Capecitabine in combination with oxaliplatin or irinotecan in elderly patients with advanced colorectal cancer: results of a randomized phase II study.

BACKGROUND: To determine the efficacy and tolerability of capecitabine combined with oxaliplatin (CAPOX) or irinotecan (CAPIRI) as first-line treatment in patients with advanced/metastatic colorectal cancer aged > or =70 years. PATIENTS AND METHODS: Patients aged > or =70 years were randomly assigned to receive CAPOX [oxaliplatin 65 mg/m(2) intravenously (i.v.) days 1 and 8 and capecitabine 1000 mg/m(2) orally b.i.d. days 1-14; q21d] or CAPIRI (irinotecan 80 mg/m(2) i.v. days 1 and 8 and capecitabine 1000 mg/m(2) orally b.i.d. days 1-14; q21d). The primary study end point was overall response rate (ORR). RESULTS: Ninety-four patients were enrolled. In an intent-to-treat analysis, 2 complete responses (CRs) and 16 partial responses (PRs) were reported with CAPOX (ORR 38%), and 2 CRs and 15 PRs with CAPIRI (ORR 36%; P = 0.831). Median time to progression was 8 months for CAPOX and 7 months for CAPIRI (P = 0.195), with median survival times of 19.3 months and 14.0 months (P = 0.165), respectively. Global health status was improved in 45% and in 21% of patients in the CAPOX and CAPIRI arms, respectively. The most common treatment-related grade 3-4 adverse events in CAPIRI versus CAPOX patients were diarrhea (32% versus 15%; P = 0.052) and neutropenia (23% versus 6%; P = 0.021). CONCLUSION: CAPOX and CAPIRI had similar efficacy in elderly patients, although CAPOX seemed to be better tolerated.

[Downstaging after neoadjuvant therapy for rectal cancer modifies the planned original surgery]. / Il downstaging dopo terapia neoadiuvante del cancro del retto modifica l'intervento originariamente programmato.

Cancer of the rectum has been for more years burdened with a heavy rate of local relapse about 30%. The introduction of total meso-rectum excision has reduced the rate of up to 5-8%. Later more studies proved how the preoperative radiotherapy was able to reduce the rate of local relapse. The Authors introduce studies about downstaging after neoadjuvant chemoradiotherapy for rectal cancer and discuss about their own series from 2005 to 2007.

Gemcitabine combined with oxaliplatin (GEMOX) as salvage treatment in elderly patients with advanced ovarian cancer refractory or resistant to platinum: a single institution experience.

Both oxaliplatin (OXA) and gemcitabine (GEM) have shown single agent activity in patients with recurrent ovarian cancer. Response rates to second-line therapies remain low and there is a need to develop more effective regimens. In view of the synergistic effect of using GEM followed by OXA, we studied these agents in elderly patients with recurrent ovarian cancer refractory or resistant to first-line chemotherapy using platinum with or without paclitaxel. The aim of the study was to evaluate the efficacy and toxicity of combination GEM 1000 mg/m(2) Day 1 i.v. and OXA 100 mg/m(2) in 2h infusion Day 2; treatment was repeated every 2 weeks for 6 courses or until progression of disease or intolerable toxicity. The study was monoinstitutional and started in November 2002. 21 patients, median age 68.6 years (range 65-82) have been treated. Median Performance Status was 0-1, all had at least 1 prior platinum based chemotherapy and 11 had received also a taxane. Patients received a median of 6 cycles of treatment (range 4-11). There were 2 patient (9%) with complete response, 3 patients (14%) achieved a partial response. Low profile toxicity (grade 1-2, WHO criteria) was observed: nausea/vomiting 52%, thrombocytopenia 13%, neuropathy 28%. The GEMOX combination is well tolerated and even in this small group of patients, encouraging responses were documented.

Phase II trial of a biweekly regimen of fluorouracil and leucovorin plus irinotecan in patients with previously untreated advanced gastric cancer.

To investigate the therapeutic value and safety of the biweekly regimen of 5-fluorouracil (5-FU) and leucovorin (LV) plus irinotecan (CPT-11) in patients with previously untreated advanced gastric cancer (AGC). A total of 50 patients (M/F 35/15; median age = 65) with AGC, none of whom had received chemotherapy for advanced disease, were accrued in this trial. Fifteen patients (30%) were 70 years old or older. At the time of their accrual, cytotoxic chemotherapy, consisting of LV 100 mg/m(2) (2-hour i.v. infusion) followed by 5-FU 400 mg/m(2) (bolus) and 5-FU 600 mg/m(2) (22-hour continuous infusion) on therapeutic days 1 and 2 plus CPT-11 180 mg/m(2) (1-hour infusion) on day 1, was initiated. Treatment courses were repeated every 2 weeks until evidence of progressive disease, unacceptable toxicity or withdrawal of consent. All patients were assessable for toxicity and 48 of 50 for response evaluation, having completed at least four courses of chemotherapy. Complete response was achieved in 2 patients (4%, intent to treat) and partial response in 16 (32%) (overall response rate, 36%; 95% confidence interval [CI]: 22%-50%). Twenty-four patients (48%) had stable disease and 6 patients (16%) progressed. The median time to progression was 8 months (95% CI: 6-10 months) and median overall survival 14 months (95% CI: 6-22 months). Between the subgroups of patients <70 years old and 70 or older, there were no significant differences in efficacy. One toxic death occurred. Treatment tolerance was generally mild to moderate and easy to treat. The main grade 3/4 toxicities were neutropenia (32%), diarrhea (16%), and anemia (8%). Grade 3-4 neutropenia was the only treatment-related serious adverse event significantly more common in patients older than those aged <70 (53.3% vs 22.8%, respectively; P = 0.03). Our data suggest that the biweekly regimen of LV and 5-FU plus CPT-11 in untreated patients with AGC is active and has an acceptable safety profile. Further evaluation of this regimen seems to be warranted in a phase III trial.

Reduced dose intensity of docetaxel plus capecitabine as second-line palliative chemotherapy in patients with metastatic gastric cancer: a phase II study.

BACKGROUND: A phase II study was conducted to evaluate the efficacy and safety of a combination regimen of a reduced dose intensity of docetaxel (Taxotere) plus capecitabine in pretreated patients with metastatic gastric cancer. PATIENTS AND METHODS: Twenty-eight patients with documented progression on or within 3 months of a cisplatin-based chemotherapy were enrolled between April 2004 and November 2006. Docetaxel (60 mg/m2 on day 1) plus capecitabine (1000 mg/m2 twice daily on days 1-14) were given every 3 weeks. RESULTS: All patients were assessable for safety and 25 (89%) for tumor response. Median age was 63 years, and median follow-up was 13.3 months. Overall response rate was 29% (95% confidence interval 11% to 46%), while an additional 36% had stable disease. The median time to progression and median overall survival was 4 and 6 months, respectively. The most common clinical adverse events (all grades) were neutropenia (78%), hand foot syndrome (HFS) (53%), fatigue and alopecia (50%) and diarrhea (43%). However, with the exception of grade 3-4 neutropenia, which was seen in 36% of patients, other severe adverse events were rare. There were no treatment-related deaths. Treatment delays or dose reductions were necessary in 18 out of 104 cycles. CONCLUSIONS: A reduced dose intensity of docetaxel plus capecitabine is a valuable regimen for second-line treatment in this setting of patients. This approach warrants further investigation as a promising chemotherapy option for chemonaive patients with metastatic gastric cancer.

Lapatinib in breast cancer.

Aberrant activation of some members of human epidermal growth factor receptor (HER) family plays a key role in breast carcinogenesis. Lapatinib is an oral dual tyrosine kinase inhibitor selective for inhibition of epidermal growth factor receptor (EGFR/ErbB1) and HER2/ErbB2. Having more targets, probably its antitumor activity could be more efficient. Clinical data have shown that lapatinib is active in HER2-positive breast cancer as monotherapy, in combination with trastuzumab, and in trastuzumab-resistant patients. Phase I clinical trials have shown also that lapatinib is well tolerated, with mild diarrhea and skin rush as common toxic effects and low incidence of cardiotoxicity. Phase II and III clinical trials' data provide encouraging evidence of the clinical effectiveness of lapatinib in advanced or metastatic breast cancer and for its potential in patients with brain metastases. Interim results from the large, phase III trial in 392 patients showed that in combination with capecitabine lapatinib almost doubled time to progression when compared with capecitabine alone. Several clinical trials that explore the efficacy of lapatinib in combination with conventional chemotherapeutic agents [paclitaxel (Taxol), capecitabine and platinoids], hormonotherapy and other target therapies are ongoing in advanced breast cancer or in neo-adjuvant and adjuvant settings. Our improved understanding of the biology of breast cancer and the use of biomarkers for identification of specific subtypes are allowing us to bring patient-specific novel therapies such as lapatinib to the clinic.

Dasatinib: a new step in molecular target therapy.

The chimeric BCR-ABL gene, originated by the Philadelphia chromosome, encodes a fusion protein, BCR-ABL, bearing unregulated tyrosine kinase activity, the pivotal pathogenetic step of chronic myeloid leukemia (CML). Imatinib, an inhibitor of the BCR-ABL tyrosine kinase, significantly improves the outcome of patients with CML. Although the majority of CML patients are responsive to imatinib, a subset of patients loses the response and some progress to accelerated- or blast-phase CML. The understanding of mechanisms of imatinib resistance has led to the development of novel BCR-ABL inhibitors; among these, dasatinib emerged as the most promising, being approximately 300-fold more potent than imatinib; it also inhibits SRC family kinases. Preliminary data, after the introduction of dasatinib in clinical trials, in patients with CML, suggest that this drug is safe and well tolerated; furthermore, the majority of patients with imatinib-resistant disease achieved objective responses, although the durability of responses remains to be defined. Recently, dasatinib emerged as a potent inhibitor of imatinib-resistant protein tyrosine kinase (KIT) activation loop mutants and it is able to induce apoptosis in mast cell and leukemic cell lines expressing these mutations. The preclinical data concerning its activity on several human solid tumor lines widen new opportunities for their use outside CML.

Role of liposomal anthracyclines in breast cancer.

Anthracyclines are among the most effective drugs for patients with breast cancer. Their use, however, has been limited by associated toxic effects, including myelosuppression, alopecia, nausea and vomiting, stomatitis, and most importantly, cardiotoxicity. Liposomal anthracyclines were developed to increase the therapeutic index of conventional anthracyclines by maintaining antitumor efficacy while improving the safety profile. There are currently two liposomal formulations available for treatment of advanced disease: a not pegylated liposomal doxorubicin and a pegylated liposomal doxorubicin. This review will focus on both liposomal formulations of doxorubicin which are approved in Europe and Canada for use in patients with metastatic breast cancer.

Adjuvant chemotherapy with epirubicin, leucovorin, 5-fluorouracil and etoposide regimen in resected gastric cancer patients: a randomized phase III trial by the Gruppo Oncologico Italia Meridionale (GOIM 9602 Study).

BACKGROUND: This randomized, multicenter, phase III trial evaluated the efficacy and safety of the combination of epirubicin, leucovorin, 5-fluorouracil and etoposide (ELFE regimen) as adjuvant therapy for radically resected gastric cancer patients. PATIENTS AND METHODS: From June 1996 to June 2001, 228 stage IB-IIIB gastric cancer patients were enrolled. All patients received a total or subtotal gastrectomy with at least a D1 lymphoadenectomy and were randomly assigned to receive surgery alone or surgery followed by chemotherapy. RESULTS: A total number of 630 cycles was delivered with a median number of 5. With a median follow-up of 60 months, the 5-year overall survival (OS) was 48% in the treatment arm and 43.5% in the control arm [hazard ratio (HR) 0.91; 95% confidence interval (CI) 0.69-1.21; P = 0.610); the 5-year disease-free survival (DFS) was 44% in the treatment arm and 39% in the control arm (HR 0.88; 95% CI 0.78-0.91; P = 0.305). In node-positive patients, the 5-year OS was 41% in the treatment arm and 34% in the control arm (HR 0.84; 95% CI 0.69-1.01; P = 0.068), while the 5-year DFS was 39% in the treatment arm and 31% in the control arm (HR 0.88; 95% CI 0.78-0.91; P = 0.051). The most common grade 3-4 toxic effects according to World Health Organization criteria were hematological and gastrointestinal. CONCLUSIONS: In radically resected gastric cancer patients, adjuvant chemotherapy with ELFE regimen does not improve OS over surgery alone.

Weekly paclitaxel plus capecitabine in advanced breast cancer patients: dose-finding trial of GOIRC and GOL.

BACKGROUND: Paclitaxel and capecitabine have demonstrated a synergic effect and significant antitumor activity in patients with advanced breast cancer. A weekly schedule of paclitaxel obtained a response rate of 50-68% in advanced breast cancer and less serious side-effects. PATIENTS AND METHODS: Thirty-two patients with advanced breast cancer pretreated with chemotherapy were enrolled in a dose-finding trial to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of paclitaxel given on days 1, 8 and 15 of each cycle combined with capecitabine given twice daily from day 1 through day 14, every 21 days. Three patients were recruited at one of six dose levels (paclitaxel 70-100 mg/m2, capecitabine 1650-2500 mg/m2). RESULTS: Thirty-two patients were accrued and 31 were evaluated for toxicity. One DLT has been experienced at level VI as diarrhea grade 3. We determined dose level V as the MTD, but we recommend dose level IV for phase II studies (capecitabine 1250 mg/m2 orally twice daily plus paclitaxel 80 mg/m2 intravenously weekly), owing to cumulative toxicity at level V. The objective response rate was 43%. CONCLUSIONS: Weekly paclitaxel plus capecitabine is a safety and active chemotherapy in previously treated metastatic breast cancer.

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.

FOLFIRI regimen in advanced colorectal cancer: the experience of the Gruppo Oncologico dell'Italia Meridionale (GOIM).

PURPOSE: To verify the experience of the GOIM in the treatment of advanced colorectal cancer patients with the FOLFIRI combination therapy. PATIENTS AND METHODS: Patients entered in three consecutive trials of the GOIM (protocols no. 9706, 9901, and 2301) were reported in this analysis. A total of 287 chemotherapy-naive patients were treated with FOLFIRI regimen: Irinotecan 180 mg/m(2) on day 1 with LV5FU2 regimen (LV at 100 mg/m(2) administered as a 2-hour infusion before FU at 400 mg/m(2) as an intravenous bolus injection, and FU at 600 mg/m(2) as a 22-hour infusion immediately after 5FU bolus injection on day 1 and 2); the treatment was repeated every 2 weeks. RESULTS: 287 patients entered in these three trials, and 264 (92%) were evaluable for response. The overall response rate was 34.5% (95% confidence interval [CI]: 29% to 40%). When only assessable patients were analyzed, overall response rate was 37% (95% CI: 31% to 43%). Median time to progression, median duration of response and survival were 7 months, 10.5 months and 14 months, respectively. All but three patients were evaluable for toxicity which was globally mild; grade 3-4 toxicity was uncommon, and gastrointestinal disturbances were the most common. CONCLUSIONS: FOLFIRI regimen is effective and well-tolerated as first-line treatment in patients with advanced colorectal cancer. Further studies needed to evaluate the improvement in results with the addition of new drugs to this combination therapy.

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.

A randomised factorial trial of sequential doxorubicin and CMF vs CMF and chemotherapy alone vs chemotherapy followed by goserelin plus tamoxifen as adjuvant treatment of node-positive breast cancer.

The sequential doxorubicin --> CMF (CMF=cyclophosphamide, methotrexate, fluorouracil) regimen has never been compared to CMF in a randomised trial. The role of adding goserelin and tamoxifen after chemotherapy is unclear. In all, 466 premenopausal node-positive patients were randomised to: (a) CMF x 6 cycles (CMF); (b) doxorubicin x 4 cycles followed by CMF x 6 cycles (A --> CMF); (c) CMF x 6 cycles followed by goserelin plus tamoxifen x 2 years (CMF --> GT); and (d) doxorubicin x 4 cycles followed by CMF x 6 cycles followed by goserelin plus tamoxifen x 2 years (A --> CMF --> GT). The study used a 2 x 2 factorial experimental design to assess: (1) the effect of the chemotherapy regimens (CMF vs A --> CMF or arms a+c vs b+d) and (2) the effect of adding GT after chemotherapy (arms a+b vs c+d). At a median follow-up of 72 months, A --> CMF as compared to CMF significantly improved disease-free survival (DFS) with a multivariate hazard ratio (HR)=0.740 (95% confidence interval (CI): 0.556-0.986; P=0.040) and produced a nonsignificant improvement of overall survival (OS) (HR=0.764; 95% CI: 0.489-1.193). The addition of GT after chemotherapy significantly improved DFS (HR=0.74; 95% CI: 0.555-0.987; P=0.040), with a nonsignificant improvement of OS (HR=0.84; 95% CI: 0.54-1.32). A --> CMF is superior to CMF. Adding GT after chemotherapy is beneficial for premenopausal node-positive patients.

Weekly paclitaxel as first-line chemotherapy in elderly advanced breast cancer patients: a phase II study of the Gruppo Italiano di Oncologia Geriatrica (GIOGer).

BACKGROUND: First-line chemotherapy regimens suitable for elderly advanced breast cancer patients are still not defined. PATIENTS AND METHODS: Women with stage III or IV breast cancer aged > or =70 years were enrolled in a phase II study aimed to evaluate both activity and toxicity of weekly paclitaxel. Among 46 planned patients, at least 18 responses and not more than seven unacceptable toxic events are required for a favourable conclusion. Paclitaxel 80 mg/m(2) was administered weekly for 3 weeks every 28 days. RESULTS: Unacceptable toxicity occurred in seven out of 46 patients evaluated for toxicity [15.2%; exact 95% confidence interval (CI) 7.6% to 28.2%] and was represented by one case of febrile neutropenia, one case of severe allergic reaction and five cases of cardiac toxicity. Among 41 patients evaluated for response, a complete response occurred in two (4.9%) patients and a partial response in 20 (48.8%), with an overall response rate of 53.7% (exact 95% CI 38.7% to 67.9%). The median progression-free survival was 9.7 months (95% CI 8.5-18.7) and median survival was 35.8 months (95% CI 19-not defined). CONCLUSIONS: Weekly paclitaxel is highly active in elderly advanced breast cancer patients. Data on cardiovascular complications, however, indicate the need for a careful monitoring of cardiac function before and during chemotherapy.

Randomised, open-label, phase II trial of paclitaxel, gemcitabine and cisplatin versus gemcitabine and cisplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium.

The purpose of the study was to evaluate the antitumor activity and the safety of paclitaxel combined with gemcitabine and cisplatin in patients affected by advanced transitional cell carcinoma of the urothelium (TCC). Eighty-five patients affected by advanced TCC and measurable disease were randomized to receive either paclitaxel at dosage of 70 mg/m2, gemcitabine 1000 mg/m2 and cisplatin 35 mg/m2 on days 1 and 8 every 3 weeks (GCP) or gemcitabine 1000 mg/m2 on days 1, 8, 15 and cisplatin 70 mg/m2 on day 2 every 4 weeks (GC). All enrolled patients were considered evaluable for response and toxicity (intention to treat). The observed response rate was 43% for GCP and 44% for GC combination, respectively. Median time to treatment failure was 32 weeks for GCP and 26 weeks for GC and overall survival 61 vs 49 weeks, respectively (p-value not significant). Grade 3-4 neutropenia was observed in 49% of patients treated with GCP vs 35% of those treated with GC (P=0.05) and grade 3-4 thrombocytopenia was observed in 36% of GCP treated patients as compared to 21% of those treated with GC (P=0.01). Seven patients over 70 years old or with poor PS were removed from the study: 6 patients from GCP group (2 toxic deaths, 2 grade 4 myelotoxicity and 2 grade 3 asthenia) and 1 from GC group was lost to follow-up after the first cycle. The combination of paclitaxel, gemcitabine and cisplatin is effective in the treatment of TCC. However, the addition of paclitaxel to the combination of gemcitabine plus cisplatin seems to increase toxicity, therefore it seems not suitable for poor PS patients and those over 70 years old. Larger and more powered studies are needed to exactly define the role of paclitaxel in this combination.

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.

An escalating dose finding study of liposomal doxorubicin and vinorelbine for the treatment of refractory or resistant epithelial ovarian cancer.

BACKGROUND: The aim of this study was to determine the maximum tolerated dose (MTD) of liposomal doxorubicin (LD)-vinorelbine (V) in patients with refractory or resistant ovarian cancer. PATIENTS AND METHODS: Thirty patients were eligible. Seven levels were studied [LD 25-V20 (three patients enrolled); LD 30-V20 (three); LD 35-V20 (three); LD 20-V25 (three); LD 25-V25 (three); LD 30-V25 (10); LD 35-V25 (five)]. LD was given on day 1, while V was given on days 1 and 8 every 21 days. Cohorts of three patients were enrolled at each level, and another three patients were planned, if one dose-limiting toxicity (DLT) was registered. RESULTS: DLT was observed in four patients: two febrile neutropenia, one grade 4 thrombocytopenia and one grade 3 palmar-plantar erythrodysesthesia (PPE) at level 7 (LD 35-V25). Thus, liposomal doxorubicin 30 mg/m(2) plus vinorelbine 25 mg/m(2) was the MTD. The most frequent toxicity was neutropenia. Fifteen patients (50%) experienced grade 3 neutropenia and 10 (33.3%) grade 4 neutropenia. Non-hematological toxicity was mild. Mucositis and PPE were the most frequent toxicities, but in most cases were grade 1. Out of 29 assessable patients, six (20.7%; 95% confidence interval 10%-39%) experienced an objective response, with one complete response. CONCLUSIONS: In patients with refractory or resistant ovarian cancer, the recommended doses for the combination studied are liposomal doxorubicin 30 mg/m(2) (day 1) plus vinorelbine 25 mg/m(2) (day 1 and 8). Neutropenia is the most frequent toxicity, while non-hematological toxicity is mild. Substantial activity was recorded and a phase II study is justified.

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.

Phase III multicenter randomized trial of amifostine as cytoprotectant in first-line chemotherapy in ovarian cancer patients.

BACKGROUND: A phase III multicenter randomized trial has been designed in order to address whether amifostine (WR-2721, Ethyol), an organic thiophosphate cytoprotector, can protect ovarian cancer patients from toxicity induced by carboplatin-paclitaxel chemotherapy. PATIENTS AND METHODS: Patients were randomly assigned to receive carboplatin [area under the curve (AUC) 5 mg.min/ml] and paclitaxel (175 mg/m(2)) with (arm A) or without (arm B) amifostine (910 mg/m(2)) every 21 days for six cycles. RESULTS: One-hundred and eighty-seven patients were accrued: 93 patients in arm A and 94 patients in arm B. There was no difference in terms of erythrocytopenia between the two arms; grade 3-4 thrombocytopenia was higher in arm A (3.3% versus 0.6%; P = 0.0010). There was no significant reduction of grade 3-4 leukopenia in arm A (11.8% versus 13.8%). The incidence of grade 3-4 neutropenia was lower in arm A (31.3% versus 37.9%; P = 0.03), as was the incidence of severe mucositis (4.7% versus 15.4% in arm A versus arm B, respectively; P <0.0001). Finally, amifostine appears to be protective against neurotoxicity (grade 3-4 neurotoxicity 3.7% versus 7.2%; P = 0.02). With a median follow-up of 24 months (range 2-41), time to progression was similar between the two groups. CONCLUSIONS: We showed that amifostine can exert some protection from the cumulative toxicity associated with this regimen. The results need to be confirmed in other randomized trials with this combination.