Joaquín Montalar

Randomized Phase III Study of Gemcitabine-Cisplatin Versus Etoposide-Cisplatin in the Treatment of Locally Advanced or Metastatic Non–Small-Cell Lung Cancer

PURPOSE We conducted a randomized trial to compare gemcitabine-cisplatin with etoposide-cisplatin in the treatment of patients with advanced non-small-cell lung cancer (NSCLC). The primary end point of the comparison was response rate. PATIENTS AND METHODS A total of 135 chemotherapy-naive patients with advanced NSCLC were randomized to receive either gemcitabine 1,250 mg/m2 intravenously (IV) days 1 and 8 or etoposide 100 mg/m2 IV days 1 to 3 along with cisplatin 100 mg/m2 IV day 1. Both treatments were administered in 21-day cycles. One hundred thirty-three patients were included in the intent-to-treat analysis of response. RESULTS The response rate (externally validated) for patients given gemcitabine-cisplatin was superior to that for patients given etoposide-cisplatin (40.6% v 21.9%; P = .02). This superior response rate was associated with a significant delay in time to disease progression (6.9 months v 4.3 months; P = .01) without an impairment in quality of life (QOL). There was no statistically significant difference in survival time between both arms (8.7 months for gemcitabine-cisplatin v 7.2 months for etoposide-cisplatin; P = .18). The overall toxicity profile for both combinations of drugs was similar. Nausea and vomiting were reported more frequently in the gemcitabine arm than in the etoposide arm. However, the difference was not significant. Gemcitabine-cisplatin produced less grade 3 alopecia (13% v 51%) and less grade 4 neutropenia (28% v 56% ) but more grade 3 and 4 thrombocytopenia (56% v 13%) than did etoposide-cisplatin. However, there were no thrombocytopenia-related complications in the gemcitabine arm. CONCLUSION Compared with etoposide-cisplatin, gemcitabine-cisplatin provides a significantly higher response rate and a delay in disease progression without impairing QOL in patients with advanced NSCLC.

Circulating Endothelial Cells and Microparticles as Prognostic Markers in Advanced Non-Small Cell Lung Cancer

Background Circulating endothelial cells and microparticles have prognostic value in cancer, and might be predictors of response to chemotherapy and antiangiogenic treatments. We have investigated the prognostic value of circulating endothelial cells and microparticles in patients treated for advanced non-small cell lung cancer. Methodology/Principal Findings Peripheral blood samples were obtained from 60 patients before first line, platinum-based chemotherapy +/− bevacizumab, and after the third cycle of treatment. Blood samples from 60 healthy volunteers were also obtained as controls. Circulating endothelial cells were measured by an immunomagnetic technique and immunofluorescence microscopy. Phosphatidylserine-positive microparticles were evaluated by flow cytometry. Microparticle-mediated procoagulant activity was measured by the endogen thrombin generation assay. Results: pre- and posttreatment levels of markers were higher in patients than in controls (p<0.0001). Elevated levels of microparticles were associated with longer survival. Elevated pretreatment levels of circulating endothelial cells were associated with shorter survival. Conclusions/Significance Circulating levels of microparticles and circulating endothelial cells correlate with prognosis, and could be useful as prognostic markers in patients with advanced non-small cell lung cancer.

Phase II trial assessing the combination of gemcitabine and cisplatin in advanced non-small cell lung cancer (NSCLC).

BACKGROUND There is need for more active and better tolerated combinations in non-small cell lung cancer (NSCLC). The Spanish Lung Cancer Group (SLCG) therefore conducted this phase II study to define the efficacy and toxicity profile of the combination of higher doses than usual of gemcitabine along with cisplatin in patients with advanced NSCLC. PATIENTS AND METHODS Forty patients with pathologically documented advanced NSCLC were included in this trial (34 men, six women; aged 34-74 years; mean 64 years). Twenty-two patients had unresectable stage IIIB disease and 18 had stage IV disease. Karnofsky performance status was > or =70%. In five patients, surgery had previously been performed and four patients had received radiotherapy. Gemcitabine at a dose of 1200 mg/m2 was administered weekly (days 1, 8 and 15) and cisplatin 100 mg/m2 on day 15 of each 28-day cycle. RESULTS Responses were scored according to standard World Health Organization criteria. Of 40 assessable patients, 19 had a partial response for an overall response rate of 47.5% (95% confidence interval (CI) 32-64%). To date, median survival for the whole group is 10.4 months (95% CI 6.2-11.7 months), with a 1-year survival rate of 35%. Toxicity was mainly haematological. Seven patients (18%) had grade 4 neutropenia (one episode of febrile neutropenia). Thrombocytopenia (12.8% grade 3 and 2.6% grade 4) was not associated with clinical bleeding. One patient had a grade 4 transient rise in transaminase. There was no grade 3 or 4 renal toxicity. There was no grade 4 symptomatic toxicity. The most common grade 3 toxicities were nausea and vomiting (28.2%) and alopecia (10.3%) both related to cisplatin. CONCLUSIONS Gemcitabine can be safely administered at a dose of 1200 mg/m2 in combination with cisplatin. Thrombocytopenia seems to be less than in schedules with cisplatin given on day 1. The results of this studyshow promising activity (47.5% response rate) with modest toxicity. As this combination of gemcitabine and cisplatin deserves further evaluation in prospective randomized trials, the SLCG is comparing gemcitabine-cisplatin with etoposide-cisplatin in a phase III randomized study.

Cost-Benefit Analysis of a Follow-up Program in Patients with Breast Cancer: A Randomized Prospective Study

Abstract:  Increasing the number of breast cancer patients in follow‐up involves increased costs and, with limited health care resources, there is a need to evaluate the cost‐benefit to the patient of follow‐up regimens. We present a randomized prospective study to evaluate the cost‐benefit of intensive follow‐up in the early detection of relapses in patients with breast cancer. One hundred and twenty‐one patients were randomized to standard clinical follow‐up (n = 63) or to an intensive follow‐up (n = 58) that included diagnostic laboratory tests and imaging designed to detect early relapse following curative treatment. All patients had annual mammography. The number of scheduled outpatient appointments kept were 359 in the standard clinical follow‐up and 355 in the intensive follow‐up group. After a median of 3 years of follow‐up, there were 28 relapses, 11 in standard clinical follow‐up, and 13 in the intensive follow‐up group. The overall cost of follow‐up was 24,567 euros in the standard clinical follow‐up group and 74,171 euros in the intensive follow‐up group. Performing complimentary investigations in breast cancer follow‐up is associated with higher costs without difference in early detection of relapses.

SNPs and taxane toxicity in breast cancer patients

AIM In order to identify genetic variants associated with taxanes toxicity, a panel with 47 SNPs in 20 genes involved in taxane pathways was designed. PATIENTS & METHODS Genomic DNA of 113 breast cancer patients was analyzed (70 taking docetaxel, 43 taking paclitaxel). RESULTS Two SNPs associated with docetaxel toxicity were identified: CYP3A4*1B with infusion-related reactions; and ERCC1 Gln504Lys with mucositis (p≤0.01). Regarding paclitaxel toxicity: CYP2C8 HapC and CYP2C8 rs1934951 were associated with anemia; and ERCC1 Gln504Lys with neuropathy (p≤0.01). CONCLUSION Genes involved in DNA repair mechanisms and reactive oxygen species levels influence taxane toxicity in cancer patients treated with chemotherapy schemes not containing platinum. These findings could lead to better treatment selection for breast cancer patients.

Primary Lymphoma of Bone: A Clinico-Pathological Review and Analysis of Prognostic Factors

Primary non-Hodgkin’s bone lymphoma (PBL) is an uncommon malignancy first described by Oberling in 1928 [1], and established as a different clinical entity in 1939 [2]. It represents 7% of all bone tumors and less than 5% of non-Hodgkin’s extranodal lymphomas [3]. A retrospective review was performed with all consecutive patients with PBL diagnosed and treated at our center between January 1975 and December 2000. All patients had histological confirmation of non-Hodgkin’s lymphoma and were classified according to the Working Formulation. Tumor burden was evaluated with the M.D. Anderson criteria. Staging was based on the Ann Arbor classification. Assessment of response was performed according to the WHO criteria. Survival curves were estimated with the Kaplan –Meier method, and compared by means of the log-rank test. The Cox’s proportional hazard model was used to identify independent prognostic factors of survival. Age, stage, extranodal involved areas, performance status, and serum LDH levels, included in the International Prognostic Index (IPI) [4] were analyzed together. Patient characteristics are shown in Table I. All patients received treatment for PBL with either chemotherapy (1 patient, 5%), radiotherapy (3 patients, 14%), or combined chemotherapy+radiotherapy (17 cases, 81%). Chemotherapy schedules included anthracyclines in 83% cases. The most frequent employed of them was CHOP. The median dose of radiotherapy delivered was 40 Gy, with a boost of 500 cGy on primary lesions. Patients with PBL treated with chemotherapy received a median of 6 cycles (range, 1 – 12). Sixteen patients achieved a complete response (76%), 1 showed a disease stabilization (5%), and 4 patients progressed (19%). Six patients had a recurrence of the disease (29%), 2 of them primarily treated with radiotherapy alone, 1 case treated with chemotherapy alone, and 3 patients treated with combined modality. At the time of data analysis, with a median follow-up of 87 months (range, 7 – 297), 12 patients (57%) are alive and disease-free, while 9 have died, in 6 cases due to progression of non-Hodgkin’s lymphoma (29%) and in 3 due to other causes (radiation-induced osteosarcoma,

Response predicting factors to recombinant human erythropoietin in cancer patients undergoing platinum‐based chemotherapy

The response to epoetin‐α treatment is hard to predict in cancer patients receiving chemotherapy.

Vinorelbine, ifosfamide and cisplatin as first-line treatment in patients with inoperable non-small cell lung cancer

To assess, in a multicenter setting, the effectiveness of a combination of vinorelbine, ifosfamide and cisplatin in the treatment of non-small cell lung cancer, 123 patients (males=116) with a mean age of 60 years (range 27-75) with stage IIIb/IV non-small cell lung cancer (NSCLC) and performance status <or=2 were treated with vinorelbine (VNR; 25 mg/m(2)) on days 1 and 8; ifosfamide (IFO; 3 g/m(2)) on day 1; and cisplatin (CDDP; 80 mg/m(2)) on day 1, in repeated cycles of 21 days. Response rates, overall patient survival and toxicity profiles of the three-drug combination were assessed. The number of evaluable patients was 112, with a total of 441 cycles administered (mean=3.6 cycles/patient). Dose intensities (mg/m(2)/week; calculated in patients who concluded the proposed treatment and expressed as mean, median, and standard deviation) were: VNR 13.65, 13.32, 4.7; IFO 918.88, 868.97, 258.1; CDDP 23, 24.68, 6.98. Response rates were: complete response=3 (2.4%); partial response=58 (47.2%%); stable disease=20 (16.3%). The most frequent toxic events were nausea and vomiting (G1=33%, G2=31%, G3=8%). Neutropenia was the dose limiting toxicity (G1=6%, G2=11%, G3=10%, G4=7%). Alopecia G3 was a common undesirable effect in all the patients. Time to progression was 296 days (95% confidence interval 261-332) and the mean survival time was 338 days (95% CI 301-374). We conclude that the described therapeutic schedule is effective with good survival rates and response ratios together with a good tolerance and an acceptable toxicity level.

Long-term results after combined modality treatment for non-metastatic osteosarcoma

Since the introduction of multimodality treatment, the prognosis of patients with high-grade non-metastatic osteosarcoma has significantly improved. A retrospective review was performed to assess the long-term results of this approach in a single centre setting, and to investigate the impact of potential clinical prognostic factors. Between 1985 and 1993, 35 patients with stage II-A and II-B osteosarcoma underwent preoperative chemotherapy (high-dose methotrexate), wide surgery, and adjuvant chemotherapy (cisplatin-doxorubicin/bleomycin-cyclophosphamide-dactinomycin) (modified T-10A protocol). There were 19 males and 16 females. Median patient age was 17 y (range 12–42). Primary tumour sites were the extremities (83%) and axial bones (17%). In spite of an unfavourable grade 3–4 histologic response rate to high-dose methotrexate of 12%, 31 (88%) patients were able to undergo limb-sparing surgery and 28 (80%) were rendered disease free after the planned therapy. Median follow-up was 8 y. The actuarial overall survival and disease-free survival rates were 64% and 49% at 5 y, and 59% and 49% at 10y, respectively. Tumour size and primary site were significant prognostic factors for survival in univariate analyses. In conclusion, long-term survival after combined modality treatment can be achieved in more than 60% of patients with localised osteosarcoma, including non-appendicular lesions. Limb-sparing surgery is a realistic goal for most cases. The prognostic value of tumour necrosis and the efficacy of neoadjuvant chemotherapy should be interpreted according to individual high-dose methotrexate scheduling.

Management of Advanced Pancreatic Cancer with Gemcitabine Plus Erlotinib: Efficacy and Safety Results in Clinical Practice

CONTEXT The combination of gemcitabine and erlotinib is a standard first-line treatment for unresectable, locally advanced or metastatic pancreatic cancer. We reviewed our single centre experience to assess its efficacy and toxicity in clinical practice. METHODS Clinical records of patients with unresectable, locally advanced or metastatic pancreatic cancer who were treated with the combination of gemcitabine and erlotinib were reviewed. MAIN OUTCOME MEASURES Univariate survival analysis and multivariate analysis were carried out to indentify independent predictors factors of overall survival. RESULTS Our series included 55 patients. Overall disease control rate was 47%: 5% of patients presented complete response, 20% partial response and 22% stable disease. Median overall survival was 8.3 months). Cox regression analysis indicated that performance status and locally advanced versus metastatic disease were independent factors of overall survival. Patients who developed acne-like rash toxicity, related to erlotinib administration, presented a higher survival than those patients who did not develop this toxicity. CONCLUSIONS Gemcitabine plus erlotinib doublet is active in our series of patients with advanced pancreatic cancer. This study provides efficacy and safety results similar to those of the pivotal phase III clinical trial that tested the same combination.