Paclitaxel-ifosfamide-carboplatin combination chemotherapy regimen in advanced uterine and adnexal malignant mixed Mullerian tumours.

BACKGROUND: Malignant mixed Mullerian tumours (MMMTs) of the uterus and adnexa represent aggressive gynaecologic malignancies with a high rate of loco-regional and distant failure. For that reason, we evaluated the paclitaxel-ifosfamide-carboplatin (TICb) combination in patients with advanced MMMTs. METHODS: Female patients with advanced MMMTs, WHO-PS 0-2, no prior chemotherapy for systemic disease, unimpaired haemopoietic and organ function were eligible. Chemotherapy was administered at the following doses; paclitaxel: 175 mg m(-2) on day 1, ifosfamide: 2.0 g m(-2) day(-1)--days 1 and 2, and carboplatin at a target area under the curve 5 on day 2, with prophylactic G-CSF from day 3. RESULTS: Forty patients of a median age 61 (45-72) years, performance status 0-2 with advanced MMMTs of the uterus (n=34), tubes (n=2) or ovary (n=4) have entered and all were evaluable for response and toxicity. Responses were as follows: 27 out of 40 (67.5%) evaluable patients responded, with 11 complete responses and 16 partial responses, while 10 had stable disease, and 3 developed progressive disease. The median response duration was 9 months (range, 4-40 months), median progression-free survival 13 months (range, 3-42 months), while median overall survival 18 months (range, 4-48 months). Grade 3/4 neutropenia was recorded in 22 out of 40 (55%)--with 13 developing grade 4 (≤7 days) and 7 out of 40 (17.5%) of patients at least one episode of febrile neutropenia. CONCLUSION: In this study, it appears that the TICb combination, yielded important activity with manageable toxicity in females with advanced MMMTs warranting further randomised comparison with current standard regimens.

Phase II study of liposomal cisplatin (Lipoplatin) plus gemcitabine versus cisplatin plus gemcitabine as first line treatment in inoperable (stage IIIB/IV) non-small cell lung cancer.

BACKGROUND: Lipoplatin is a new liposomal cisplatin designed to reduce cisplatin toxicities without reducing efficacy. In the present randomized phase II study, we examined the efficacy and safety of a Lipoplatin-gemcitabine versus a cisplatin-gemcitabine combination as first line treatment in advanced NSCLC. PATIENTS AND METHODS: Patients with advanced (stages IIIB-IV) NSCLC received up to six 21-day cycles of Lipoplatin 120 mg/m(2) (days 1, 8, 15) and gemcitabine 1000 mg/m(2) (days 1+8) (arm A; LipoGem) versus cisplatin 100mg/m(2) (day 1) and gemcitabine 1000 mg/m(2) (days 1+8) (arm B; CisGem). The primary objective was objective response rate (ORR). Secondary objectives were disease control rate (DCR), progression-free survival (PFS), duration of response and overall survival (OS). Another secondary objective was safety and tolerability of the LipoGem combination. RESULTS: Eighty-eight patients (n=88) entered the study; 47 patients were treated with LipoGem versus 41 patients treated with CisGem. Efficacy was assessed in patients who completed at least 1 cycle of treatment; ORR was 31.7% in arm A versus 25.6% in arm B and DCR was 70.7% versus 56.4%, respectively. A preliminary efficacy of LipoGem versus CisGem in the adenocarcinoma histological subtype of NSCLC showed 16.7% versus 45.8% PD. Treatment in arm A was better tolerated with myelotoxicity and a transient mild elevation of serum creatinine as the dominant side effects; the only grade 4 adverse event was neutropenia noted in 2% of the patients. There was a significant reduction in nephrotoxicity in the LipoGem arm (0% versus 5% grade III, p-value<0.001) as well as in nausea vomiting (2% versus 12% grade III, p-value<0.001). In addition, less antiemetics and G-CSF were administered in arm A. CONCLUSION: Overall, Lipoplatin appears to have lower toxicity, mainly renal toxicity as well as higher efficacy than cisplatin when combined with gemcitabine in advanced NSCLC.

Evaluation of the paclitaxel-ifosfamide-cisplatin (TIP) combination in relapsed and/or metastatic cervical cancer.

BACKGROUND: Recurrent or metastatic cervical cancer represents an aggressive malignancy with a high rate of locoregional and distant failure. Therefore, we evaluated the three-drug combination of paclitaxel-ifosfamide-cisplatin (TIP). METHODS: Systemic chemotherapy-naive patients with advanced metastatic/relapsed cervical cancer and a World Health Organization (WHO) performance status (PS) of 0-2 were eligible. TIP chemotherapy doses were paclitaxel 175 mg m(-2) on day 1, ifosfamide 2.5 g m(-2) on days 1+2, and cisplatin 40 mg m(-2) on days 1+2, with prophylactic granulocyte-colony stimulating factor. RESULTS: A total of 42 patients with recurrent/metastatic cervical cancer are evaluable for response and toxicity: median age: 56 (25-74) years; PS: 1 (0-2); histologies - squamous: 35, adenosquamous: 5, and adenocarcinoma: 2. Responses were overall response rate (RR): 62% (95% confidence interval (CI): 47.3-76.7%), with complete response (CR): 26% (95% CI: 12.7-39.3%), and partial response (PR): 36% (95% CI: 21.5-49.9%). Responses according to the relapse site were overall RR: 32% (95% CI: 13.7-50.3%) within previously irradiated pelvis vs 75% (95% CI: 57.7-92.3%) in extra-pelvic sites. Median time to progression (TTP) was 7 (range, 2-34+) months and median overall survival (OS) was 16.5 (range, 3-36+) months. Toxicities included grade 3-4 neutropenia: 83% (21% febrile neutropenia), grade 3-4 thrombocytopenia: 9%, no grade 3 neuropathy (35% grade 2), grade 2 asthenia/fatigue 15%, and no treatment-related deaths. CONCLUSION: TIP is an active regimen with acceptable toxicity in advanced/relapsed cervical cancer.

Multicenter phase-II trial of irinotecan plus oxaliplatin [IROX regimen] in patients with poor-prognosis cancer of unknown primary: a hellenic cooperative oncology group study.

BACKGROUND: Cancer of unknown primary (CUP) lacks established therapy although it affects 3% of cancer patients. We evaluated the irinotecan-oxaliplatin combination (IROX regimen) in previously untreated patients with non-favorable subsets of unknown primary carcinomas. METHODS: This was a multicenter phase-II trial. Protocol treatment consisted of oxaliplatin 80 mg/m(2) followed by irinotecan 160 mg/m(2) administered every 3 weeks. The primary end points were response rate and toxicity, and secondary end points were time to progression and survival. RESULTS: Forty-seven patients with liver, bone or multiple visceral metastases entered into the trial and received a median 6 chemotherapy cycles (1-11). The regimen was very well tolerated with one febrile neutropenia case and six cases with diarrhea grade 3 (16%). In intent-to-treat analysis the tumor response rate was 13% (95% CI = 4.8-25.7%) and 12 patients (27%, 95%CI 13.9-40.4%) had at least 4 months' duration of disease stabilization. The median time to progression was 2.7 months and the median survival was 9.5 months, with 40% of patients alive at 1 year. CONCLUSIONS: The IROX regimen demonstrated similar efficacy and a favorable toxicity profile compared to other more toxic chemotherapy combinations in patients with poor-prognosis CUP.

Docetaxel-ifosfamide combination in patients with advanced breast cancer failing prior anthracycline-based regimens: results of a phase I-II study.

The established clinical activity of docetaxel and ifosfamide as single agents in anthracycline pre-treated breast cancer, led us to conduct a phase I-II study to define the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and clinical activity of the docetaxel+ifosfamide combination in this setting. Patients with histologically confirmed metastatic breast cancer, after failure on prior anthracycline-based chemotherapy, were treated at successive dose levels (DLs) in cohorts of 3-6 with escalated doses of docetaxel 70-100 mg/m(2) over 1 h on day 1 followed by ifosfamide 5-6 g/m(2) divided over days 1+2 (2.5-3.0 g/m(2)/day over 1 h), every 21 days. G-CSF was added once dose-limiting neutropenia was encountered at a certain DL and planned to be incorporated prophylactically in subsequent higher DLs. Between March 1997 and December 2002, 65 patients with a median age of 57 years (range, 32-72) and performance status (WHO) of 1 (range, 0-2) were treated at 5 DLs as follows; 21 in phase I DLs (DL1: 3, DL2: 6, DL3: 3, DL4: 6, and DL5: 3) and the remaining 44 were treated at DL4 (total of 50 patients at DL4), which was defined as the level for phase II testing. All patients were assessable for toxicity and 62 for response. DLT (with the addition of G-CSF after DL2) was reached at DL5 with 2/3 initial patients developing febrile neutropenia. Clinical response rates (RRs), on an intention-to-treat basis, in phase II were: 56%; (95% CI, 42.2-69.7%); 4 CRs, 24 PRs, 10 SD and 12 PD. The median response duration was 7 mo (3-24 mo), median TTP 6.5 mo (0.1-26 mo), and median OS 13 mo (0.1-33 mo). Grade 3/4 toxicities included: neutropenia in 72% of patients, with 60% developing grade 4 neutropenia (

HER-2/neu status of primary breast cancer and corresponding metastatic sites in patients with advanced breast cancer treated with trastuzumab-based therapy.

BACKGROUND: The aim of this prospective study was to investigate whether there were changes in HER-2/neu status in newly-developed metastatic lesions following treatment with trastuzumab in advanced breast cancer patients overexpressing HER-2/neu. The utility of serological assays for HER-2/neu in such patients was also studied. PATIENTS AND METHODS: Sixteen patients with HER-2/neu-overexpressing tumors (15 were 3+ by immunohistochemistry (IHC) and one 2+ by IHC and positive by the chromogenic in situ hybridization (CISH) test) were included in the study. Fourteen patients underwent biopsy and 2 patients fine-needle aspiration (FNA) of newly-developed metastatic lesions following trastuzumab treatment. All samples were assayed for HER-2 by IHC and by the CISH test. Serial serum HER-2/neu (S-HER-2) levels were measured prior to (baseline values) and during trastuzumab-based treatment by enzyme-linked immunosorbent assay (ELISA) (cut-off point: 10 ng/ml) in all patients. The patients were divided into 2 groups: those with "altered HER-2/neu status" and those with "conserved HER-2/neu status" in the metastatic region. RESULTS: Six out of the 16 (37%) ("altered HER-2/neu status") newly-developed metastatic lesions lost their HER-2/neu overexpression and scored 0 or +1 by IHC or negative on the CISH test, while in the remaining cases (10/16, 62.5%) ("conserved HER-2/neu status"), the HER-2/neu status was unchanged (+3 by IHC or a positive CISH test). Baseline S-HER-2 levels were elevated in 5 out of 16 patients (3 of "altered HER-2/neu status", 2 of "conserved HER-2/neu status"). The serum HER-2 (S-HER-2) levels declined and returned within the normal ranges in all these 5 patients as a response to trastuzumab treatment. Following the disease progression, the S-HER-2 levels of the 3 patients with "altered HER-2/neu status" remained normal, while those of 2 with "conserved HER-2/neu status" increased. There was no statistically significant difference in the number of chemotherapeutic treatments or the median time of treatment with trastuzumab or chemotherapy between the 2 groups. Time to tumor progression (TTP) was significantly shorter in the "altered HER-2/neu status" patients (median TTP for "altered HER-2/neu status": 9.5 months, and for "conserved HER-2/neu status": 12 months; p <0.001). CONCLUSION: These data suggest that, for most patients with metastatic breast cancer treated with trastuzumab, the HER-2/neu expression as measured by IHC and/or CISH in newly-developed metastatic lesions was unchanged. However, a remarkable percentage of cases lost HER-2/neu overexpression. It is not clear whether this finding implies resistance or sensitivity to trastuzumab.

Comparison of docetaxel and docetaxel-irinotecan combination as second-line chemotherapy in advanced non-small-cell lung cancer: a randomized phase II trial.

BACKGROUND: The aim of this study was to evaluate whether docetaxel (taxotere) treatment with or without irinotecan improved patient outcomes with similar toxicity in recurrent non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with recurrent platinum-refractory NSCLC with Eastern Cooperative Oncology Group performance status of 0-2 were randomized to either docetaxel 30 mg/m(2) and irinotecan 60 mg/m(2) (days 1 and 8) or docetaxel 75 mg/m(2) (day 1), both administered every 3 weeks. RESULTS: A total of 130 patients were randomized. The response rate (RR) (20% versus 14%), overall survival (6.5 months versus 6.4 months) and 1-year survival (37% versus 34%) were similar in the combination and docetaxel arms, respectively. The combination arm demonstrated a longer time to tumor progression (TTP) (5.6 versus 4.8 months; P=0.065). Grade 3-4 neutropenia and anemia were similar in the combination and docetaxel arms. Grades 3-4 non-hematological toxicity (except diarrhea) was mild and was similar in the two groups. Grade 3-4 thrombocytopenia (17% versus 6%; P=0.04) and diarrhea (12% versus 3%; P=0.05) occurred more frequently in the combination arm. CONCLUSIONS: The administration of irinotecan with docetaxel in platinum-refractory NSCLC prolonged TTP, but did not improve significantly RR, median survival or 1-year survival. Second-line docetaxel monotherapy offers significant and reproducible efficacy in platinum-refractory NSCLC.

Dose escalation of docetaxel and ifosfamide in patients with advanced breast cancer failing prior anthracyclines: mature results of a phase I-II study.

PURPOSE: Single-agent docetaxel and ifosfamide are clinically active in anthracycline-pretreated advanced breast cancer. We conducted a phase I-II study aiming to define the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), and the activity of the docetaxel-ifosfamide combination in this setting. PATIENTS AND METHODS: Cohorts of 3-6 patients with histologically confirmed metastatic breast cancer after prior anthracycline-based chemotherapy were treated at successive dose levels (DLs) with escalated doses of docetaxel (70-100 mg/m(2) over 1 h on day 1), followed by ifosfamide 5-6 g/m(2) divided over days 1 and 2 (2.5-3.0 g/m(2)/day over 1 h), and recycled every 21 days. G-CSF was added once dose-limiting neutropenia was encountered at a certain DL and planned to be incorporated prophylactically in subsequent higher DLs. RESULTS: Sixty-five patients (median age 57 years, range 32-72) and performance status (PS) (World Health Organization-WHO) of 1 (range 0-2) were treated at 5 DLs as follows: 21 in phase I DLs (DL1: 3, DL2: 6, DL3: 3, DL4: 6, and DL5: 3) and the remaining 44 were treated at DL4 (total of 50 patients at DL4), which was defined as the level for phase II testing. All patients were evaluable for toxicity and 62 for response. DLT (with the addition of G-CSF after DL2) was reached at DL5 with 2/3 initial patients developing febrile neutropenia. Clinical response rates (RRs), on an intention-to-treat basis, in phase II were 56% (95% CI 42.2-69.7): complete remission (CR) 4, partial remission (PR) 24, stable disease (SD) 10 and progressive disease (PD) 12. The median response duration was 7 months (range 3-24), the median time to progression (TTP) 6.5 months (range 0.1-26), and the median overall survival (OS) 13 months (range 0.1-33). Grade 3/4 toxicities included neutropenia in 72% of patients-with 60% developing grade 4 neutropenia (

Gemcitabine and oxaliplatin (GEMOX) in patients with cisplatin-refractory germ cell tumors: a phase II study.

BACKGROUND: To investigate the efficacy and toxicity of the combination of gemcitabine and oxaliplatin (GEMOX) in patients with relapsed or cisplatin-refractory non-seminomatous germ cell tumors (NSGCT). PATIENTS AND METHODS: Twenty-nine patients with relapsed or cisplatin-refractory NSGCT were treated with gemcitabine 1000 mg/m2 on days 1 and 8 followed by oxaliplatin 130 mg/m2 on day 1 every 3 weeks for a maximum of six cycles. Twenty-four patients (83%) were considered refractory and five (17%) absolutely refractory to cisplatin. RESULTS: Twenty-eight patients were assessable for response. Overall, nine patients (32%) achieved a favourable response (complete response, four; partial response, five). One of the complete responders relapsed after 7 months and went into disease-free status lasting for 11+ months after resection of lung metastases. The rest of the complete responders are continuously disease-free at 14+, 19+ and 28+ months with the study regimen plus or minus surgery. One of the complete responders had absolutely cisplatin-refractory disease and another one presented with a late relapse. Toxicity was primarily hematological and generally manageable: 62% of patients experienced grade 3/4 neutropenia, 10% neutropenic fever and 41% grade 3/4 thrombocytopenia. Non-hematological toxicity consisted mainly of nausea/vomiting. Three patients (10%) developed grade 3 neurotoxicity and discontinued treatment. CONCLUSIONS: The combination of GEMOX is an active, moderately toxic and easily administered regimen in patients with relapsed or cisplatin-refractory NSGCT. The 14% long-term disease-free status accomplished in this heavily pretreated patient population is quite encouraging.

Oxaliplatin plus high-dose leucovorin and 5-fluorouracil in pretreated advanced breast cancer: a phase II study.

BACKGROUND: The purpose of this study was to evaluate the efficacy and toxicity of oxaliplatin plus 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes. PATIENTS AND METHODS: Fifty anthracycline- and taxane-pretreated MBC patients were treated with oxaliplatin 85 mg/m(2) as a 2-h infusion on day 1, LV 200 mg/m(2)/day as a 2-h infusion followed by bolus 5-FU 400 mg/m(2)/day and a 22-h infusion of 5-FU 600 mg/m(2)/day for 2 consecutive days. Treatment was repeated every 3 weeks. Patients were evaluated for response every two cycles. RESULTS: The median age was 51 years (range 34-75). Twenty patients (40%) had received three or more chemotherapeutic regimens, 64% had three or four metastatic sites and 78% had visceral metastases. All patients had prior exposure to anthracyclines and taxanes. Based on an intention-to-treat analysis, one patient (2%) achieved a complete response and 16 (32%) a partial response, for a 34% overall response rate. Twenty-one patients (42%) had stable disease and 12 (24%) progressive disease. The median time to tumor progression was 5.3 months (range 0.5-12.8) and the median overall survival was 12.3 months (range 0.5-19.2). Toxicity was mild to moderate. Grade 3/4 neutropenia and thrombocytopenia occurred in 32% and 18%, respectively. Febrile neutropenia was experienced by three patients (6%), who were successfully treated. Grade 3/4 neurotoxicity was reported in 14% of the patients and gradually declined after treatment discontinuation. Cycle delays were reported in 28% of patients and dose reductions in 26%. Alopecia, nausea-vomiting, diarrhea and mucositis were not significant. There were no treatment-related deaths. CONCLUSION: The combination of oxaliplatin plus 5-FU/LV seems to be an active regimen in patients with MBC and prior exposure to anthracyclines and taxanes with a good safety profile. The incidence of severe toxicity was quite low and the compliance of patients to the treatment was satisfactory. The results obtained with this regimen could be considered encouraging in this heavily pretreated group of breast cancer patients with a high incidence of visceral metastases.

Docetaxel in combination with dacarbazine in patients with advanced melanoma.

OBJECTIVES: The number of agents that are active in patients with metastatic melanoma is limited and cure is not a realistic objective for treatment at this stage. The aim of the study was to evaluate the efficacy and safety of new combination regimen cosisting of docetaxel and dacarbazine (DTIC), as first-line chemotherapy, in patients with advanced melanoma. PATIENTS AND METHODS: Patients with advanced melanoma (including cerebral metastases) were eligible. Docetaxel 80 mg/m(2), i.v. over 1 h infusion on day 1, and DTIC 400 mg/m(2), i.v. over 45 min on days 1 and 2, were given every 21 days, for six cycles. All patients were premedicated, prior to each course, with methylprednisolone per os. RESULTS: Forty-one patients entered the study. Thirty-nine were assessable for response and 40 for toxicity. Objective responses were seen in 10 patients (24% of the eligible; 95% CI = 12.4-40.3%, 26% of the assessable and 28% of patients with cerebral metastases were excluded). Three of them achieved a complete response (7%; 95% CI = 1.5-19.9) and 7 a partial response (17%; 95% CI = 7.1-32.0), while 8 patients demonstrated stabilization of their disease (20%; 95% CI = 8.8-34.9). After a median follow-up of 20 months, the median time to progression was 7 months (range 0.5-22) and the median survival was 10 months (1-24+). The main toxicity (G3-4) was neutropenia which occurred in 8/40 (20%) patients. Additional patients had reversible G3-4 toxicities including alopecia, nausea and vomiting and fatigue; 3 of them presented mild to moderate hypersensitivity reactions to docetaxel. No toxic death was noted. CONCLUSIONS: The combination of docetaxel and DTIC is active and well tolerated in patients with advanced melanoma. While this combination is at least as effective as various combination regimens, it does not differ from that reported for single-agent DTIC.

Paclitaxel (175 mg/m2) plus carboplatin (6 AUC) versus paclitaxel (225 mg/m2) plus carboplatin (6 AUC) in advanced non-small-cell lung cancer (NSCLC): a multicenter randomized trial. Hellenic Cooperative Oncology Group (HeCOG).

PURPOSE: The combination of paclitaxel and carboplatin has become a widely used regimen in NSCLC due to phase II reports of moderate toxicity, reasonable activity and easy outpatient administration. Purpose of our present prospective study was to evaluate the dose response relationship of paclitaxel. PATIENTS AND METHODS: Since July 1996, 198 patients with non-operable NSCLC and measurable disease without previous chemotherapy entered the trial. Ninety nine patients (group A) were randomized to receive paclitaxel 175 mg/m2 in three-hour infusion plus carboplatin dosed to an area under the concentration-time curve of 6 every 3 weeks and 99 (group B) to receive the same regimen with paclitaxel increased to 225 mg/m2. Eligibility criteria included WHO performance status 0-2, documented inoperable stage IIIA and IIIB, IV, no brain metastasis, no prior chemotherapy and adequate renal and hepatic function. Patients in both groups were well-matched with baseline disease characteristics. RESULTS: In group A with 90 evaluable patients, the response rate was 25.6% (6 CR, 17 PR) whereas in group B with 88 evaluable patients, the response rate was 31.8% (3 CR, 25 PR), P = 0.733. Median time to progression favored the high-dose paclitaxel (4.3 vs. 6.4 months, P = 0.044). The median survival was 9.5 months for group A versus 11.4 months for group B (P = 0.16). The one-year survival was 37% for group A and 44% for group B (P = 0.35). The best prognostic factor for one-year survival was the response rate (P < 0.0001). With a relative dose intensity of paclitaxel 0.94 in both groups, neurotoxicity (P = 0.025) and leucopenia (P = 0.038) were more pronounced in group B patients. No toxic death was observed. CONCLUSIONS: Higher dose paclitaxel prolongs the median time to progression but causes more neurotoxicity and leucopenia. The better response rate, the longer overall and better one-year survival seen with the higher dose of paclitaxel are not statistically significant.

Combination chemotherapy with paclitaxel plus carboplatin versus paclitaxel plus gemcitabine in inoperable non-small cell lung cancer: a phase III randomized study. Preliminary results. Hellenic Cooperative Oncology Group.

Gemcitabine plus paclitaxel and paclitaxel plus carboplatin are active and well tolerated in patients with advanced non-small cell lung cancer, showing similar rates of response and survival. The Hellenic Cooperative Oncology Group conducted a randomized phase III trial comparing gemcitabine plus paclitaxel with paclitaxel plus carboplatin. Patients were randomly assigned to two groups. Group A received paclitaxel 200 mg/m2 plus carboplatin (area under the curve = 6) on day I. Group B received paclitaxel in identical fashion to group A plus gemcitabine 1,000 mg/m2 on days I and 8 every 3 weeks. A minimum of two cycles and a maximum of six cycles was allowed. To date, 127 eligible patients (63 in group A and 64 in group B) have been randomized; the median follow-up time is 4.6 months. Preliminary results suggest that both combinations can be given in full doses and are well tolerated. Grade 3/4 neutropenia was mild but more prominent in group A (10% v 3%, respectively) while thrombocytopenia was not significant for either group. Moreover, severe neurotoxicity, hepatotoxicity, or cardiac toxicity has not been observed in the vast majority of patients in either group. Although patients in group B experienced higher response rates (37.5%) than those in group A (21.8%), the difference between the groups was not statistically significant. Definite conclusions about this study cannot be made until more data are available.

Phase II study of pegylated liposomal doxorubicin: inactive in recurrent small-cell lung cancer. A Hellenic Cooperative Oncology Group Study.

PURPOSE: Although clinical experience with liposomal doxorubicin is still limited in solid tumours, single agent Caelyx (pegylated liposomal doxorubicin) treatment has shown promising results in AIDS-related Kaposi's sarcoma, metastatic breast and ovarian cancer and anecdotally in other solid tumours. This is the first report of its use in small-cell lung cancer (SCLC). The objective of this multicenter phase II study was to evaluate the safety, tolerance and anti-tumour activity of Caelyx as monotherapy in patients with recurrent SCLC. PATIENTS AND METHODS: A total of 14 patients with recurrent SCLC who had not received prior treatment with doxorubicin, were accrued into this phase II study. All patients had progressed or relapsed after first-line chemotherapy. All but one had achieved objective responses to first-line treatment with median duration of five months (range 2-18 months) but half of them had experienced 'refractory' relapses (within 3-4 months). Study treatment consisted of Caelyx 50 mg/m2 (1-hour i.v infusion every 4 weeks for 6 cycles). RESULTS: No responses were seen but in three patients disease was stabilised for a median of three months. The median number of cycles was 2 per patient, with 11 of 14 patients not completing 6 cycles of Caelyx treatment. From those, five patients were removed from the study after only one cycle due to rapid disease progression, and one was withdrawn after three cycles due to prolonged toxicity. Overall, treatment was well tolerated with no episodes of grade 4 toxicity and only two episodes of grade 3 toxicities: one of thrombocytopenia and one of prolonged palmar-plantar erythrodysesthesia (PPE). CONCLUSIONS: These results demonstrate limited activity of Caelyx in this patient population, which may be related to the poor prognostic features of such patients. Our findings are in agreement with previous observations that doxorubicin-containing combinations are rarely active in platinum/etoposide failures. However, as in other studies the favourable toxicity profile of Caelyx is confirmed.

Parameters that influence the outcome of nausea and emesis in cisplatin based chemotherapy.

Some factors have demonstrated an influence on emesis and antiemetic response. In order to study these factors, 306 patients (pts) entered this study receiving cisplatin based combination chemotherapy (CT) (100 mg/m3, with ondansetron (8 mg, 3 times daily for 4 days) as the only antiemetic treatment. Known factors that influence the result of antiemetic therapy such as age, sex, performance status (Karnofsky), site of primary tumor, weight loss, anxiety, depression, psychological problems related to CT (psychological PRC) etc, were included in the evaluation. We evaluated the number of vomits, retches and nausea. The existence of psychological PRC was found to be a prominent factor for the development of nausea and emesis, being at the same time strongly associated with scaling variables (Gralla, retching and nausea grading) used to measure the severity of nausea and emesis (p = 0.001). Stress was also a significant predictor; patients with stress had an almost two times higher probability to develop nausea or retching compared to patients without stress indications (p = 0.001), while the occurrence of retching was marginal. Younger patients (less than 40 years old) were found to be almost three times more susceptible to retching compared to older patients (more than 40 years old) (P 0.006). With all possible evaluations, we concluded that significant factors are psychological PRC, stress and age. In conclusion, three factors, age, stress and psychological PRC, should be taken seriously into consideration in the design of future trials evaluating antiemetic treatment, as well as in the every-day clinical practice, in order to provide patients with a better quality of life during emetogenic CT.

Combination chemotherapy with low doses of weekly Carboplatin and oral Etoposide in poor risk small cell lung cancer.

Sixty patients with poor prognostic features, either with extensive disease (ED) or limited disease (LD) small cell lung cancer (SCLC), were treated on an out-patient basis with Carboplatin 80 mg/m2 weekly for 3 weeks and oral Etoposide, at a dose of 100 mg, every other day for 21 days. The treatment was repeated every 5 weeks. Responding patients with LD were also treated with thoracic irradiation and those who achieved complete response (CR) received prophylactic cranial radio-therapy. The overall response rate (RR) was 32.1% with 8.9% CR. The responses were better for LD (RR 58.3%, CR 25%, partial response, PR 33.3%), than those for ED (RR 25%, CR 4.5%, PR 20.5%). The median time to progression (TTP) was 4.8 months and the median survival 5.5 months. These poor results could be attributed to the bad performance status and the presence of visceral and brain metastases in this group of patients. The results could also be due to the lower maximum concentration (Cmax) and higher T1/2 of Etoposide, as measured in the blood and urine probably due to the modified regimen used in our study and to the organ insufficiency in this selected group of patients. Although, toxicity was generally mild and manageable, two toxic deaths occurred. In conclusion, this regimen appears to have a lower efficacy in terms of response and survival than that obtained in other studies using Cisplatin or Carboplatin plus Etoposide in a similar way. Therapy with this regimen, though less toxic, may not be a reliable alternative in elderly patients with visceral metastases and ECOG performance status > or = 2.

A randomized comparative study of antiemetic prophylaxis with ondansentron in a single 32-mg loading dose versus 8 mg every 6 h in patients undergoing cisplatin-based chemotherapy.

In several studies a single dose of 32 mg was compared to an ondansentron (OND) administration schedule of every 6 h, yielding no differences in overall efficacy. The aim of this randomized comparative study was to identify differences of these two schedules on an hour-to-hour control of nausea and vomiting, during the first 24 h in patients receiving cisplatin (CDDP)-based chemotherapy. One hundred ten patients were randomly assigned to two groups (A and B); all received combination chemotherapy with CDDP at a dose of 100 mg/m2. OND was administered as follows: group A: 8 mg, 30 min before the infusion of CDDP, and repeated every 6 h after the first dose (totally 4 doses) in the first 24 h, and group B: 32 mg before CDDP, as a loading dose and this was the total dose for the first 24 h. No overall difference was noticed during the first 24 h, as well as the next 3 days from the infusion of CDDP in the intensity of vomits, vomits without gastric content (retches), and nausea. In a more detailed monitoring of the distribution of emetic episodes during the first 24 h, there were important differences between these two antiemetic schedules: for group A an increased vomiting with or without gastric content between midnight and 6 p.m. was observed, and for group B between 6 p.m. and midnight (vomits with p 0.03, and without gastric content p 0.02). Preloading with the total 24-hour dose of OND 32 mg exhibits a more potent antiemetic activity during the initial 18 h, becoming weaker over the last 5 h of the first day, whereas the every-6-hour schedule leaves periods of poor emesis control between dosing intervals.

Factors that influence the antiemetic activity of metoclopramide to cisplatin based chemotherapy.

Some clinical parameters play a role in developing effective antiemetic therapy. In the present study, 310 patients entered and 301 were evaluable. They received cisplatin based combination chemotherapy (100 mg/m2), with antiemetic therapy based in metoclopramide, at a standard dose and schedule (2 mg/kg in 5 doses). Patient characteristics such as age, sex, performance status (Karnofsky), site of primary tumor, weight loss >15%, previous chemotherapy, previous radiotherapy, history of vomiting during pregnancy, additional drugs (dexamethasone, alprazolam), in the antiemetic regimen were included in the evaluation. We also studied the manifestation of anxiety and depression and the presence of psychosocial problems related to therapy, evaluated them with specific psychological indexes modified for our study. We evaluated incidence of vomiting, retches, and nausea, with several scales. We distinguished three groups of factors influencing nausea and vomiting. Factors that predicted for increased nausea and vomiting was gender (women), stress and age (younger patients experienced more prolonged duration and higher grades of nausea). The addition of alprazolam (a sedative drug) and dexamethasone, was associated with decreased incidence of nausea and vomiting. The weight loss (increased nausea and decreased vomiting control according to Gralla's scale). Previous chemotherapy decreased the number of patients without nausea and vomiting control according to Gralla's scale. Patients with previous radiotherapy presented an increased grade of nausea. Patients with head and neck cancer presented less nausea with shorter duration, less frequent episodes of vomiting. Patients with ovarian cancer presented increased mean number of retches. In conclusion, despite difficulties in assessing nausea and vomiting among clinical trials, several factors, especially stress, gender, weight loss, additional drugs (corticosteroids and sedatives) may play an important role in modulating the antiemetic response.

Paclitaxel (175 mg/m2) plus carboplatin versus paclitaxel (225 mg/m2) plus carboplatin in non-small cell lung cancer: a randomized study.

A recent phase II study by our group documented a response rate of 27% with the combination paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) 175 mg/m2 plus carboplatin dosed to a target area under the concentration-time curve of 7 in patients with advanced non-small cell lung cancer. In an effort to evaluate the dose-response relationship of paclitaxel with quality of life, we initiated a phase III prospective trial. Patients with inoperable non-small cell lung cancer were randomized into two groups. Group A received paclitaxel 175 mg/m2 plus carboplatin dosed to an area under the concentration-time curve of 6 every 3 weeks. Group B received the same regimen, with paclitaxel increased to 225 mg/m2. Since July 1996, 49 patients have entered the study, 29 in group A and 20 in group B. Patient and tumor characteristics were well distributed between both groups. In group A, 16 patients were evaluable, with one complete response, six partial responses, three stable disease, and six progressive disease. In group B, 12 patients were evaluable, with two partial responses, four stable disease, and six progressive disease. Treatment was well tolerated in both groups. More neurotoxicity and neutropenia were noticed with high-dose paclitaxel. There were no drug-related deaths. It is too early to draw definite conclusions regarding response and survival, but regarding toxicity, it seems that paclitaxel 225 mg/m2 plus carboplatin dosed to an area under the concentration-time curve of 6 is well tolerated without the use of growth factors. Although the results are premature, quality of life does not seem to be affected by the increased paclitaxel dose.

Paclitaxel and carboplatin in inoperable non-small-cell lung cancer: a phase II study.

BACKGROUND: Based on the high activity of single-agent paclitaxel and the superior one-year survival rates of patients with non-small-cell lung cancer (NSCLC) treated with carboplatin, a phase II trial was initiated using both agents in patients with inoperable stages III and IV disease to investigate the efficacy and toxicity of the combination. PATIENTS AND METHODS: Since July 1995, 60 patients fulfilling all eligibility criteria entered this study. All patients received paclitaxel 175 mg/m2 as a three-hour infusion, and carboplatin dosed to an area under the concentration-time curve of seven, every three weeks. No granulocyte colony-stimulating factor was given. Of the 56 male and four female patients, the median age was 57 years (range 29 to 75 years) and the median Eastern Co-Operative Oncology Group performance status was one. Most of the patients had stage IV (34) adenocarcinoma (31) with low differentiation (28). The median number of chemotherapy cycles was three, with a range of one to eight. RESULTS: Of 55 evaluable patients, 15 (27.3%) achieved partial responses, 15 (27.3%) had stable disease, and 25 (45.4%) had progressive disease. The median survival was 8.95 months and 21.6% of the patients survived more than one year. Grade 2/3 nonhematologic toxicity included alopecia (59%), neurotoxicity (3%), and myalgia/arthralgia (10%). Grade 2/3 neutropenia occurred in 14% of patients, whereas grade 3/4 thrombocytopenia was seen in only 4%. One patient died of complications of a severe allergic reaction. CONCLUSION: Combination treatment using paclitaxel and carboplatin is active and well tolerated in patients with inoperable non-small-cell lung cancer. The dose-response relationship to paclitaxel and results of comparison with other platinum-based regimens remain to be determined.