Postoperative Cisplatin-based Chemotherapy Research Articles

P2.17-09 Exploring the Impact of Age on the Efficacy of Adjuvant Chemotherapy After Radical Resection in Non- Small Cell Lung Cancer

Most adults diagnosed with Non Small Cell Lung Cancer (NSCLC) are over 65 years old. For those with resectable disease postoperative cisplatin-based chemotherapy (PC) has been shown to offer a significant survival advantage. However elderly patients are poorly represented in clinical trial cohorts, here we shall explore our regional experience of treating these patients. Patients receiving PC with Vinorelbine 25mg/m2, D1 and 8/ Cisplatin 75mg/m2 (VC) following surgery for NSCLC between January 2004 and April 2017 were identified from the electronic computer database. Patients with synchronous tumours or metastatic disease were excluded. 165 patients were identified, 63 (38%) ≥65yrs (range 65-77yrs). All were ECOG PS 0-1. 12 patients had Stage 1B disease (7 ≥65yrs), 63 Stage II A (20 ≥65yrs), 40 Stage IIB (21 >65yrs) and 50 Stage IIIA/B disease (17 >65yrs). 53.9% of patients ≥ 65yrs compared to 81% patients < 65yrs completed 4 cycles of PC.19% of patients required dose reductions due to toxicity, 12 were over 65yrs. Grade 3/4 neutropenia occurred in 21.2% of patients (18<65yrs vs. 17 ≥65 yrs) and febrile neutropenia in 9 patients ≥ 65yrs vs. 11<65yrs. No toxic deaths were recorded. Overall 85 (51.5%) patients, 26 ≥65yrs had radiological evidence of disease recurrence. The median time to recurrence was 26.19 months, no significant difference was found in time to relapse based on age (p=0.21). Kaplan Meyer analysis revealed no significant difference in overall survival based on age (p=0.77, HR1.069 95%CI 0.68-1.67). Mortality 6 months post chemotherapy in patients ≥ 65yrs was 1.58% vs. 2.94% inpatients < 65yrs. This illustrates in routine practice, PC using VC is deliverable in older patients of good PS with resected NSCLC. Though they may experience more toxicity from PC the benefits in terms of disease recurrence and overall survival were equivalent to patients <65yrs.

P3.01-23 Imaging Modalities for Surveillance and Follow-Up of Patient with Lung Cancer After Adjuvant Chemotherapy

Non-small cell lung cancer (NSCLC) represents over 80% of lung tumours. If diagnosed early, treatment is surgical with curative intent. The addition of postoperative cisplatin-based chemotherapy has demonstrated a significant survival advantage and is generally accepted as a standard treatment in patients of good performance status. Despite this, risk of relapse remains high and current ESMO (2017) guidance suggests ‘NSCLC patients treated with radical intent should be followed for treatment-related complications, detection of treatable relapse or occurrence of second primary lung cancer. Recommendations for surveillance, include regular review, physical exam and imaging. This should be tailored to suitability of individual patients for further intervention. Local practice mandates a chest x-ray (CXR) with CT and/or PET follow-up of anomalies. Between January 2004 and May 2017 165 patients underwent surgical resection for Stage 1B-IIIA NSCLC. We identified all patients within this cohort with radiological evidence of thoracic recurrence who had relapsed following postoperative chemotherapy. Electronic patient care records were used for data collection. Patient characteristics, surveillance modalities and overall survival (OS) from date of diagnosis to first relapse were analysed. Imaging modalities detecting recurrence and OS were determined using Kaplan-Meier methodology (SPSS). 89 patients were identified, the median age was 62 years (range 42-77 years). Patients underwent surveillance initially every 3 months following completion of postoperative chemotherapy. Median time to relapse was 25.6 months (range 0.53 to 50.9 months). 62 patients (69.7%) had radiological confirmed evidence of disease recurrence. 4 (6.5%) had relapsed with extra-thoracic recurrence. 28 patients (45.2%) had confirmed intra thoracic disease recurrence on CXR despite chest CT imaging performed at designated time intervals. However, 27 patients (43.5%) that underwent surveillance with CXR had confirmed intra thoracic disease recurrence with chest CT imaging. Median OS for CXR detected recurrence was 27.5 months (range 6.5 – 99.1 months) and 27.45 months (range 5.9 to 104.2 months) for chest CT detected recurrence (p-value 0.46). There is a paucity evidence specifically around the follow-up and surveillance modalities aimed at detecting relapse to improve survival after curative intent therapy in NSCLC. Our data demonstrate that 3 monthly CXR is an appropriate surveillance modality for initial detection of intra-thoracic disease recurrence.

Diagnosis and multi-modality treatment of adult pulmonary plastoma: Analysis of 18 cases and review of literature

The clinical data of 18 patients with PB from April 1989 to April 2013 was analyzed retrospectively, including 11 men and 7 women, aged 45 and 76 years old (mean 53 years). There were 12 cases of PB occurring in right lung and other cases in left lung. Among them, 3 patients had no symptoms, and 15 patients displayed symptoms of cough, chest pain, asthenia or minor haemoptysis. Overall, 11 patients had a preoperative diagnosis of lung cancer, 7 patients were preoperatively diagnosed as the other diseases, which included lung benign tumor (n=5) and mediastinal mass (n=2). All patients received a radical resection. Six patients received postoperative cisplatin-based chemotherapy, and two patients received postoperative irradiation with the dose of 55 Gy. Histologically, 14 cases of 18 patients had biphasic pulmonary blastoma and four cases had well differentiated fetal adenocarcinoma. A total of 12 patients died in a period of 6-36 months after operation, and 1 case was lost after 2 years of follow up. The median survival time was 19 months. PB is a rare primary lung malignant embryonal neoplasm. Despite its assumed embyonal origin, the tumor has a predilection for adults. A preoperative correct diagnosis is very difficult in spite of modern diagnostic imaging and biopsy techniques. Surgical resection is the main method for diagnosis and treatment. Postoperative chemotherapy or irradiation can help eliminate tumor remnants. Its prognosis is very poor, especially for the biphasic type.

PARP1 impact on DNA repair of platinum adducts: Preclinical and clinical read-outs

Evaluation of DNA repair proteins might provide meaningful information in relation to prognosis and chemotherapy efficacy in Non-Small Cell Lung Cancer (NSCLC) patients. The role of Poly(ADP-Ribose) Polymerase (PARP) in DNA repair of platinum adducts has not been firmly established. We used a DNA repair functional test based on antibody recognition of cisplatin intrastrand platinum adducts on DNA. We evaluated the effect of PARP inhibition on DNA repair functionality in a panel of cisplatin cell lines treated by the clinical-grade pharmacological inhibitor CEP8983 (a 4-methoxy-carbazole derivate) and the commercially available inhibitor PJ34 (phenanthridinone). We determined PARP1 protein expression in whole tumor sections from the International Adjuvant Lung cancer Trial (IALT)-bio study and tested a 3-marker PARP1/MSH2/ERCC1 algorithm combining PARP1 tumor status with previously published data. Chemosensitivity of cisplatin in NSCLC cell lines was correlated with the accumulation of cisplatin DNA adducts (P=0.0004). Further, the pharmacological inhibition of PARP induced a 1.7 to 2.3-fold increase in platinum adduct accumulation (24h) in A549 cell line suggesting a slow-down of platinum DNA-adduct repair capacity. In parallel, PARP1 inhibition increased the sensitivity to cisplatin treatment. In patient samples, PARP1 expression levels did not influence patient survival or the effect of platinum-based post-operative chemotherapy in the global IALT-bio population (interaction P=0.79). Among cases with high expression of all three markers (triple positive), untreated patients had prolonged survival with a median DFS of 7.8 years, (HR=0.34, 95%CI [0.19–0.61], adjusted P=0.0003) compared to triple negative patients (1.4 years). Remarkably, triple positive patients suffered from a detrimental effect (4.9-year reduction of median DFS) by post-operative cisplatin-based chemotherapy (HR=1.79, 95%CI [1.01–3.17], adjusted P=0.04, chemotherapy vs. control). Combinatorial sub-group analysis of the 3 markers further suggested that PARP1 tumor positivity might constitute a molecular context with high theranostic interest of ERCC1 and MSH2 in NSCLC. In conclusion, our data confirm that platinum DNA adduct accumulation is linked to chemosensitivity, which increase by pharmacological PARP inhibitors points to a role of PARP-dependent DNA repair in the process. We further suggest DNA repair biomarkers should be analyzed in a larger context of multiple DNA repair pathway regulation.

Adjuvant chemotherapy for surgically resected non–small cell lung cancer

Despite surgical resection, patients with early-stage (I to IIIA) non-small cell lung cancer (NSCLC) are at considerable risk of recurrence and death from their lung cancer. In recent years, multiple, large, randomized trials assessing the efficacy of adjuvant chemotherapy for resected NSCLC have been reported. Three of 6 trials with 300 or more patients with early-stage NSCLC have demonstrated that adjuvant cisplatin-based chemotherapy can significantly improve 5-year survival in carefully selected patients with resected NSCLC. These benefits have been confirmed in a meta-analysis of modern cisplatin-based adjuvant trials. The most consistent benefit has been reported in patients with resected stage II and IIIA NSCLC. The benefit of adjuvant chemotherapy in patients with resected stage IB NSCLC is less concrete. Herein, we review the results of the major adjuvant chemotherapy trials and their implications for the treatment of patients with completely resected NSCLC. A future challenge will be to identify the subsets of patients who will derive the greatest benefit from adjuvant chemotherapy. Current trials are also underway to define the role of novel targeted therapies, such as inhibitors of the epidermal growth factor receptor and monoclonal antibodies, in adjuvant treatment strategies.

Expression of MRP1, BCRP, LRP and ERCC1 as prognostic factors in non-small cell lung cancer patients receiving postoperative cisplatin-based chemotherapy

The development of resistance to chemotherapy is one of the major obstacles in the treatment of non-small cell lung cancer (NSCLC). The purpose of this study was to investigate the prognostic value of multidrug resistance protein 1 (MRP1), breast cancer resistance protein (BCRP), lung resistance-related protein (LRP), and excision repair cross-complementing 1 (ERCC1) in NSCLC patients receiving cisplatin-based adjuvant chemotherapy (cisplatin plus vinorelbine or gemcitabine) after tumor resection. We used semiquantitative reverse-transcription polymerase chain reaction to detect the expression of MRP1, BCRP, LRP and ERCC1 mRNA in surgical resection specimens of 60 patients with stage IB through IIIA NSCLC. The expression level of each gene was analyzed in relation to clinicopathological factors, tumor-free survival (TFS), and overall survival. The results showed that stage IIIA (p=0.011), N1 and N2 status (p=0.008), high expression of MRP1 (p=0.034) and LRP (p=0.018) were associated with shorter TFS. Stage IIIA (p=0.0105), N1 and N2 status (p=0.009), high expression of MRP1 (p=0.021) and ERCC1 (p=0.012) were related to a shorter overall survival. Cox multivariate analyses revealed that early stage (p=0.013 and p=0.024), negative lymph node status (p=0.006 and p=0.011), and low MRP1 expression (p=0.022 and p=0.035) were independent predictors of favorable TFS and overall survival, respectively. Additionally, ERCC1 (p=0.019) was an independent predictor of favorable overall survival.

Adjuvant therapy for resected non-small cell lung cancer.

Surgery remains the initial treatment for patients with early-stage non-small cell lung cancer (NSCLC). The frequent occurrence of distant metastases and local regional failure after surgical resection would indicate that additional treatment is necessary. Early trials of adjuvant chemotherapy and postoperative radiation were often plagued by small patient sample size, inadequate surgical staging, and ineffective or antiquated treatment. A 1995 meta-analysis found a nonsignificant reduction in risk of death for postoperative cisplatin-based chemotherapy. This was followed by a new generation of randomized phase III trials some of which have reported a benefit for chemotherapy in the adjuvant setting. Based on the results of these trials, platin-based chemotherapy has become the standard of care for resected stages II and IIIA NSCLC. The role of postoperative radiation therapy remains to be defined. In the future, improvement in survival outcomes from adjuvant treatment is likely to result from the evaluation of novel agents, identification of tumor markers predictive of disease relapse, and definition of factors that determine sensitivity to therapeutic agents. Some of the molecularly targeted agents such as the angiogenesis and epidermal growth factor receptor inhibitors are being incorporated into clinical trials. Gene expression profiles and proteomics are techniques being used to create prediction models to identify patients at risk for disease relapse. Molecular markers such as ERCC1 may determine response to treatment. Increasing the understanding of the molecular makeup of lung cancer will hopefully increase cure rates for patients by maximizing the efficacy of the adjuvant therapy.

Expression of MRP1, BCRP, LRP and ERCC1 as prognostic factors in non-small cell lung cancer patients receiving postoperative cisplatin-based chemotherapy

The development of resistance to chemotherapy is one of the major obstacles in the treatment of non-small cell lung cancer (NSCLC). The purpose of this study was to investigate the prognostic value of multidrug resistance protein 1 (MRP1), breast cancer resistance protein (BCRP), lung resistance-related protein (LRP), and excision repair cross-complementing 1 (ERCC1) in NSCLC patients receiving cisplatin-based adjuvant chemotherapy (cisplatin plus vinorelbine or gemcitabine) after tumor resection. We used semiquantitative reverse-transcription polymerase chain reaction to detect the expression of MRP1, BCRP, LRP and ERCC1 mRNA in surgical resection specimens of 60 patients with stage IB through IIIA NSCLC. The expression level of each gene was analyzed in relation to clinicopathological factors, tumor-free survival (TFS), and overall survival. The results showed that stage IIIA (p=0.011), N1 and N2 status (p=0.008), high expression of MRP1 (p=0.034) and LRP (p=0.018) were associated with shorter TFS. Stage IIIA (p=0.0105), N1 and N2 status (p=0.009), high expression of MRP1 (p=0.021) and ERCC1 (p=0.012) were related to a shorter overall survival. Cox multivariate analyses revealed that early stage (p=0.013 and p=0.024), negative lymph node status (p=0.006 and p=0.011), and low MRP1 expression (p=0.022 and p=0.035) were independent predictors of favorable TFS and overall survival, respectively. Additionally, ERCC1 (p=0.019) was an independent predictor of favorable overall survival.

Adjuvant Chemotherapy for Non–Small-Cell Lung Cancer: A Fading Effect?

Non–small-cell lung cancer (NSCLC) is the leading cause of cancer death for men and women in most industrialized countries. Surgery is the primary treatment modality for patients with early-stage operable NSCLC. Approximately half of these patients eventually experience relapse after resection, with a twoto three-fold higher proportion of distant metastases over local recurrences. Five-year survival rates for early-stage NSCLC range from 60% to 70% in stage I, 40% to 50% in stage II, and only 25% to 30% in patients with stage IIIA tumors. The 1995 meta-analysis published by the Non–SmallCell Lung Cancer Collaborative Group suggested an absolute survival advantage at 5 years of 5% with cisplatin-based chemotherapy (hazard ratio [HR] 0.87; 95% CI, 0.74 to 1.02; P .08). However, most of the early trials were small and underpowered. In the late 1990s, larger adjuvant trials were performed, three of which demonstrated a statistically significant survival benefit from cisplatin-based chemotherapy. Absolute 5-year survival differences ranged from 4% to 15% (HR 0.69 to 0.86). In the recently updated individual data-based Medical Research Council meta-analysis and in Lung Adjuvant CisplatinEvaluation(LACE), the5-yearabsolutebenefitwithchemotherapy ranged from 4% to 5.3% (HR 0.87; 95% CI, 0.81 to 0.93; P .0000001; and HR 0.89; 95% CI, 0.82 to 0.96; P .004, respectively). In the updated Medical Research Council metaanalysis, the effect of chemotherapy in addition to surgery versus surgery alone was studied in 8,147 patients (from 30 trials), with a median follow-up of 5.3 years across all trials. In the LACE study, data were pooled from 4,584 patients in five recent randomized adjuvant cisplatin-based chemotherapy trials and reported with a median follow-up of 5.1 years (range, 3.1 to 5.9 years). On the basis of these results, postoperative cisplatin-based chemotherapy is now widely accepted as treatment for patients with NSCLC. In the current issue of the Journal of Clinical Oncology, Strauss et al report mature data from the Cancer and Leukemia Group B (CALGB) trial 9633. They randomly assigned 344 patients who underwent complete resection for stage IB (T2N0) disease to four postoperative cycles of paclitaxel (200 mg/m) and carboplatin (area under the curve 6), the most frequently used doublet chemotherapy for NSCLC in the United States, compared with surgery alone. Although the initial interim analysis for survival was positive and prompted early termination of the study, survival was no longer significantly different between the two arms after a median follow-up of 74 months (HR 0.83; 90% CI, 0.64 to 1.08; P .12. In an unplanned subgroup analysis, a benefit seemed to appear for patients with tumors 4 cm in diameter (HR 0.69; 90% CI, 0.48 to 0.99; P .043). This study highlights several issues.

Lung Adjuvant Cisplatin Evaluation: A Pooled Analysis by the LACE Collaborative Group

Several recent trials have shown a significant overall survival (OS) benefit from postoperative cisplatin-based chemotherapy in patients with non-small-cell lung cancer (NSCLC). The aim of the Lung Adjuvant Cisplatin Evaluation was to identify treatment options associated with a higher benefit or groups of patients who particularly benefit from postoperative chemotherapy. Individual patient data were collected and pooled from the five largest trials (4,584 patients) of cisplatin-based chemotherapy in completely resected patients that were conducted after the 1995 NSCLC meta-analysis. The interactions between patient subgroups or treatment types and chemotherapy effect on OS were analyzed using hazard ratios (HRs) and log-rank tests stratified by trial. With a median follow-up time of 5.2 years, the overall HR of death was 0.89 (95% CI, 0.82 to 0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy. There was no heterogeneity of chemotherapy effect among trials. The benefit varied with stage (test for trend, P = .04; HR for stage IA = 1.40; 95% CI, 0.95 to 2.06; HR for stage IB = 0.93; 95% CI, 0.78 to 1.10; HR for stage II = 0.83; 95% CI, 0.73 to 0.95; and HR for stage III = 0.83; 95% CI, 0.72 to 0.94). The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR = 0.80; 95% CI, 0.70 to 0.91), etoposide or vinca alkaloid (HR = 0.92; 95% CI, 0.80 to 1.07), or other (HR = 0.97; 95% CI, 0.84 to 1.13). Chemotherapy effect was higher in patients with better performance status. There was no interaction between chemotherapy effect and sex, age, histology, type of surgery, planned radiotherapy, or planned total dose of cisplatin. Postoperative cisplatin-based chemotherapy significantly improves survival in patients with NSCLC.

Molecularly Tailored Adjuvant Chemotherapy for Resected Non-small Cell Lung Cancer: A Time for Excitement and Equipoise

In patients with previously-untreated, completely-resected pathologic stage II–III non-small cell lung cancer, 4 months of postoperative cisplatin-based chemotherapy reduces the risk of death by approximately 20%. To date, the only prospectively validated prognostic and predictive factor which can be used to guide clinical practice is pathologic stage. Higher stage patients have a worse prognosis, but derive more benefit from adjuvant chemotherapy. Numerous molecular markers are being developed with the potential to help decide which patients to treat with adjuvant chemotherapy, and which drugs to use. This paper will review the molecular markers which are having immediate impact on treatment decisions in routine practice, and which merit further study in the next generation of adjuvant chemotherapy trials.

A pooled analysis of the effect of age on adjuvant cisplatin-based chemotherapy for completely resected non-small cell lung cancer (NSCLC)

7553 Background: Adjuvant cisplatin-based chemotherapy (CT) has been shown to increase survival in NSCLC, but uncertainty exists concerning its efficacy and toxicity in elderly patients (≥ 70). Methods: We performed a pooled analysis using individual patient data from 4,584 patients in the LACE database with resected stage IA-III NSCLC enrolled in 5 randomized trials, comparing postoperative CT to no CT (ALPI, ANITA, BLT, IALT and JBR10). Patient and treatment characteristics, CT toxicity and delivery, overall survival, disease-free survival (DFS) and cause-specific mortality were compared among 3 age groups: 3,269 (71%) young (&lt;65), 901 (20%) mid-category (65–69) and 414 (9%) elderly (≥70). The analysis was performed on an intent-to-treat basis. Cox models stratified by trials and adjusted for age, associated drug, planned radiotherapy, total dose of cisplatin (&lt;300, 300, &gt;300), gender, stage, performance status, type of surgery and histology were used with a test for trend to study the effect of CT on survival according to age. Results: Baseline characteristics differed among the age groups, but this was due mainly to the different trial populations and designs. No difference in severe toxicity rate was observed among the age groups. Elderly patients received significantly smaller total doses of cisplatin than the other patients (Chi2-test: p&lt;0.0001) and also the cisplatin doses received were more often lower than the planned one (Kruskal-Wallis test: p&lt;0.0001). The Hazard ratio (HR) of death for the young patients was 0.82 (95% CI 0.73–0.92), 0.86 (95% CI 0.70–1.07) for the mid category and 1.01 (95% CI 0.78–1.32) for elderly patients (test for trend: p=0.17). The HR for DFS was 0.79 (95% CI 0.71–0.87) for the young, 0.76 (95% 0.62–0.93) for the mid category and 0.94 (95% CI 0.73–1.22) for the elderly patients (test for trend: p=0.35). More elderly patients died from non- lung cancer related causes (10% young, 16% mid category and 20% elderly; p&lt;0.0001). Conclusions: The survival benefit from cisplatin-based adjuvant therapy for NSCLC patients was not significantly different according to age, but this may be due to lack of power. Supported by unrestricted grants from PHRC and LNCC No significant financial relationships to disclose.

Cisplatin Versus Carboplatin for Patients With Metastatic Non-Small-Cell Lung Cancer--An Old Rivalry Renewed

Cisplatin Versus Carboplatin for Patients With Metastatic Non-Small-Cell Lung Cancer--An Old Rivalry Renewed

The Role of Induction Therapy for Resectable Non-Small Cell Lung Cancer

Lung cancer is the leading cause of cancer death among men and women in the US. Surgical resection is potentially curative; however, even after complete resection many patients experience systemic recurrence and subsequently die of their disease. As a means of reducing the chances of recurrence there has been significant interest in combining chemotherapy with surgical resection. Recently, several large phase III clinical trials have demonstrated a significant survival benefit with adjuvant or postoperative cisplatin-based chemotherapy. Use of preoperative or induction chemotherapy has also been an area of active investigation; however, the trials that have demonstrated a survival benefit were small in size, and there has not been widespread acceptance of this treatment approach. The trials of induction chemoradiotherapy have generally been performed in patients with locally advanced disease, frequently in patients with involvement of the level 2 mediastinal lymph nodes (N2). The results of the recent US Intergroup trial, 0139, which compared induction chemoradiotherapy followed by surgical resection versus nonsurgical therapy with chemoradiotherapy in patients with resectable stage IIIA-N2 disease, revealed equivalent overall survival between the two treatment approaches. The results of an unplanned subset analysis of patients who were treated with lobectomy in the surgical arm have generated significant interest and debate. When the strategy of induction therapy is used, pathological clearance of the mediastinal lymph nodes is a significant prognostic factor for overall survival. Current investigations are attempting to determine the optimal method of assessing this critical prognostic factor. The toxicity, efficacy and proper selection of patients for induction therapy, particularly induction chemoradiotherapy, will be assessed in ongoing and future clinical trials.

Has genetic profiling finally come of age in NSCLC?

Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB–IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trialAdjuvant vinorelbine plus cisplatin extends survival in patients with completely resected NSCLC, better defining indication of adjuvant chemotherapy. Full-Text PDF Adjuvant chemotherapy for resected non-small-cell lung cancer—ANITA takes the stageIn this issue of The Lancet Oncology, Douillard and colleagues report the final results of the ANITA trial,1 which confirms the benefit of postoperative cisplatin-based chemotherapy for patients with completely resected stage IB–III non-small-cell lung cancer (NSCLC)2,3 and, along with a meta-analysis,4 helps to establish pathological stage as an important, and so far the only, predictor of benefit from adjuvant chemotherapy. Full-Text PDF

Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB–IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial

Whether adjuvant chemotherapy improves survival of patients with non-small-cell lung cancer (NSCLC) is not known. We aimed to compare the effect of adjuvant vinorelbine plus cisplatin versus observation on survival in patients with completely resected NSCLC. 840 patients with stage IB-IIIA NSCLC from 101 centres in 14 countries were randomly assigned to observation (n=433) or to 30 mg/m(2) vinorelbine plus 100 mg/m(2) cisplatin (n=407). Postoperative radiotherapy was not mandatory and was undertaken according to every centre's policy. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN95053737. 367 patients in the chemotherapy group and 431 in the control group received their assigned treatment. 301 (36%) patients had stage IB disease, 203 (24%) had stage II disease, and 325 (39%) had stage IIIA disease. Tolerance to chemotherapy mainly included neutropenia in 335 (92%) patients and febrile neutropenia in 34 (9%); seven (2%) toxic deaths were also recorded. Compliance was greater with cisplatin than with vinorelbine (median dose intensity 89% [range 17-108] vs 59% [17-100]). After a median follow-up of 76 months (range 43-116), median survival was 65.7 months (95% CI 47.9-88.5) in the chemotherapy group and 43.7 (35.7-52.3) months in the observation group. Adjusted risk for death was significantly reduced in patients assigned chemotherapy compared with controls (hazard ratio 0.80 [95% CI 0.66-0.96]; p=0.017). Overall survival at 5 years with chemotherapy improved by 8.6%, which was maintained at 7 years (8.4%). Adjuvant vinorelbine plus cisplatin extends survival in patients with completely resected NSCLC, better defining indication of adjuvant chemotherapy.

Multimodality therapy for thymic carcinoma (TCA): results of a 30-year single-institution experience.

The aim of this study was to correlate the clinicopathologic features and therapeutic approaches with the outcome of patients with thymic carcinoma (TCA), an aggressive, uncommon malignancy of the anterior mediastinum. TCA is morphologically distinct from thymoma, a cytologically bland, often encapsulated, locally invasive, rarely metastatic tumor. The Roswell Park Cancer Institute tumor registry was used to identify patients with TCA or invasive thymic neoplasm of the epithelial type (TNET). Between 1971 and 2001, 22 patients had a pathologic diagnosis of TCA and/or TNET. The mean age at diagnosis was 53 years (range: 19-77), and the male/female ratio was 3:1 (16/6). Initial symptoms were respiratory in about half the patients (10/22). Complete surgical resection was done in five patients. Postoperative cisplatin-based chemotherapy and radiation was administered to seven patients. Pathologic examination showed low grade(n = 14), intermediate grade (n = 7), and high grade (n = 1) TCA. Capsular invasion was present in 83% of the specimens. As of June 2002, nine patients are alive and eight are disease free. The median survival is 44.7 months. Locally invasive disease precluded complete surgical resection in more than half of our cases. Incomplete surgical resection did not preclude long-term survival if multimodality platinum-based therapy was used.

Ovarian endometrioid tumors with yolk sac tumor component, an unusual form of ovarian neoplasm. Analysis of six cases.

The clinical, morphological, and immunohistochemical findings in six cases of ovarian endometrioid tumors (five endometrioid carcinomas and one carcinosarcoma) with a yolk sac tumor (YST) component are described. The age of the patients ranged from 31 to 73 years (average, 53), and only two patients were premenopausal. Two cases were stage Ia tumors, three stage III, and one stage IV. A substantial postoperative elevation of alpha-fetoprotein (AFP) was seen in two patients and a mild increase in another two. All six patients had surgery and postoperative cisplatin-based chemotherapy regimens, four of whom died of tumor 3 to 14 months after surgery without response to treatment. Only a stage Ia patient is alive and well 1 year after surgery. The tumors were large (average, 17 cm). Benign endometrioid lesions were found in the homolateral ovary in two cases and in the contralateral ovary in another two. All cases had endometrioid ovarian carcinomas (EOC) of various types admixed with typical YST components. Immunohistochemically, EOC areas differed from YST in their positivity for OC 125, CA 19.9, and nuclear estrogen and progesterone receptors and in their negativity for AFP, which was conspicuously positive in the YST areas. The clinicopathological profile of ovarian endometrioid tumors with YST also differs from that of YST in that it occurs in the same age range as EOC, it shows coexistence of benign endometrioid lesions, and it has a poor response to chemotherapy. The histological pattern in transitional areas may be difficult to differentiate from "endometrioid-like" (enteroblastic) YST and clear cell tumors. Ovarian endometrioid tumors with YST component should be considered a variant of endometrial carcinoma. Its recognition is necessary in view of its unusually aggressive behavior and poor prognosis.

Outcome analysis for patients with persistent nonteratomatous germ cell tumor in postchemotherapy retroperitoneal lymph node dissections.

We review the long-term outcome of patients with viable nonteratomatous germ cell tumor (NTGCT) in retroperitoneal lymph node dissection (RPLND) specimens after primary or salvage chemotherapy, and the impact of postoperative therapy with two courses of standard-dose cisplatin-based induction chemotherapy. All patients with viable NTGCT in postchemotherapy RPLND specimens from surgeries performed at Indiana University between July 1975 and March 1991 were retrospectively reviewed. Of 580 postchemotherapy RPLNDs performed, 133 had viable NTGCT in their pathology specimens. Of these 580 postchemotherapy RPLNDs, 417 were performed after primary chemotherapy, and 43 (10%) had viable NTGCT in their pathology specimens. There were 163 RPLNDs performed after salvage chemotherapy and 90 (55%) had viable NTGCT in their pathology specimens. After primary chemotherapy, 34 of 43 had complete resections, and 27 of the 34 received postoperative cisplatin-based chemotherapy. Nineteen of 27 (70%) are continuously disease-free (c-NED). All seven who received no postoperative chemotherapy have relapsed. After salvage chemotherapy, 53 of 90 had complete resections. Of those 53, 25 received postoperative chemotherapy, and nine (36%) are c-NED. Twenty-eight received no postoperative chemotherapy, and 12 (43%) are c-NED. Overall, 43 of 133 patients had incomplete resections, and only four are currently disease-free. There were four postoperative deaths (PODs). (1) Incomplete resection of viable NTGCT after primary or salvage chemotherapy portends a very poor prognosis. (2) For patients with complete resection of viable NTGCT following primary chemotherapy, two additional courses of cisplatin-based chemotherapy appear to be safe and effective therapy for reducing the risk of relapse. (3) Additional standard-dose chemotherapy appears to offer no benefit to patients with viable NTGCT in the resected specimen after salvage chemotherapy.

Intraperitoneal chemotherapy versus no treatment in patients with ovarian carcinoma who are in complete clinical remission.

The optimal management of patients with ovarian carcinoma who are in complete clinical remission after completion of postoperative cisplatin-based chemotherapy has not been established. In this study, the outcomes of two groups of such patients were compared. One group of 25 patients underwent a second-look laparotomy and subsequently received three courses of intraperitoneal chemotherapy (IP group). The other group of 12 patients was not reexplored and received no additional treatment (NT group). A trend for better survival in the IP group was found compared with the NT group. There was no difference in the duration of the progression-free interval. More effective treatment for the consolidation of complete clinical remission in patients with ovarian carcinoma is needed.