Long-term survival in advanced non-squamous NSCLC patients treated with first-line bevacizumab-based therapy.

BACKGROUND/AIM: First-line bevacizumab-based therapies have been shown to improve clinical outcomes in patients with non-squamous non-small-cell lung cancer (NSCLC). We aimed to descriptively analyse patients with non-squamous NSCLC who received a long-term period of maintenance bevacizumab. PATIENTS AND METHODS: This retrospective study included 104 patients who had already reached a progression-free survival (PFS) of at least 9 months. RESULTS: Median overall survival and PFS were 30.7 and 15.1 months, respectively. The overall response rate was 83 %. Weight loss ≤5 %, ECOG PS = 0, or low number of metastatic sites seem to be predictive factors of good evolution. The incidence of bevacizumab-related adverse events appeared to be similar as the previous studies. CONCLUSION: Our findings show that there is a long-term survivor group whom the administration of bevacizumab resulted in a relevant prolongation of response without new safety signals. Due to the population heterogeneity, it was not possible to identify the standardised predictive factors.

SEOM clinical guidelines for the treatment of follicular non-Hodgkin's lymphoma.

Follicular non-Hodgkin's lymphoma (FL) is a nodal B lymphoid malignancy that originates from the germinal center of a lymph node. FL is the second most frequent lymphoma subtype. The course of the disease is usually characterised by a typically indolent clinical course, with a median survival rate of 8-10 years, although most patients relapse after treatment. Diagnosis should always be based on a surgical specimen like an excisional node lymph biopsy. The first-line treatment of FL will depend of extension disease, tumour burden, patient symptoms, performance status and also patient decision. The addition of rituximab to conventional chemotherapy has improved ORR, PFS and OS. As first line in patients that need treatment, a combination of chemotherapy with rituximab induction followed by 2 years of rituximab maintenance is the best option. High-dose chemotherapy with autologous stem-cell transplantation in first line has not shown improvement and is not recommended as first-line therapy. Before any treatment decision in relapsed patients, a repeat biopsy is mandatory to rule out a transformation into large cell aggressive lymphoma. Standard treatment is controversial, depends on the efficacy of prior treatment, duration of the time-to-relapse, patient's age and histological findings at relapse.

SEOM clinical guidelines for the treatment of Hodgkin's lymphoma.

Hodgkin lymphoma (HL) is an uncommon B cell lymphoid malignancy representing approximately 10-15 % of all lymphomas. HL is composed of two distinct disease entities; the more commonly diagnosed classical HL and the rare nodular lymphocyte-predominant HL. An accurate assessment of the stage of disease and prognostic factors that identify patients at low or high risk for recurrence are used to optimize therapy. Patients with early stage disease are treated with combined modality strategies using abbreviated courses of combination chemotherapy followed by involved-field radiation therapy, while those with advanced stage disease receive a longer course of chemotherapy often without radiation therapy. High-dose chemotherapy (HDCT) followed by an autologous stem cell transplant (ASCT) is the standard of care for most patients who relapse following initial therapy. Brentuximab vedotin should be considered for patients who fail HDCT with ASCT.

Prognostic significance of circulating tumor cells in advanced non-small cell lung cancer patients treated with docetaxel and gemcitabine.

PURPOSE: To evaluate the association in the change of circulating tumor cell (CTC) levels and clinical outcomes (PFS and OS) in patients with advanced non-small cell lung cancer (NSCLC) treated homogenously with docetaxel and gemcitabine administered every 2 weeks. METHODS: We prospectively evaluated 37 patients for CTC levels at baseline and after 2 months of chemotherapy (before third cycle). Detection was carried out with the CellSearch system. RESULTS: Nine of the 37 patients (24 %) had ≥2 CTCs at the baseline determination. Median progression-free survival (PFS) was 4.3 months (95 % CI 2.5-8.3) for patients with CTC 0-1 as compared to 9.4 months (95 % CI 1.2-12.2) for those with CTC ≥2 (p = 0.3506). Median overall survival (OS) was 8.1 (95 % CI 2.8-16.3) and 12.2 (95 % CI 1.4-12.2) months for patients with 0-1 CTCs and ≥2 CTCs, respectively (p = 0.7639). Patients with a second CTC quantification were classified as: group 1, CTC = 0-1 at baseline and CTC = 0-1 after second chemotherapy cycle (18 patients); group 2, CTC ≥2 at baseline and CTC = 0-1 after second determination (5 patients). Median PFS was 7.7 and 9.9 months for group 1 and group 2, respectively (p = 0.4467). CONCLUSIONS: CTCs ≥2 at baseline were detected only in 24 % of this group of patients with advanced NSCLC and poor performance status. No significant differences in PFS and OS between patients with or without CTCs at baseline were observed.

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.

Adjuvant therapy with bemiparin in patients with limited-stage small cell lung cancer: results from the ABEL study.

INTRODUCTION: The haemostatic system plays an important role in the process of cancer development and spread. Anticoagulants, mainly low molecular weight heparins, could prolong survival in cancer patients, particularly in patients with lung cancer, beyond prevention of thromboembolic events. METHODS: In a multicenter, investigator-initiated, open-label, randomized, sequential study, 38 patients with newly-diagnosed, limited-stage small-cell lung cancer were randomized to receive standard chemoradiotherapy or the same therapy plus 3,500 IU daily of bemiparin for a maximum of 26 weeks. The primary outcome was progression-free survival. RESULTS: The study was terminated early due to slow recruitment. Median progression-free survival was 272 days with chemoradiotherapy alone and 410 days in the bemiparin group; hazard ratio, 2.58 (95% confidence interval [CI], 1.15-5.80); p=0.022. Median overall survival was 345 days with chemoradiotherapy alone and 1133 days in the bemiparin group; hazard ratio, 2.96 (95% CI, 1.22-7.21); p=0.017. The rate of tumor response was similar in both study arms. There was no significant between-group difference in the rates of major bleeding. Toxicity related with the experimental treatment was minimal. CONCLUSION: The addition of bemiparin to first line therapy with chemoradiotherapy significantly increases survival in patients with newly-diagnosed, limited-stage small-cell lung cancer. (Funded by the Instituto Científico y Tecnológico, University of Navarra. ClinicalTrials.gov identifier: NCT00324558).

[Non-Hodgkin lymphomas with systemic presentation in patients with HIV infection. Clinical and prognostic factors in a series evaluated before the introduction of the highly active antiretroviral therapy (HAART)]. / Linfomas no hodgkinianos de presentación sistémica e infección por VIH. Análisis clínico y de factores pronóstico en una serie tratada antes de la introducción del tratamiento antirretrovírico de gran actividad.

PATIENTS AND METHOD: We studied patients with acquired human immunodeficiency virus (HIV) infection that developed non-Hodgkin's lymphoma (NHL) from January 1985 to October 2001. RESULTS: 44 patients (36 men, 8 women; median age 34 years) were included. Burkitt's lymphoma was diagnosed in 34%, and diffuse large cell B lymphoma in 29.5%. A history of AIDS diagnosis was detected in 20 cases (45%). International prognostic index (IPI) was 0-1 in 19 patients (43%), 2 in 12 (27%) and higher than 3 in 13 (30%). Chemotherapy was used in 64% of the patients, radiation therapy in 2% and both in 11%. Criteria for partial response were reached in 13 patients (29%), for complete remission in 2 (4%) and for stabilization in 1 (2%). Nine (20%) patients are alive (5 without disease), 22 (50%) died because of NHL, 5 (11%) died because of treatment associated toxicity and 8 died because of other causes. Median survival were 3 months, with a 1-year survival estimate of 24% and a 2-year survival estimate of 14%. In the univariate analysis of prognostic factors, IPI = 0-1 in comparison with IPI = 2-5 (p = 0.000), physical status (PS) < or = 2 (p = 0.021) and absence of B symptoms (p = 0.012) were significant. In the multivariate analysis, IPI = 0-1 was also significant (p = 0.000). CONCLUSIONS: Patients with HIV and NHL has multiple factors of poor prognosis. The survival is limited and chemotherapy toxicity is high. Patients with low IPI are a subgroup with better prognosis.

Toxic megacolon: a rare presentation of primary lymphoma of the colon.

Primary colonic lymphoma is rare and accounts for less than 1% of colon malignancies. Moreover, diffuse neoplastic invasion of the colon is exceptional. This case describes a patient with primary non-Hodgkin's lymphoma of the colon presenting as toxic megacolon. This unique presentation is the first case reported in the literature of a diffuse colonic lymphoma diagnosed in the setting of a toxic megacolon. Histological confirmation was performed on the piece of colectomy.

Preoperative high-dose cisplatin versus moderate-dose cisplatin combined with ifosfamide and mitomycin in stage IIIA (N2) non small-cell lung cancer: results of a randomized multicenter trial.

Preoperative chemotherapy has become an accepted treatment for stage IIIA (N2) non small-cell lung cancer (NSCLC). The majority of induction regimens employ cisplatin, although the importance of cis-platin dose in combination is unclear. A randomized trial was conducted to address whether higher pre-operative cisplatin doses result in improved survival and increased pathologic complete response in NSCLC. Patients with stage IIIA clinically enlarged and biopsy-proven N2 lesions were randomly assigned to receive either high-dose cisplatin (HDCP) (100 mg/m2) or moderate-dose cisplatin (MDCP) (50 mg/ m2) in combination with ifosfamide (3 g/m2) and mitomycin (6 mg/m2). Disease was restaged after 3 cycles, and those patients with response or stable disease underwent thoracotomy. From March 1993 to February 1997, 83 patients were randomized: 46 received HDCP, and 37 received MDCP. Clinical characteristics were well matched. Radiographic response rate was 59% for HDCP patients and 30% for MDCP patients (P = 0.01). Thoracotomy was performed in 71 patients (86%), 58 of whom had resectable disease. Complete resection rate was 61% in the HDCP group, and 51% in the MDCP group (P = 0.5). Postoperative mortality was 11%. Pathologic complete response was observed in one patient who received MDCP. Median survival in the HDCP and MDCP groups was 13 and 11 months, respectively (P = 0.3). In conclusion, higher radiographic response rate is observed in patients who receive HDCP, but this study fails to show any significant improvement in either overall survival or pathologic complete response in this group of patients.

Preresectional chemotherapy in stage IIIA non-small-cell lung cancer: a 7-year assessment of a randomized controlled trial.

In 1989, we began a multicenter study to evaluate the potential benefit of preoperative chemotherapy with cisplatin, ifosfamide and mitomycin over surgery alone in CT-visible N2 non-small-cell lung cancer. We present here a 7-year assessment of this randomized trial. Sixty patients were randomized to receive either surgery alone or three cycles of mitomycin 6 mg/m2, ifosfamide 3 g/m2 and cisplatin 50 mg/m2, given intravenously on day 1 of each cycle at 3-week intervals and followed by surgery. All patients received thoracic irradiation after surgery. The resected tumors were evaluated for the presence of K-ras gene point mutations. Treatment arms were well-balanced in characteristics such as gender, age, histology, and tumor size. Mediastinoscopy and/or mediastinotomy (Chamberlain procedure) with a biopsy was performed in all patients with N2 stage detected by CT scan of the chest (83% of the patients in the preresectional chemotherapy arm and 63% of those in the surgery arm). In eight of the 25 patients (32%) who had mediastinoscopy in the preresectional chemotherapy arm, the initially positive mediastinal lymph nodes were downstaged. For the 30 patients who received preresectional chemotherapy, overall median survival was 22 months (95% CI, 13.4 30.6). Of the 30 patients who received surgery alone, overall median survival was 10 months (95% CI, 7.4-12.6; P = 0.005 by the log rank test). Updated survival data reveals a plateau in the preresectional chemotherapy group, and this still significant long-term survival benefit prompts us to hypothesize that even with short-term preresectional chemotherapy, the natural history of still resectable CT-visible N2 non-small cell lung cancer is favorably altered. The results of our study mirror the long-term survival recently reported in the MD Anderson randomized study.

Long-term follow-up and prognostic factors in Ewing's sarcoma. A multivariate analysis of 116 patients from a single institution.

The records of 116 patients from a single center (1970-1993) with newly diagnosed Ewing's sarcoma or primitive neuroectodermal tumor were reviewed retrospectively. The aim of this study was to ascertain the impact of pretreatment variables on disease-free survival. Median age was 14 years (range 1-34). Twenty patients presented with metastatic disease. Treatment consisted of systemic multiagent chemotherapy plus local irradiation (39%), wide resection (22%), or both (35%). Median potential follow-up was 10.7 years (range 2-26). Three patients developed second malignancies (1 breast carcinoma, 2 acute myeloid leukemias). Median time to relapse was 24 months (range 3-143). The actuarial disease-free survival was 37.4% at 5 years, 33.3% at 10 years and 27.8% at 15 years. Neoadjuvant chemotherapy and a therapy-induced tumor necrosis > or = 90% were associated with a better outcome. Patients undergoing surgical resection had a superior disease-free survival than those treated without surgery (45 vs. 18% at 10 years, p = 0.0009). Multiple regression analysis showed that raised serum lactate dehydrogenase levels (p < 0.001), hypoalbuminemia (p = 0.001) and distant metastases at diagnosis (p = 0.03) were independent adverse prognostic factors. In conclusion, one third of patients with Ewing's sarcoma become long-term survivors with combined modality treatment. Late relapses and second neoplasms are of concern. Prognostic factors should be considered in the selection of therapy, and the value of serum albumin warrants confirmatory studies.

Pretreatment prognostic factors for survival in small-cell lung cancer: a new prognostic index and validation of three known prognostic indices on 341 patients.

AIMS: a) To identify which pretreatment clinical or blood parameters were predictive of patients survival in small-cell lung cancer (SCLC) in a retrospective analysis. b) To validate three known prognostic indices: Royal Marsden Model (index 1), London Group (index 2) and Manchester Score (index 3). PATIENTS AND METHODS: From 1981 to 1993, 341 SCLC patients were treated with chemotherapy with or without surgery or radiotherapy. Univariate and multiple regression analyses of survival were performed and the feasibility of these models was explored, index 1: Karnofsky index, albumin, sodium and alkaline phosphatase; index 2: ECOG performance status (PS), albumin and alanine transaminase; and index 3; lactate dehydrogenase (LDH), disease extent, sodium, Karnofsky index, alkaline phosphatase and bicarbonate. RESULTS: Significant prognostic factors for survival after univariate and multiple regression analysis were: disease extent, PS, creatine kinase, neutrophilia, LDH, hypoalbuminemia, hyperglycemia and bicarbonate. A new prognostic index was performed that included LDH, hypoalbuminemia, neutrophilia, disease extent and PS. It defined three prognostic groups (PG). Median survival and two-year survival for these PG were 12.3, 8 and 3.4 months and 16.5%, 2.3% and 0%, respectively. The following PG were identified after application of the three models proposed: Index 1 identified two PG with 0% and 16.6% two-year survival (P < 0.001); index 2 detected three PG with 0%, 5% and 15.7% two-year survival (P < 0.001) and index 3 detected three PG with 0%, 2.5% and 16.2% two-year survivals, respectively (P < 0.001). CONCLUSION: A new prognostic index is proposed allowing identification of three different PG. The feasibility of three known prognostic models was validated and demonstrated. Variables other than disease extent or PS (albumin or LDH) should be taken into account in designing future clinical trials.

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.

Mutated K-ras gene analysis in a randomized trial of preoperative chemotherapy plus surgery versus surgery in stage IIIA non-small cell lung cancer.

The observation that the proteins encoded by ras genes play a central role in the signalling pathways used by cells to respond to growth factors and the fact that mutated ras proteins are constantly promoting cell division have led to a PCR-based hunt for additional clinical information. In the present study, K-ras analysis draws the following conclusions: (1) K-ras point mutation frequency was higher in the surgery group (10 of 24 patients) than in the chemotherapy-surgery group (3 of 20 patients). (2) Mutated K-ras was predominantly observed at codon 12 but five mutations appeared at codon 61. (3) Mutations were identified in the squamous cell carcinoma histological NSCLC subtype except in four cases corresponding to adenocarcinoma. (4) A multifarious pattern of substitutions, especially at codon 12, were noted with aspartic K 12 substitutions more prone to develop bone metastases. (5) Although a genotypic K-ras classification of NSCLC may not yet be formulated, our accumulated data (unpublished) suggest a trend toward it. (6) Patients with mutated K-ras tumors in the surgery group had no different survival than those with normal K-ras. However our pooled data as well as other authors' results assert that mutated K-ras constitute an additional prognostic datum that deserves to be included together with TNM classification. In the design of new preoperative (neoadjuvant) chemotherapy trials, stratification of tumors by K-ras status deserves to be further investigated in order to correlate with response, relapse and survival. Mutated K-ras genotype merits further research. Finally, the paradigm of uneven histological distribution and mutated K-ras spectra among researchers should serve as a stimulus to search for further contributions in this field.

Extragonadal germ cell tumors: prognostic factors and long-term follow-up.

The records of 23 patients (22 male and 1 female, median age 28 years) with extragonadal germ cell tumors (EGCT) treated between 1974 and 1993 were reviewed retrospectively to investigate long-term survival and prognostic factors. Treatment consisted of cisplatin-based chemotherapy plus local irradiation or surgery. There were 7 seminomas, 5 poorly differentiated carcinomas (PDC) with elevated biomarkers, and 11 nonseminomatous germ cell tumors (NSGCT). The primary sites were retroperitoneum (10 cases), mediastinum (5 cases), pineal gland (4 cases) and other (4 cases). Two partial and 14 complete responses (69.6% overall) were achieved with primary therapy. After a median follow-up of 63 months, 10 (43.5%) patients live disease-free and 5-year survival is 55%. Seminomas showed an excellent outcome. Retroperitoneal NSGCT behaved like testicular neoplasms. Between nonseminoma patients, PDC histology and mediastinal primary were associated with the worst prognoses. EGCT patients should be treated and reported separately according to histology and primary site.

A randomized trial of mitomycin/ifosfamide/cisplatin preoperative chemotherapy plus surgery versus surgery alone in stage IIIA non-small cell lung cancer.

The efficacy of surgery or radiotherapy as conventional treatment for stage IIIA non-small cell lung cancer (NSCLC) is limited. Recent studies have pointed out that preoperative chemotherapy may improve survival. To reconcile the two approaches, we undertook a multidisciplinary randomized trial to examine the possible synergism between preoperative chemotherapy and surgery in improved survival. Stage IIIA NSCLC patients were randomly assigned to receive either three preoperative courses of mitomycin/ifosfamide/cisplatin chemotherapy and surgery or surgery alone. The median survival was significantly greater in the chemotherapy plus surgery group than in the surgery group (26 months v 8 months; P < .001). However, the prognostic value of the mutated K-ras gene data presented awaits the analysis of larger sample populations. Similarly, the role of high-dose cisplatin in inducing higher pathologic complete remissions has to be corroborated in future randomized trials.