Diagnosis of metastatic tumors in cerebrospinal fluid samples using thin-layer cytology.

OBJECTIVE: To evaluate the application of ThinPrep liquid-based cytology (LBC) and present our experience using LBC in the diagnosis of metastatic tumors in cerebrospinal fluid (CSF) samples. STUDY DESIGN: We examined 38 cytologic specimens of CSF, processed by ThinPrep technique. Of these, 18 presented with a previously diagnosed primary malignancy. Various immunocytochemical markers were performed. RESULTS: ThinPrep technology provided preservation of cytomorphologic features, high cellularity per slide and clear background. Analysis revealed 8 breast carcinomas, 5 lung carcinomas, 4 lymphomas, 3 adenocarcinomas of the gastrointestinal tract, 1 squamous cell carcinoma of uterine cervix and 1 urinary bladder carcinoma. Fifteen samples were negative for malignancy. CONCLUSION: CSF cytology is the only examination that verifies the presence of malignancy. Thin monolayer technology is suggested as an appropriate diagnostic method for metastatic tumors in CSF in everyday routine and seems to be a valuable tool for further management and planning of treatment.

Expression of a molecular marker panel as a prognostic tool in gastric cancer patients treated postoperatively with docetaxel and irinotecan. A study of the Hellenic Cooperative Oncology Group.

INTRODUCTION: This study evaluated the prognostic role of vascular epidermal growth factor (VEGF), thymidylate synthase (TS), topoisomerase I (Topo-I), topoisomerase IIalpha (Topo-IIalpha) and E-cadherin (E-cadh) tumor expression, in patients with resectable gastric cancer, who were treated postoperatively with the docetaxel/irinotecan combination. PATIENTS AND METHODS: Forty-five patients with resectable gastric cancer were treated with 6 cycles of docetaxel 30 mg/m2 and irinotecan 110 m/m2 on day 1 and d8 every 21 days. All specimens were examined by using immunohistochemistry (IHC) for the expression of VEGF, TS, Topo-I, Topo-IIalpha and E-cadh. RESULTS: Positivity for TS was significantly correlated with age and for VEGF with diffuse histological type and good PS. No significant correlation was observed among Topo-I, Topo-IIalpha and E-cadh positivity with any of the clinicopathological parameters studied. Median overall survival (OS) was 31.7, and disease-free survival (DFS) 26 months, respectively. None of the above-investigated molecular markers were significantly associated with OS and DFS. Finally, according to the univariate analysis for survival, only advanced stages (III, IV) of the disease implied risk of death, mainly due to lymph node involvement and, to a lesser extent, tumor size. None of the studied molecular markers were found to be independent prognostic markers. CONCLUSION: These results should be interpreted very cautiously, due to the limited number of patients studied, as well as the limitations of the IHC technique.

Intensive weekly chemotherapy with docetaxel, epirubicin and carboplatin with G-CSF support in patients with advanced gastric cancer: a Hellenic Cooperative Oncology Group (HeCOG) phase II study.

Chemotherapy is an established modality in the management of patients with advanced gastric cancer but the optimal regimen has not been defined yet. Platinum and the anthracyclines and more recently docetaxel have shown activity in this tumor. The primary objective of this phase II study was to assess the efficacy and safety of an intensified regimen of weekly docetaxel/epirubicin/carboplatin (DECb) with growth factor support in previously untreated patients with advanced gastric cancer. A total of 72 patients with measurable disease received docetaxel at a dose of 30 mg/m2, epirubicin at a dose of 30 mg/m2 and carboplatin to a target area under the curve (AUC) of 2, every week for 6 consecutive weeks followed by 2 weeks' rest, with filgrastim support. Analysis was performed on an intention to treat basis. The main toxicity was hematologic with grade 3/4 neutropenia occurring in 35% of the patients. Other grade 3/4 toxicities included anemia (7%), thrombocytopenia (14%) and leucopenia (26%). The relative dose intensity of docetaxel and epirubicin was 62%. The overall response rate was 21%, the median time to tumor progression was 4.1 months and the median survival 7.3 months. Intensified weekly treatment with DECb has modest activity in the treatment of advanced gastric cancer. Myelotoxicity limits adequate drug delivery.

Paclitaxel plus carboplatin versus gemcitabine plus paclitaxel in advanced non-small-cell lung cancer: a phase III randomized trial.

PURPOSE: We conducted this randomized study comparing the activity and toxicity of paclitaxel and gemcitabine (PG) and paclitaxel and carboplatin (PC) combinations for the treatment of advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naive patients were randomized to paclitaxel 200 mg/m(2) on day 1 plus either carboplatin at an area under the concentration-time curve of 6 on day 1 (group A) or gemcitabine 1,000 mg/m(2) on days 1 and 8 (group B) every 3 weeks. A retrospective cost analysis was conducted using Student's t test to compare independent samples between groups. RESULTS: A total of 509 patients (group A, 252 patients; group B, 257 patients) were enrolled; all characteristics were well balanced. The median survival time was 10.4 months (95% confidence interval [CI], 8.8 to 12 months) for group A and 9.8 months (95% CI, 8.0 to 11.7 months) for group B (P =.32). Respective 1-year survival rates were 41.7% and 41.4%. The response rate for group A was 28.0% (2% complete response [CR], 26% partial response [PR] [95% CI, 22% to 34%]), and the response rate for group B was 35.0% (5% CR, 30% PR) [95% CI, 29% to 41%]) (P =.12). Toxicity was mild. Grades 3/4 neutropenia, thrombocytopenia, and anemia for groups A and B were seen in 15% and 15%, 2% and 1%, and 5% and 2%, respectively. The mean total cost (outpatient clinic visits plus chemotherapy drug fee) for group A (euro; 7,612.64) versus group B (euro; 7,484.77) was not statistically significant (P <.66). CONCLUSION: The PG combination is as equally active and well tolerated as the PC combination in patients with advanced NSCLC.

Irinotecan and oxaliplatin combination, as second-line treatment, in fluoropyrimidine-pretreated advanced colorectal cancer. A phase II study by the Hellenic Cooperative Oncology Group (HeCOG).

BACKGROUND: The management of patients with fluoropyrimidine-resistant advanced colorectal cancer remains Investigational. Irinotecan and oxaliplatin have proved effective in first-line treatment in combination with 5-fluorouracil. STUDY DESIGN: From February 1998 to September 2002, 34 patients with 5-fluorouracil-pretreated advanced colorectal cancer were enrolled in the study. Median age was 67 years (range, 32-76) and median performance status was 1. Twenty-one patients had multiple liver metastases. Other sites of disease included lungs, abdomen, pelvis, lymph nodes, bones and skin. They received six 28-day cycles of oxaliplatin (85 mg/m2 in a 2-h infusion on days 1 and 15) and irinotecan (80 mg/m2 in a 30-minute infusion on days 1, 8 and 15 immediately following oxaliplatin). RESULTS: Thirteen patients (39%) completed treatment. The most common grade Ill-lV toxicities were diarrhea (27%), anemia (6%), neutropenia (18%), alopecia (6%) and peripheral neuropathy (6%). Thirteen patients (39%) received G-CSF support, and there were 2 episodes of febrile neutropenia. There were no treatment-related deaths. Six patients (18%) had a partial remission and another 11 (33%), disease stabilization. There were no complete remissions. Median time to progression was 6.6 months (range, 0.8-20.1) and median survival 10.6 months (range, 0.8-52.9). CONCLUSIONS: Irinotecan and oxaliplatin combination has modest activity as second line treatment of 5-fluorouracil-resistant advanced colorectal cancer. Further research is warranted for the development of more effective and less toxic regimens in this setting.

Significance of immunocytochemical expression of E-cadherin, N-cadherin and CD44 in serous effusions using liquid-based cytology.

OBJECTIVE: To assess the diagnostic utility of E-cadherin (E-cad), N-cadherin (N-cad) and CD44 to discriminate adenocarcinoma cells from benign and malignant mesothelial cells in body cavity fluids and to clarify the origin of cancer cells. STUDY DESIGN: A total of 120 ThinPrep (Cytyc Corp., Boxborough, Massachusetts, U.S.A.) cytologic specimens of serous effusions, which included 22 cases of reactive mesothelium, 6 cases of malignant mesothelioma and 92 cases of metastatic adenocarcinoma from various sites, were immunostained for E-cad, N-cad and CD44. RESULTS: Eighty-three of 92 metastatic adenocarcinomas (90.21%) expressed E-cad, while 1 of 6 malignant mesotheliomas and 1 of 22 cases of reactive mesothelium were positive for E-cad. All 6 cases of mesothelioma expressed N-cad, whereas most cases of metastatic adenocarcinomas were negative. CD44 immunoreactivity was seen in 18 of 22 (81.81%) benign effusions and in 21 of 92 (22.82%) metastatic adenocarcinomas. CONCLUSION: The combination of E-cad, N-cad and CD44 appears to be a useful panel for distinguishing metastatic adenocarcinoma, mesothelioma and reactive mesothelium and also for clarifying the exact histogenetic origin of cancer cells. This is of great importance in a few otherwise-insoluble cases because of differences in tumor treatment and prognosis.

Continuation of trastuzumab beyond disease progression is feasible and safe in patients with metastatic breast cancer: a retrospective analysis of 80 cases by the hellenic cooperative oncology group.

Despite the widespread use of trastuzumab in the management of patients with HER2-overexpressing metastatic breast cancer, its optimal duration of administration is unknown. We retrospectively reviewed the medical records of 80 such patients who received trastuzumab monotherapy or combination chemotherapy beyond disease progression in order to register their clinical course. Median age of the patients was 54 years. Ninety-one percent had 3+ HER2 overexpression and 9% had 2+ HER2 overexpression. Fifty-six percent of patients had previously been treated with chemotherapy for advanced disease. The most commonly used combinations in first- and second-line treatments were trastuzumab with paclitaxel and trastuzumab with vinorelbine, respectively. In total, 32 responses were observed, most of them during the second or third line of treatment. Severe toxicities frequently seen (in = 5% of patients) were neutropenia (25%), thrombocytopenia (11.5%), infection (10%), peripheral neuropathy (9%), nausea/vomiting (6%), stomatitis (6%), diarrhea (6%), constipation (6%), edema (6%), and myalgias/arthralgias (5%). Median survival from diagnosis of advanced disease was 43.4 months (range, 6.4-91.7+), whereas median survival from disease progression after trastuzumab administration was 22.2 months (range, 0.01-32.9+). In conclusion, this retrospective analysis suggests that continuation of trastuzumab beyond disease progression in patients with HER2-overexpressing metastatic breast cancer is feasible and safe. Randomized studies are warranted.

Paclitaxel and liposomal doxorubicin (Caelyx) combination in advanced breast cancer patients: a phase II study.

Due to the cumulative cardiotoxicity of doxorubicin in cancer treatment, the tendency of the physician to find a substitute has led to the use of liposomal encapsulated doxorubicin, as well as other similar compounds. Doxorubicin and paclitaxel, two of the most active agents for breast cancer, have often been used in combination for this condition. In the present study we combined liposomal doxorubicin with paclitaxel with the intention of diminishing the toxicity of the cardiac muscle. Twenty-three patients were evaluated for response rate, survival and toxicity. All patients had metastatic disease and were chemotherapy-naïve after generalization of the disease. Liposomal doxorubicin was infused at a dose of 30 mg/m(2) and paclitaxel at a dose of 175 mg/m(2) once every 3 weeks. The response rate was complete in 2 patients (8.70%) and partial in 14 patients (60.87%) totalling 69.57%. The median duration of response was 6 months (range 2-13+) and median survival was 10 months (range 4-20+). Cardiotoxicity, myelotoxicity and gastrointestinal toxicity were well-tolerated. The high hand-foot adverse reaction (47.83%) inhibited the continuation of treatment in half of the patients and due to this toxicity the trial was terminated after the 23rd patient.

Hormone refractory advanced prostate cancer treated with estramustine and paclitaxel combination.

BACKGROUND: The objective of the present study was to investigate the effectiveness of weekly paclitaxel administration in combination with oral estramustine in patients with prostate cancer refractory to hormonal manipulation. PATIENTS AND METHODS: Between 1999 and 2000, 41 patients were included in the study. All patients had disease progression while on treatment with LH-RH and antiandrogens. After being off hormonal therapy for at least 4 weeks, oral estramustine 520 mg twice daily and 60 minutes paclitaxel 60 mg/m2 once weekly, were administered. In total 152 courses were given (median 3.71). RESULTS: Toxicity was well-tolerated. The most common adverse effect was low-grade (I-II) neurotoxicity. Objective partial responses were observed in 9 (22%) patients; when PSA decrease was included the total number of responders was 25 (61%) patients. Median survival was 17 months (range 4-42+ months). CONCLUSION: Long-term median and overall survival was achieved in patients with prostate cancer refractory to hormonal treatment, with oral estramustine and weekly paclitaxel administration. Toxicity was acceptable.

Combination docetaxel (Taxotere), fluorouracil, and leucovorin (TFL), as first-line chemotherapy in advanced gastric cancer: a Hellenic Cooperative Oncology Group phase II study.

BACKGROUND: We assessed the efficacy and safety profile of a docetaxel (Taxotere; Sanofi-Aventis, France), fluorouracil (FU), and leucovorin (LV) combination (TFL), as first-line chemotherapy in patients with advanced gastric cancer. METHODS: Fifty-eight patients with advanced gastric cancer were entered in this phase II study. The chemotherapy regimen (TFL) was administered in an outpatient setting as follows: docetaxel 7 mg/m2 on day 1 and FU 50 mg/m2 and LV 30 mg/m2 on days 1 to 3, every 3 weeks for six cycles. RESULTS: On an intent-to-treat basis, 4 complete (7%) and 11 partial responses (19%) were observed, with an objective overall response rate of 26%; in addition, 22 patients (38%) had stable and 15 (26%) had progressive disease. For 6 (10%) patients, response could not be evaluated. Responses were noted at all metastatic sites. With a median follow-up of 55 months, median survival was 9 months; median time to progression, 5.9 months; and median duration of response, 10 months. Toxicity was manageable and no toxic death was reported. Neutropenia was the most frequent severe toxicity and occurred in 30% of the patients. The main non-hematologic toxicities were alopecia (76%), diarrhea (30%), and stomatitis (30%). CONCLUSION: The results of this phase II study seem to indicate that the TFL regimen has moderate activity in patients with advanced gastric cancer, with acceptable toxicity.

Preclinical studies on NSC290205 aza-steroid alkylator activity in combination with adriamycin against lymphoid leukaemia.

Summary NSC290205 (A) is an hybrid synthetic antineoplastic ester that is a combination of a d-lactam derivative of androsterone and an alkylating derivative of N,N-bis(2-chloroethyl)aniline. We tested NSC290205 for synergistic antileukaemic activity with adriamycin (ADR), (i) in vitro against the human lymphoid leukaemia cell lines: CCRF-CEM, MOLT-4, and RPMI-8226, (ii) in vivo against P388 lymphocytic and L1210 lymphoid murine leukaemias (at incipient and advanced phase). Our results indicated significant cytostatic and cytotoxic synergy of NSC290205 and ADR in vitro. We further examined these results in vivo by replacing cyclophosphamide in the standard CHOP (cyclophosphamide, hydroxydaunomycin, Oncovin, prednisone) regimen with NSC290205 (AHOP) and comparing the efficiency of these two regimens in vivo. Although treatment of P388 and L1210 with cyclophosphamide or NSC290205 alone yielded equivalent results, AHOP produced a clear benefit for survival compared with CHOP against advanced leukaemias, confirming the in vitro observations [higher percentage increase in median lifespan of treated animals over the untreated (control): 188% and 239% in L1210, 308% and 353% in P388, P < 0.01, for CHOP and AHOP respectively]. AHOP also proved to be more genotoxic and cytostatic than CHOP, inducing higher sister chromatid exchange levels and cell division delays on P388 cells in vivo. NSC290205 showed superior antineoplastic potential against lymphoid leukaemia and significant synergy with ADR, producing an excellent therapeutic outcome.

Paclitaxel and gemcitabine, as first-line chemotherapy, combined with trastuzumab in patients with advanced breast cancer: a phase II study conducted by the Hellenic Cooperative Oncology Group (HeCOG).

PURPOSE: Advanced breast cancer (ABC) is an incurable disease. Standard first-line treatment for patients with HER-2/neu overexpressing tumors includes the combination of the humanized monoclonal antibody trastuzumab with chemotherapy, mainly paclitaxel. This combination is the first to demonstrate a survival advantage in this group of patients. To improve on these results, we investigated a triplet, paclitaxel-gemcitabine-trastuzumab (TGH), in a phase II study. PATIENTS AND METHODS: Patients with ABC were accrued to the study. Treatment consisted of paclitaxel 80 mg/m2/week, gemcitabine 1000 mg/m2 every 2 weeks, and trastuzumab 4 mg/kg loading dose and then 2 mg/kg/week. Patients were treated on study for a total of 12 weeks. Response evaluation was performed at the end of the 12 weeks. Continuation of treatment beyond the 12 weeks was left to the discretion of the investigator. Primary study endpoint was response. Toxicity assessment and survival were secondary endpoints. RESULTS: Between November 2000 and May 2002, 40 patients were accrued and 32 patients completed all 12 weeks of therapy. One patient died of septic shock during therapy. Grade III and IV neutropenia was seen in 12.5% of cases each. Grade III anemia was seen in two patients, and grade III and IV thrombocytopenia in three and two patients, respectively. Both paclitaxel and gemcitabine were delivered at 86% of the planned dose intensity. Six patients achieved a complete response (CR) and 15 a partial response for an overall response rate of 52.5%. An additional 25% demonstrated stable disease and 20% progressive disease. Median duration of response was 14 months. All six patients who achieved CR are still in CR for 6 to 19 months. After a median follow up of 12.2 months, 19 patients have progressed and 7 have died. Median time to progression is 13.7 months, whereas median survival has not been reached. CONCLUSION: TGH is a well-tolerated and effective regimen for the first-line treatment of ABC. Randomized comparison between paclitaxel, trastuzumab, and triplets are warranted.