Induction TPF followed by concomitant treatment versus concomitant treatment alone in locally advanced head and neck cancer. A phase II-III trial.

BACKGROUND: Platinum-based chemoradiation (CCRT) is the standard treatment for Locally Advanced Head and Neck Squamous-Cell Carcinoma (LAHNSCC). Cetuximab/RT (CET/RT) is an alternative treatment option to CCRT. The efficacy of induction chemotherapy (IC) followed by chemoradiation compared to chemoradiation alone has not been demonstrated in randomized clinical trials. The goals of this phase II-III trial were to assess: (i) the overall survival (OS) of IC versus no-induction (no-IC) and (ii) the Grade 3-4 in-field mucosal toxicity of CCRT versus CET/RT. The present paper focuses on the analysis of efficacy. MATERIALS AND METHODS: Patients with LAHNSCC were randomized to receive concomitant treatment alone [CCRT (Arm A1) or CET/RT (Arm A2)], or three cycles of induction docetaxel/cisplatin/5 fluorouracil (TPF) followed by CCRT (Arm B1) or followed by CET/RT (Arm B2). The superiority hypothesis of OS comparison of IC versus no-IC (Arms B1 + B2 versus A1 + A2) required 204 deaths to detect an absolute 3-year OS difference of 12% (HR 0.675, with 80% power at two-sided 5% significance level). RESULTS: 414 out of 421 patients were finally analyzed: 206 in the IC and 208 in the no-IC arm. Six patients were excluded because of major violation and one because of metastatic disease at diagnosis. With a median follow-up of 44.8 months, OS was significantly higher in the IC arm (HR 0.74; 95% CI 0.56-0.97; P = 0.031). Complete Responses (P = 0.0028), Progression Free Survival (P = 0.013) and the Loco-regional Control (P = 0.036) were also significantly higher in the IC arm. Compliance to concomitant treatments was not affected by induction TPF. CONCLUSIONS: IC followed by concomitant treatment improved the outcome of patients with LAHNSCC without compromising compliance to the concomitant treatments. The degree of the benefit of IC could be different according to the type of the subsequent concomitant strategy. CLINICAL TRIAL NUMBER: NCT01086826, www.clinicaltrials.gov.

Concomitant chemoradiotherapy versus induction docetaxel, cisplatin and 5 fluorouracil (TPF) followed by concomitant chemoradiotherapy in locally advanced head and neck cancer: a phase II randomized study.

BACKGROUND: Concomitant chemoradiotherapy (CT/RT) is the standard treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN). We evaluated the efficacy of induction docetaxel (Taxotere), cisplatin, and 5-fluorouracil (TPF) before CT/RT versus CT/RT alone. PATIENTS AND METHODS: Patients with stage III-IVM0 SCCHN, Eastern Cooperative Oncology Group performance status of zero to one, were randomly assigned to receive CT/RT alone (arm A: two cycles of cisplatin 20 mg/m(2), days1-4, plus 5-fluorouracil 800 mg/m(2)/day 96 h continuous infusion, during weeks 1 and 6 of radiotherapy) or three cycles of TPF (arm B: docetaxel 75 mg/m(2) and cisplatin 80 mg/m(2), day 1, and 5-fluorouracil 800 mg/m(2)/day 96 h continuous infusion, every 3 weeks) followed by the same CT/RT. The primary end point was the rate of radiologic complete response (CR) at 6-8 weeks after the end of CT/RT. RESULTS: A total of 101 patients were randomly allocated to the study (51 arm A; 50 arm B). CR rates were 21.2% (arm A) versus 50% (arm B). Median progression-free survival and overall survival were, respectively, 19.7 and 33.3 months (arm A) and 30.4 and 39.6 months (arm B). Hematologic and non-hematologic toxic effects during CT/RT were similar in the two arms. CONCLUSION: Induction TPF followed by CT/RT was associated with higher radiologic CR in patients with locally advanced SCCHN with no negative impact on CT/RT feasibility.

Multicentre randomised phase III study comparing the same dose and schedule of cisplatin plus the same schedule of vinorelbine or gemcitabine in advanced non-small cell lung cancer.

This study compares two cytotoxic regimens comprising the same dose and schedule of cisplatin (CP) plus vinorelbine (VNR) or gemcitabine (GEM) administered under the same schedule to patients with advanced non-small cell lung cancers (NSCLC). From April 1998 to February 2003, 285 patients were randomised to receive either VNR 25 mg/m(2) on days 1 and 8 as an intravenous (i.v.) bolus plus CP 75 mg/m(2) on day 1 (regimen A) or GEM 1200 mg/m(2) on days 1 and 8 as an i.v. 30-min infusion plus CP 75 mg/m(2) on day 1 (regimen B). Both treatments were recycled every 21 days. If no progression had occurred after six cycles, the patients continued to receive VNR or GEM monochemotherapy weekly. Cross-over of the two single agents was considered if disease progression occurred. Objective response (OR), time to progression (TTP) and overall survival (OS) were analysed according to the intention-to-treat principle. 272 patients were ultimately eligible (137 on A and 135 on B). Their main characteristics were: male/female ratio 214/58; median age 63 (range 32-77) years; median Karnofsky Performance Status (PS) 80 (range 70-100); stage IIIB 34%, stage IV 61%, recurrent disease 5%; histology - epidermoid 29%, adenocarcinoma 53%, other NSCLC 18%. The characteristics of the patients in the two arms were well matched. The following response rates were observed in regimens A and B, respectively: complete response (CR) 0.7% and 3.7%, partial response (PR) 31.9% and 22.2% (P = 0.321). Median CR+PR duration was 8 months in both arms. Clinical benefit represented by an improvement in symptoms was evident in 25.7% and 28.1%, respectively. Median TTP was 5 months in both arms and median OS 11 months in both arms. Grade III-IV neutropenia occurred in 30.7% and 17.7% of the patients in arms A and B, respectively (P = 0.017); thrombocytopenia occurred in 0% and 9.3% (P = 0.004), respectively. No difference in the incidence of anaemia was observed. Non-haematological toxicity was generally mild: a higher incidence of grade 1-2 peripheral neurotoxicity and grade 1-2 local toxicity with regimen A and grade 1-2 liver toxicity with regimen B was reported. A pharmaco-economic comparison showed a difference between the two doublets, principally due to the different costs of VNR and GEM. Under the study conditions the combination of VNR or GEM with the same dose and schedule of CP produced similar OR, clinical benefits, TTP and OS in advanced NSCLC, and only mild toxicological differences were observed. Pharmaco-economic evaluation favoured the CP + VNR doublet.

Activity of high-dose epirubicin in advanced non-small cell lung cancer.

24 patients with unresectable non-small cell lung cancer (NSCLC) (14 stage IIIB and 10 stage IV) with a performance status of 70% or higher and without liver metastases received 120-165 mg/m2 epirubicin as an intravenous bolus every 21-28 days up to the maximum cumulative dose of 900 mg/m2. 6 patients (25%) (95% confidence limits 9.8-46.7%) achieved partial remission for a median duration of 7.5 months (range: 3-13+). The median dose actually administered per course was 120 mg/m2 in responsive and non-responsive patients. The dose-limiting side-effect was neutropenia. 1 patient receiving the higher dose died of drug-related infection. Other non-dose-related grade 3 side-effects were alopecia (100%) and vomiting (17%). In 4 patients, the treatment was interrupted because of a greater than 10% reduction in the left ventricular ejection fraction as calculated by radionuclide angiocardiography. None of these patients suffered from cardiac symptoms. The median survival was 10 months (range 1-16). These data suggest that epirubicin at 120-135 mg/m2 may have higher antitumour activity than standard doses in patients with NSCLC. Further studies are needed to clarify whether or not high-dose epirubicin increases, the risk of cardiotoxicity compared to standard doses.

An open randomised cross-over study on granisetron versus ondansetron in the prevention of acute emesis induced by moderate dose cisplatin-containing regimens.

The aim of the study was to compare granisetron (GRA) with ondansetron (OND) in the prevention of acute emesis in consecutive chemotherapy-naive patients admitted to our department to receive a cytotoxic treatment containing cisplatinum (CP) at a dose > or = 50 mg/m2. Eligible patients were randomised at their first cycle to receive either OND or GRA with cross-over of the anti-emetic treatment on the second cycle. The cytotoxic treatments included five different multidrug regimens containing CP (median dose 60 mg/m2, range 50-70 mg/m2) administered on day 1 and repeated every 21-28 days. OND was administered at the dose of 8 mg x 3 i.v. on day 1 and 8 mg x 2 orally on day 2. GRA was always administered at the dose of 3 mg i.v. on day 1. 124 patients entered the study. 58 patients received OND at their first cycle and 66 received GRA. Complete protection of acute emesis with OND and GRA was observed, with the first and second cycles combined as follows: nausea 53 and 60%, vomiting 68 and 71%, respectively (no statistically significant difference). The cross-over analysis comprising 101 patients confirmed no difference between the two anti-emetic treatments. 21 patients (19%) on OND and 14 patients (12%) on GRA suffered headaches (P = 0.15). 25 (25%) patients preferred OND, 45 (45%) preferred GRA, while 31 (30%) expressed no preference (P = 0.003). However, these differences also depended on the sequence of anti-emetics in the cross-over. In conclusion, in this study, a single dose of GRA is demonstrated to be as effective as multiple doses of OND in the prevention of acute emesis.

High-dose epirubicin for untreated patients with advanced tumours: a phase I study.

In a phase I study, epirubicin was administered as an intravenous bolus at an initial dose of 105 mg/m2 in untreated patients with advanced tumours considered resistant to antineoplastic treatment. A 15 mg/m2 dose escalation was done every 3 patients if toxicity was below grade 3 or every 6 patients if at least 1 patient had grade 3 toxicity. 18 patients entered the study. The dose was (mg/m2): 105 (3 patients), 120 (3), 135 (3), 150 (6) and 165 (3). The maximally tolerated dose was 165 mg/m2. The dose-limiting toxicity was neutropenia. Other side-effects were nausea/vomiting (78%) and alopecia (100%). 4 patients stopped treatment because of a decrease in left ventricular ejection function, without clinical signs of cardiotoxicity. A complete response was observed in a patient with abdominal metastases from unknown origin at 105 mg/m2 and a partial response in 2 out of 7 patients with non-operable non-small cell lung cancer, at 135 and 150 mg/m2, respectively. The recommended dose for phase II trial is 135-150 mg/m2.

Multicenter randomized clinical trial on high-dose epirubicin plus cis-platinum versus vinorelbine plus cis-platinum in advanced non small cell lung cancer.

BACKGROUND: High dose Epirubicin (HD-EPI) (>90 mg/m2) and Vinorelbine (VNR) demonstrated antitumor activity as single agent (about 20%) in the treatment of advanced NSCLC. This trial compares these two agents combined with cisplatin (CP). PATIENTS AND METHODS: From August 1992 to February 1996, 228 patients with locally advanced or metastatic NSCLC were randomized to receive either EPI 120 mg/m2 as i.v. bolus plus Cisplatin (CP) 60 mg/m2 on day 1 (regimen A) or VNR 25 mg/m2 as i.v. bolus on day 1 and 8 plus CP 60 mg/m2 on day 1 (regimen B). Both treatments were recycled every 21 days up to a maximum cumulative dose of EPI of 840 mg/m2 or 12 cycles. Eligible patients were 212 and 198 patients were evaluable for objective response (95 in arm A and 103 in arm B). The main characteristics of eligible patients were: male/female 179/33; median age 61 (42-72); median Karnofsky PS 80 (70-100); stage IIIA 12%, stage IIIB 40%, stage IV 41%, recurrence 7%; histotype: epidermoid 48%, adenoca 36%, others 16%. RESULTS: The following response rates were observed in regimens A and B, respectively; CR, 1 and 2%, PR, 32 and 25% (P = 0.4567). Median CR + PR duration was 9 and 8 months, respectively. Median survival was 10.5 and 9.6 months, respectively. Grade III-IV leucopenia occurred in 38 and 21% in arm A and arm B, respectively(P = 0.01), thrombocytopenia in 6 and 0% (P = 0.02), anemia in 8 and 7% (n.s.). Non-hematological toxicity was moderate and the only difference between the treatments was alopecia (88 vs. 33% in arm A and B, respectively). Supraventricular arrhythmia occurred in three patients on regimen A; a >15% LVEF absolute decrease was observed in 9 (22.5%) and three (14%) patients on arm A and arm B, respectively (n.s.). No congestive heart failure was observed. CONCLUSION: HD-EPI+CP and VNR+CP are both active combinations in advanced NSCLC with a similar response rate, response duration and survival but regimen A was significantly more toxic (myelosuppression and alopecia).

Idarubicin metabolism and pharmacokinetics after intravenous and oral administration in cancer patients: a crossover study.

The pharmacokinetics and metabolism of 4-demethoxydaunorubicin (idarubicin, IDA) were studied in 21 patients with advanced cancer after i.v. (12 mg/m2) and oral (30-35 mg/m2) treatment according to a balanced crossover design. Patients were divided into four groups: subjects who showed normal liver and kidney function (group N), those who presented with normal kidney function and liver metastases (group L), those with kidney dysfunction (creatinine clearance, less than or equal to 60 l/h; group R), and those with both liver and kidney dysfunction (group LR). Five patients showed variations in liver or kidney function after the first treatment and were considered to be nonevaluable for the crossover study but evaluable for the liver/kidney function study; some of them appeared in different groups for the i.v. as opposed to p.o. treatments. After i.v. administration, IDA plasma levels followed a triphasic decay pattern. The main metabolite observed in all patients was the 13C-reduced compound (IDAol), which attained plasma levels 2-12 times higher than those of the parent compound. IDA pharmacokinetics was not dependent on the presence of liver metastases but was related to the integrity of kidney function. Analysis of variance indicated a significant correlation between IDA plasma clearance and creatinine clearance; it was also found that IDA plasma clearance was lower in patients whose creatinine clearance was less than 60 ml/min [group N, 122.8 +/- 44.0 l/h; group L, 104.4 +/- 27.7 l/h (P = 0.58) vs group R, 83.4 +/- 18.3 l/h (P = 0.037)]. The IDAol terminal half-life and mean residence time (MRT) were significantly increased in patients with impaired kidney function [MRT: group N, 63.6 +/- 10.8 h; group L, 69.9 +/- 10.2 h (P = 0.27) vs group R, 83.2 +/- 10.9 h (P = 0.025) and t1/2 gamma: group N, 41.3 +/- 10.1 h; group L, 47.0 +/- 7.4 h (P = 0.31) vs group R, 55.8 +/- 8.2 h (P = 0.025)]. After oral treatment, drug absorption occurred during in the first 2-4 h after IDA administration; a biphasic decay pattern was observed thereafter. The main metabolite observed in all patients was again IDAol. The AUC of IDAol was greater after oral administration than after i.v. treatment in proportion to the AUC of IDA (i.v.: AUC-IDAol/AUC-IDA, 2.4-18.9; p.o.: AUC-IDAol/AUC-IDA, 4.1-21.4). Following oral dosing, a substantial amount of 4-demethoxydaunomycinone (AG1) was found in 11/21 patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Phase II study of sequential treatment of advanced non-small-cell lung cancer: three cycles of high-dose epirubicin plus cisplatin followed by weekly vinorelbine.

Previous phase I, II, and III studies on high-dose epirubicin (HDEPI), alone or in combination with cisplatin (CP), indicate an interesting activity of this drug in the treatment of non-small-cell lung cancer (NSCLC). However, the toxicological profile of HDEPI limits its prolonged use. In our experience, vinorelbine (VNR) seems to be a suitable drug for long-term monotherapy for advanced NSCLC. On these grounds, advanced NSCLC patients were treated with the following strategy: 3 consecutive cycles of CP 60 mg/m2 and HDEPI 120 mg/m2 on day 1, every 3 weeks; then, irrespective of response, weekly VNR at a dose of 25 mg/m2 was administered at home. From December 1996 to March 1998, 25 patients entered the study. After receiving 3 cycles of CP/HDEPI, 8 patients (32%) had a partial response and 3 (12%) had a minor response. Nine patients had stable disease (36%) and 4 (16%) had progressive disease. Twenty-three patients received weekly VNR, and the median number of administrations was 10 (range, 1-38). After VNR treatment, we observed a partial response in 2 patients who previously had stable disease. Therefore, the overall response rate to sequential treatment was 40%; median time to progression was 7 months (range, 2-26 months). The major toxicities due to the CP/HDEPI regimen were neutropenia (72%) and alopecia (80%). During the VNR treatment, grade 3/4 neutropenia was seen in 36% of patients. The doses and the timing of VNR administrations were modified according to toxicity. Symptoms such as cough, dyspnea, and pain, present in 21 patients before the treatment, improved in 11 cases (52%). Median overall survival is 9 months (range, 3-40+ months); one patient is still alive after 40 months. One- and 2-year survival rates are, respectively, 44% and 16%. This study confirms the activity of CP/HDEPI in NSCLC and indicates that the sequential treatment of CP/HDEPI for 3 cycles followed by weekly VNR could be considered an effective strategy for locally advanced or metastatic NSCLC.

Weekly regimen of 5-FU vs 5-FU + intermediate dose folinic acid in the treatment of advanced colorectal cancer.

Sixty-four patients with advanced colorectal cancer were randomized to receive 5-fluorouracil (5-FU) at the dose of 600 mg/sm weekly or the same regimen of 5-FU administered halfway through a 1 hour i.v. infusion of folinic acid (FA) at the dose of 200 mg/sm. A partial remission (PR) was obtained in 1/30 patients (3%) treated with 5-FU and in 9/34 patients (26%) treated with 5-FU + FA (P = 0.028). The objective response was accompanied by an improvement in subjective status and general conditions. The median duration of PR in 5-FU + FA arm was 10 months (range: 6-17). The median time to progression was 5 and 6 months in patients treated with 5FU and 5FU + FA, respectively (not a statistically significant difference). There were no cases of grade 4 toxicity. A higher, but not statistically significant, incidence and intensity of diarrhoea was observed in the 5-FU + FA arm. However, 14 patients on 5-FU + FA as opposed to 3 on 5-FU had to stop the treatment temporarily because of side-effects (P = 0.011). Median survival was higher with 5-FU + FA treatment (10 vs 7 months), but the difference is not statistically significant. This study confirms that the addition of an intermediate dose of FA enhances the cytotoxicity of 5-FU. Although its clinical advantage was limited, this weekly 5-FU + FA regimen appears useful in the treatment of advanced colo-rectal cancer on a outpatient basis.

Comparative crossover trial of two intravenous doses of granisetron (1 mg vs 3 mg) + dexamethasone in the prevention of acute cis-platinum-induced emesis.

BACKGROUND: The 5HT3 receptor antagonist Granisetron (GRA) is available on the market as a 1 mg vial in USA and as a 3 mg vial in Europe. This study aimed to compare the two i.v. doses of GRA (3 mg vs 1 mg), both of which combined with Dexamethasone (DEX) (20 mg) in the prevention of acute Cisplatinum (CP)-induced emesis. PATIENTS AND METHODS: One hundred and ninety-eight consecutive chemotherapy-naive cancer patients, mainly suffering from lung and bladder cancer, were randomized at their first cycle to receive either GRA 1 mg + DEX or GRA 3 mg + DEX as i.v. bolus prior to chemotherapy and crossed-over to another GRA dose at the second cycle. The cytotoxic treatment included different multi-drug regimens containing CP (median dose 60 mg/m2, range 50-70) administered on day 1 and repeated every 21-28 days. RESULTS: Of the 192 evaluable patients complete protection from acute emesis with GRA 1 and GRA 3, was observed after the 1st + 2nd cycles as follows: nausea 70% and 74%, vomiting 90% and 94%, nausea and vomiting 67% and 74% respectively (no statistically significant difference). No carry-over effect was observed on the complete protection from emesis. The crossover analysis comprising 156 patients confirmed there were no differences between the two antiemetic treatments. Twenty-seven per cent of patients preferred GRA 1, 31% preferred GRA 3, while 42% expressed no preference (P = 0.75). Nor was any difference observed for tolerability, the only reported side-effects being mild headache (16% vs 17%) and constipation (18% vs 25%). CONCLUSION: This study shows that, under the above conditions, the 1 mg and 3 mg i.v. GRA doses are comparably effective when combined with DEX 20 mg in the prevention of acute CP-induced emesis.

Combination chemotherapy with mitoxantrone, methotrexate, and mitomycin (MMM regimen) in malignant pleural mesothelioma: a phase II study.

The prognosis of malignant pleural mesothelioma is poor, with a median survival time from diagnosis of 7 to 17 months. At present there is no standardized treatment of this neoplasia. Between July 1995 and January 1999, 22 patients with malignant pleural mesothelioma were enrolled in our study. The characteristics of patients were: 16 men and 6 women; median age 61 years (range, 49-77 years); stage (according to Butchart): 8 patients stage I, 10 stage II, 2 stage III, and 2 stage IV; cytologic diagnosis in 5 cases and histologic diagnosis in 17 cases. The treatment consisted of mitoxantrone 10 mg/m2 intravenous (IV) or intrapleural (IPL), methotrexate 35 mg/m2 IV, and mitomycin 7 mg/m2 IV on day 1 and repeated every 3 weeks, with mitomycin in alternate cycles (MMM regimen). One complete response (4.5%) (42 months of duration) and 6 partial responses (27.3%) (5, 5, 7, 9, 14, and 19 months of duration) were achieved; the overall response rate (ORR) was 31.8% (95% CI, 12.4-51.3%); 7 patients were stable under this treatment (31.8%). According to the pathologic type, ORR for the only epithelial type was 39.9% (95% CI, 15.2-64.8%). Median time to progression was 6 months (range, 1-22). The overall median survival time was 13.5 months (range, 1-50); the median survival time of responders significantly differed from that of nonresponders (18.0 versus 8.5 months; p = 0.017). This treatment produced a considerable clinical benefit, with improvement of dyspnea (68.4%) and pain (33.3%); 15 of 19 patients (78.9%) with pleural effusion at the time of diagnosis showed an important reduction in pleural fluid during chemotherapy. Hematologic toxicity was the main side effect; World Health Organization grade III to IV of neutropenia, anemia, and thrombocytopenia were observed in 81.8%, 13.6%, and 22.7% of patients, respectively. From the data presented here, this regimen can be considered active in the treatment of malignant pleural mesothelioma.

Prospective phase II study of single-agent gemcitabine in untreated elderly patients with stage IIIB/IV non-small-cell lung cancer.

The purpose of this study was to evaluate the efficacy and tolerability of single-agent gemcitabine in untreated elderly patients with stage IIIb/IV non-small-cell lung cancer (NSCLC). Since April 1997, 46 consecutive patients have been enrolled in this multicenter study. Gemcitabine 1,000 mg/m2 was administered as a 30-minute intravenous infusion on days 1, 8, and 15 every 28 days. Primary patient characteristics were: male/female 38/8; median age 73 years (range: 70-82 years); median Karnofsky performance status (PS) 90 (range: 70-100); stage IIIb 61% and stage IV 39%; histotype: epidermoid 48%, adenocarcinoma 43%, and large cell carcinoma 9%. No complete response was observed, but 10 (21.7%) patients achieved partial response (PR) (95% confidence limits: 11-36%), 27 (58.7%) had stable disease (SD), and 7 (15%) progressed early (at the first evaluation). The median duration of PR and SD was 8 months (range: 4-23+ months) and 4 months (range: 2-9 months), respectively. Subjective response evaluating PS and symptoms such as dyspnea, pain, and cough was evaluated in 40 patients; 11 (27.5%) improved, 15 (37.5%) remained stable, and 14 (35%) worsened. The median time to progression was 4 months, the median survival was 9 months, and 1-year survival was 44%. After a median follow-up of 10.5 months, 14 patients are still alive. There were no grade 4 toxicities. Grade 3 neutropenia and thrombocytopenia occurred in 19% and 2% of patients, respectively. Nonhematologic toxicities were mild. Grade I/II side effects of nausea/vomiting, transient fever, increase of hepatic transaminases, transient peripheral edema at lower extremity (not related to cardiac or renal disease or phlebothrombosis) were reported. This phase II study confirms the activity and favorable toxicity profile of single-agent gemcitabine in the treatment of elderly patients with advanced NSCLC.

A randomized clinical trial with a weekly regimen of 5-fluorouracil with or without folinic acid in advanced gastrointestinal adenocarcinomas: a preliminary report.

Eighty patients with advanced gastrointestinal tumors (64% with colorectal cancer) entered a phase III prospective randomized study with 5-fluorouracil (5-FU) vs 5-FU + folinic acid (FA) The treatment included 5-FU, 600 mg/m2/week for 6 weeks, given as i.v. bolus alone (arm A), or administered by rapid injection half-way through a one-hour infusion of FA, 200 mg/m2/week for 6 weeks (arm B). Partial remission (PR) was achieved in 1 out of 30 (3%) evaluable patients for 6 months in arm A, and in 10 out of 34 (29%) patients in arm B, with a median duration of 8 months (range 6-17) (comparison of the response rate: P = 0.005). In patients with colorectal cancer the response rate was 5% and 27% in arm A and in arm B respectively (P = 0.06). Two patients, who were resistant to 5-FU alone, achieved PR after treatment with 5-FU + FA. Diarrhea was observed in 14/42 patients (33%) in arm B (grade 1-2 in 10 and grade 3 in 4) and in 2/38 patients (5%) in arm A (P = 0.005). Other side effects such as nausea/vomiting, myelosuppression and stomatitis were infrequent and of mild intensity in both arms. No statistical difference in survival was detected when comparing the two groups (estimated median survival 8 months and 11 months for arm A and arm B respectively). These results seem to indicate that the weekly regimen of 5-FU + FA has a superior response rate compared to 5-FU alone, and that it is well tolerated. However, the advantage is not reflected in overall survival.

A phase II study on lonidamine combined with cisplatin and etoposide in the treatment of advanced non-small cell bronchogenic carcinoma (NSCBC).

A group of 28 patients with advanced non-small cell bronchogenic carcinoma (NSCBC) entered a phase II study on cisplatin (60 mg/m2, day 1) plus etoposide 120 mg/m2, day 1 to 3), every 3 weeks, in combination with lonidamine (150 mg p.o. t.i.d. continuously from day 1). Seven out of twenty-seven (26%) evaluable patients obtained a partial remission (median duration 22 weeks, range 7-47). Although the side effects were mild, three patients stopped the therapy because of them. Median survival was 14 months, range 2-19. Further studies are necessary to clarify the role of "biochemical modulators" in NSCBC.

Combined chemo-immuno-hormonotherapy of advanced renal cell carcinoma.

Thirty-five patients (pts.) with advanced renal cell carcinoma were treated with a combination of vinblastine (5 mg/m2/IV) plus epirubicin (50 mg/m2/IV) every 3-4 weeks, alpha-2-A-interferon (9 x 10(6) U/IM 3 times in the 1st week, then 18 x 10(6) U/IM 3 times weekly), and medroxyprogesterone acetate (2,000 mg/os/day plus 500 mg IM/week). Thirty-one patients were males and 4 were females with a median age of 63 years (range 35-75) and median performance status of 70% (range 50-90%). We observed nine partial remissions (26%) with median duration of 40 weeks (range 20-232+). Fifteen pts. had no change (43%) while 11 pts. progressed (31%). The main side-effects were: leukopenia (29/35, 83%) with median nadir of 3,100 WBC/mm3 (range 510-3,990) and fever (32/35, 91%). Thrombocytopenia occurred in 4 pts. (11%), anemia in 5 (14%), asthenia in 12 (34%), nausea/vomiting in 12 (34%), alopecia in 8 (23%) and stomatitis in 3 (8.5%). Two patients stopped the therapy with medroxyprogesterone acetate because of muscular cramps. Median survival was 65 weeks (range 6-327+). We conclude that the combination of recombinant alpha 2A-interferon-vinblastine-epirubicin and medroxyprogesterone acetate has modest but definitive activity in patients with advanced renal cell carcinoma.

Anthracyclines in non-small-cell lung cancer: do they have a therapeutic role?

BACKGROUND: Owing to its low level of activity together with its potential cardiotoxicity, doxorubicin (DXR) has been considered as having a marginal role in the treatment of NSCLC. Its analogue, epirubicin (EPI), has also shown a poor antitumor activity in the treatment of NSCLC when used at 'standard' doses (= 90 mg/m2). On the contrary, high-dose epirubicin (HD-EPI) (> 90 mg/m2) has demonstrated antitumor activity as a single agent in the treatment of advanced NSCLC in six small phase II studies (mean 25%, range 17%-36%). RESULTS: A series of consecutive studies on the activity of HD-EPI alone or in combination regimens were carried out at the Division of Medical Oncology of S. Orsola-M. Malpighi Hospital. After activity was confirmed in advanced disease with doses between 120 and 165 mg/m2 (PR in 6 of 24 = 25%), a phase II study was carried out on the combination of HD-EPI 120 mg/m2 + cisplatinum (CP) 60 mg/m2 in stage IIIB-IV NSCLC. PR was achieved in 54% of 35 patients with a median survival of nine months. A subsequent multicenter phase III trial compared HD-EPI and vinorelbine (VNR), both combined with CP. Two hundred twenty-eight patients with locally advanced or metastatic NSCLC were randomized to receive either EPI 120 mg/m2 plus CP 60 mg/m2 on day 1 or VNR 25 mg/m2 on day 1 and 8 plus CP 60 mg/m2 on day 1. Both treatments were recycled every 21 days. Eligible patients were 212 and 210 patients evaluable for objective response (100 on HD-EPI and 110 on VNR), respectively. The CR + PR rate was 32% vs. 26% (P = NS) for a median duration of nine and eight months, respectively. Median survival was 10 and 9.5 months, respectively. Grade III-IV leucopenia occurred in 38% and 21% on HD-EPI and VNR, respectively (P = 0.01), thrombocytopenia in 6% and 0% (P = 0.02), anemia in 8% and 7% (NS). Non-hematological toxicity was moderate and the only difference between the treatments was alopecia (88% vs. 33% on HD-EPI and VNR, respectively). Supraventricular arrhythmia occurred in three patients on HD-EPI; a > 15% LVEF decrease by MUGA scan was observed in 22.5% and 14% patients on HD-EPI and VNR, respectively (NS). No congestive heart failure was observed. CONCLUSIONS: EPI can be safely administered at a dose of 120-135 mg/m2 in non-pretreated patients showing a significant antitumor activity in NSCLC. If the cumulative dose of 800-900 mg/m2 is not exceeded, clinical manifestations of cardiotoxicity are very rare. However, grade 3-4 myelotoxicity and alopecia are very common and can limit the use of this drug in the palliative treatment of this disease. Interesting results are observed in an ongoing pilot study that employed HD-EPI + CP + VNR + G-CSF in the induction therapy of locally advanced NSCLC.

Folinic acid plus 5-FU based chemotherapy in squamous cell carcinoma of the head and neck: Bologna experience.

BACKGROUND: The principal aim of our policy in the cytotoxic treatment of advanced squamous cell carcinoma of the head and neck (SCCHN) is to reduce toxicity, to maintain or increase the response rate and consequently to improve the quality of life for these patients. In locally advanced disease the aim is to reduce the volume of the tumor and to treat micrometastases in order to achieve a better outcome of the subsequent local treatment (i.e., surgery and/or radiotherapy). In these patients the aim is to prolong survival. PATIENT AND METHOD: We have employed 3 different multi-drug regimens with 5-FU+FA combination in 87 consecutive patients with SCCHN. Two regimens (B1, C) have been used for recurrent and/or metastatic disease and only one (B2) for previously untreated patients with locally advanced SCCHN. Regimen B1: cisplatin (P) 30 mg/m2 i.v., 5-fluorouracil (5-FU) 500 mg/m2 i.v., folinic acid racemic form (d, 1-FA) 200 mg/m2 i.v., bleomycin (B) 15 mg im 1st and 2nd day; Regimen C: P 60 mg/m2 1st day, 5-FU 500-750 mg/m2 continuous infusion, FA 50 mg po every 4 hours, B 15 mg im 2nd and 3rd day; Regimen B2 is similar to the B1 but lasts 3 consecutive days (instead of 2) and for every 3 weeks (instead of 4). It consists of 3 cycles before surgical treatment or radiotherapy. RESULTS: There are no statistical differences in the Objective Response (OR) for the regimens B1 (39%) and C (34%). Grade 3-4 toxicity is higher in regimen B1 (50%) than in regimen C (< or = 8%). CONCLUSION: Regimen C is less toxic regimen B1 with no significant difference in the OR. The primary treatment study is still ongoing but the preliminary results are promising: the remission rate is 92% (22/24, 1CR + 21 PR) and the median survival is 18 months (range 3-38+).

A phase II study of high-dose epirubicin plus cisplatinum in advanced non-small-cell lung cancer (NSCLC).

Thirty-seven patients with unresectable NSCLC received epirubicin (EPI) as i.v. bolus at the dose of 120 mg/sm+cisplatinum (CP) at the dose of 60 mg/sm every 28 days up to the maximum cumulative dose of 840 mg/sm of EPI. Of 35 evaluable patients, 19 (54%) (95% confidence limits: 37%-71%) achieved PR for a median duration of 10 months (range: 2-21). The majority of responsive patients experienced improvement in performance status, related-disease symptoms and body weight. Grades 3-4 leukopenia occurred in 42% of the patients. In five patients there was a > 10% reduction in the left ventricular ejection fraction as calculated by radionuclide angiocardiography. None of these patients suffered from cardiac symptoms. The median survival was 9 months (range 2-26). This study shows that inclusion of HD-EPI in a combination regimen contributes to obtaining a high remission rate in advanced NSCLC.

Controlled clinical study on the use of dichloromethylene diphosphonate in patients with breast carcinoma metastasizing to the skeleton.

Thirty-eight normocalcemic patients with bone metastases from breast carcinoma were randomized to receive dichloromethylene diphosphonate (CL2MDP) in addition to their specific antitumor treatment (chemotherapy and/or hormone therapy), at a dose of 300 mg/day/i.v. or placebo for the first 7 dys. The CL2MDP treatment then continued at a dose of 100 mg day/i.m. for 3 weeks and finally at 100 mg i.m. on alternate days for at least another 2 months. In both groups of patients there was a reduction in the intensity of pain (Scott-Huskisson analog), but there was a more frequent reduction in the daily consumption of analgesics in patients treated with CL2MDP (p = 0.02). Unlike the controls, the patients who received CL2MDP presented a significant reduction in urinary calcium (p = 0.003) and in hydroxyproline (p = 0.05) on the 7th day. As regards the clinical evolution, negative events such as the appearance of hypercalcemia, pathological fractures, new bone lesions or a substantial increase in the preexisting ones, were observed in 9 of the 12 evaluable patients treated with placebo and in 3 out of 9 treated with CL2MDP. Thickening of the preexisting osteolytic lesions was reported in 2 patients treated with CL2MDP. Tolerance was excellent: only a few patients complained of pain at the intramuscular drug injection site.