AND METHODS: From June 1997 until November 2000, 604 patients with T1-3N1M0 or T3N0M0 tumors were randomized to three cycles of epirubicin 110 mg/m2 followed by three cycles of paclitaxel 250 mg/m2 followed by three cycles of 'intensified' CMF (cyclophosphamide 840 mg/m2, methotrexate 47 mg/m2 and fluorouracil 840 mg/m2) (group A), or to four cycles of epirubicin followed by four cycles of CMF, as in group A (group B). All cycles were given every 2 weeks with granulocyte colony-stimulating factor support. RESULTS: A total of 595 patients were eligible. Median follow-up was 61.7 months for group A and 62 months for group B. The 3-year DFS was 80% in group A and 77% in group B. Survival rates were 93% and 90%, respectively. The effect of treatment on the hazard of death was different according to hormonal receptor status. More specifically, in patients with negative receptor status the hazard of death was significantly higher for group B (hazard ratio 2.42). Both regimens were well tolerated and severe acute side-effects were infrequent. No cases of severe cardiotoxicity or acute leukemia were recorded. CONCLUSIONS: The present study failed to demonstrate a significant difference in DFS or OS between the two treatment groups. However, our study has shown clearly that high-dose paclitaxel can be safely incorporated to dose-dense sequential chemotherapy.

Combination of pegylated liposomal doxorubicin (PLD) and paclitaxel in patients with advanced soft tissue sarcoma: a phase II study of the Hellenic Cooperative Oncology Group.

Patients with soft tissue sarcoma (STS), even after complete local disease control, often relapse locally or with distant metastases. This multicenter phase II study was conducted to evaluate the safety and efficacy of the combination of pegylated liposomal doxorubicin (PLD) and paclitaxel, as first-line treatment in patients with advanced STS. In all, 42 patients with locally advanced or metastatic STS, median age 54 years and median Eastern Cooperative Oncology Group performance status (PS) 1 were treated with PLD 45 mg m(-2) and paclitaxel 150 mg m(-2), every 28 days for a total of six cycles. Histological types included mainly leiomyosarcomas (43%), malignant fibrous histiocytomas (14%) and liposarcomas (12%). At study entry, 69% of patients had distant metastases. Overall response rate was 16%, including one complete (CR 2%) and six partial responses (PRs 14%), while an additional 14 patients had disease stabilization (SD 33%). At median follow-up 41.5 months, median time to progression (TTP) was 5.7 months with median overall survival (OS) 13.2 months. Grade 3-4 toxicities included neutropenia (17%), anaemia (15%), neurotoxicity (5%) and palmar-plantar erythrodysesthesia (9%). There were no treatment-related deaths. The combination of PLD and paclitaxel is a safe and well-tolerated regimen demonstrating modest efficacy as first-line treatment in patients with advanced STS.

The prognostic significance of the immunohistochemical expression of p53, bcl-2, c-erb B-2 and cathepsin-D in ovarian cancer patients receiving platinum with cyclophosphamide or paclitaxel chemotherapy.

PURPOSE: To evaluate the prognostic significance of the immunohistochemical expression of p53, bcl-2, c-erbB-2 and cathepsin-D in epithelial ovarian cancer (EOC). METHODS: We analyzed 100 patients with ovarian carcinoma, FIGO Stage IC-IV who underwent primary cytoreductive surgery and received adjuvant chemotherapy with cyclophosphamide and a platinum analogue (CP) (n = 46) or paclitaxel and a platinum analogue (TP) (n = 54). Immunohistochemical expression was studied on paraffin-embedded tissue from the primary tumor. RESULTS: After a median follow-up of 55 months median progression-free survival (PFS) and overall survival (OS) were 16 and 41 months, respectively. Positive bcl-2 staining and absence of cathepsin-D expression were associated with an increased complete response rate in the CP group (p = 0.011 and p = 0.003) but not in the TP group. PFS and OS were not associated with the expression of any of the markers studied. FIGO stage (p = 0.006) and histology (p = 0.047) were the only independent prognostic factors for survival. CONCLUSION: Bcl-2 and cathepsin D expression are associated with response to CP but not TP chemotherapy. P53, bcl-2, c-erb B-2 and cathepsin D expression was not correlated with PFS and OS in our study.

CD40L overexpression on T cells and monocytes from patients with systemic lupus erythematosus is resistant to calcineurin inhibition.

To explore the regulatory defects underlying the overexpression of CD40 ligand (CD40L, CD154) in human lupus we studied the effects of cyclosporin-A (CsA), which blocks Ca2+/calcineurin-dependent CD40L gene expression, on peripheral blood-derived T cells and monocytes. In contrast to control subjects, CsA failed to inhibit the prolonged CD40L expression observed in vitro on anti-CD3-activated lupus T cells. Resistance to CsA was not restricted to CD4+ or CD8+ T cell subsets and was disease activity-independent. Experiments assessing the effects of dexamethasone on CD40L expression, as well as of CsA on the early activation marker CD69 expression and on surface CD40L cleavage, confirmed the unique regulation of CD40L in lupus T cells. On the other hand, co-culture with anti-CD3-activated T cells caused surface CD40L expression on monocytes, which was not an Fc receptor-mediated event. Lupus monocytes clearly overexpressed CD40L comparing to healthy and disease-control monocytes, and, similarly to lupus T cells, displayed a prominent resistance to CsA inhibitory effects. These findings indicate that, besides Ca2+/calcineurin-dependent mechanisms, other pathways are involved in the dysregulation of CD40L in SLE immune cells, dissection of which may have important therapeutic implications.

Dose-dense sequential adjuvant chemotherapy with epirubicin, paclitaxel and CMF in high-risk breast cancer.

Dose-dense sequential chemotherapy appears to be a promising approach in the management of patients with operable breast cancer. We evaluated the tolerability of such a novel chemotherapeutic regimen in high-risk patients. From February 1995 until September 1997, 49 women with histologically confirmed breast cancer and > or =10 involved axillary nodes were treated postoperatively with three cycles of epirubicin (110 mg/m(2)) followed by three cycles of paclitaxel (250 mg/m(2) in a 3-hour infusion) followed by three cycles of 'intensified' CMF (cyclophosphamide 840 mg/m(2), methotrexate 57 mg/m(2), fluorouracil 840 mg/m(2); E-T-CMF). All cycles were repeated every 2 weeks with G-CSF support. Ovarian ablation with monthly injections of triptorelin for 1 year was performed in premenopausal patients and tamoxifen was prescribed for 5 years to all women with positive receptor status after the completion of chemotherapy. A total of 456 cycles of chemotherapy were administered, 363 (80%) of them at full dose. Forty-seven (96%) patients received all 9 cycles of chemotherapy. Relative dose intensity of epirubicin was 0.98, of paclitaxel 0.97, of cyclophosphamide 0.99, of methotrexate 0.98 and of fluorouracil 0.99. Grade 3--4 toxicities included anemia (8%), leukopenia (8%), peripheral neuropathy (6%), neutropenia (4%), thrombocytopenia (4%), stomatitis (2%), diarrhea (2%), fatigue (2%) and hypersensitivity reaction (2%). Febrile neutropenia occurred in 2 patients. Alopecia was universal. After a median follow-up of 3 years, 11 women (22%) relapsed and 4 (8%) died. The 3-year actuarial disease-free survival rate was 72% and the 3-year overall survival rate 90%. The E-T-CMF regimen is well tolerated, as adjuvant treatment, in patients with operable breast cancer with promising activity and deserves further evaluation in phase III studies.

Dose-dense sequential chemotherapy with epirubicin and paclitaxel in advanced breast cancer.

The purpose of this study was to evaluate the activity and toxicity profile of dose-dense sequential chemotherapy with epirubicin (EPI) and paclitaxel in advanced breast cancer (ABC). From January to September 1997, 41 patients with recurrent or metastatic (stage IV) breast cancer were enrolled in the study. Their median age was 57 (range, 33-77) years and median performance status 0 (range, 0-2). Twenty patients had received adjuvant chemotherapy. The chemotherapeutic regimen consisted of 4 cycles of EPI 110 mg/m2 every 2 weeks followed by 4 cycles of paclitaxel, 225 mg/m2 over 3 hours every 2 weeks. G-CSF was administered prophylactically on days 2-10 of each cycle. 34 (83.0%) patients completed all 8 cycles of chemotherapy. A total of 304 cycles were administered, 259 (85.0%) of them at full dose. Thirty (10.0%) cycles were delivered with a delay. The relative median dose intensities of EPI and paclitaxel were 0.95. Most common grade 3-4 side effects were anemia (15.0%) neutropenia (12.0%), thrombocytopenia (5.0%), nausea/vomiting (10.0%), febrile neutropenia (7.5%), and alopecia (90.0%). Overall, 8 (19.5%) patients achieved a complete and 15 (36.5%) a partial response. Median duration of response was 8.4 (range, 3.1-15.5+) months. After a median follow-up of 18.5 months, median time to progression was 8.7 (range, 0.5-21+) months; median survival has not been reached yet. Dose-dense sequential chemotherapy with EPI and paclitaxel shows promising activity as first-line treatment in ABC. Randomized studies comparing this type of chemotherapy with the classical administration of the two drugs together every 3 weeks are ongoing.

Distant cutaneous metastasis from carcinoma of the uterus. A case report.

Cutaneous metastasis from intraabdominal carcinoma is relatively rare. When it is present it is usually located in the skin overlying the neoplasm [1]. Carcinoma of the uterus metastatic to the skin accounts for 9% of all cutaneous metastases. Distant metastasis is extremely rare. Such a metastasis to the skin of the big toe of the lower limb is presented.

First-line chemotherapy with paclitaxel by three-hour infusion and carboplatin in advanced breast cancer (final report): a phase II study conducted by the Hellenic Cooperative Oncology Group.

PURPOSE: To evaluate the activity and toxicity of the combination of paclitaxel given by three-hour infusion, and carboplatin as first-line chemotherapy in patients with advanced breast cancer (ABC). BACKGROUND: Paclitaxel is an active agent in ABC. Furthermore, our group has shown that the combination of paclitaxel and carboplatin is effective in anthracycline-resistant ABC. PATIENTS AND METHODS: From January 1996 until March 1997, 66 women with ABC were treated with paclitaxel (175 mg/m2) by three-hour infusion followed by carboplatin at an AUC of 6 mg x min/ml every three weeks. The median age of the patients was 56 years (range 28-75). A total of 39 patients had received adjuvant chemotherapy and 22 of them were treated with an anthracycline or mitoxantrone-containing regimen. RESULTS: A total of 324 cycles (median: six) were administered, 273 (85%) of them at full dose. The median number of delivered cycles was six. The median delivered dose intensity (DI) of paclitaxel was 55.1 mg/m2/week (range 30.5-69.3) and the relative DI was 0.95 (range 0.5-1.2). Eight patients (12%, 95% confidence interval (CI): 5%-22%) achieved complete and 28 (42%, 95% CI: 30%-55%) partial responses. Grade 3-4 toxicities included anemia (5%), granulocytopenia (24%), thrombocytopenia, nausea/vomiting and allergic reaction (3% each), myalgias/arthralgias and neurotoxicity (1.5% each). Febrile neutropenia occurred in eight (12%) patients. Alopecia was universal. After a median follow-up of 17.3 (range 0.07-24.5) months, 48 (72%) patients have demonstrated tumor progression and 24 (36%) have died. Median time to progression was 8.6 (range 0.07-23+) months and median survival 20.4 (range 0.07-24.5+) months. CONCLUSIONS: The combination of paclitaxel and carboplatin has moderate activity in ABC and can be easily delivered on an outpatient basis with manageable toxicity. This regimen may be useful especially in patients to whom anthracyclines or cisplatin administration is precluded because of other concomitant diseases.

First-line treatment of advanced non-small-cell lung cancer with docetaxel and cisplatin: a multicenter phase II study.

PURPOSE: To evaluate the efficacy and safety of the docetaxel-cisplatin combination in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naïve patients with histologically confirmed, measurable stage IIIB or IV NSCLC, a World Health Organization (WHO) performance status of 0-2 and adequate bone marrow, renal, hepatic and cardiac function were eligible for the study. Patients received docetaxel (100 mg/m2) as an one-hour infusion on day 1 and cisplatin (80 mg/m2) as a 30-min infusion with appropriate hydration on day 2. Granulocyte colony-stimulating factor (G-CSF; 150 micrograms/m2, SC) was given on days 3 to 13. Treatment was repeated every three weeks. RESULTS: Fifty-three patients were enrolled (28 with stage IIIB and 25 with stage IV). One complete and 23 partial responses were observed (overall response rate (OR): 45%; 95% CI: 34.1%-61.8%). The response rate was 57% and 32% in patients with stages IIIB and IV disease (P = NS). The median time to progression was 36 weeks and the median survival 48 weeks; the one-year survival was 48%. Grade 3-4 neutropenia occurred in 23 patients, 15 of whom were hospitalized for neutropenic fever; two patients died of sepsis. Grade 2 neurotoxicity was observed in six patients and grade 3 in five patients; grade 3 fatigue occurred in seven patients, grade 3-4 mucositis in four patients and grade 3-4 diarrhea in six patients. Mild allergic reactions and oedema were observed in five and four patients, respectively. The median dose intensity was 30 mg/m2/week for docetaxel and 24 mg/m2/week for cisplatin, corresponding to 91% and 89% of the specified protocol doses, respectively. CONCLUSIONS: The docetaxel-cisplatin combination is an active regimen in advanced NSCLC, but hematologic toxicity remains high despite the prophylactic use of G-CSF.

Does free to total ratio of prostate-specific antigen alter decision-making on prostatic biopsy?

OBJECTIVES: For patients with prostate specific antigen (PSA) values of 4-10 ng/mL, some urologists perform prostatic biopsies depending upon the findings of digital rectal examination (DRE) and transrectal ultrasonography (TRUS), and others perform biopsies on most of these men regardless of the findings of DRE and TRUS. The purpose of this study was to examine whether the information given by the measurement of the ratio of free to total (F/T) PSA can alter decision-making on prostatic biopsy. METHODS: One hundred and two (102) men with PSA values between 4 and 10 ng/mL, were included in this study. All men were examined with DRE and TRUS; a F/T PSA ratio was also measured, and six prostatic biopsies were taken from each patient. RESULTS: In 102 men who were biopsied, 22 (21.5%) prostatic carcinomas were identified. Among these 22 cancer patients, 13 had abnormal findings in DRE and/or TRUS and would have been biopsied and diagnosed anyway. If we use only the F/T PSA ratio (cut-off value 0.20) to decide whom to biopsy, we would have diagnosed 16/22 cancers; the difference between these two procedures was not statistically significant (P = 0.17). If we decide to biopsy those patients who have abnormal findings in DRE and/or TRUS and those who have a F/T PSA ratio < 0.20, we would diagnose 20/22 cancers (P = 0.05) and at the same time, reduce the unnecessary biopsies from 80 to 41 (48%). With a PSA value between 4 and 10 ng/mL and no findings in DRE and TRUS and at the same time with a F/T PSA ratio > or = 0.20, we would have to perform biopsies in 20.5 men to find one cancer. On the other hand, in patients with suspicious findings in DRE and/or TRUS and a F/T PSA ratio < 0.20, in every two men that we biopsy we would find one cancer. CONCLUSION: We believe that among patients with PSA values between 4 and 10 ng/mL after performing DRE and TRUS, the additional information of F/T PSA ratio can help since it increases the number of cancers detected and reduces the number of unnecessary biopsies.

Expression of ras p21 and myc p62 oncoproteins in small cell and non small cell carcinoma of the lung.

Ras p21 and myc p62 expression has been examined immunohistochemically in seventy specimens of bronchial carcinomas. Both ras and myc oncoproteins were found to be overexpressed at a higher frequency in non small cell carcinomas (squamous cell carcinomas and adenocarcinomas) compared to the small cell carcinoma specimens; however only myc p62 overexpression was found to be statistically significant. Also, ras p21 oncoprotein expression was frequently overexpressed in adenocarcinomas compared to squamous cell carcinomas (p less than 0.05). Overexpression of c-myc p62 was found to correlate with poorly differentiated squamous cell carcinomas compared to the well and moderately differentiated tumors. The results of this study indicate that both the ras and myc oncogenes are important in the progression of bronchial carcinomas.

C3 polymorphism in Greece.

The polymorphism of the third component of the human complement (C3) was investigated in a sample of 1,055 unrelated healthy individuals from nine different areas of Greece. The estimated gene frequencies were: C3S = 0.786 and C3F = 0.211. Three individuals were found to have rare variant C3 types. The allele frequencies resemble those reported for other Caucasian populations.