ABSTRACT
The feasibility of the docetaxel-ifosfamide combination, as well as the definition of maximum tolerated doses (MTD) in a previous phase I study, led us to continue evaluating the regimen in an extended phase II study in patients with HER2-non-overexpressing, anthracycline pre-treated advanced breast cancer. Patients with histologically confirmed metastatic breast cancer failing prior anthracycline-based chemotherapy were treated with docetaxel 100 mg/m2 over 1 h on day 1 followed by ifosfamide 5 g/m2 divided over days 1 and 2 (2.5 g/m2/day over 1 h), and recycled every 21 days with prophylactic granulocyte-colony stimulating factor (G-CSF) administration from day 3-until a neutrophil count >10,000/microl. Between March 1999 and June 2002, 71 patients with a median age of 55 years (range, 28-72) and performance status (World Health Organization; WHO) of 1 (range, 0-2) were treated; all were assessable for toxicity and 70 patients for response. Clinical response rates (RRs), on an intention-to-treat basis were: 41/71 [58%; 95% CI, 46.5-69.5%]; 7 complete remissions (CRs), 34 partial remissions (PRs), 15 stable disease (SD) and 15 progressive disease (PD). The median response duration was 7.5 months (2-28 months), median time-to-progression (TTP) 6 months (0.1-30 months), and median overall survival (OS) 12 months (0.1-36 months). Grade 3/4 toxicities included; neutropenia in 63% of patients-with 52% developing grade 4 neutropenia (>or=7 days) and in 11% of these febrile neutropenia (FN), while no grade 3/4 thrombocytopenia was observed. Other toxicities included; peripheral neuropathy grade 2 only in 7%, grade 1/2 reversible central nervous system (CNS) toxicity in 11%, no renal toxicity, grade 2 myalgias in 7%, grade 3 diarrhea in 4%, skin/nail toxicity in 11%, and grade 1/2 fluid retention in 28% of patients. The present report has demonstrated encouraging activity of the docetaxel-ifosfamide combination in anthracycline-pretreated, HER2-negative advanced breast cancer. Therefore, future randomized phase III studies versus single-agent docetaxel or currently established combinations of the latter with other agents in this setting with established clinical activity, such as capecitabine or gemcitabine, will be warranted.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/drug therapy , Adult , Aged , Anthracyclines/therapeutic use , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/metabolism , Docetaxel , Female , Humans , Ifosfamide/administration & dosage , Ifosfamide/adverse effects , Ifosfamide/therapeutic use , Middle Aged , Receptor, ErbB-2/metabolism , Taxoids/administration & dosage , Taxoids/adverse effects , Taxoids/therapeutic useABSTRACT
PURPOSE: Treatment options in patients with recurrent non-small cell lung cancer (NSCLC) remain limited as a result of poor activity of most agents after failure of platinum-based therapy. In the present phase I-II study, we evaluated the feasibility and efficacy of bi-weekly gemcitabine (GEM) + irinotecan (CPT-11) in patients with relapsed NSCLC. PATIENTS AND METHODS: Patients with advanced NSCLC, WHO-performance status (PS) = 2, prior taxane/platinum-based chemotherapy were eligible. Chemotherapy was administered in a dose-escalated fashion in subgroups of 3-6 patients until dose-limiting toxicity (DLT) was encountered as follows: CPT-11 150 or 180 mg/m(2) followed by GEM 1,200-1,800 mg/m(2), both on days 1 + 15, recycled every 28 days in four dose levels (DLs). RESULTS: Forty-nine patients entered the phase I and II part of the study (phase I: 12-phase II: 37 + 3 at DL-3), and 40 patients were evaluable for a response in phase II and all for toxicity: median age, 61 years (range 36-74); PS, 1 (0-2); gender, 43 males/6 females-histologies; adenocarcinoma, 25; squamous, 20; large cell, 4. Metastatic sites included lymph nodes, 38; bone, 5; liver, 4; brain, 3; lung nodules, 14; adrenals, 13; other, 3. All patients had prior taxane + platinum-based treatment, and 42 patients had prior docetaxel-ifosfamide-cisplatin/or-carboplatin regimens. DLT was observed at DL-4 and included 2/3 cases with grade 3 diarrhea-1/3 of these with febrile neutropenia. The recommended DL for phase II evaluation was DL3: GEM, 1,500 + CPT-11-180 mg/m(2). Objective responses in phase II were PR, 6/40 [15%; 95% confidence interval (CI), 5-31%]; stable disease, 16/40 (40%; 95% CI, 21-53%); and progressive disease, 18/40 (45%; 95% CI, 28.5-62.5%). The median time-to-progression was 4 months (range 1-12) and median survival 7 months (range 1.5-42 +), while 1-year survival was 20%. Grade 3/4 neutropenia was seen in 18% of patients (6% grade 4) and 6% incidence of febrile neutropenia. No Grade 3/4 thrombocytopenia were seen, grade 3 diarrhea in 6% of patients and grade 2 in 15% of patients, while other grade 3 non-hematologic toxicities were never encountered. CONCLUSIONS: Bi-weekly GEM + CPT-11 is active and well tolerated in patients with advanced NSCLC failing prior taxane + platinum regimens, and represents an effective and convenient combination to apply in the palliative treatment of relapsed NSCLC particularly after failure of first-line docetaxel + platinum-based regimens.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Adult , Aged , Antibiotics, Antineoplastic/administration & dosage , Antineoplastic Agents/administration & dosage , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Blood Cell Count , Bridged-Ring Compounds/administration & dosage , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/psychology , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Diarrhea/chemically induced , Diarrhea/epidemiology , Dose-Response Relationship, Drug , Female , Humans , Irinotecan , Lung Neoplasms/pathology , Lung Neoplasms/psychology , Male , Middle Aged , Neutropenia/chemically induced , Neutropenia/epidemiology , Organoplatinum Compounds/administration & dosage , Patient Compliance , Quality of Life , Survival Analysis , Taxoids/administration & dosage , GemcitabineABSTRACT
Multifocal osteosarcoma represents a rare and aggressive type of osteosarcoma in which multiple bone lesions are detected simultaneously in the absence of pulmonary or any other visceral organ involvement. Despite a multidisciplinary approach, overall survival remains poor and disease progresses, leading to death within 1 yr of diagnosis. Here we report a case of an 18-yr-old patient with extensively metastatic osteosarcoma developing diffuse calcification in lung, pleural, diaphragm, pericardial, subcutaneous metastases, and mediastinal lymph nodes after intensive multiagent chemotherapy. We provide an extensive review of the literature together with presentation of different aspects regarding the debate on the multicentric versus metastatic hypotheses for multifocal osteosarcoma. An update on the current understanding of the molecular features of this disease is also included.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Neoplasms/drug therapy , Bone Neoplasms/pathology , Calcinosis , Osteosarcoma/drug therapy , Osteosarcoma/secondary , Adolescent , Bone Neoplasms/classification , Combined Modality Therapy , Fatal Outcome , Humans , Magnetic Resonance Imaging , Male , Neoplasm Metastasis , Neoplasms, Multiple Primary/classification , Neoplasms, Multiple Primary/pathology , Osteosarcoma/classification , Tomography, X-Ray ComputedABSTRACT
PURPOSE: In the present phase II study we evaluated the docetaxel-ifosfamide-carboplatin (DICb) combination in the outpatient setting in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with advanced NSCLC (stages IIIB/IV), WHO performance status (PS) <2, and no prior chemotherapy were eligible. Chemotherapy drug doses were: docetaxel: 80 mg/m2, ifosfamide: 3.5 g/m2, and carboplatin at a target area under the curve of 5 (based on Calvert's formula), all on day 1, followed by prophylactic G-CSF. RESULTS: Fourty patients were entered and all are evaluable for response and toxicity: median age: 64 (48-72); PS: 1 (0-1); gender: 29 males/11 females; stages: IIIB: 13 (33%), IV: 27 (67%). Metastatic sites at diagnosis included: lymph nodes: 25; bone: 7; liver: 4; brain: 5; lung nodules: 13; adrenals: 6. Responses were as follows: 22/40 [55%; 95% confidence interval (CI), 54-81%] evaluable patients responded: 4 complete responses, 18 partial responses, 11 had stable disease, and 7 had progressive disease. The median response duration was 7 months (range 2-14 months), median time to progression 9 months (range 2-18 months) and median overall survival 11 months (range 3-46+ months). 1-year survival was 47.5%. Grade 3/4 toxicities included: neutropenia 28/40, with 12 developing grade 4 and 12% febrile neutropenia, thrombocytopenia grade 3: 3/40 and grade 4: 1/40, no grade 3 neuropathy, grade 1 CNS toxicity in 3, no renal toxicity, 8 grade 2 diarrhea and 4 grade 3 vomiting. CONCLUSION: In the present phase II study the DICb combination yielded important activity and good tolerability in advanced NSCLC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Actuarial Analysis , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/administration & dosage , Carcinoma, Non-Small-Cell Lung/secondary , Docetaxel , Drug Administration Schedule , Female , Humans , Ifosfamide/administration & dosage , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Quality of Life , Survival Analysis , Taxoids/administration & dosage , Treatment OutcomeABSTRACT
BACKGROUND: The aim of this study was to evaluate the predictive value of cerebrospinal fluid (CSF) tumor marker levels in patients with breast cancer and carcinomatous meningitis. MATERIAL/METHODS: Serial CSF and serum tumor marker (CEA, CA-15.3, CA-125, and CA-19.9) measurements were performed in five patients with breast cancer developing carcinomatous meningitis in an attempt to correlate these with clinical outcome under treatment. RESULTS: CSF tumor marker levels correlated with response to treatment and outcome in each patient; despite achieving negative CSF cytology after therapy, in two patients it heralded disease progression. CONCLUSIONS: Given our findings, CSF tumor marker evaluation may provide a reliable means and surrogate end-points of monitoring response of carcinomatous meningitis to treatment. Therefore, large studies to assess the value of CSF tumor marker changes in carcinomatous meningitis are warranted.
Subject(s)
Biomarkers, Tumor/cerebrospinal fluid , Breast Neoplasms/complications , Meningeal Neoplasms/diagnosis , Meningeal Neoplasms/therapy , Meningitis/diagnosis , Meningitis/therapy , Aged , Breast Neoplasms/cerebrospinal fluid , Breast Neoplasms/therapy , Humans , Meningeal Neoplasms/cerebrospinal fluid , Meningeal Neoplasms/complications , Meningitis/cerebrospinal fluid , Meningitis/complications , Middle Aged , Neoplasm Staging , Predictive Value of Tests , Survival Rate , Treatment OutcomeABSTRACT
The aim of the present study was to evaluate the predictive value of cerebrospinal fluid (CSF) tumor marker levels in patients with breast cancer and carcinomatous meningitis. Serial CSF and serum tumor marker (CEA, CA-15.3, CA-125, and CA-19.9) measurements were performed in five patients with breast cancer developing carcinomatous meningitis in an attempt to correlate these with clinical outcome under treatment. CSF tumor marker levels correlated with response to treatment and outcome in each patient, and, despite achieving negative CSF cytology after therapy in two patients, it heralded disease progression. Given our findings, CSF tumor marker evaluation may provide a reliable means and surrogate end-points of monitoring response of carcinomatous meningitis to treatment. Therefore, large studies to assess the value of CSF tumor marker changes in carcinomatous meningitis are warranted.
Subject(s)
Biomarkers, Tumor/cerebrospinal fluid , Breast Neoplasms/complications , Meningeal Neoplasms/therapy , Meningitis/therapy , Aged , Breast Neoplasms/cerebrospinal fluid , Breast Neoplasms/therapy , Carcinoembryonic Antigen/metabolism , Disease Progression , Female , Humans , Meningeal Neoplasms/cerebrospinal fluid , Meningeal Neoplasms/diagnosis , Meningitis/cerebrospinal fluid , Meningitis/diagnosis , Middle Aged , Mucin-1/metabolism , Neoplasm Staging , Predictive Value of Tests , Survival Rate , Treatment OutcomeABSTRACT
The activity of single-agent docetaxel in patients with platinum pretreated non-small cell lung cancer (NSCLC) has been established in two recent large randomized phase III trials, either against best supportive care or versus single-agent vinorelbine/ifosfamide. Moreover, single-agent gemcitabine has demonstrated significant activity and clinical benefit in platinum- and paclitaxel-pretreated advanced NSCLC. Combination regimens employing these two agents in various doses and schedules have recently been initiated. The gemcitabine/docetaxel combination with or without G-CSF support as salvage therapy of NSCLC pre-treated with platinum+/-paclitaxel-based regimens has been evaluated in four recently published phase II clinical studies and has been shown to represent a tolerable and active regimen in this setting, yielding a 10-33% response rate, thus, warranting randomized comparisons to single-agent gemcitabine or docetaxel, drugs currently recommended in second-line treatment of advanced NSCLC.