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.

Randomised comparison of ceftazidime and imipenem as initial monotherapy for febrile episodes in neutropenic cancer patients.

With the availability of new, broad-spectrum antibiotics, initial therapy with a single agent has become an alternative to classic combinations in the management of febrile, neutropenic cancer patients. The aims of this study were to compare the efficacy of ceftazidime and imipenem as empirical monotherapy of febrile episodes in neutropenic patients, and to examine the frequency with which second-line antibiotics (amikacin, vancomycin, or both) were required. A prospective clinical trial was carried out in a single centre. Eligible patients with solid tumours or lymphoma were randomised to receive monotherapy with ceftazidime or imipenem. In the event of no response, amikacin and/or vancomycin were added in 48-72 h intervals (sequentially, or according to clinical or microbiological data). Efficacy was evaluable for 111 assessable episodes. Median neutrophil count at entry was 100 cells/microliters and median duration of neutropenia was 4 days. Febrile episodes were classified as microbiologically (34%) or clinically documented (42%), and fever of unknown origin (24%). Gram-negative infections (57%) predominated over gram-positive isolates (30%). The overall success rate with monotherapy (69% versus 70%), or with modification (20% versus 23%) were equivalent for ceftazidime and imipenem (P = 0.75). The mortality in this series was 5%. Single-agent therapy with either ceftazidime or imipenem is effective for the empirical treatment of febrile episodes in neutropenic patients with solid tumours. Early addition of amikacin and/or vancomycin resolves most failures of the first step.

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.

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

Translocation (11;22) in Ewing's sarcoma.

A cytogenetic study carried out by a direct method on the tumor of a patient with Ewing's sarcoma showed a t(11;22) in the six cells studied. The fact that this structural alteration was detected by a direct method indicates that the translocation is present in Ewing's sarcoma cells and that this alteration, when detected in established cell lines and short-term cultures, is not an alteration induced by the conditions of culture.

Cytogenetic study in six Spanish patients with Burkitt's lymphoma.

A cytogenetic study carried out on affected tissues of six children with Burkitt's lymphoma revealed five cases with a typical translocation (8q-; 14q+) and one with a variant t(2p-; 8q+). Additional cytogenetic variations were present in three cases. One had two acrocentric marker chromosomes comprised of material from chromosome #1 (1q21----q44) translocated to the Y gonosome. The other two cases had a cytogenetic alteration of chromosome #12. Cytogenetic studies carried out systematically in Burkitt's lymphoma could be a great help in possibly establishing differences in the biologic and clinical aspects of cases presenting with the t(8;14) versus cases with variant translocations, as this would allow for classification of these patients into groups which, at present, cannot be differentiated using other diagnostic methods.

Cefepime monotherapy as an empirical initial treatment of patients with febrile neutropenia.

Currently, monotherapy is considered a valid alternative to the combination antibiotic treatments used for initial, empirical management of febrile neutropenia. The advent of new cephalosporins warrants assessment. The aim of this study was to prospectively evaluate the effectiveness of cefepime monotherapy in the treatment of cancer patients with febrile granulocytopenia (< 1000 leukocytes/muL and/or < 500 neutrophils/muL). A prospective, multicenter, nonrandomized trial was conducted. Initial treatment consisted of iv cefepime, 2 g every 8 h. If the patient was still febrile after 72 h, amikacin, vancomycin/teicoplanin, and amphotericin B were added sequentially. Response was evaluated according to EORTC criteria. One hundred twenty episodes were analyzed in 81 males and 39 females (median age, 52 yr; range, 15-83). The median leukocyte count at the time of diagnosis was 781 microL(-1) (range, 100-2600) and the median neutrophil count was 173 microL(-1) (range 0-500). The median duration of neutropenia (< 1000 neutrophils/microL) was 4.8 d (range, 3-20). Fifty-two episodes (44%) were confirmed microbiologically (42 presented as bacteremia), 31 with Gram-positive bacteria and 21 with Gram-negative bacteria, 47 (39.3%) were confirmed clinically, 16 (13.3%) were considered as probable infections, and 5 (4.2%) as doubtful infections. Protocol success was achieved in 110 episodes (91.7%), 8 (6.6%) were treatment failures, and 2 (1.7%) were not evaluable. Ninety-nine episodes (83.3%) were controlled with cefepime monotherapy, with 19 other episodes requiring additional antibiotics: amikacin in 7 (5.8%), amikacin + vancomycin/teicoplanin in 12 (10.1%). Three patients (2,5%) died during an episode of neutropenic fever. Cefepime is effective as an initial, empirical treatment of febrile neutropenia. The early addition of amikacin and/or vancomycin resolves most of the monotherapy failures, which seem somewhat lower than with other monotherapies.

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/bleo-mycin-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 10 y, 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.

Metastatic follicular thyroid carcinoma to the kidney: a case report.

Clinically detectable well-differentiated metastatic thyroid cancer to the kidney is rare, with only 12 cases reported in the medical literature. The authors report a case of metastatic thyroid carcinoma to the kidney in a patient with widespread dissemination. She underwent total thyroidectomy, radical left nephrectomy, radioactive ablation with I-131, radiotherapy, and thyroid suppression therapy. Well-differentiated thyroid metastatic cancer can be amenable to treatment with successful long-term results.

[Hipercalcemia and non-Hodgkin's lymphomas. Report of three patients (author's transl)]. / Hipercalcemia en linfomas no hodgkinianos: a propósito de tres observaciones.

Three out of 140 patients with non-hodgkin's lymphoma treated in a Department of Internal Medicine showed hypercalcemia during their clinical course. Hypercalcemia was symptomatic in two patients causing renal failure in one of them and a metabolic encephalopathy in the other. In the third case hypercalcemia was a casual finding. Serum calcium levels varied between 14.8 and 16.6 mg/100 ml; serum phosphate and tubular reabsorption of phosphate were normal. Alkaline phosphatase were high in the three cases. Bone disease was present in two cases. Transient responses were obtained with the administration of prednisone and calcitonin associated to forced diuresis. Indomethacin was ineffective. Pathogenesis of hypercalcemia could be related to the release of an osteoclastic activator factor. The role of prostaglandins and the presence of PTH-like mechanisms were discarded in our cases by indirect methods. The poor prognosis of patients with non-hogkin's lymphoma and hypercalcemia in stressed.

[Infections due to herpes-varicella viruses in Hodgkin's disease (author's transl)]. / Infecciones por herpes virus-varicela en la enfermedad de Hodgkin.

The infections due to herpes-varicella viruses occurring in 191 patients with Hodgkin's disease form the basis of this report. There were overall 41 episodes (26.7%) in 40 patients, distributed as follows: varicella in three cases, atypical herpes-varicella in two cases, and herpes zoster in 36 cases, the latter showing systemic spread in seven instances, one to the central nervous system (myelitis) and six to the skin. The mortality was 2.5% of all infections, and 33% of the varicella cases. Morbidity was apparent as postherpetic neuralgia in seven patients (19.4%), postherpetic paraplegia in one case (2.5%), and severe thrombocytopenia in another case (2.5%). The statistical study of the factors contributing to the development of reactivation episodes demonstrated that neither age, sex, or previous splenectomy were influential. The results obtained in relation to the stage and histologic type of Hodgkin's disease can not be fully evaluated because of the artifact introduced by other variables such as type of therapy and observation time. There was a clear relationship with the aggressiveness of therapy, because 81.7% of the viral episodes occurred in patients submitted to total radiotherapy with or without chemotherapy, or with partial radiotherapy plus chemotherapy. In the patients with systemic spread there was a clear relationship with prior splenectomy (p less than 0.005). The clinical features of these patients are commented upon.

VEGF and TSP1 levels correlate with prognosis in advanced non-small cell lung cancer.

PURPOSE: There is a need for biomarkers that may help in selecting the most effective anticancer treatments for each patient. We have investigated the prognostic value of a set of angiogenesis, inflammation and coagulation markers in patients treated for advanced non-small cell lung cancer. PATIENTS AND METHODS: 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. Angiogenesis, inflammation and coagulation markers vascular endothelial growth factor (VEGF), their soluble receptors 1 (VEGFR1) and 2 (VEGFR2), thrombospondin-1 (TSP-1), interleukin-6 (IL6), sialic acid (SA) and tissue factor (TF) were quantified by ELISA. RESULTS: Except for TSP-1, pre- and post-treatment levels of all markers were higher in patients than in controls (p < 0.05). There was a positive and significant correlation between VEGF and VEGFR2 before treatment. VEGF also correlated with inflammatory markers IL-6 and SA. Moreover, there was a positive and significant correlation between levels of VEGFR1 and TF. Decreased levels of TSP-1 and increased levels of VEGF were associated with shorter survival. Bevacizumab significantly modified angiogenesis parameters and caused a decrease of VEGF and an increase of TSP-1. CONCLUSION: Angiogenesis, inflammation and coagulation markers were increased in NSCLC patients. Increased levels of VEGF and low levels of TSP-1 correlated with a poor prognosis.

Pain in clinical oncology: patient satisfaction with management of cancer pain.

BACKGROUND: Despite effective analgesic therapy, inadequate pain control is frequently perceived by patients and caregivers. AIMS: To assess satisfaction with management of pain in cancer patients. METHODS: Between January and May 2007, a cross-sectional multicentre study was conducted in 64 Medical Oncology Departments throughout Spain. A total of 525 outpatients with oncological diseases completed a questionnaire with demographic data, characteristics and intensity of pain, and perceptions and attitudes towards pain management at the time of a routine clinical visit. Physicians also completed a questionnaire with tumour-related and treatment-related data. Cluster analysis was used to classify patients into three groups (satisfied, neither satisfied nor dissatisfied or neutral, dissatisfied) according to pain intensity and satisfaction with treatment. RESULTS: Patients satisfied with their analgesic treatment (33%) had lower pain intensities and, when regularly asked about their pain, considered their physicians to be more involved in their treatment. Neither satisfied nor dissatisfied patients (neutral) (44%) had higher mean pain intensities. Two-thirds of them achieved marked relief of their pain and also thought that physicians were aware of their situation. Dissatisfied patients (23%) had moderate to severe pain intensities, and said that they were asked less frequently about their pain, and thought that their physicians were less involved in their analgesic treatment. CONCLUSION: Physician-patient communication and information provided to patients are essential aspects of patient perceptions and attitudes towards control of cancer-related pain. Pain is seen as a condition that may be controlled but affects the capacity to lead a normal life.

Cost-benefit analysis of a follow-up program in patients with breast cancer: a randomized prospective study.

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.