Adjuvant chemotherapy with cisplatin, etoposide, fluorouracil and leucovorin for gastric carcinoma.

PURPOSE: The aim of this study was to evaluate the efficacy of cisplatin, etoposide, 5-fluorouracil (5-FU), and leucovorin (L; CEFL) combination chemotherapy given as adjuvant treatment to patients with stage III gastric cancer. PATIENTS AND METHODS: A total of 33 patients who had undergone curative resection for stage III gastric adenocarcinoma were enrolled in our adjuvant chemotherapy protocol to receive 6 cycles of CEFL starting within 8 weeks from surgery. CEFL consisted of cisplatin 30 mg/m2 on days 1-3; 5-FU 300 mg/m2 continuous infusion on days 1-3; and etoposide 90 mg/m2 on days 1-3. Cycles were repeated every 4 weeks. Relapse-free survival (RFS) and overall survival (OS) were estimated using Kaplan-Meier method. Comparison between groups was carried out using log-rank test. RESULTS: Treatment was completed by 30 (91%) patients. After a mean follow-up of 31 months 15 (50%) patients have relapsed. Mean RFS was 31 months (range 6 to 114+). Patients with stage IIIA disease had longer RFS that those with stage IIIB (37 vs. 25 months, p>0.05). Mean OS was 35 months (range 4 to 114+), while stage IIIA patients survived longer than IIIB ones (42 vs. 27 months, p>0.05). Principal side effects of therapy were from the bone marrow and the gastrointestinal tract. There were 2 treatment-related deaths due to neutropenic sepsis. CONCLUSION: CEFL regimen appears to be an effective adjuvant treatment for patients with stage III gastric carcinoma as it prolongs both RFS and OS. However, its pronounced myelotoxicity requires the prophylactic use of granulocyte colony stimulating factor (G-CSF).

Second line chemotherapy with methotrexate and gemcitabine in patients with relapsing head and neck cancer.

PURPOSE: The aim of this study was to evaluate the efficacy and toxicity profile of the combination of methotrexate and gemcitabine given as second-line treatment in patients with relapsing and/or metastatic head and neck cancer (HNC). PATIENTS AND METHODS: A total of 21 patients with HNC who had relapsed after first-line treatment with cisplatin-containing regimens were enrolles. Treatment consisted of intravenous (i.v.) administration of methotrexate 30 mg/m(2) and gemcitabine 800 mg/m(2) on days 1, 8, and 15 in cycles of 28 days. Primary sites included the larynx, tongue, nasopharynx, hypopharynx, nasal cavity, and parotid gland. The study end point was the evaluation of treatment efficacy and toxicity. RESULTS: Seven (33%) patients received only 1 or 2 cycles and discontinued treatment because of disease progression. Among 14 patients evaluable for respone, 1 complete (CR) and 2 partial responses (PR) were observed, yielding a response rate of 21.4%. The patient with CR remains relapse-free for 74(+) months. The 2 PR patients relapsed after 14 and 25 months and are still alive at 18 and 32 months, respectively. Seven patients showed minor response (MR) or stable disease (SD) with symptomatic relief lasting 4-12 months (mean 8). All but 2 of adequately treated patients (12/14 or 85.7%) attained a clinical benefit response (CBR). Mean time to progression (TTP) of all patients was 8 months (range 1-74(+)), while mean overall survival (OS) was 14 months (range 1-74(+)). Toxicity was mild to moderate and easily manageable. CONCLUSION: Methotrexate and gemcitabine combination is an effective second-line treatment for patients with relapsing and/or metastatic HNC. Moreover, this regimen is well tolerated with mild to moderate, easy to treat, toxicity.

Correlation of tissue transglutaminase expression on breast cancer tissue with time to relapse, overall survival, and clinical and molecular prognostic factors: a preliminary report.

PURPOSE: To correlate tissue transglutaminase (TTG) expression with the expression of molecules with prognostic significance in breast cancer patients and with classical clinical parameters (disease stage, histological grade, overall survival (OS), relapse rate, disease progression and time to treatment failure-TTF). PATIENTS AND METHODS: Paraffin-embedded tissue specimens from 68 breast cancer patients were studied retrospectively for TTG expression, estrogen (ER) and progesterone (PG) receptors, c-erbB-2, p53, Bcl-2, and Ki-67. Sixty-seven patients were females (mean age 60.5 years). Histology was ductal carcinoma in 53 (inflammatory in 2 and mucinous in 1 of them), lobular in 13 and tubular in 2 cases. Grade was 1 and 2 in 45 cases and 3 in 23. Forty-six patients had early-stage disease (I - IIB) and 22 advanced (IIIA - IV). RESULTS: Fifty patients had at least 1 favorable molecular prognostic factor while all but 3 had at least 1 unfavorable prognostic factor. Twenty-nine (42.6%) patients have relapsed so far (mean TTF 31.4 months). Fifty-two (76.5%) patients are still alive (mean OS 38.5 months). Of the 59 patients with nodal and/or metastatic disease 54 were expressing TTG and 32 Bcl-2. Five were not expressing either one while 22 were expressing both. Of the 9 patients without nodal and/or metastatic disease all but one were expressing TTG and Bcl-2. Analyzing these subgroups of patients there was sufficient evidence that TTG expression was correlated with a trend for prolonged survival both in patients with localized and extensive disease, while the coexpression with Bcl-2 was correlated with a trend for prolongation of TTF and OS, both in relapsing and nonrelapsing patients. However, these differences did not reach statistical significance. Similar comparisons of TTG expression with the presence of adverse prognostic factors verified a beneficial effect of TTG expression on OS in all subgroups. CONCLUSION: Our data suggest that TTG is an independent favorable prognostic factor for survival, possibly enhancing the apoptotic effect of chemotherapy.

Sequential chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil in patients with locally advanced head and neck cancer.

The purpose of this phase II trial was to evaluate the toxicity of a sequential chemoradiotherapy approach using docetaxel, cisplatin, and 5-fluorouracil (5-FU) (DCF) with granulocyte colony-stimulating factor support in previously untreated patients with locally advanced head and neck cancer (HNC). Secondary endpoints included preliminary assessment of response. Patients with locally advanced HNC, a World Health Organization performance status 0 to 2, and no prior history of chemotherapy or radiotherapy were included. Treatment consisted of docetaxel 80 mg/m2 (1-hour infusion) on day 1, cisplatin 40 mg/m2 (1-hour infusion) on days 2 and 3, and 5-fluorouracil 1,000 mg/m2 (24-hour continuous infusion), on days 1 to 3, repeated every 28 days for a maximum of 4 cycles per patient. All patients received granulocyte colony stimulating factors subcutaneously between days 4 and 9. Radiation therapy (RT) to the primary tumor site and neck lymph nodes was planned within 5 weeks of the last cycle of chemotherapy. The primary tumor site received 60 to 70 Gy. Twenty patients (median age 56 years, range: 40-72 years) received a total of 60 cycles of DCF. The median number of cycles was 3 (range: 1-4 cycles). All patients were evaluable for toxicity and response. The most common acute nonhematologic toxicities from DCF induction chemotherapy included alopecia, mucositis, peripheral sensory neuropathy, onycholysis, and asthenia. Febrile neutropenia developed in two patients and grade IV diarrhea in one patient. There were no treatment-related deaths. The overall response rate (RR) after DCF induction chemotherapy was 90% (95% confidence interval [CI]: 76.8-103.1%). After the completion of RT, the overall RR was 95% with a complete response rate of 73% (95% CI: 49.9-90.1%). Organ preservation was achieved in eight patients with laryngeal cancer and one patient with base of tongue involvement. After a median follow-up of 36 months (range: 5-43 months) the median disease-free and overall survival have not been reached yet. The 1- and 2-year survival rates were 85% and 60%, respectively. Sequential chemoradiotherapy with DCF and growth factor support is feasible and very active, with durable responses in patients with locally advanced head and neck cancer. Further evaluation of this modality is justified in the context of a clinical trial.

Combination chemotherapy with docetaxel, cisplatin, and 5-fluorouracil in previously treated patients with advanced/recurrent head and neck cancer: a phase II feasibility study.

The purpose of this phase II feasibility trial was to determine the efficacy and toxicity of docetaxel combined with cisplatin and 5-fluorouracil in patients with locally advanced and/or recurrent squamous cell carcinoma of the head and neck. Nineteen patients entered the study. The majority had received prior radiotherapy but were chemotherapy naive. Treatment consisted of docetaxel 80 mg/m2 day 1, cisplatin 40 mg/m2 days 2 and 3, and 5-fluorouracil 1,000 mg/m2 by continuous infusion days 1 to 3. The cycle was repeated every 28 days. Most patients received granulocyte colony-stimulating factor, 150 microg/m2/day subcutaneously between days 4 and 8. The median number of chemotherapy cycles per patient was four. Dose reduction was done in three patients with no treatment delays. Of the 16 evaluable for response, seven patients (44%) demonstrated an objective response, including two complete and five partial ones; eight patients (50%) had stable disease; and one patient had progressive disease. The median time to progression was 7.5 months (range: 4-17.5 months). The median survival was 11 months (range: 1-18 months) and 1-year survival was 49%. Febrile neutropenia was recorded in 15% of courses. There were no toxic deaths. In conclusion, the combination of docetaxel, cisplatin, and 5-fluorouracil is an active regimen against previously treated squamous cell carcinoma of the head and neck with acceptable toxicity.

Front-line treatment of metastatic breast cancer with docetaxel and epirubicin: a multicenter dose-escalation study. The Greek Breast Cancer Cooperative Group (GBCCG).

PURPOSE: To determine the maximum tolerable dose (MTD) and the dose-limiting toxicity (DLT) of docetaxel (D) in combination with epirubicin (Epi) in patients with advanced breast cancer. PATIENTS AND METHODS: Forty-seven chemotherapy-naïve metastatic breast cancer patients aged < 75 years with PS (WHO) 0-2 and adequate bone marrow, renal, liver and cardiac function, were enrolled in the study. Epi was given as a five-min bolus i.v. infusion on day 1 (d1) in escalated doses with increments of 10 mg/m2; D was given in a one-hour infusion after appropriate premedication on either day 1 or on day 2 in escalated doses with increments of 10 mg/m2. The patients' median age was 60 years, 42 (89%) had a PS (WHO) 0-1, 16 (34%) were premenopausal and 25 (53%) had visceral disease. RESULTS: When the two drugs were given on the same day, the MTD1 was reached at the doses of Epi 60 mg/m2 and D 80 mg/m2; administration of G-CSF could not result in a dose intensification. When the drugs were given on two consecutive days, the MTD2 was reached at the doses of Epi 80 mg/m2 (d1) and D 90 mg/m2 (d2). The dose-limiting events were febrile neutropenia and grade 4 neutropenia, which developed in 30 (64%) patients during the study; among 227 delivered cycles grade 3-4 neutropenia occurred in 64 (28%) cycles but only 22 (10%) of them were complicated by fever. There were no septic deaths. Grade 1-2 neurosensory toxicity occurred in nine (19%) patients, mild edema in eight (17%) and allergic reactions in five (11%). Four (9%) patients presented a greater than 10% decrease of LVEF and treatment discontinuation was required in two of them; none of the patients developed congestive heart failure. Nevertheless, one patient suddenly died 10 days after treatment initiation of myocardial ischemia, and this death is considered treatment-related. Five (14.7%) complete and thirteen (38.2%) partial responses (ORR: 53.9%; 95% confidence interval: 36.1%-69.7%) were observed in 34 evaluable patients. Ten (29.4%) and six (17.6%) patients had stable and progressive disease, respectively. The median duration of response and time to tumor progression were five and seven months, respectively. The median survival has not yet been reached. CONCLUSIONS: The combination of epirubicin and docetaxel is a feasible and well tolerated regimen, but the MTD depends on the administration schedule of the drugs.

Clinical activity and benefit of irinotecan (CPT-11) in patients with colorectal cancer truly resistant to 5-fluorouracil (5-FU).

The aim of this prospective study was to assess the efficacy, clinical benefit and safety of CPT-11 (irinotecan) in patients with stringently-defined 5-fluorouracil-resistant metastatic colorectal cancer (CRC). 107 patients with documented progression of metastatic CRC during 5-FU were treated with CPT-11 350 mg/m2 once every 3 weeks in a multicentre phase II study. Tumour response and toxicity were assessed using WHO criteria. Changes in performance status (PS), weight and pain were also measured. The WHO response rate was 13/95 (13.7%, 95% CI 7.5% to 22.3%) eligible patients with a median duration of response of 8.5 months (37 weeks, range: 18-53+). There was also a high rate of disease stabilisation (44.2%) with a median duration of 4.8 months. The probability of being free of progression at 4 months was 50%. Median survival from first administration of CPT-11 was 10.4 months or 45 weeks (range: 3-66+ weeks). There was weight stabilisation or gain in 81% (73/90) of patients, a favourable outcome in PS in 91% (82/90) (improvement of WHO PS 2 or stabilisation of PS 0-1), and pain relief in 54% (26/48). There were no toxic deaths. Neutropenia was short-lasting and non-cumulative. Diarrhoea grade > or = 3 occurred in 7% of cycles and 28/107 (26%) of patients. CPT-11 350 mg/m2 once every 3 weeks has an encouraging degree of activity in progressive metastatic CRC truly resistant to 5-FU with a relatively high rate of tumour growth control translated into clinical benefit. The toxicity profile of CPT-11 is becoming better understood and has been considerably improved.

Combination chemotherapy with docetaxel, vinorelbine and cisplatin as first-line treatment of advanced non-small-cell lung cancer: a multicenter phase II study of the Greek Cooperative Group for Lung Cancer.

Vinorelbine, docetaxel and cisplatin have documented single-agent activity in non-small-cell lung cancer (NSCLC); a multicenter phase II trial was initiated in order to evaluate the tolerance and efficacy of their combination. A total of 24 chemotherapy-naive patients with measurable stage IIIB or IV NSCLC and performance status (PS; WHO) 0-2 entered the study. Vinorelbine (20 mg/m2 i.v.) was given on days 1 and 15, cisplatin (60 mg/m2) on day 1, and docetaxel (100 mg/m2) on day 16, in cycles of 28 days. Recombinant human granulocyte colony-stimulating factor (150 microg/m2 s.c.) was administered prophylactically from day 17 to day 27. One pathological complete (4%) and six partial responses (25%) were documented (overall response 29%; 95% CI 11.6-49.2%). A total of five patients (21%) had stable and 12 (50%) progressive disease. The median duration of response was 28 weeks and the median time to tumor progression 36 weeks; the median survival was 20 weeks. Grade 3-4 neutropenia occurred in 16 patients (67%) while 13 of them (54%) developed febrile neutropenia. Grade 4 mucositis occurred in two patients (8%) and one of them also presented grade 4 diarrhea. There were four treatment-related deaths: two from sepsis, one from massive hemoptysis due to a pulmonary abscess and one from acute myocardial ischemia 7 days post-chemotherapy. In conclusion, the high incidence of neutropenic episodes and treatment-related deaths led to an early discontinuation of patient enrollment. This combination, in the schedule and the doses used, could not be recommended for off protocol treatment of patients with advanced NSCLC.

Treatment of advanced and relapsing breast cancer with a combination of paclitaxel and mitoxantrone. South-Central Hellenic Oncology Group.

A multicenter nonrandomized study was designed to assess the efficacy (response rate and duration of relapse-free survival) and safety of the combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) 200 mg/m2 given as a 3-hour intravenous infusion with premedication every 3 weeks, followed by mitoxantrone 12 mg/m2, given as an intravenous push every 3 weeks, in patients with metastatic breast carcinoma. So far, 30 patients have entered the study and 27 are evaluable for response. All patients had advanced metastatic breast cancer and have been extensively pretreated with chemotherapy (28 patients), radiotherapy (13 patients), and hormonotherapy (24 patients). Fourteen patients (46.7%) have been previously treated with anthracyclines, and disease progressed in seven (23.3%) during anthracycline treatment. One patient had a complete remission and 14 a partial remission for a total remission rate of 55.6%. One of the 15 patients entering remission developed heart failure and was withdrawn from the protocol after 4 months in remission. She then relapsed and died 9 months after entering protocol. The remaining 14 patients continue to respond and their remission durations range from 4+ to 12+ months (mean, 9 months; 95% confidence interval [CI] 7.96 to 10.04). Eleven patients (40.7%) developed minor responses or disease stabilization lasting from 1.5 to 11.4+ (mean, 3.5 months; 95% CI, 1.9 to 6.0) and one of them had disease progression after 3.5 months and is still alive whereas another one who had disease progression died at 1.5 months. Four patients failed to respond and their disease progressed during protocol treatment; two of them died at 6.7 months while the other two are alive at 3.4 and 9.8 months. Overall survival ranged from 1.5 to 13+ months (mean, 6.7 months; 95% CI, 5.5 to 7.9). In the group of 14 anthracycline-pretreated patients, seven showed a partial remission, six a minor response or disease stabilization, and one had disease progression. Response duration ranged from 1.5 to 12+ months (mean, 6.1 months; 95% CI, 4.2 to 8.0); the three patients whose disease progressed died at 1.5, 6.7, and 8.8 months. Bone marrow toxicity was dose-limiting and caused treatment delays as well as dose de-escalation of both drugs in eight patients.

Immunohistochemical expression of EGF-R in malignant surface epithelial ovarian neoplasms (SEON).

EGF-R expression was found to be increased in 40% of malignant epithelial ovarian neoplasms by an immunohistochemical method. No correlation was found between EGF-R expression and clinical stage. There was a suggestion of reduced survival among tumours with positive EGF-R expression.

The immunohistochemical expression of proliferating cell nuclear antigen (PCNA/cyclin) in malignant and benign epithelial ovarian neoplasms and correlation with prognosis.

Proliferating cell nuclear antigen (PCNA)/cyclin is considered to be a marker of cell proliferation. The aim of this study was to evaluate the expression of PCNA/cyclin in epithelial ovarian neoplasms (EON) as well as the possible correlation with degree of differentiation, tumour stage and overall survival. The material consisted of 34 benign and 40 malignant EON. Positive nuclear staining was detected in 2/34 (6%) of benign and 23/39 (59%) malignant EON (P < 0.001). Most cases in the high proliferation group were diagnosed in advanced clinical stages. There was no difference in overall survival between nuclear PCNA positive and negative patients, as well as the high and the low proliferation group. In conclusion, the role of PCNA as a marker of malignant potential and prognosis in EON merits further investigation.

Two magnetic methods for articulatory measurements.

We present two magnetic methods for measuring articulatory activities. Unlike previous methods, the magnetic fields are uniform. Three alternating magnetic fields induce voltages in two detectors, a magnetic potentiometer and a flat coil. Thus we are able to measure jaw and tongue movements during speech production. These methods are biologically safe. The miniaturized detectors do not disturb the speech movements. Some preliminary results are presented. These methods can also be applied for other kinds of vectorial distance measurement.