Autoantibodies against DFS70 (dense fine speckles 70) antigen have recently been identified among antinuclear antibodies (ANA) in patients with various inflammatory diseases and in patients with different types of cancer. These antibodies are recognized using indirect immunofluorescence (IIF) on HEp-2 cells, by a fine speckled nuclear staining in interphase HEp-2 cells and a positive reaction in the chromosome region of mitotic cells. Given that the DFS70 protein is also known as the lens epithelium-derived growth factor, this study was performed with two objectives: (a) to assess the prevalence of these antibodies in patients sent for ANA testing and in 334 patients with different types of neoplasia and (b) to determine whether the lens tissue was a suitable substrate for the detection of antibodies specific to lens proteins. During routine workup for ANA detection by the IIF method, we found 172 DFS70-positive sera among 21,516 consecutive samples (prevalence, 0.8%). In the group of patients with neoplastic disease, 6 of 334 (1.8%) were anti-DFS70-positive. DFS70-positive sera were then assayed by the IIF method on cryostatic sections of mouse eye at a dilution of 1:40 with an anti-human IgG conjugate. Among the 172 DFS70-positive samples detected by the ANA screening, 32 (19%) were strongly reactive against the reticular fibers of the lens; 8 (5%) were positive only to the corneal epithelium (nuclear negative); 5 (3%) were positive both for the cornea and the lens fibers; 13 (7%) stained only the nuclei of lens and cornea cells, and 4 (2%) were positive against the ciliary muscle. Among the patients with neoplastic diseases, only one with lung cancer reacted weakly with the reticular fibers of the lens. Sera from 20 healthy blood donors were negative. In this preliminary study, we have shown that the prevalence of anti-DFS70 antibodies is much lower than previously reported, both in patients screened for ANA and in patients with cancer. We have also seen that some DFS70-positive sera have antibodies that recognize antigens of the lens. Further studies are needed to investigate the fine specificity and the possible significance of these new autoantibodies.

This study was designed to evaluate the activity and tolerability of irinotecan and docetaxel in patients with previously treated non-small cell lung cancer (NSCLC). Eligibility included recurrent or progressive NSCLC, previous chemotherapy, age ≥18 years, ECOG PS ≤2. Treatment consisted of irinotecan (160 mg/m2 i.v.), followed by docetaxel (65 mg/m2 i.v.) on day 1 of a 21-day cycle, for a maximum of 6 cycles. Forty patients were enrolled. Median age was 60 years and median ECOG PS was 1. All patients were evaluable for toxicity and 31 (78%) were evaluable for response. A total of 125 cycles was administered (median, 3; range, 1–6). Most common grade 3–4 toxicities were neutropenia (62%), neutropenic fever (22%), and diarrhea (32%). Response rate was 10%; a further 40% of patients achieved stable disease. All responses were observed in patients with ECOG PS ≤1, age <70 years, and who had received only one prior chemotherapy regimen. Median time to progression was 2.8 months and median survival was 7.4 months. Because of significant toxicity and limited activity, further investigation of irinotecan plus docetaxel in second line NSCLC is not recommended.

17014 Background: Topotecan is the only single agent currently approved for the treatment of relapsed or recurrent SCLC, showing activity both in chemotherapy-refractory (RR 2–14%) and in chemotherapy-sensitive patients (RR 14–38%). The role of topotecan in combination with other active agents is still under investigation. Methods: Aim of this phase II study is to assess the activity and safety of topotecan (1mg/sqm iv d1–5) plus gemcitabine (1250 mg/sqm iv d1) in relapsed or recurrent SCLC patients. Treatment is repeated every 4 weeks, up to a maximum of 6 cycles. Eligibility criteria: histologically or cytologically confirmed SCLC; documented progressive disease after ≥ 1 chemotherapy regimen; age ≥ 18 yrs; ECOG PS 0–2; measurable disease (RECIST); no prior treatment with topotecan or gemcitabine; adequate hematologic, hepatic and renal function; brain metastases are allowed. Results: A total of 44 patients have been enrolled. Patient characteristics are as follows: median age, 64 yrs (range 35–77); male/female, 35/9; ECOG PS 0/1/2, 12/21/11 patients; 68% patients had sensitive disease (recurrence > 3 months after first-line chemotherapy) and 32% patients had refractory disease (failure ≤3 months after first-line chemotherapy). One-hundred and seventeen chemotherapy courses have been administered (median 2, range 1–6). The following preliminary results refer to 37 patients. Grade 3–4 toxicities: 54% neutropenia, 16% anemia, 46% thrombocytopenia, 13% neutropenic fever, 27% fatigue. One toxic death was observed. Objective responses have been documented in 9 patients, for an overall response rate of 24% (3% CR, 21% PR); SD was observed in 7 patients (19%), PD in 17 patients (46%). Four early deaths were reported. Median time to progression is 8.9 weeks. Median survival time is 16.3 weeks, and 1-year survival rate is 14%. Conclusions: Based on these preliminary results, the combination of topotecan plus gemcitabine shows moderate activity and an acceptable toxicity profile in previously treated SCLC patients. However, it is unlikely that the addition of gemcitabine improves the outcome compared to single agent topotecan. No significant financial relationships to disclose.

Aims and background: Rarely are conclusions from clinical trials summarized in international consensus conferences and promptly transferred to patient care. The adjuvant therapy for colorectal cancer used in daily clinical practice in Italy is described and compared with the recommendations of the 1990 NIH Consensus Conference.Patients and methods: We audited prescriptions of adjuvant systemic therapies for Italian colorectal cancer patients in 82 centers during a fixed one-week period.Results: Among 434 patients receiving adjuvant chemotherapy there were 139 (42.5%) colon cancer patients with N- and 169 (51.7%) with N+ regional nodal involvement. Treatment at academic centers, a young age, T4 and a low total number of lymph nodes removed at surgery were the factors potentially justifying the decision for adjuvant chemotherapy in stage II colon cancer patients. The most common chemotherapy used was a bolus of 5-fluorouraci/fiolinic acid for 6 months (75.8%). Adjuvant radiotherapy was not administered to 37 (38.5%) of 96 patients with stage II and III rectal cancer.Conclusions: The study shows that a substantial proportion of patients on adjuvant treatment at a certain time point in a large enough sample of Italian centers are stage II (potential over-treatment) and that an under-treatment of stage II and III rectal cancer patients (lack of radiotherapy) occurs too often in daily clinical practice in this country.

Aim of this study was to determine the activity and toxicity of a sequential chemotherapy regimen in advanced non-small cell lung cancer (NSCLC). Fifty-one previously untreated stage IIIB/IV NSCLC patients were enrolled to receive two cycles of cisplatin plus paclitaxel (80/175 mg/m2 every 21 days), followed by two cycles of vinorelbine (30 mg/m2 on days 1 and 8 every 21 days), followed by two cycles of gemcitabine (1000 mg/m2 on days 1, 8, and 15 every 28 days). Forty-one patients (82%) completed the planned six cycles. Grade 3–4 neutropenia was the major toxicity (41% of patients) and it was mainly associated with vinorelbine administration. Response rate after cisplatin plus paclitaxel was 18%; this percentage increased to 41% after vinorelbine, and it reached 43% upon completion of the entire six cycle treatment program. Median survival time was 14.4 months, 1-year survival rate was 53%, and 2-year survival rate was 18%. Median time to disease progression was 6.8 months. This sequential chemotherapy regimen is feasible and active in patients with advanced NSCLC. This pilot experience provides the basis for an ongoing randomized phase III trial comparing our sequential regimen versus cisplatin plus gemcitabine.

7363 Background: Two phase III trials have demonstrated an improvement in survival with docetaxel compared to other single-agents or best supportive care in previously treated NSCLC patients. Still, the combination of docetaxel with another active agent may be feasible and provide further improvement. In vitro studies have demonstrated the synergistic cytotoxicity of irinotecan followed by docetaxel; previous phase I/II studies have assessed the feasibility of this combination in several tumor types. Methods: In this multicenter phase II study, we evaluated the activity and toxicity of irinotecan (160 mg/sqm iv d1) plus docetaxel (65 mg/sqm iv d1) in relapsed or progressing NSCLC patients. Cycles were repeated every 3 weeks up to a maximum of 6 courses. Eligibility criteria: age ≥ 18 yrs; ECOG PS 0–2; measurable disease (RECIST); no prior treatment with irinotecan or docetaxel; adequate hematologic, hepatic and renal function; brain metastases allowed. The impact of treatment on quality of life and tumor-related symptoms was assessed by the EORTC questionnaires QLQ-C30 and LC-13. Results: Thirty-nine patients have been enrolled. Patient characteristics: median age, 61 yrs (46–73); male/female, 29/10; ECOG PS 0/1/2, 13/20/6 patients; adenocarcinoma 36%, squamous cell carcinoma 31%; previous platinum-based treatment, 95%; previous paclitaxel-containing treatment, 46%. One-hundred and sixteen cycles have been given (median 2, range 1–6). Thirty-seven patients are evaluable for toxicity. Grade 3–4 toxicities include 59% neutropenia, 10% anemia, 24% neutropenic fever, 32% diarrhea; 16% nausea/vomiting, 16% fatigue. There has been PR in 3 patients (8%); SD in 11 patients (30%); PD in 13 patients (35%). Median time to progression is 2.7 months; median survival (MST) is 8.4 months. Compliance with quality of life assessment is high (79%). Conclusions: The combination of irinotecan and docetaxel has an acceptable toxicity profile in previously treated NSCLC patients. Although response rate is low, disease stabilization occurred in 30% of patients and an encouraging MST has been observed. No significant financial relationships to disclose.

Surgery with or without adjuvant radiotherapy (RT) is the standard treatment of esophageal cancer. Preoperative radio- and chemotherapy (CT) have been introduced to improve prognosis. We report a phase II prospective non-randomized trial of preoperative RT (42 Gy/25) plus CT (cisplatin 20 mg/mq/day plus 5-fluorouracil 600 mg/mq/day, 1-5 weeks) for the treatment of thoracic esophageal cancer. From 1993, 50 patients were enrolled (40 men and 10 women, mean age 57 years, range 30-75 years). Squamous cell carcinoma accounted for 90% of cases; 10% were adenocarcinoma. Downstaging of the disease was obtained in 77.3% of cases; there were 13 (29.5%) complete responses (CR) and 21 (47.7%) partial responses (PR). Median survival was 28 and 25 months, respectively, for CR and partial response (PR) plus stable disease (SD) and progressive disease (PD) (P = 0.05). Progressive-free median survival was 22 and 17 months, respectively, for CR and PR + SD + PD (P = 0.08). Multimodal treatment of esophageal cancer showed promising results, although not significant, in terms of survival and disease progression for patients achieving a complete pathologic response.

The combination of cisplatin (CDDP 100 mg/m2 on day 1) and 5-fluorouracil (5-FU 1,000 mg/m2 continuous intravenous (i.v.) infusion days 1-5) is the most widely used chemotherapy regimen for the treatment of advanced head and neck carcinomas, with a response rate of 70-90% but with a survival and a duration of response which are not impressive. Most patients relapse in < or = 2 years and die of cancer. We evaluated the activity of a CDDP (90 mg/m2 on day 1), 5-FU (900 mg/m2/120 h continuous i.v. infusion from day 1), and mitomycin C (MMC 6 mg/m2 on day 1) regimen in advanced or recurrent head and neck squamous cell carcinoma (HNSCC). Fifty-six patients were treated and evaluated for response and toxicity: 5 (9%) complete responses (CR) and 36 (64%) partial responses, (PR) were observed (response rate 73%). The median duration of response was 12 months, and median survival was 15 months. At a median follow-up of 14 months, the estimated overall survival at 1 year was 65%; at 2 years, it was 35%. Grade 3-4 toxicity was noted in 14 patients, mostly hematologic; overall toxicity required a dose-intensity decrease in 20.2% of all cycles. No treatment-related deaths occurred. The regimen showed a good response rate and an encouraging median duration of response with a good tolerability profile.

Twenty three patients (18 males) were followed from January 1993 to July 1996 for primary central nervous system malignancy: glioblastoma multiforme (GM) (15 patients), anaplastic astrocytoma (AA) (8 patients). Ninety one cycles (average 4 cycles per patient) of intraarterial chemotherapy (IACH) were administered. The IACH included: Carboplatin (CBP) 250 mg/m2 and Vepesid (VP16) 150 mg/m2 infusion; both drugs in normal saline, 100 ml and 250 ml, were infused over 15 and 30 min respectively. IACH was repeated every two weeks four or six times according to response to chemotherapy. IACH was preceded by i.v. methylprednisolone 40mg and pure anti-emetic (5HT3 serotonin uptake inhibitors) and subcutaneous daily doses of G-CSF following IACH to prevent neutropenia. The whole treatment required a 24h hospital admission. The IACH was well-tolerated and toxicity (Miller's grade, WHO) included: two cases of reversible pulmonary embolism (8.6%) three and ten days respectively after therapy (one patient had atrial fibrillation, two cases grade 2 vomiting, two grade 1 anaemia and three grade 3 thombocytopenia (13%). Response to therapy was evaluated in 21 out of 23 patients, two having not yet received at least four IACH cycles: 4 PRO (3 GM, 1 AA), 15 SD (10 GM, 5 AA) and 2 PR (AA). Seventeen patients responded to IACH (SD + RO) (74%), and the PRs belonged to the AA group. Survival duration was from 16 + to 108 weeks. IACH with CP and VP16 warrants further studies focussing on drug dose and schedule. A prospective randomized multicentric trial evaluating radiotherapy and systemic chemotherapy plus/minus IACH is currently underway.

Proionged exposure to 5-fluorouracil (5-FU) is effective for gastrointestinal mallgnancy (GIM) and it is considered synergistic or additive to concurrent radiotherapy. Oral 5-FU (OF) could represent an easy therapy. The present study prospectively tested the toxicity and effectiveness of OF in GIM by means of 5-FU mannitol-coated tabiets (MCT) at 275 or 225 mg/m2/day according to the patients age (65 years cut-off) for a period of 4 weeks every 7 weeks. Also the drug given over 5 days a week for 4 weeks was studied to assess OF toxicity over a time corresponding to that used in standard radiotherapy. Quality of life (LQ) was analyzed. Patients were 27 Individuals (20 males), aged 43–70 years, pretreated with radiotherapy (four patients) or I.v. 5-FU-based chemotherapy (five patients), and with progressive malignancy of colorectum (six patients), stomach (five patients), pancreas (four patients) and liver (two patients). The total number of cycles was 91 and 16 patients had more than two cycles. Myelotoxicity was consistently absent; other toxicities greater than WHO grade 1 were: nausea (grada 2 in four patients), diarrhes (grade 2 in six and grade 3 in 11), palmar erithema (grade 2 in one), brown-turning skin (grade 2 in one) and CNS (grade 2 in one). Diarrhea was less frequent (p=0.007) in gastric and in colorectal than in pancress and liver cancer patients. in the 10 patients given the drug of 5 days a week, diarrhea was practically absent. LQ was above 90%. Fourteen patients (51%) had total arrest of disease, and 2 among 16 colorectal cancer patients had PR (12.5%). in conclusion, the MCT-OF was tolerated and as effective as the classic i.v. 5-FU at non-myelosuppressive dose. The MCT-OF dose recommended for further studies is 275 mg/m2/day (or 225 above 65 years) for 4 weeks followed by a 2 week rest period.

The synthetic pentapeptide (Arg-Lys-Asp-Val-Tyr; TP-5) corresponding to the active site of the hormone thymopoietin, was given at the dose of 300 mg/m2/day (1 day), higher than the usually administered, to a group of 27 immunodepressed patients in order to determine the tolerability and the immunomodulatory activity. The examination of a series of hematological parameters including counts of differential clustering of lymphocytes by cytofluorimetric analysis was performed 24 hr and 48 hr after treatment, and repeated at different intervals up to 14 days after treatment. TP-5 caused a significant increase of circulating lymphocytes and particularly of CD3+CD4+ and CD3+CD8+ subtypes, peaking at 48 hr and maintaining the increased values up to the last examination on day 14 from treatment. A faster increase (zenith at 24 hr) was observed for CD4+ cells, in comparison with CD8+ cells (zenith at 48 hr). The number of patients that increased total lymphocytes or lymphocyte subset after treatment ranged between 52.6 (CD4+ cells) and 69.2% (NK cells), whereas about 7.7% (NK cells) to 36.9% (CD4+ cells) remained unchanged and a smaller amount of 10.5% (CD4+ and CD8+ cells) or 23.1% (NK cells) showed a decrease greater than 10% of their respective basal value. No significant relationship between responders and non-responders can be found on the basis of previous treatments, cancer type, sex or age.

Cancer of the ovary is the fifth cause of cancer death in women, and the majority of patients have advanced stage disease at the time of presentation [1]. Clinical responses can be achieve with current regimens in over half of patients but only a minority enjoy prolonged disease free survival [2]. Consequently there is a need for innovative strategies to improve the prognosis in advanced stage patients. We have treated 52 consecutive patients, since September ‘87, with advanced ovarian cancer, utilizing a combination regimen based on the association between CTX and high-dose EPI-ADM in delayed administration.