Second-line treatment with intravenous gemcitabine and oral etoposide in platinum-resistant advanced ovarian cancer patients: results of a phase II study.

OBJECTIVE: The outcome of advanced ovarian cancer patients has not significantly improved since the introduction of platinum. One of the major reasons for this failure is the lack of an effective second-line treatment. In this phase II trial we tested the combination of gemcitabine and etoposide in 2 different groups of patients. Group 1 consisted of patients showing disease progression or relapse within 6 months of first-line platinum-based chemotherapy. Group 2 comprised heavily pretreated patients showing progression during the last chemotherapy attempt. METHODS: Thirty-four patients were enrolled. Gemcitabine was administered at a dose of 1,000 mg/m(2) on days 1 and 8 and etoposide was administered orally at 100 mg/day on days 8-12 for 6 courses. RESULTS: Eighteen patients (52.9%) had an objective response and the median duration of the response was 10.3 months. Our chemotherapy regimen showed a low toxicity and good patient compliance. In 5 patients the treatment had to be delayed and in only 2 patients it was discontinued. CONCLUSIONS: The combination of gemcitabine and oral etoposide seems to be a safe and effective second-line treatment for platinum-resistant ovarian cancer patients. Additional data on larger series are warranted to better define the activity of this combination regimen.

A phase II trial with cisplatin-paclitaxel cytotoxic treatment and concurrent external and endocavitary radiation therapy in locally advanced or recurrent cervical cancer.

BACKGROUND: Five randomized studies have demonstrated a beneficial effect of adding cisplatin-based chemotherapy to radiation therapy in the treatment of cervical carcinoma. In the present phase II study, we evaluated the response and toxicity of cisplatin-Taxol chemotherapy combined with concomitant radiotherapy in patients with locally advanced cervical carcinoma (LACC) and locally recurrent cervical carcinoma (LRCC). PATIENTS AND METHODS: In 2000, this phase II study was initiated with a chemotherapy regimen of cisplatin (75 mg/m(2)) and Taxol (175 mg/m(2)) every 21 days, for four cycles, concomitant with external radiotherapy and high-dose-rate brachytherapy. Pelvic radiotherapy was started 2 weeks after the first chemotherapy cycle, while the first brachytherapy insertion was carried out during the fourth chemotherapy cycle. SCC marker was determined before treatment and after every chemotherapy cycle. RESULTS: All of the 27 patients treated achieved a complete clinical response. Two patients with LACC experienced distant recurrence 22 and 24 months after complete response, respectively, and 1 patient with LRCC had local progression 6 months after the end of radiotherapy. Although generally tolerable, neutropenia grade 3-4 in 4 patients and anemia grade 3 in 2 patients were observed, and 1 patient experienced grade 2 neurotoxicity; toxicity due to radiotherapy was moderate. CONCLUSIONS: Concomitant cisplatin-Taxol chemoradiotherapy seems to be well tolerated, and results, even in this small series, are encouraging.

Combined regimen of cisplatin, doxorubicin, and alpha-2b interferon in the treatment of advanced malignant pleural mesothelioma: a Phase II multicenter trial of the Italian Group on Rare Tumors (GITR) and the Italian Lung Cancer Task Force (FONICAP).

BACKGROUND: The cisplatin-doxorubicin combination has shown moderate activity in malignant pleural mesothelioma (MPM; objective response, 25%), and preclinical studies suggest that interferons (IFNs) may have an antiproliferative effect on mesothelioma cell lines with a marked increase in cisplatin cytotoxicity. Therefore, the combined chemoimmunotherapy regimen is an worthwhile approach to evaluate in a Phase II trial. METHODS: From December 1995 to June 1999, 37 previously untreated patients with MPM were treated with cisplatin 60 mg/m(2) intravenously on Day 1 plus doxorubicin 60 mg/m(2), recycled every 3-4 weeks and IFN-alpha-2b, 3 x 10((6)) international units subcutaneously 3 times a week for a total of 6 courses or until progression. Inclusion criteria were histologic diagnosis of MPM and measurable disease defined by computed tomography scan or magnetic resonance imaging. RESULTS: Thirty-four patients were assessable for toxicity and 35 for efficacy according to World Health Organization criteria. One hundred thirty-five courses were administered with a median of 4 cycles per patients. Seventy-six percent of patient presented at least 1 episode of severe myelosuppression (Grade 3 and 4). Severe anemia and thrombocytopenia occurred in 30% and 24% of patients, respectively. Sixty percent of patients presented constitutional symptoms. In the 35 patients assessable for response, the overall response rate was 29% (95% confidence interval, 15-47%). The median duration of response was 8.4 months. With a median follow-up of 19.6 months, the median survival was 9.3 months. One- and 2-year survival was 45% and 34%, respectively. CONCLUSIONS: This combined regimen has definite activity in MPM. However, toxicity, particularly myelosuppression and fatigue, is not negligible and may limit its application.

Comparison of micronuclei frequencies in mono-, bi- and poly-nucleated lymphocytes from subjects of a residential suburb and subjects living near a metallurgical plant.

Spontaneous baseline frequencies of micronuclei in mono-, bi- and poly-nucleated lymphocytes were analyzed, using the cytokinesis-block technique, in 103 subjects living in a residential suburb (Genova-Nervi), and in 203 subjects living in an urban industrialized area near a metallurgical plant and a coke factory (Genova-Cornigliano). Statistical analysis showed that the average frequency of micronucleated binucleated lymphocytes (MnBNL) was significantly higher (1.42-fold) in donors of Nervi than in donors of Cornigliano living in a contaminated environment. In contrast, the average frequency of micronucleated polynucleated lymphocytes (MnPNL) was significantly higher (1.66-fold) in donors of Cornigliano than in donors of Nervi. The existence in the whole population examined of a positive correlation between frequency of MnBNL and frequency of MnPNL and the absence of a positive correlation between frequency of bi- and poly-nucleated lymphocytes and frequency of MnPNL suggest that the formation of MnPNL is a consequence of genetic damage and not of mitotic errors arising during the division of bi- and poly-nucleated cells. In agreement with previous findings the frequency of MnBNL increased with age and was significantly higher in females than in males; unexpectedly it was higher in non-smokers/non-drinkers than in smokers/drinkers.

Induction chemotherapy followed by concurrent standard radiotherapy and daily low-dose cisplatin in locally advanced non-small-cell lung cancer.

Both induction chemotherapy and concurrent low-dose cisplatin have been shown to improve results of thoracic irradiation in the treatment of locally advanced non-small-cell lung cancer (NSCLC). This phase II study was designed to investigate activity and feasibility of a novel chemoradiation regimen consisting of induction chemotherapy followed by standard radiotherapy and concurrent daily low-dose cisplatin. Previously untreated patients with histologically/cytologically proven unresectable stage IIIA/B NSCLC were eligible. Induction chemotherapy consisted of vinblastine 5 mg m(-2) intravenously (i.v.) on days 1, 8, 15, 22 and 29, and cisplatin 100 mg m(-2) i.v. on days 1 and 22 followed by continuous radiotherapy (60 Gy in 30 fractions) given concurrently with daily cisplatin at a dose of 5 mg m(-2) i.v. Thirty-two patients were enrolled. Major toxicity during induction chemotherapy was haematological: grade III-IV leukopenia was observed in 31% and grade II anaemia in 16% of the patients. The most common severe toxicity during concurrent chemoradiation consisted of grade III leukopenia (21% of the patients); grade III oesophagitis occurred in only two patients and pulmonary toxicity in one patient who died of this complication. Eighteen of 32 patients (56%, 95% CI 38-73%) had a major response (11 partial response, seven complete response). With a median follow-up of 38.4 months, the median survival was 12.5 months and the actuarial survival rates at 1, 2 and 3 years were 52%, 26% and 19% respectively. The median event-free survival was 8.3 months with a probability of 40%, 23% and 20% at 1, 2 and 3 years respectively. Induction chemotherapy followed by concurrent daily low-dose cisplatin and thoracic irradiation, in patients with locally advanced NSCLC, is active and feasible with minimal non-haematological toxicity. Long-term survival results are promising and appear to be similar to those of more toxic chemoradiation regimens, warranting further testing of this novel chemoradiation strategy.

Dose-intensive first-line chemotherapy with epirubicin and continuous infusion ifosfamide in adult patients with advanced soft tissue sarcomas: a phase II study.

This phase II study was designed to verify the activity and safety of an intensive epirubicin/ifosfamide schedule in untreated soft tissue sarcoma (STS) patients by using both the agents at the identified maximal tolerated doses. 39 adult patients were treated with epirubicin at 55 mg/m2, on days 1 and 2 (total dose per cycle 110 mg/m2) combined with ifosfamide at 2.5 g/m2 days 1-4 (total dose per cycle 10 g/m2), with equidose mesna uroprotection and G-CSF support. Treatment was given on an ambulatory basis, at 3-week intervals. The overall objective response (OR) rate was 59% (95% confidence interval, CI, 43-72%), with 5 complete responses (13%) at 18 partial responses (46%); 12 partial responders were rendered disease-free following surgery. The median survival time was 19 months, being 23 and 13 months, respectively, for responding and non-responding patients. The median time to response was 40 days (range 21-60). Treatment-related toxicity was overall acceptable. The OR of 59% was the highest ever reported in our consecutive studies in advanced STS, confirming that improved therapeutic efficacy can be obtained with intensified regimens in such a disease; both the response duration and survival were also longer. The observed activity proved to be interesting with regard to the high response rate in the lung (86%), as well as the proportion of patients rendered disease-free by early surgery after the achievement of a partial response (55%). Both these findings may be important in the multimodality approach to patients with lesions potentially resectable for cure.

Radioimmunoguided surgery with different iodine-125 radiolabeled monoclonal antibodies in recurrent colorectal cancer.

Sixty-four patients with recurrent or metastatic colorectal cancer underwent radioimmunoguided surgery (RIGS). Thirty patients (Group A) were preoperatively injected with radiolabeled monoclonal antibody (MAb) B72.3, a whole IgG1 that reacts with tumor-associated glycoprotein (TAG-72) antigen. Thirty-four patients (Group B) were given monoclonal antibody FO23C5, an F(ab')2 which reacts with the carcinoembryonic antigen (CEA). The use of F(ab')2 antibodies ensured a lower time interval from the preoperative injection of the radiolabeled MAb to surgery. This interval was 22.7 days for Group A patients and 10.9 days for Group B patients. The correct RIGS identification of tumor sites occurred in 80.4% of Group A patients and in 92.6% of Group B patients. Additional information capable of modifying surgical strategy was obtained in 23.3% of Group A patients and in 8.8% of Group B patients. This difference was due to the different patterns of biodistribution and pharmacokinetics of the two MAbs. Although FO23C5 yields an improved diagnostic resolution for macroscopic tumor sites, we believe that B72.3 or other whole IgG1 should be the first choice for RIGS in recurrent or metastatic colorectal cancer patients.

Tamoxifen and the endometrium: findings of pelvic ultrasound examination and endometrial biopsy in asymptomatic breast cancer patients.

The need for endometrial surveillance in breast cancer patients undergoing adjuvant treatment with tamoxifen is still controversial. In this study, 164 asymptomatic breast cancer patients (110 on treatment with tamoxifen, 20 mg/day, and 54 controls) were examined with pelvic ultrasound and endometrial biopsy. No differences in ultrasound and biopsy findings were observed in the pre- and perimenopausal group between patients treated with tamoxifen and controls. Postmenopausal patients on tamoxifen had a significantly thicker endometrium (mean+/-SD, 7.2+/-8.5 vs. 1.5+/-4.3 mm, p=0.00002) and significantly larger uterine volume (mean+/-SD, 63.2+/-39.9 vs. 43.7+/-38.8 cm3, p=0.0001) than controls. Fifty-four percent of patients on tamoxifen had an endometrial thickness > or = 5 mm, often with multiple irregular sonolucencies suggesting the presence of cysts. Ultrasound findings, however, did not correlate with the presence of endometrial abnormalities on biopsy, and no endometrial cancer or atypical hyperplasia were found. This lack of correlation makes questionable the use of routine sonography in asymptomatic breast cancer patients on tamoxifen. Obtaining routine endometrial samples, on the other hand, may be difficult in some patients because of cervical stenosis or refusal. Until the benefits of endometrial surveillance will be proved, asymptomatic patients should not be submitted routinely to ultrasound examination or biopsy, but encouraged to report promptly any abnormal vaginal bleeding.