Modulation of 5-fluorouracil as adjuvant systemic chemotherapy in colorectal cancer: the IGCS-COL multicentre, randomised, phase III study.

The aims of this multicentre, randomised phase III trial were to evaluate: (1) the role of levamisol (LEV); and (2) the role of folinic acid (FA), added to 5-fluorouracil (5FU) in the adjuvant treatment of colorectal cancer. Patients with histologically proven, radically resected stage II or III colon or rectal cancer were eligible. The study had a 2x2 factorial design with four treatment arms: (a) 5FU alone, (b) 5FU+LEV, (c) 5FU+FA, (d) 5FU+LEV+FA, and two planned comparisons, testing the role of LEV and of FA, respectively. From March 1991, to September 1998, 1327 patients were randomised. None of the two comparisons resulted in a significant disease-free (DFS) or overall (OAS) survival advantage. The hazard ratio (HR) of relapse was 0.89 (95% confidence intervals (CI): 0.73-1.09) for patients receiving FA and 0.99 (95% CI 0.80-1.21) for those receiving LEV; corresponding HRs of death were 1.02 (95% CI: 0.80-1.30) and 0.94 (95% CI 0.73-1.20). Nonhaematological toxicity (all grade vomiting, diarrhoea, mucositis, congiuntivitis, skin, fever and fatigue) was significantly worse with FA, while all other toxicities were similar. In the present trial, there was no evidence that the addition of FA or LEV significantly prolongs DFS and OAS of radically resected colorectal cancer patients.

Phase II study of sequential hormonal therapy with anastrozole/exemestane in advanced and metastatic breast cancer.

Hormonal therapy is the preferred systemic treatment for recurrent or metastatic, post-menopausal hormone-receptor-positive breast cancer. Previous studies have shown that there is no cross-resistance between exemestane and reversible aromatase inhibitors. Exposure to hormonal therapy does not hamper later response to chemotherapy. Patients with locally advanced or metastatic, hormonal receptor positive or unknown, breast cancer were treated with oral anastrozole, until disease progression, followed by oral exemestane until new evidence of disease progression. The primary end point of the study was clinical benefit, defined as the sum of complete responses (CR), partial responses (PR) and > 24 weeks stable disease (SD). In all, 100 patients were enrolled in the study. Anastrozole produced eight CR and 19 PR for an overall response rate of 27% (95% CI: 18.6-36.8%). An additional 46 patients had long-term (> 24 weeks) SD for an overall clinical benefit of 73% (95% CI: 63.2-81.4). Median time to progression (TTP) was 11 months (95% CI: 10-12). A total of 50 patients were evaluated for the second-line treatment: exemestane produced one CR and three PR; 25 patients had SD which lasted > or = 6 months in 18 patients. Median TTP was 5 months. Toxicity of treatment was low. Our study confirms that treatment with sequential hormonal agents can extend the period of time during which endocrine therapy can be used, thereby deferring the decision to use chemotherapy.

Prevalence and management of pain in Italian patients with advanced non-small-cell lung cancer.

Pain is a highly distressing symptom for patients with advanced cancer. WHO analgesic ladder is widely accepted as a guideline for its treatment. Our aim was to describe pain prevalence among patients diagnosed with advanced non-small-cell lung cancer (NSCLC), impact of pain on quality of life (QoL) and adequacy of pain management. Data of 1021 Italian patients enrolled in three randomised trials of chemotherapy for NSCLC were pooled. QoL was assessed by EORTC QLQ-C30 and LC-13. Analgesic consumption during the 3 weeks following QoL assessment was recorded. Adequacy of pain management was evaluated by the Pain Management Index (PMI). Some pain was reported by 74% of patients (42% mild, 24% moderate and 7% severe); 50% stated pain was affecting daily activities (30% a little, 16% quite a bit, 3% very much). Bone metastases strongly affected presence of pain. Mean global QoL linearly decreased from 64.9 to 36.4 from patients without pain to those with severe pain (P<0.001). According to PMI, 616 out of 752 patients reporting pain (82%) received inadequate analgesic treatment. Bone metastases were associated with improved adequacy and worst pain with reduced adequacy at multivariate analysis. In conclusion, pain is common in patients with advanced NSCLC, significantly affects QoL, and is frequently undertreated. We recommend that: (i). pain self-assessment should be part of oncological clinical practice; (ii). pain control should be a primary goal in clinical practice and in clinical trials; (iii). physicians should receive more training in pain management; (iv). analgesic treatment deserves greater attention in protocols of anticancer treatment.

Supportive care in patients with advanced non-small-cell lung cancer.

The present study describes supportive care (SC) in patients with advanced non-small-cell lung cancer (NSCLC), evaluating whether it is affected by concomitant chemotherapy, patient's performance status (PS) and age. Data of patients enrolled in three randomised trials of first-line chemotherapy, conducted between 1996 and 2001, were pooled. The analysis was limited to the first three cycles of treatment. Supportive care data were available for 1185 out of 1312 (90%) enrolled patients. Gastrointestinal drugs (45.7%), corticosteroids (33.4%) and analgesics (23.8%) were the most frequently observed categories. The mean number of drugs per patient was 2.43; 538 patients (45.4%) assumed three or more supportive drugs. Vinorelbine does not produce substantial variations in the SC pattern, while cisplatin-based treatment requires an overall higher number of supportive drugs, with higher use of antiemetics (41 vs 27%) and antianaemics (10 vs 4%). Patients with worse PS are more exposed to corticosteroids (42 vs 30%). Elderly patients require drugs against concomitant diseases significantly more than adults (20 vs 7%) and are less frequently exposed to antiemetics (12 vs 27%). In conclusion, polypharmacotherapy is a relevant issue in patients with advanced NSCLC. Chemotherapy does not remarkably affect the pattern of SC, except for some drugs against side effects. Elderly patients assume more drugs for concomitant diseases and receive less antiemetics than adults.

Adjuvant chemotherapy in gastric cancer: 5-year results of a randomised study by the Italian Trials in Medical Oncology (ITMO) Group.

BACKGROUND: The aim of this study was to determine the efficacy of the EAP regimen (etoposide, adriamycin and cisplatin) followed by the Machover schedule (fluorouracil and folinic acid) given as adjuvant treatment to patients with poor prognostic factors (N+ or T3/4). PATIENTS AND METHODS: Before randomisation, the subjects were stratified on the basis of node involvement (N+ or N-) and the time from surgery to randomisation (< or = 21 days or > 22 days). The surgical procedures for sub-total or total gastrectomy with D2 dissection were standardised among the participating centres. RESULTS: Between December 1992 and December 1997, 274 patients were enrolled: 137 in the treatment arm and 137 in the control arm. The majority of the patients (90%) were N+. After a median follow up of 66 months (range 2-83), the 5-year overall survival (OS) was 52% in the treatment arm and 48% in the control arm [hazard ratio (HR) 0.93; 95% confidence interval (CI) 0.65-1.34]; the 5-year disease-free survival (DFS) was 49% and 44%, respectively (HR: 0.83; 95% CI 0.59-1.17). Among the patients with N-/N+ (1-6), the 5-year OS was 61% in the treatment group and 60% in the control group; in those with N+ (1-6), it was 42% and 22%. The treatment was completed by 87% of patients. Drug-related grade 3/4 WHO toxicities included leukopenia (21%), nausea and vomiting (14%), mucositis (9%), neutropenia (3%) and thrombocytopenia (2%). There were two deaths due to sepsis. CONCLUSIONS: Although our results are not statistically significant, there was a limited relative risk reduction in the patients receiving adjuvant therapy (17% in DFS and 7% in OS). The data suggest that D2 surgery may have a favourable impact on OS.

Gemcitabine plus epirubicin in advanced pancreatic cancer: a phase II multicenter trial.

The aim of this phase II multicenter trial was to evaluate the activity of a novel combination of gemcitabine (GEM) and epirubicin (EPI) in advanced pancreatic cancer patients. Clinical benefit and response rate were the main efficacy end-points. From December 1997 to October 1999, 30 consecutive patients with measurable advanced pancreatic cancer were enrolled. Gemcitabine was administered intravenously in 30 min at a dose of 800 mg/m2 on days 1, 8, 15 followed by i.v. injection of epirubicin 25 mg/m(2); treatment was repeated every 28 days. With regard to clinical benefit response, 8/21 patients (38%) experienced significant palliation of tumor-related symptoms; the median symptom control time was 25 weeks. No complete responses were recorded while 6 patients achieved a partial remission, for an overall response rate of 20%; 10 patients (30%) had a stable disease and 14 (46%) had progressive disease. The median time to progression was 14 weeks. Median survival was 26 weeks, with 6 patients (20%) having long-term survival at 46 weeks. In general, chemotherapy was well tolerated; 9 patients (30%) suffered from WHO grade 3-4 haematological toxicity and 5 patients (16.6%) suffered from grade 3 non-haematological toxicity. In conclusion, the GEM plus EPI regimen represent a feasible approach for improvement of clinical benefit in advanced pancreatic cancer patients, but confirmatory investigations are required.

Activity and toxicity of gemcitabine and gemcitabine + vinorelbine in advanced non-small-cell lung cancer elderly patients: Phase II data from the Multicenter Italian Lung Cancer in the Elderly Study (MILES) randomized trial.

BACKGROUND: Following the demonstration that vinorelbine improves survival and quality of life compared with best supportive care in elderly patients with advanced non-small-cell lung cancer (NSCLC), we started the three-arm prospective Multicenter Italian Lung Cancer in the Elderly Study (MILES) trial of vinorelbine, gemcitabine and gemcitabine + vinorelbine. DESIGN: Within the randomized phase 3 trial, pilot single-stage phase 2 studies were planned for gemcitabine and for gemcitabine + vinorelbine. Eligible patients are aged 70 or more, with stage IV or IIIb (with metastatic supraclavear nodes or malignant pleural effusion) NSCLC. Single-agent gemcitabine is given at 1200 mg/m(2) on days 1 and 8; in the combination, gemcitabine is given at 1000 mg/m(2) and vinorelbine at 25 mg/m(2), both on days 1 and 8, every 3 weeks. RESULTS: As planned 49 patients were enrolled in each group. Median age was 74 in both groups. Two-thirds of patients had stage IV disease. The response rate was 18.4% (95% exact CI 8.8-32.0) with both treatments. With single-agent gemcitabine main toxicities were grade 4 thrombocytopenia and grade 2 hepatic toxicity, in one patient each, and grade 2 pulmonary toxicity in two patients. With gemcitabine + vinorelbine combination there were grade 4 neutropenia and thrombocytopenia (one patient each), grade 3 anemia requiring red blood cell transfusion (two patients), and grade 4 fever in two patients. Four patients, with severe cardiac comorbidities, suffered grade 3 heart toxicity with atrial flutter or fibrillation, followed by congestive heart failure responsive to treatment. CONCLUSION: Both single-agent gemcitabine and the gemcitabine + vinorelbine combination are sufficiently active and tolerable to allow continuation of the MILES study.

Biweekly irinotecan or raltitrexed plus 6S-leucovorin and bolus 5-fluorouracil in advanced colorectal carcinoma: a Southern Italy Cooperative Oncology Group phase II-III randomized trial.

PURPOSE: The aim of this randomised trial was to evaluate the activity and toxicity of a biweekly regimen including 6S-leucovorin-modulated 5-fluorouracil (LFA-5-FU), combined with either irinotecan (CPT-11 + LFA 5-FU) or raltitrexed (Tomudex) (TOM + LFA-5-FU), in advanced colorectal cancer patients, and to make a preliminary comparison of both these experimental regimens with a biweekly administration of LFA-5-FU modulated by methotrexate (MTX + LFA-5-FU). PATIENTS AND METHODS: One hundred fifty-nine patients with advanced colorectal carcinoma previously untreated for the metastatic disease (34 of them previously exposed to adjuvant 5-FU) were randomly allocated to receive: CPT-11, 200 mg/m2 i.v. on day 1, followed on day 2 by LFA, 250 mg/m2 i.v. infusion and 5-FU, 850 mg/m2 s i.v. bolus (arm A); TOM, 3 mg/m2 i.v. on day 1, followed on day 2 by LFA, 250 mg/m2 i.v. infusion and 5-FU, 1050 mg/m2 i.v. bolus (arm B); or MTX, 750 mg/m2 i.v. on day 1, followed on day 2 by LFA, 250 mg/m2 i.v. infusion and 5-FU, 800 mg/m2 i.v. bolus (arm C). Courses were repeated every two weeks in all arms of the trial. Response rate (RR) was evaluated after every four courses. The sample size was defined to have an 80% power to detect a 35% RR for each experimental treatment, and to show a difference of at least 4% in RR with the standard treatment if the true difference is 15% or more. RESULTS: The RRs were: 34% (95% confidence interval (95%, CI): 21%-48%) in arm A, including 3 complete responses (CRs) and 15 partial responses (PRs), 24% (95% CI: 14%-38%) in arm B, including 2 CRs and 11 PRs, and 24% (95% CI: 14%-38%), with 2 CRs and 11 PRs, in arm C. After a median follow-up time of 62 (range 18-108) weeks, the median time to progression was 38, 25, and 27 weeks for arm A, B, and C, respectively. With 94 patients still alive, the one-year probability of survival was 61%, 54%, and 59%, respectively. WHO grade 3 or 4 neutropenia and diarrhoea affected 46% and 16%, respectively, of patients treated with CPT-11 + LFA 5-FU. Median relative dose intensity over eight cycles (DI8) was 78% for CPT-11 and 82% for 5-FU. Severe toxicities of TOM + LFA-5-FU were neutropenia (16%) and diarrhoea (16%), but median relative DI8 was 93% for TOM, and 82% for 5-FU. CONCLUSIONS: CPT-11 + LFA-5-FU compares favorably in term of activity and toxicity with other combination regimens including CPT-11 and continuous infusional 5-FU. The hypothesis of a RR 15% higher than the MTX + LFA-5-FU treatment can not be ruled out after this interim analysis. The TOM + LFA 5-FU regimen showed a RR and a toxicity profile very close to the MTX + LFA 5-FU combination, and dose not deserve further evaluation in advanced colorectal cancer patients.

Gemcitabine plus vinorelbine in advanced non-small cell lung cancer: a phase II study of three different doses. Gem Vin Investigators.

Our aim was to study the activity and toxicity of the gemcitabine plus vinorelbine (Gem Vin) combination and to identify the optimal dose. Previously untreated patients aged < 70 years, with stage IV or IIIb (not candidates for radiotherapy) non-small cell lung cancer were eligible. Studied dose-levels of Gem Vin, administered on days 1 and 8 every 3 weeks, were (mg m(-2)): level I = 1000/25; level II = 1200/25; level III = 1000/30; level IV = 1200/30. A feasibility study was performed at each dose-level, followed by a single-stage phase II study. Dose-level IV was unfeasible because of grade 4 neutropenia. Overall, out of 126 patients enrolled in phase II studies, there were one complete and 32 partial responses (response rate 26%: 95% CI 18-34%). Response rates were 27.9%, 21.4% and 29.3% at levels I, II and III, respectively. The treatment was well tolerated. Toxicity was less frequent and severe at level I. Overall median survival was 33 weeks (95% CI 28-40). Descriptive quality of life analysis showed that patients with a worse baseline global health status score tended to drop out of the study earlier than those with a better score. Gem Vin is feasible at different doses. It is sufficiently active and well tolerated. A phase III study to compare the effect on quality of life of Gem Vin (level I) vs cisplatin-based chemotherapy is ongoing.

Amifostine plus cisplatin plus vinorelbine in the treatment of advanced non small cell lung cancer: a multicenter phase II study.

PURPOSE: to evaluate the activity and toxicity of the combination cisplatin plus vinorelbine plus amifostine in advanced non small cell lung cancer (NSCLC). PATIENTS AND METHODS: a two-stage Simon design was applied. To proceed after the first stage, responses from seven of 19 patients were needed. Overall, 17 responses from 40 treated patients were required to comply with the design parameter. Inclusion criteria were cyto-histologically proven stage IIIB-IV NSCLC; age of 70 years or less; Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less; normal cardiac, hepatic, renal and bone marrow functions; and no previous chemotherapy. Patients were staged by physical examination, biochemistry, chest radiograph, brain, thoracic and abdominal computed tomographic (CT) scans, and bone scan. All patients received cisplatin 100 mg/m(2) intravenously (iv) day 1, vinorelbine 25 mg/m(2) iv days 1-8-15-22, amifostine 740 mg/m(2) iv day 1 every 4 weeks up to six cycles. Eleven of 40 enrolled patients were stage IIIB and 29 stage IV, with a median age of 57 years (range, 38-70 years). RESULTS: all patients were evaluable for response and toxicity (intention to treat analysis). We observed 20 (50%) objective responses, with four (10%) complete responses. Median time to progression was 20 weeks, and median survival was 45 weeks. The toxicity was manageable. The reported main toxicities were neutropenia grade 4 in 10% of patients, grade 1 and grade 3 nephrotoxicity both in 5% of patients and grade 1 amifostine-related hypotension in 15% of patients. CONCLUSION: these data show that cisplatin plus vinorelbine plus amifostine is an active and feaseable regimen in stage IIIB-IV NSCLC. A phase III trial comparing cisplatin plus vinorelbine versus cisplatin plus vinorelbine plus amifostine in advanced NSCLC is warranted.

FEP regimen (epidoxorubicin, etoposide and cisplatin) in advanced gastric cancer, with or without low-dose GM-CSF: an Italian Trial in Medical Oncology (ITMO) study.

The new regimens developed over the last few years have led to an improvement in the treatment of advanced gastric cancer, and our previous experience confirmed the fact that the combination of etoposide, doxorubicin and cisplatin (EAP regimen) is an active treatment that leads to interesting complete remission rates. The primary end point of the present multicentre, randomized, parallel-group phase II study was to determine the activity of the simplified 2-day EAP schedule in patients with locally advanced or metastatic gastric cancer, and to verify whether the addition of low doses of granulocyte-macrophage colony-stimulating factor (GM-CSF) made it possible to increase dose intensity. Of the 62 enrolled patients, 30 were randomized to receive epirubicin 35 mg m(-2), etoposide 120 mg m(-2) and cisplatin 45 mg m(-2) (FEP) on days 1 and 2 every 28 days and 32 to receive the same schedule plus subcutaneous GM-CSF (molgramostin) 150 microg day(-1) on days 5-14 every 21 days. The patients were stratified by age and the number of disease sites. The characteristics of the patients were well balanced between the two groups. The objective response rate of the patients as a whole was 34% (21 out of 62; 95% confidence interval 22-46), with only one complete remission. The median response duration was 4.5 months (range 1-24 months). The median time to treatment failure was 5 months (range 1-14 months), without any difference between the two groups. The median survival of the patients as a whole was 9 months. Full doses were administered in 92% and 94% of the cycles in the control and GM-CSF arms respectively. The average dose intensity calculated for all drugs was 0.96% in the control and 1.27% in the GM-CSF group. CTC-NCI grade 3-4 neutropenia was reported in 39% vs 45% of patients, thrombocytopenia in 11% vs 35% (P = 0.020) and anaemia in 7% vs 35% (P = 0.014). The FEP combination is as active (OR: 34%) in the treatment of patients with advanced gastric cancer as the EAP regimen, although it leads to fewer complete remissions. The patients randomized to receive low-dose GM-CSF achieved a significantly higher dose intensity than controls (P = 0.0001).

Carboplatin plus vinorelbine, a new well-tolerated and active regimen for the treatment of extensive-stage small-cell lung cancer: a phase II study. Gruppo Oncologico Centro-Sud-Isole.

PURPOSE: To evaluate the activity and toxicity of the combination carboplatin plus vinorelbine in extensive small-cell lung cancer (SCLC). PATIENTS AND METHODS: A two-stage optimal Simon design was applied. To proceed after the first stage, responses from 8 of 11 treated patients were needed. Overall, 31 responses of 43 treated patients were required to comply with the design parameters. Inclusion criteria were cytohistologically proven SCLC; extensive disease; age of 70 years or less; Eastern Cooperative Oncology group performance status (ps ECOG) of 2 or less; normal cardiac, hepatic, renal, and bone marrow functions; and no previous chemotherapy. Patients were staged by physical examination; biochemistry; chest radiograph; brain, thoracic; and abdominal computed tomographic (CT) scans, and bone scan. All patients received carboplatin 300 mg/m2 intravenously (i.v.) day 1 and vinorelbine 25 mg/m2 i.v. on days 1 and 8 every 4 weeks up to six cycles. Of 43 enrolled patients, 36 were men and 7 women, with a median age of 63 years (range, 46 to 70 years). RESULTS: All patients were assessable for response and toxicity. We observed 32 (74%) objective responses, with 23% complete responses. Median time to progression was 25 weeks, and median survival was 37 weeks. The treatment was well tolerated. The reported main toxicities were leukopenia grade 3 in 21% of patients and grade 4 in 5% of patients, anemia grade 2 in 11% of patients and grade 3 in 2% of patients, and thrombocytopenia grade 3 in 7% of patients. CONCLUSION: These data show that carboplatin plus vinorelbine is an active and well-tolerated regimen in extensive SCLC. In view of the activity, low toxicity, and ease of administration, it may be a reasonable alternative to more toxic cisplatin-containing regimens.

Thyroid metastases from a ductal carcinoma of the breast. A case report.

A case of bilateral thyroid metastases from ductal carcinoma of the breast is presented with emphasis on some unusual clinical findings: presentation after a long disease-free interval; clinical signs mimicking an acute thyroiditis; cystic structure of the left-sided metastatic nodule. Fine needle aspiration cytology from both nodules showed highly atypical tumor cells, such as to warrant a differential diagnosis between metastatic breast cancer on the one hand and anaplastic and medullary carcinoma of the thyroid on the other. Immunophenotypic study of the neoplasm on a cell block preparation of the aspirated material showed negativity for both thyroglobulin and calcitonin; instead, the tumor cells were strongly stained with antibodies against the "breast-related" markers alpha-lactalbumin and gross cystic disease fluid protein-15. Therefore, immunochemistry allowed us to establish a definite diagnosis of metastatic breast disease of the thyroid, thereby avoiding surgical procedures.

Vinorelbine is well tolerated and active in the treatment of elderly patients with advanced non-small cell lung cancer. A two-stage phase II study.

More than 30% of lung cancers arise in patients aged 70 years or more; however, because elderly patients are not considered to tolerate chemotherapy, they are generally excluded from clinical trials and are not considered eligible for aggressive cisplatin-based chemotherapy in clinical practice. The aims of the present study were to test tolerability and activity of weekly vinorelbine in advanced non-small cell lung cancer (NSCLC) patients aged 70 years or more, and to define whether minimum conditions existed for a randomised comparison with best supportive care. The study was designed as a multicentre two-stage phase II trial according to Simon's optimal design: 8 or more responses out of 43 treated patients were expected at the end of the trial. Patients aged 70 years or more were eligible if they had a cytological or histological diagnosis of NSCLC at stage IIIb-IV and a performance status less than or equal to two according to the ECOG scale. Vinorelbine was given intravenously (i.v.) at a dose of 30 mg/m2 every week for 12 doses. As planned, 43 patients entered the study; median age was 73 years (range 70-80); 11 patients were older than 75 years. Median dose-intensity (mg/m2/week) of vinorelbine was 21.2 (range 7.5-30) and was not affected by age of patients. Toxicity was generally mild, mainly haematological and never life-threatening. ECOG performance status improved in 26% of patients; cough and pain improved in more than 40% of patients symptomatic at entry, while dyspnoea improved in 28%; approximately half the patients had a stabilisation of their symptoms. 10 patients (23-95% exact confidence interval (CI): 12-39%) obtained a partial response. Median time to progression was 11 weeks (95% CI 8-30) and median survival 36 weeks (95% CI 28-53). One-year estimated progression-free and overall survival rates are 16% and 36%, respectively. In conclusion, vinorelbine was well tolerated and active in the treatment of elderly NSCLC patients. A phase III trial (ELVIS-Elderly Lung Cancer Vinorelbine Italian Study) comparing best supportive care versus best supportive care plus vinorelbine is now ongoing.

Lymph node Merkel cell carcinoma with no evidence of cutaneous tumor--report of two cases.

We report two cases of Merkel cell carcinoma within inguinal and axillary lymph nodes, respectively, showing no clinico-pathologic evidence of a primary (extranodal) tumor; one of our patients was alive with no evidence of disease five years and ten months after the surgical excision of the neoplasm with no postoperative chemotherapy. The diagnosis of nodal Merkel cell carcinoma needs to be supported by a careful immunohistochemical study: in fact, cytokeratin- and neurofilament-positive paranuclear "dots", as well as epithelial antigens and neuroendocrine markers may be variably expressed in tumor cells, thus requiring the application of a complete antibody panel. In the presence of a nodal Merkel cell tumor, an exhaustive clinico-radiologic search for a primary tumor must be carried out. After the exclusion of any reasonable starting point of the neoplasm, a provisional diagnosis of "primary" nodal Merkel cell carcinoma may be acceptable; since a primary extracutaneous tumor is expected to follow a less aggressive course than a metastatic one, follow-up data may provide indications as to the truly extracutaneous origin of Merkel cell carcinoma.

A multicentre, double-blind, randomised trial comparing ondansetron versus ondansetron plus dexamethasone in the prophylaxis of cisplatin-induced delayed emesis.

The aim was to compare the efficacy of ondansetron and a combination of ondansetron plus dexamethasone in the prophylaxis of cisplatin-induced delayed emesis over three consecutive courses of chemotherapy. Cancer patients scheduled to receive for the first time cisplatin (>50 mg/m(2)) in combination with other cytotoxic agents, were recruited in a multicentre, randomised, double-blind study and treated with ondansetron 8 mg i.v. and dexamethasone 20 mg i.v. Twenty-four hours after the start of chemotherapy, patients were randomised to treatment either with oral ondansetron 8 mg bd plus placebo on days 2-5 (group A) or with oral ondansetron 8 mg bd plus oral dexamethasone 8 mg bd on days 2-3, and 4 mg bd on days 4 and 5 (group B). Two hundred and thirty-six cancer patients were recruited into the study. Complete protection from delayed vomiting/nausea in group A and group B was Obtained in 50/39% and in 63/42% of patients, respectively in the first course; in 55/34% and in 64/40% in the second and in 49/31% and 60/37% in the third. Logistic regression analysis reveals a statistically significant difference in incidence of emesis between the combination of ondansetron plus dexamethasone and ondansetron alone (P<0.05). The same model, however, shows no difference in incidence of nausea between the two treatment regimens. Ondansetron plus dexamethasone reduces the risk of delayed emesis following cisplatin chemotherapy as compared to ondansetron alone.

Cisplatin/carboplatin + etoposide + vinorelbine in advanced non-small-cell lung cancer: a multicentre randomised trial. Gruppo Oncologico Campano.

A multicentre randomised phase III trial in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC) was undertaken to compare the therapeutic activity and toxicity of a cisplatin/carboplatin-etoposide-vinorelbine combination with that of a cisplatin-etoposide regimen. Patients with advanced (stage IIIB-IV) NSCLC were randomised, after stratification for stage (IIIB-IV) and performance status (0-1 and 2), to receive either (A) CDDP 40 mg m-2 + VP16 100 mg m-2 on days 1-3 as standard treatment or (B) CBDCA 250 mg m-2 on day 1 + CDDP 30 mg m-2 on days 2 and 3 + VP16 100 mg m-2 on days 1-3 + NVB 30 mg m-2 on day 1. Therapy was recycled on day 29 in both arms. We hypothesised a 15% minimum increment in the response rate with the experimental regimen over the 25% expected activity rate of the standard regimen. A two-stage design was chosen, which permitted the early termination of the trial (after the accrual of 52 patients in each arm) if the difference in response rates between the two regimens was less than 3% at the end of the first stage. A total of 112 patients (arm A = 57, arm B = 55) were enrolled in the study (53 with stage IIIB and 59 with stage IV), of which 105 eligible patients were evaluable for response on an "intention to treat' basis. Seven patients were excluded because they did not fulfil the inclusion criteria. Fifteen responses were observed in arm A (28%, 95% CI = 17-42) and 13 (one complete) in arm B (25%, 95% CI = 13-37). On multivariate logistic analysis, treatment did not affect the response rate, while stage IV and performance status 2 were significantly associated with a lower probability of response. Median survivals were similar in the two arms (31 vs 27 weeks). The experimental regimen was associated with an extremely poor median survival in patients with poor performance status (21 weeks). On Cox analysis, treatment failed to show a significant impact on survival: stage IV (relative risk = 1.6. CI = 1.0-2.6, P = 0.036) was the only prognostic variable significantly associated with a worse survival outcome and, although poor performance status adversely affected survival, this effect did not reach the level of statistical significance (relative risk = 1.6, CI = 0.98-2.5; P = 0.063). There were no significant differences in non-haematological toxicities between the two arms, although three patients in the control arm had to discontinue the treatment because of the persistence of severe nephrotoxicity (two patients) or neurotoxicity (one patient). In contrast, a significant increase in both neutropenia and thrombocytopenia was observed in the experimental arm. Four treatment-related deaths were registered in arm B (two due to neutropenic sepsis, one to myocardial failure and one to acute renal failure) compared with one toxic death (acute renal failure) in arm A. In view of these results, the trial was stopped and the null hypothesis (< 15% increase in response rate with the experimental regimen) has been accepted. Therefore, our combination does not deserve further evaluation as first-line treatment in advanced NSCLC patients. As our data suggest that an aggressive chemotherapy might have a negative impact on survival of patients with poor performance status, trials to evaluate the activity of new regimens should be conducted separately for each subset of patients with different performance status.

[Repetitive movements of the upper limbs: results of exposure evaluation and clinical investigation in refinishing ceramic ornaments]. / Movimenti repetitivi degli arti superiori: risultati della valutazione dell'esposizione e dell'indagine clinica nella rifinitura di ceramiche artistiche.

An evaluation was made of the degree of exposure to risk and the frequency of disorders attributable to biomechanical overload of the upper limb in workers performing finishing operation on ceramic vases and cups in a ceramics factory. The risks were first evaluated against a checklist, then subsequently an assessment was made of the tasks found to feature the highest risks, using an ergonomic analysis method, which identified activities associated with a large number of actions per minute (> 50). The 22 female workers performing the tasks in question underwent a risk-targeted physical examination which included an electroneurographic test using surface electrodes. The clinical test detected an extremely high frequency of carpal tunnel syndrome cases, in addition to other upper limb disorders. In particular, nine female workers (41%) were found to be suffering from carpal tunnel syndrome, and five (22%) from other pathologies of the upper limbs (4 scapulo-humeral periarthritis, 1 epicondylitis). As a result of the findings arising out of this study, immediate preventive measures were adopted; moreover, it has become evident that further epidemiological studies on larger sample populations are needed.

[Repetitive movements of the upper limbs: results of exposure evaluation and clinical investigation in the production and packaging of ice cream]. / Movimenti ripetitivi degli arti superiori: risultati della valutazione dell'esposizione e dell'indagine clinica nella produzione e confezionamento di gelati.

An evaluation was made of the degree of exposure to risk and the frequency of disorders attributable to biomechanical overload of the upper limb in workers employed on packaging in an ice cream factory. The risks were first evaluated against a checklist, then subsequently an assessment was made of the tasks found to feature the highest risks, using an ergonomic analysis method. The method identified several jobs, such as placing ice cream coupes and such like in boxes, as requiring a large number of actions per minute (> 30) and considerable muscular strength. The 59 female workers performing the packaging operations were given a risk-targeted physical examination. The clinical test detected an extremely high frequency of carpal tunnel syndrome, (7.1%) epicondylitis (5.2%) and scapulo-humeral periarthritis (3.5%) in the over 35 years age group, with respect to a control population not exposed to risk. The authors conclude that the repetitiveness of the actions, the use of gloves due to prolonged contact with frozen products and the effects of the low temperatures themselves, may have favoured the spread of the disorders that appeared in this population of workers. These findings must be further supported by more in-depth epidemiological studies.

Double biochemical modulation of 5-fluorouracil by methotrexate and levo-folinic acid in the treatment of advanced digestive tract malignancies.

The aim of this study was to evaluate the activity and toxicity of a double biochemical modulation of 5-fluorouracil (5-FU) by means of methotrexate (MTX) and levo-folinic acid (LFA) in patients with advanced carcinoma of the digestive tract, and to assess the prognostic significance of MTX serum concentrations achieved in these patients. 94 patients affected by advanced carcinoma of the colon-rectum, stomach or biliary tract (47 of them previously untreated) received a regimen consisting of MTX 500 mg/m2 as a 2-h i.v. infusion on day 1, followed by LFA 250 mg/m2 as a 2-h i.v. infusion and 5-FU 600 mg/m2 as an i.v. bolus on day 2. Cycles were repeated every 2 weeks. Treatment was administered until tumour progression or for a maximum of 24 courses. MTX serum level was assessed soon after and 24 h (24-h MTXs) after its infusion in 61 patients. One complete and 22 partial responses were obtained, giving an overall activity of 24% (95% confidence interval, 16-34%). Response rate was 30% in chemotherapy-naive patients (colorectal, 26%; gastric, 37%; and biliary-tract, 22%) and 19% in those previously treated (all with fluoropyrimidines). A poor performance status adversely affected the response and survival of patients. The toxicity of treatment was very mild, and occurrence of severe diarrhoea (11% of patients) and mucositis (3%) was lower than that reported with other modulations of 5-FU. A cut-off value of 24-h MTXs was identified as a strong prognostic indicator. Patients with 24-h MTXs > or = 2 microM had a significantly better probability of response (37% versus 5%; P = 0.032), longer progression-free survival (5.3 versus 2.3 months; P = 0.023) and overall survival (10.8 versus 8.3 months; P = 0.045) on multivariate analysis. In chemotherapy-naive colorectal cancer patients, those with 24-h MTXs > or = 2 microM had a response rate of 38% (3/8), with a 19.6-month median survival time, as compared to no responses (0/4) and a 9.9-month median survival in the group with a lower serum concentration. The achievement of such MTX serum levels yielded a 31% (4/13) response rate even in colorectal patients who had previously received a 5-FU-FA treatment.