Phase III randomized study of fotemustine and dacarbazine versus dacarbazine with or without interferon-α in advanced malignant melanoma.

BACKGROUND: The effect of the addition of fotemustine and/or interferon (IFN) to standard therapy with dacarbazine alone in patients with advanced malignant melanoma was investigated in a multicenter, randomized 2x2 factorial design trial. METHODS: A total of 260 patients were randomly assigned to one of four treatment groups: (A) fotemustine and dacarbazine repeated on 3-week cycle; (B) same treatment as (A) plus IFN-α2b three times per week; (C) dacarbazine alone repeated on 3-week cycle; (D) same treatment as (C) plus IFN-α2b three times per week. Two comparisons were planned to assess the efficacy of fotemustine (groups A+B vs. C+D) and IFN-α2b (groups A+C vs. B+D). RESULTS: Addition of fotemustine did not significantly improve overall survival (OS) (p=0.28) or progression-free survival (PFS) (p=0.55); Hazard ratio (HR) for OS was 0.93 (95% CI 0.71-1.21). Similarly, addition of IFN-α2b did not improve OS (p=0.68) or PFS (p=0.65); HR for OS was 0.92 (95% CI 0.70-1.20). Overall response rate was not improved by the addition of either fotemustine (p=0.87) or IFN-α2b (p=0.57). The combination of all three drugs resulted in the highest occurrence of adverse events. CONCLUSIONS: No significant improvement in outcomes were observed with the addition of either fotemustine or IFN-α2b to dacarbazine. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01359956.

Factors predicting the occurrence of germline mutations in candidate genes among patients with cutaneous malignant melanoma from South Italy.

Clinical predictors for germline mutations of candidate genes in large clinic based population of patients with cutaneous malignant melanoma (CMM) are widely awaited. Using denaturing high-performance liquid chromatography (DHPLC) analysis and DNA sequencing, 557 consecutively-collected CMM patients originating from South Italy were screened for CDKN2A germline mutations; subsets of them were screened for mutations in the BRAF and BRCA2 genes. Seven CDKN2A mutations were detected in 14 (2.5%) CMM patients. Relative risk of carrying a CDKN2A mutation for CMM patients was demonstrated to significantly increase with the presence of familial recurrence of melanoma (risk ratio (RR)=6.31; p=0.0009), multiple primary melanomas (RR=3.43; p=0.0014), and early onset age (RR=4.56; p=0.0026). All CDKN2A mutations were observed in non-Sardinian patients (14/441; 3.2%), whereas BRAF and BRCA2 genes were found mutated in Sardinian patients (3/116; 2.6%). Such indicators of the presence of CDKN2A mutations will be useful in counselling patients about undergoing genetic testing. Our findings strongly suggest that mutation rates of candidate cancer genes may deeply vary among CMM patients from different geographical areas.

Serial detection of circulating tumour cells by reverse transcriptase-polymerase chain reaction assays is a marker for poor outcome in patients with malignant melanoma.

BACKGROUND: Detection of circulating malignant cells (CMCs) through a reverse transcriptase-polymerase chain reaction (RT-PCR) assay seems to be a demonstration of systemic disease. We here evaluated the prognostic role of RT-PCR assays in serially-taken peripheral blood samples from patients with malignant melanoma (MM). METHODS: One hundred forty-nine melanoma patients with disease stage ranging from I to III were consecutively collected in 1997. A multi-marker RT-PCR assay was used on peripheral blood samples obtained at time of diagnosis and every 6 months during the first two years of follow-up (total: 5 samples). Univariate and multivariate analyses were performed after 83 months of median follow-up. RESULTS: Detection of at least one circulating mRNA marker was considered a signal of the presence of CMC (referred to as PCR-positive assay). A significant correlation was found between the rate of recurrences and the increasing number of PCR-positive assays (P = 0.007). Presence of CMC in a high number (> or =2) of analysed blood samples was significantly correlated with a poor clinical outcome (disease-free survival: P = 0.019; overall survival: P = 0.034). Multivariate analysis revealed that presence of a PCR-positive status does play a role as independent prognostic factors for overall survival in melanoma patients, adding precision to the predictive power of the disease stage. CONCLUSION: Our findings indicated that serial RT-PCR assay may identify a high risk subset of melanoma patients with occult cancer cells constantly detected in blood circulation. Prolonged presence of CMCs seems to act as a surrogate marker of disease progression or a sign of more aggressive disease.

Cisplatin and gemcitabine with either vinorelbine or paclitaxel in the treatment of carcinomas of unknown primary site : results of an Italian multicenter, randomized, phase II study.

BACKGROUND: : To date, the standard treatment for patients who have carcinoma of unknown primary site has not been established. METHODS: : In this randomized Phase II study, 66 previously untreated patients (33 patients per arm) with carcinomas of unknown primary site received cisplatin (35 mg/m2) and gemcitabine (1000 mg/m2) with either paclitaxel (70 mg/m2) or vinorelbine (25 mg/m2), and all drugs were administered intravenously on Days 1 and 8 of a 21-day cycle. Twenty-nine patients (44%) presented with > or =2 involved sites. The pathologic diagnosis was mainly adenocarcinoma (48 patients; 72.7%) and squamous carcinoma (7 patients; 10.6%). RESULTS: : In the first arm, 16 patients (48.5%) experienced an objective response, and 9 patients (27.2%) had disease stabilization. In the vinorelbine-containing arm, 14 patients (42.3%) experienced an objective response, and 8 patients (24.2%) had disease stabilization. The median response duration and the median time to progression were similar in both treatment arms; the median overall survival was 9.6 months (95% confidence interval, 7.11-12.09 months) for patients who received the cisplatin/gemcitabine/paclitaxel regimen and 13.6 months (95% confidence interval, 6.61-20.59 months) for patients who received the vinorelbine combination. Grade 3 and 4 toxicities were more frequent in the paclitaxel-containing arm. CONCLUSIONS: : Both combinations satisfied the 2-step design, demonstrating antitumor activity without relevant differences in response rates or response duration; however, the vinorelbine-containing regimen yielded superior results both in terms of overall survival (13.6 months vs 9.6 months) and in terms of treatment tolerability. Therefore, according to a pick the winner attitude, the combination of cisplatin/gemcitabine/vinorelbine may be considered in the design of future randomized, Phase III trials for patients with carcinomas of unknown primary site.

Feasibility of sequential therapy with FOLFIRI followed by docetaxel/cisplatin in patients with radically resected gastric adenocarcinoma. A randomized phase III trial.

OBJECTIVE: Combination therapies of fluorouracil (FU) with irinotecan (CPT-11) and docetaxel plus cisplatin have been proven to be active in metastatic gastric cancer. In this paper, we present the results of a phase III trial in which these two combinations given sequentially were compared to mitomycin C (MMC) monochemotherapy in an adjuvant setting. METHODS: 169 patients with radically resected gastric cancer were randomized to receive CPT-11 (180 mg/m2 day 1), leucovorin (100 mg/m2 days 1-2), FU (400-600 mg/m2 days 1-2, q 14; for four cycles; FOLFIRI regimen), followed by docetaxel (85 mg/m2 day 1), cisplatin (75 mg/m2 day 1, q 21; for three cycles; arm A), or MMC (8 mg/m2 days 1-2 as 2-hour infusion, q 42; for four cycles; arm B). All patients had histologically confirmed gastric carcinoma with nodal positivity or pT3/4. A total of 166 patients (85 in arm A and 81 in arm B) were treated. Adjuvant treatment was completed in 76% of the patients in arm A and in 70% of the patients in arm B. The main grade 3/4 side effects recorded were neutropenia in 35%, with only 1 febrile patient, and diarrhea in 11% in arm A, and thrombocytopenia in 10% and neutropenia in 7% in arm B. The FOLFIRI regimen and docetaxel/cisplatin given in sequence was well tolerated and feasible in adjuvant setting. This sequence treatment currently represents the experimental arm of an ongoing multicenter trial.

Cost of insurance policies for investigator-initiated cancer clinical trials in Italy.

BACKGROUND: Clinical trials with non-profit promoters are frequently performed in oncology and represent a highly valuable source of information. METHODS: To describe the costs of insurance policies and their determinants, data were collected from 12 Italian non-profit promoters of cancer trials. The cost of policies was expressed as per-patient premium. RESULTS: Sixty-two quotations issued by only two companies were collected, relative to 44 trials proposed for quotation between December 1998 and February 2003. Only the date of quotation was significantly associated with the cost (P = 0.0003) of quotations by Company A for policies with a deductible, with cost increasing over time. Date of quotation (P = 0.0002), sample size (P = 0.008) and number of study arms (P = 0.02) were independently associated with the cost of no-deductible policies quoted by Company A. Only the number of study arms was significantly associated with cost (P = 0.0001) in no-deductible policies quoted by Company B. CONCLUSION: There is insufficient competition among companies for insurance of cancer trials with non-profit promoters. Many variables that affect the trial risk profile from a clinical perspective are not associated with insurance cost. Date of quotation is among the strongest determinants of the cost, which has sharply increased over time. This trend may become a serious problem for non-profit promoters of cancer clinical trials.

The combination of the selective cyclooxygenase-2 inhibitor celecoxib with weekly paclitaxel is a safe and active second-line therapy for non-small cell lung cancer: a phase II study with biological correlates.

PURPOSE: The selection of effective schedules of treatment for metastatic non-small cell lung cancer still remains a challenge for the oncologist. The present multicentric phase II study was designed in order to investigate the activity and safety of the combination of weekly paclitaxel and celecoxib as second-line treatment for non-small cell lung cancer. As a secondary endpoint, the possible correlation of biomarkers with objective response was investigated in a subset of patients. PATIENTS AND METHODS: Patients with platinum-refractory non-small cell lung cancer and Eastern Cooperative Oncology Group performance status 0-2 entered the present phase II study. Paclitaxel was administered at the dose of 80 mg/m(2) i.v. weekly for 6 weeks, followed by a 2-week rest, and celecoxib, 400 mg p.o. b.i.d. administered continuously. A cycle consisted of 8 weeks of treatment. Determination of circulating vascular endothelial growth factor and interleukin 6 was performed at baseline and every two cycles. RESULTS: Fifty-eight patients were enrolled: median age, 60 years (range, 30-77 years); male/female ratio = 44/14; performance status, 0, 31 patients; 1, 25 patients; and 2, two patients. Predominant histotype was adenocarcinoma (34 cases), and most patients had at least two sites of disease. According to the intent-to-treat analysis, 14/58 objective responses (24.1%) and 24/58 (41.3%) stabilizations of disease were observed, with a median duration of 4 months (range, 2-22+ months) and 5 months (range, 1-13 months), respectively. Median time to progression and median overall survival were 5 and 11 months, respectively. One-year survival was 42.5%. The main toxicity was neuropathy (4% of grade 3). Preliminary results suggest that decrease in serum vascular endothelial growth factor level is significantly associated with clinical response. DISCUSSION: Combination of celecoxib and weekly paclitaxel is safe and active new regimen in pretreated non-small cell lung cancer. Toxicity appears not to be worsened by the addition of celecoxib. According to preliminary results, serum vascular endothelial growth factor level seems to be predictive of response, suggesting that it should be further investigated as a surrogate marker of response.

Weekly dose-dense cisplatin-epirubicin-paclitaxel administration with granulocyte colony-stimulating factor support does not substantially improve prognosis in extensive disease small-cell lung cancer. A SICOG phase II study.

PURPOSE: The present study was aimed at defining the antitumor activity of the cisplatin-epirubicin-paclitaxel (PET) weekly administration with granulocyte colony-stimulating factor (G-CSF) support in chemonaive small-cell lung cancer patients with extensive disease (ED-SCLC). METHODS: Chemonaive ED-SCLC patients received cisplatin 30 mg/sqm, epirubicin 50 mg/sqm and paclitaxel 120 mg/sqm, weekly, with G-CSF (5 microg/kg from day 3 to 5) support, for a maximum of 12 weeks. RESULTS: Thirty-nine patients were treated, for a total of 354 cycles delivered. Eight complete (21%), and 22 partial responses (56%) were recorded, giving a 77% (95% CI = 61-89%) objective response rate (ORR). After 14 (range, 7-28)-month median follow-up, 24 deaths have occurred. Median progression-free and overall survival were 7 months and 11 months, with 1- and 2-year projected survivals of 45 and 24%, respectively. No toxic deaths occurred. Grade 4 neutropenia and thrombocytopenia occurred in 4 (10%) and 1 (3%) patients, respectively. Only one case of neutropenic sepsis was recorded, while hemorrhagic thrombocytopenia was never observed. Emesis, loss of appetite, mucositis and fatigue were the main nonhematological toxicities, being severe in 9, 8, 4 and 7 patients, respectively. CONCLUSIONS: The weekly PET combination with G-CSF support represents an active therapeutic approach in chemonaive ED-SCLC patients. However, both ORR and median survival does not seem substantially better than those achievable with a standard regimen. In view of that, and in consideration of the relevant nonhematological toxicity, this approach should not be pursued outside clinical trials.

Biweekly docetaxel-irinotecan treatment with filgrastim support is highly active in antracycline-Paclitaxel-refractory breast cancer patients.

PURPOSE: To evaluate the feasibility and activity of combination treatment with docetaxel (DTX) and irinotecan (CPT-11), given together every other week, combined with filgrastim support, in anthracycline- and paclitaxel-pretreated breast cancer (BC) patients. PATIENTS AND METHODS: Advanced BC patients pretreated with anthracycline- and paclitaxel-based chemotherapy were eligible. DTX (80 mg/m2) and CPT-11 (100 mg/m2) were given biweekly with filgrastim support (300 microg/day on days 4-7). RESULTS: Fifty patients (48 with metastatic and 2 with locally advanced cancer) were enrolled, with a total of 318 cycles being delivered. Thirty-one patients had visceral localizations. All patients had received epirubicin plus paclitaxel, with or without cisplatin, as front-line treatment for advanced disease. Overall, fatigue and diarrhea were the main chemotherapy-related toxicities in this study, being severe in 10 (20%) and 4 (8%) patients. Grade 3 or 4 neutropenia and thrombocytopenia occurred in 18 (36%) and 6 (12%) patients, respectively. Red blood cell transfusions were required in 4 patients. A total of 32 objective responses were registered (overall response rate, ORR = 64%, 95% confidence interval = 49-77%), including 8 complete responses (16%). An additional 8 patients showed stable disease. After a median follow-up of 18 (range 4-29) months, 30 patients were still alive, and 19 were progression free; median progression-free and overall survivals were 10 and 23 months, respectively. CONCLUSIONS: Biweekly DTX/CPT-11 with G-CSF support is a well-tolerated and highly effective approach in anthracycline-/paclitaxel-pretreated patients. The very promising ORR and survival outcome observed in this subset of patients with a poor prognosis suggest that this regimen might play a major role in the management of this disease.

Temozolomide and cisplatin in avdanced malignant melanoma.

BACKGROUND: Temozolomide (TMZ) is an oral alkylating agent; it produces DNA methyl adducts, which are removed by the DNA repair enzyme AGAT. In vitro studies suggest that CDDP may enhance the antitumor activity of TMZ due to the ability of cisplatin (CDDP) to down-regulate AGAT activity. In a previous phase I study, the combination of TMZ and CDDP was tested, and the recommended dose for each drug was defined. On the basis of these results, we designed a phase II study to evaluate the activity and safety profile of the TMZ-CDDP association in patients with advanced melanoma. PATIENTS AND METHODS: From March 2001 to March 2002, 37 patients with metastatic melanoma, not amenable to surgery, were enrolled in this study. All eligible patients were treated with the combination of CDDP 75 mg/m2 i.v. d 1, TMZ 200 mg/m2 p.o. days 1-5 recycled every 4 weeks. Interferon alpha2b (IFN alpha2b) was administered at the end of chemotherapy to responsive patients at the dose of 5 M.I. U s.c. 3 times a week for 1 year. RESULTS: A total of 174 courses were administered, with a median number of 4 courses/patient (range 1-10). After chemotherapy, 9 CRs and 9 PRs were observed for an overall response rate of 48.6% (95% C.I., 31.9%-65.6%). One of 5 patients with initial brain metastases showed a complete response to the therapy. Five out of 9 CR patients were still with no evidence of recurrence, ranging from 28+ to 82+ weeks. The median survival time was 48 weeks. The schedule was well tolerated, with the most frequent adverse events reported being nausea and vomiting (59%), alopecia (14%) and fatigue (11%), all well controlled by supportive therapy. Haemotological toxicities were mild to moderate. Side-effects attributable to IFN alpha2b were also mild and manageable. CONCLUSION: The combination of TMZ and CDDP seems to be active in untreated patients with advanced melanoma. Absence of recurrence in the majority (5/9; 56%) of CR patients seems to indicate that IFN may act on the duration of the response to chemotherapy. The schedule was well tolerated, with nausea and vomiting as the most frequent adverse events.

New cytotoxic and molecular-targeted therapies of head and neck tumors.

PURPOSE OF REVIEW: The purpose of this review is to provide an update on novel medical treatments for head and neck cancer. RECENT FINDINGS: Despite the continuing introduction of new cytotoxic agents, such as antimetabolites (capecitabine, pemetrexed), and topoisomerase I inhibitors, the management of advanced head and neck cancer remains challenging. Epidermal growth factor receptor is an appealing target for novel therapies in head and neck cancer. Several rational approaches have been designed to abrogate epidermal growth factor receptor function, among which the development of small molecules, such as gefitinib or erlotinib, that inhibit tyrosine kinase activity, therefore abrogating the receptor's catalytic activity, autophosphorylation, and its engagement with signal transducers. The development of monoclonal antibodies, such as cetuximab, directed against the receptor's extracellular domain and competing for the binding of receptor ligands is another antireceptor strategy, because it induces epidermal growth factor receptor downregulation from the tumor cell surface. Gefitinib has been evaluated in a phase II study in head and neck cancer, at a dose of 500 mg/day. In this study, a 53% disease control rate was achieved, with a low toxicity. Currently, a phase II study at a dose of 250 mg/day is ongoing. A phase II study of erlotinib in advanced head and neck cancer has provided similar results to those of gefitinib, with a 46% control rate and an acceptable toxicity. Phase I studies of cetuximab have been carried out in advanced head and neck cancer, mainly combining the drug with chemotherapy or radiotherapy. Three phase II studies have evaluated the combination of cetuximab with platinum-based chemotherapy in pretreated patients with recurrent/metastatic head and neck cancer, with a control rate ranging from 29 to 66%. A phase III placebo-controlled trial has shown that the addition of cetuximab to cisplatin does not significantly improve median progression-free survival, despite a difference in the response rate between the two arms. Other molecular-targeted approaches in head and neck cancer include farnesyl transferase inhibitors, cell cycle regulators, and gene therapy. SUMMARY: Novel targeted therapies are highly appealing in advanced head and neck cancer, and the most clever way to use them is a matter of intense investigation.

Biweekly docetaxel-irinotecan with filgrastim support in pretreated breast and non-small-cell lung cancer patients. A phase I study.

BACKGROUND: Docetaxel (DTX) has been shown to be a very active drug in both breast cancer (BC) and non-small-cell lung cancer (NSCLC). Irinotecan (CPT-11) is also active in NSCLC, and has shown promising antitumor activity in pretreated BC. PURPOSE. To define the MTDs of these two drugs given together every other week with the use of filgrastim support in pretreated BC and NSCLC patients. PATIENTS AND METHODS: Patients (aged 18-70 years, performance status < or =2) with advanced NSCLC or BC who had received at least one prior chemotherapy regimen were candidates for this phase I study. The starting DTX and CPT-11 doses were 60 mg/m(2) and 80 mg/m(2). Doses were alternately escalated at each step by 10 mg/m(2) for both drugs. Filgrastim 300 microg/day was given subcutaneously from days 4 through 7 of each cycle. RESULTS: From April 2000, 41 patients were included in the trial (27 BC, 14 NSCLC). All BC patients had received epirubicin plus paclitaxel (with or without cisplatin) as first-line treatment. Of the 14 NSCLC patients, 12 had received cisplatin-based first-line therapy, and 8 patients had been pretreated with paclitaxel. The dose escalation proceeded through five dose levels up to DTX and CPT-11 doses of 80 mg/m(2) and 100 mg/m(2), respectively. Overall, ten patients showed dose-limiting toxicity during the first cycle, diarrhea in seven and neutropenia in the remaining three. Considering all 218 cycles delivered, grade 3 or 4 neutropenia occurred in 14 patients (34%), with only one episode of neutropenic fever, while severe diarrhea was observed in 9 patients (23%). A total of 21 objective responses were registered (four complete) for an overall response rate of 51% [95% CI 35-67]. A major response was seen in 16 of the 27 BC patients (59%) and in 5 of the 14 NSCLC patients (36%). CONCLUSIONS: DTX and CPT-11 can be safely given together biweekly at adequate doses, with filgrastim support. In view of the promising activity data in both groups, phase II studies testing this combination in pretreated BC and NSCLC patients are ongoing.

Cisplatin, raltitrexed, levofolinic acid and 5-fluorouracil in locally advanced or metastatic squamous cell carcinoma of the head and neck: a phase II randomized study.

BACKGROUND: Cisplatin (CDDP) is among the most active single agents against squamous cell carcinoma of the head and neck (SCCHN), and it is still the reference drug in the induction chemotherapy setting, when used in combination with infusional 5-fluorouracil (5-FU). Raltitrexed has been shown to be devoid of clinical activity against SCCHN when used alone; however, both preclinical and early clinical data regarding the combination raltitrexed-CDDP hold promise. Thymidylate synthase is the target enzyme of both raltitrexed and 5-FU; however, the two drugs have distinct sites of action on the enzyme and the combination of the two agents may be synergistic. We have previously shown that the combination of raltitrexed, levofolinic acid (LFA) and 5-FU has clinical activity against SCCHN; in a subsequent phase I study, cisplatin was added, and the combination of CDDP plus raltitrexed on day 1, followed by LFA and 5-FU on day 2, was judged feasible and active, since a 67% response rate was shown across all dose levels, with a 100% response rate at the recommended dose for phase II. METHODS: Patients with inoperable locally advanced or metastatic SCCHN, not pretreated with chemo- or radiotherapy were randomized to receive either CDDP 60 mg/m2 and raltitrexed 2.5 mg/m2 on day 1 and LFA 250 mg/m2 and 5-FU 900 mg/m2 on day 2 (arm A) or CDDP 65 mg/m2 and methotrexate 500 mg/m2 on day 1, and LFA 250 mg/m2 and 5-FU 800 mg/m2 on day 2 (arm B). Both treatments were repeated every 2 weeks. Evaluation for tumor response was performed after four cycles. According to Simon two-stage design, with a target complete response (CR) rate (p1) of 35%, at least 7 CR among the first 31 treated patients and 16 CR among the final sample size of 52 patients were required. RESULTS: An interim analysis was performed when 36 patients were evaluable in each arm. In arm A, 10 CR (28%) and 19 partial responses (PR) (53%) were observed, for an overall response rate of 81%. In arm B, 3 CR (8%) and 12 PR (34%) were observed, for an overall response rate of 42%. The difference in both CR and overall response rate between the two arms was statistically significant (p = 0.03 and <0.001, respectively). Therefore, the accrual was stopped in arm B and continued only in arm A. Overall, 13 CR (21%) and 34 PR (56%) were observed among the 61 patients who were accrued in arm A, for an overall response rate of 77% (95% confidence interval 64-87%). Neutropenia was the main side effect in both arms (grade 3-4 in 45 and 23 patients in arm A and B, respectively). Extrahematologic toxicity was mild in both arms; however, 2 patients in arm B died due to toxicity (grade 4 mucositis in one case, grade 4 renal toxicity in the other). CONCLUSIONS: Although response data for our experimental treatment look encouraging, the hypothesis of a 35% activity, expressed as capability to induce a CR, cannot be accepted. The results obtained in this study are not substantially different from those of other trials of CDDP-5-FU-based regimens, and our combination is unlikely to represent a major breakthrough when used in this setting.

A phase I-II study on a gemcitabine-cyclophosphamide-fluorouracil/folinic acid triplet combination in anthracycline- and taxane-refractory breast cancer patients.

PURPOSE: To define the cyclophosphamide (CTX) maximal tolerated dose when combined with fixed doses of gemcitabine, fluorouracil (5-FU) and folinic acid (leucovorin, LFA) in metastatic breast cancer patients pretreated with anthracyclines and taxanes. METHODS: Metastatic breast cancer patients aged < or = 75 years, with ECOG performance status 0-2, were eligible, provided that they had received previous anthracycline- and taxane-based chemotherapy for the advanced disease. Chemotherapy consisted of gemcitabine 1,000 mg/m(2), 5-FU 425 mg/m(2), LFA 100 mg/m(2) and escalating doses of CTX, starting from 500 mg/m(2), on days 1 and 8 every 3 weeks. The dose escalation was stopped if dose-limiting toxicity (DLT) occurred in > 33% of patients of a given cohort. After the definition of DLT, a further escalation with the addition of granulocyte colony-stimulating factor (G-CSF; on days 3-5 and 10-12) was planned. RESULTS: Since March 1999, 69 patients have entered this trial through seven different cohorts. The dose escalation was stopped at the CTX dose of 600 mg/m(2) since 3/6 patients showed DLT. A further dose escalation was attempted in the presence of G-CSF support. A CTX dose of 800 mg/m(2) proved to be safe and was chosen for the phase II. A total of 33 patients were treated at this dose level. The treatment was fairly well tolerated, grade 3-4 neutropenia and thrombocytopenia occurring in 38 and 16% of patients, respectively. No cases of sepsis or bleeding were registered. Four patients required a packed red blood cell transfusion. Severe nonhematologic toxicity was also uncommon, occurring in 10 patients. Three complete and 24 partial responses were recorded for an overall response rate of 38% (95% CI = 26-50). Two complete and 12 partial responses were recorded in the 33 patients treated in the phase II for an overall response rate (ORR) of 42% (95% CI = 25-61). CONCLUSIONS: The gemcitabine-CTX-5-FU/LFA combination is a well-tolerated treatment for poor-prognosis breast cancer patients with previous exposure to anthracyclines and taxanes. With the addition of G-CSF, a cumulative CTX dose of 1,600 mg/m(2) can be safely delivered every 3 weeks. The evidence of an ORR approaching 40% is very promising and justifies further evaluations in this subset of patients.