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.

Superiority of sequential versus concurrent administration of paclitaxel with etoposide in advanced non-small cell lung cancer: comparison of two Phase II trials.

Paclitaxel and etoposide are two chemotherapy agents with broad cytotoxic activity and different mechanisms of action and resistance. Preclinical studies of their combined cytotoxicity have yielded conflicting results. We performed two sequential Phase II trials using different sequence schedules of paclitaxel and etoposide as first-line treatment in advanced non-small cell lung cancer (NSCLC). Forty-four patients with stage IIIB or IV NSCLC were included between July 1995 and September 1996. All patients received etoposide at 100 mg/m2, given as an i.v. infusion on days 1, 2, and 3. The first 20 patients (part A) also received paclitaxel at 175 mg/m2 as a 3-h infusion on day 1, immediately prior to etoposide. The subsequent 24 patients (part B) were given the same paclitaxel dose, but on day 4. Grade 3-4 granulocytopenia was seen in 70% of the patients in part A and in 37% of those in part B (P = 0.04). Twenty-five % of the courses in part A and 4% of the courses in part B were associated with granulocyte nadir < or =500/microl (P = 0.00006). No responses were observed in part A, although disease was stabilized in 14 patients (70%). In part B, there were two complete responses and seven partial responses, for an overall response rate of 37.5% (95% confidence interval, 21-58%). In conclusion, toxicity and antitumor activity of the paclitaxel/etoposide combination may be sequence dependent. Our findings suggest that etoposide followed by paclitaxel is well tolerated and has greater activity in NSCLC than concurrent administration.

Detection of chromosome 3p alterations in serum DNA of non-small-cell lung cancer patients.

BACKGROUND: The generally dismal outcome of non-small-cell lung cancer (NSCLC) is believed to be associated with the systemic nature of this disease. In current practice, the decision to begin adjuvant chemotherapy in completely resected early stages is based on empirical criteria and has not yet been influenced by the presence of individual risk factors. Nonetheless, recent studies indicate that soluble tumor DNA is found in the serum and plasma of cancer patients, and microsatellite alterations have been identified in small-cell lung cancer and in head and neck neoplasms. PATIENTS AND METHODS: We have investigated serum DNA from 22 completely resected stage I-IIIA NSCLC patients using a polymerase chain reaction microsatellite analysis with four microsatellite markers at chromosome 3p (D3S1038, D3S1611, D3S1067 and D3S1284). RESULTS: Our analyses showed serum tumor DNA in 6 of 22 (28%) cases, with microsatellite alterations, either as a shift (changes in the size of the microsatellite sequence in the autoradiograph) or as a loss of heterozygosity (LOH). LOH in both tumor and serum DNA at one or more microsatellite markers was found in four patients. Although it is still premature to look for prognostic implications, one patient with stage I serum DNA was identified prior to the development of distant metastases. CONCLUSIONS: The findings suggest that detection of free circulating DNA in sera of NSCLC patients is incidentally linked to the systemic nature of lung cancer even at the earliest stage. These observations provide the first hint that serum tumor DNA is present in NSCLC patients. The detection of DNA from cancer cells in the sera of NSCLC patients could be useful for monitoring relapse in a relatively non-invasive way, and the potential sensitivity of this test may help in selecting candidates for adjuvant chemotherapy.

[Classical Kaposi sarcoma of aggressive course]. / Sarcoma de Kaposi clásico de comportamiento agresivo.

The aggressive variant of the classical Kaposi sarcoma (KS), though uncommon, has an utmost relevance because its evolutive characteristics entail a great morbidity and mortality. Three classical KS cases are reported which manifested an unusually aggressive course, with extensive cutaneous and visceral involvement. One of the patients was diagnosed of a non-Hodgkin lymphoma 12 months later. None of the three patients responded to the different therapeutic regimens used: polychemotherapy, monochemotherapy and interferon-alfa, respectively. The three patients died within two years after diagnosis. In KS patients with pulmonary involvement, working in coal mines was recorded as occupational antecedent. These three cases illustrate the different clinical and therapeutic characteristics of an uncommon subtype in the KS spectrum in general and of its classical variant in particular. Likewise, the possible role of occupational exposure in the etiopathogenesis of KS is discussed.

A sequence-dependent paclitaxel/etoposide phase II trial in patients with non-small cell lung cancer.

Studies conducted by the Spanish Lung Cancer Group indicate that cisplatin- or carboplatin-based chemotherapy can yield a 25% response rate, 9-month median survival time, and 30% 1-year survival rate in patients with stage III and IV non-small cell lung cancer. Phase II trials of single-agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) have an almost 30% response rate in non-small cell lung cancer. Based on these results, we decided to examine whether the sequence-dependent effects of paclitaxel/etoposide influence treatment outcome (antitumor response) and toxicity. In vitro data show a paradoxical antagonist rather than additive effect. In the first part of our study (part A), paclitaxel and etoposide were administered at the same time. In the second part (part B), etoposide preceded paclitaxel. In both parts, patients with previously untreated stage IIIB or IV non-small cell lung cancer with good performance status were eligible. In part A, etoposide (fixed dose, 100 mg/m2) on days 1, 2, and 3 was administered by 30-minute infusion; paclitaxel (175 mg/m2) was given by a 3-hour infusion on day 1. In part B, the etoposide dose and schedule were the same, but paclitaxel (same dose) was administered on day 4. Treatment in both parts was repeated every 21 days for a maximum of 10 cycles. In part A, 18 patients were entered and no objective responses were observed. In part B, 21 patients were accrued, 17 of whom had sufficient follow-up for response assessment. Seven objective responses were achieved (two complete and five partial responses, for an objective response rate of 41%). Seven patients had no change and three had progressive disease. Frequency and severity of side effects were not significantly different in either part of the study. However, grade 4 neutropenia was observed in 10 (59%) patients and one (5%) patient in parts A and B of the trial, respectively. Nonhematologic toxicity was slight. In conclusion, paclitaxel cytotoxicity is abrogated when it is given concurrently with etoposide. When etoposide precedes paclitaxel, a more effective paclitaxel/etoposide schedule is attained.

Microsatellite alterations at 5q21, 11p13, and 11p15.5 do not predict survival in non-small cell lung cancer.

We investigated the clinical implications of allelic deletions at three common sites of loss of heterozygosity (LOH) in regions 5q21, 11p15.5, and 11p13 in 86 patients with non-small cell lung cancer (NSCLC). We performed a PCR-based microsatellite polymorphism assay for detection of LOH. The microsatellite markers used were D5S82 (proximal to the APC gene), MCC (within the MCC gene), D11S904 (11p13), HRAS (within the H-ras gene), and D11S860 (11p15.5). Of the 68 informative cases at 5q21 loci, LOH was found in 14 cases (20%), whereas LOH frequency in 11p15.5 and 11p13 was 31% (19 of 61 informative cases) and 19% (12 of 63 informative cases), respectively. There was a significant correlation between 5q21 LOH and mediastinal lymph node involvement (P = 0.03). However, no differences were observed in median survival times (26 months in patients with 5q21 LOH versus 37 months in the remainder; P = 0.33) nor in patients with 11p LOH (38 months versus 32 months, respectively; P = 0.72). Cox's proportional hazards model predicted that stage was the only independent poor prognostic marker in the entire cohort of NSCLC patients. Thus, the present study revealed two important abnormalities, LOH at chromosome 5q21 and LOH at chromosome 11p, both implied in NSCLC development.

Reduced survival in patients with stage-I non-small-cell lung cancer associated with DNA-replication errors.

To better understand whether replication-error-type instability (RER+) is a frequent genetic alteration event in surgical-pathologic stage-I non-small-cell lung cancer (NSCLC) and identify whether it constitutes an independent prognostic parameter, we examined 35 surgical-pathologic stage-I-NSCLC patients with complete follow-up in all cases for at least 49 months. The tumor samples and the paired histopathologically normal lung samples for each patient were analyzed for 8 microsatellite markers located at chromosomes 3p and 2p to investigate microsatellite alterations such as RER+ and loss of heterozygosity (LOH). Single-strand-conformation-polymorphism analysis for detection of p53 and k-ras gene mutations was also carried out. Genetic data were correlated with clinical outcome and histopathologically established prognostic factors. RER+ at one or both chromosomes was identified in 24 of the 35 patients; 9 patients showed LOH. A statistically significant correlation was found between RER+ and poor prognosis (p = 0.001). Furthermore, RER+ proved to be an independent factor that predicted decreased survival, ranking first, followed by visceral pleural invasion. A trend towards worse survival was strongest in the group of patients with tumor size greater than 3 cm (T2). Patients with other genetic abnormalities, such as K-ras mutations, p53 mutations or LOH, had prognoses similar to those of patients without such aberrations. The data suggest that RER+ is common in NSCLC, that it may provide important prognostic information in stage-I NSCLC and serve as a useful marker for relapse-risk assessment in operable NSCLC patients.

[Significance of heterozygosity loss in the long arm of chromosome 5 (5q21) in small cell carcinoma of the lung]. / Importancia de la pérdida de heterozigosidad en el brazo largo del cromosoma 5 (5q21) en cáncer de pulmón no microcítico.

BACKGROUND: Loss of heterozygosity (LOH) at 5q21, where the APC/MCC genes reside, is one of the genetic alterations that characterizes lung cancer. The aim of this study was to analyse LOH frequency on chromosome 5q21 in patients with non-small cell lung cancer and its relationship with TNM staging and histological subtypes. PATIENTS AND METHODS: Tumor and corresponding normal DNA were isolated from 60 patients with non-small cell lung cancer and a subsequent polymerase chain reaction (PCR) with microsatellite markets within the APC/MCC region was performed. The PCR products were resolved by electrophoresis. The comparison between the normal and tumor DNA patterns allowed us to detect the samples harboring LOH. RESULTS: LOH at 5q21 was detected in 20% of the patients. LOH at 5q21 was found in 16% of stage I patients, 8% in stage II patients and 40% in stage IIIA patients. A trend towards worse survival was detected in stage IIIA patients with LOH at 5q21 (9 months median time survival) in comparison with patients with LOH (21 months), although the difference was not statistically significant (p = 0.11). No significant differences in LOH were observed among histological types. In addition, we found no correlation between LOH and higher frequency of mutations rate affecting K-ras and p53 genes. CONCLUSIONS: LOH at 5q21 is a frequent genetic alteration in non-small cell lung cancer and correlates with locally advanced disease (stage IIIA). Our results suggest that LOH at the 5q21 region could be a prognostic factor in non-small cell lung cancer.

Preoperative chemotherapy for stage IIIA non-small cell lung cancer.

Recent studies have shown that preoperative chemotherapy is feasible and advisable for patients with stage IIIA mediastinoscopically confirmed N2 involvement in non-small cell lung cancer. Such studies confirm the crucial pillar of attaining complete resection, and the importance of downstaging N2 disease as a useful surrogate for long-term survival. Resectability rate is about 70% in almost all studies examined. Better means of predicting resectability and relapse are addressed, such as the potential role of positron emission tomography and some hints for the management of replication error-positive non-small cell lung cancer patients. A major issue for the role of preoperative chemotherapy is how not to confuse apples and oranges. Although the role of surgery alone or radiotherapy is considered suboptimal for treatment of stage IIIA N2, whether surgery is required remains to be clarified. Furthermore, large randomized studies of chemoradiation followed by surgery versus chemoradiation alone are needed as well as modification of the current tumor, node, metastasis classification in order to better select those patients for whom preoperative chemotherapy would be beneficial. The surgeon's judgment and skill are essential in the identification of eligible patients and multimodality treatment research is also spreading toward early disease and some subsets of T4 non-small cell lung cancers.

[Positron emission tomography detection of residual disease in a case of lung cancer]. / Detección por tomografía de emisiíon de positrones de enfermedad residual en un case do cáncer de pulmón.

To date, computed tomography is considered the best procedure to detect either relapse or residual disease in non-small cell lung cancer. However, in recent years several studies have stressed the value of F-18 fluorodeoxyglucose positron emission tomography (FDG PET) which takes advantage of the enhanced glucose uptake observed in neoplastic cells. We present the case of a patient with a locally advanced non-small cell lung cancer who received trimodal treatment with induction chemotherapy followed by surgical resection and postoperative irradiation and lately developed brain metastases which were treated with chemoradiotherapy plus radiosurgery. However a small residual lesion remained in the brain magnetic resonance. Such abnormality was evaluated by means of FDG PET which did not show any increase on FDG uptake. The present case prompt us to review the role of FDG PET as a procedure that enable to detect subclinical disease and its potential usefulness taking into account the improvement in management strategies that has been attained in non-small cell lung cancer.