Prognostic factors in lung cancer in a defined geographical area over two decades with a special emphasis on gender.

INTRODUCTION: Many studies over recent decades report an increasing incidence of lung cancer in female patients. Female gender is often reported as a good prognostic factor. OBJECTIVES: The aim of the present study was to investigate prognostic factors with a special emphasis on gender. METHODS: During 1989-2008, 1497 patients in eastern Scania, a part of southern Sweden with 202,000 inhabitants, were referred to one Central Hospital and prospectively registered. All patients were grouped into four 5-year periods and were analysed for occurrence of lung cancer, patient performance status, types and stages of lung cancer and the relation to gender. RESULTS: The incidence of lung cancer more than doubled in women. The proportion of adenocarcinomas increased in females and in males to 57% (P=0.028) and 42% (P=0.001), respectively, while the frequency of small cell lung carcinomas (SCLCs) decreased in both genders to approximately 14%. Females had significantly more frequent stage 1 (16.6%) and higher surgery rate (23.1%) than males (12% and 18.2%, respectively). Females showed a higher 5-year survival rate than males (20.1% and 11.5%, respectively; P<0.001). Patients with non-small cell lung carcinoma (NSCLC) had a higher 5-year survival rate than those with SCLC (16.5% and 7.5%, respectively; P<0.01); however, there was no significant survival difference in females between NSCLC and SCLC. CONCLUSION: Female patients exhibited longer survival than males for both NSCLC and SCLC, and this was not explained by a higher frequency of stage 1 or surgery in NSCLC.

The impact of hyperfractionated radiotherapy regimen in patients with non-small cell lung cancer.

The prognosis for patients with lung cancer is poor with an average of 5-year overall survival rate of only 10-15 % taking all clinical stages together. The aim of this study was to elucidate the impact of the radiotherapy regimen on survival. Clinical data were collected from all the Swedish Oncology Departments for 1,287 patients with a diagnosed non-small cell lung cancer (NSCLC) subjected to curatively intended irradiation (≥50 Gy) during the years 1990 to 2000. The included patients were identified based on a manual search of all medical and radiation charts at the oncology departments from which the individual patient data were collected. Patients who did not have a histopathological diagnosis date and/or death date/last follow-up date as well as patients being surgically treated were excluded from the study (n = 592). Thus, 695 patients were included in the present study. Patients who received hyperfractionated radiotherapy (HR) had a higher local control rate compared with patients receiving conventional fractionation (CF) (38 vs. 49 % local relapse). The difference in survival between the two radiotherapy regimens was statistically significant in a univariate Cox analysis (p = 0.023) in favor of HR. This significance was, however, not retained in a multivariate Cox analysis (p = 0.56). Thus, the possible beneficial effects of hyperfractionation are still unclear and need to be further investigated in well-controlled prospective clinical trials, preferably including systemic treatment with novel drugs.

Swedish Lung Cancer Radiation Study Group: predictive value of age at diagnosis for radiotherapy response in patients with non-small cell lung cancer.

INTRODUCTION: The aim of the present study was to investigate the impact of age at diagnosis on prognosis in patients treated with curatively intended radiotherapy for NSCLC. MATERIAL AND METHODS: This is a joint effort among all the Swedish Oncology Departments that includes all identified patients with a diagnosed non-small cell lung cancer that have been subjected to curatively intended irradiation (≥50 Gy) treated during 1990 to 2000. Included patients had a histopathological/cytological diagnosis date as well as a death date or a last follow-up date. The following variables were studied in relation to overall and disease-specific survival: age, gender, histopathology, time period, smoking status, stage and treatment. RESULTS: The median overall survival of all 1146 included patients was 14.7 months, while the five-year overall survival rate was 9.5%. Younger patients (<55 years), presented with a more advanced clinical stage but had yet a significantly better overall survival compared with patients in the age groups 55-64 years (p = 0.035) and 65-74 years (p = 0.0097) in a multivariate Cox regression analysis. The overall survival of patients aged ≥75 years was comparable to those aged <55 years. CONCLUSION: In this large retrospective study we describe that patients younger than 55 years treated with curatively intended radiotherapy for NSCLC have a better overall survival than patients aged 55-64 and 65-74 years and that younger patients seem to benefit more from the addition of surgery and/or chemotherapy to radiotherapy. Due to the exploratory nature of the study, these results should be confirmed in future prospective trials.

Relation between smoking history and gene expression profiles in lung adenocarcinomas.

BACKGROUND: Lung cancer is the worldwide leading cause of death from cancer. Tobacco usage is the major pathogenic factor, but all lung cancers are not attributable to smoking. Specifically, lung cancer in never-smokers has been suggested to represent a distinct disease entity compared to lung cancer arising in smokers due to differences in etiology, natural history and response to specific treatment regimes. However, the genetic aberrations that differ between smokers and never-smokers' lung carcinomas remain to a large extent unclear. METHODS: Unsupervised gene expression analysis of 39 primary lung adenocarcinomas was performed using Illumina HT-12 microarrays. Results from unsupervised analysis were validated in six external adenocarcinoma data sets (n=687), and six data sets comprising normal airway epithelial or normal lung tissue specimens (n=467). Supervised gene expression analysis between smokers and never-smokers were performed in seven adenocarcinoma data sets, and results validated in the six normal data sets. RESULTS: Initial unsupervised analysis of 39 adenocarcinomas identified two subgroups of which one harbored all never-smokers. A generated gene expression signature could subsequently identify never-smokers with 79-100% sensitivity in external adenocarcinoma data sets and with 76-88% sensitivity in the normal materials. A notable fraction of current/former smokers were grouped with never-smokers. Intriguingly, supervised analysis of never-smokers versus smokers in seven adenocarcinoma data sets generated similar results. Overlap in classification between the two approaches was high, indicating that both approaches identify a common set of samples from current/former smokers as potential never-smokers. The gene signature from unsupervised analysis included several genes implicated in lung tumorigenesis, immune-response associated pathways, genes previously associated with smoking, as well as marker genes for alveolar type II pneumocytes, while the best classifier from supervised analysis comprised genes strongly associated with proliferation, but also genes previously associated with smoking. CONCLUSIONS: Based on gene expression profiling, we demonstrate that never-smokers can be identified with high sensitivity in both tumor material and normal airway epithelial specimens. Our results indicate that tumors arising in never-smokers, together with a subset of tumors from smokers, represent a distinct entity of lung adenocarcinomas. Taken together, these analyses provide further insight into the transcriptional patterns occurring in lung adenocarcinoma stratified by smoking history.

Swedish lung cancer radiation study group: the prognostic value of anaemia, thrombocytosis and leukocytosis at time of diagnosis in patients with non-small cell lung cancer.

There is a need to improve the prognostic and predictive indicators in non-small cell lung cancer (NSCLC). At present, the main focus is on genetic predictive markers while the prognostic value of the standard blood variables related to haematopoiesis has been subjected to relatively limited attention. To study the prognostic potential of haemoglobin (Hgb), platelet (Plt) and white blood cell (WBC) levels at time of diagnosis in NSCLC patients, 835 NSCLC patients, stage I-IV, who received radiotherapy with curative intention (>50 Gy), were included in the study. WBC, Plt, Hgb, gender, age at diagnosis, stage, surgery and first-line chemotherapy were studied in relation to overall survival. For patients with Hgb < 110 g/L and Hgb ≥ 110 g/L), the median survival was 11.2 and 14.5 months, respectively (p = 0.0032). For WBC > 9.0 × 10(9)/L and < 9.0 × 10(9)/L, the median survival was 11.6 and 15.4 months, respectively (p < 0.0001). For Plt > 350 × 10(9)/L and <350 × 10(9)/L, the median survival was 11.2 and 14.9 months, respectively (p < 0.0001). The median survival in patients with pathological results in all three markers was half of that in patients with normal levels of all three markers (8.0 and 16.0 months, respectively (p < 0.0001). The level of the three studied haematological biomarkers corresponds significantly to outcome in NSCLC. These results indicate that standard haematological variables may be used as guidance for the clinician in the decision-making regarding treatment intensity and patient information.

The value of induction chemotherapy for survival in patients with non-small cell lung cancer treated with radiotherapy.

AIM: The aim of the present study was to retrospectively investigate the impact of induction chemotherapy on treatment outcome in patients treated with curatively intended radiotherapy for non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with a diagnosed NSCLC that have been subjected to curatively intended irradiation (≥50 Gy) and treated in an oncology department in Sweden during the years 1990-2000 were included in the study. Operated patients and patients having received concomitant chemotherapy were excluded. The included patients were localised by a manual search of all the oncology departments' medical records and radiation charts. RESULTS: Patients treated with induction chemotherapy (n=79) had a significantly better overall survival compared with patients treated with radiotherapy alone (p=0.0097) in a univariate Cox regression analysis. A platinum/taxane combination produced the greatest survival benefit; hazard ratio=0.49 (95% confidence interval=0.31 to 0.75). CONCLUSION: We found that patients treated with induction chemotherapy in addition to radiotherapy for NSCLC have a better overall survival than patients treated with radiotherapy alone and that the best results are achieved using a platinum/taxane combination.

Swedish lung cancer radiation study group: predictive value of histology for radiotherapy response in patients with non-small cell lung cancer.

The aim of the present study was to evaluate the potential predictive value of histology in non-small cell lung cancer (NSCLC) treated with curatively intended radiotherapy. In a collaborative effort among all the Swedish Oncology Departments, clinical data were collected for 1146 patients with a diagnosed non-small cell lung cancer subjected to curatively intended irradiation (⩾50 Gy) during the years 1990 to 2000. The included patients were identified based on a manual search of all medical and radiation charts at the oncology departments from which the individual patient data were collected. Only patients who did not have a histological diagnosis date and death date/last follow-up date were excluded (n=141). Among the 1146 patients with non-small cell carcinoma eligible for analysis, 919 were diagnosed with either adenocarcinoma (n=323) or squamous cell carcinoma (n=596) and included in this study. The median survival for the 919 patients was 14.8 months, while the 5-year survival rate was 9.5%. Patients with adenocarcinoma had a significantly better overall survival compared with patients with squamous cell carcinoma (p=0.0062, log-rank test). When comparing different stages, this survival benefit was most pronounced for stages IIA-IIB (p<0.0001, log-rank test). The difference in survival between the two histological groups was statistically significant in a univariate Cox analysis (p=0.0063) as well as in two multivariate Cox analyses including demographic and treatment variables (p=0.037 and p=0.048, respectively). In this large population based retrospective study we describe for the first time that patients with adenocarcinoma have a better survival after curatively intended radiation therapy in comparison with squamous cell carcinoma patients, particularly those with clinical stages IIA-IIB.

A novel treatment approach for paediatric Gorham-Stout syndrome with chylothorax.

AIM: To expand the treatment options in paediatric Gorham-Stout syndrome (GSS) when conventional therapy is ineffective. METHOD: Two children with biopsy confirmed GSS, a rare disorder with progressive lymphangiomatosis, were treated with a combination of interferon-α-2b, low anticoagulant, low molecular weight heparin, radiotherapy and surgery. RESULTS: The combined therapy resolved the symptoms in the acute phase, and both patients have since been free of symptoms for >2 years. CONCLUSION: The successful addition of a low anticoagulant, low molecular weight heparin (tafoxiparin) to the treatment protocol in two paediatric cases of the GSS may justify the use of this approach in similar cases.

Multicentre phase II trial of paclitaxel and carboplatin with concurrent radiotherapy in locally advanced non-small cell lung cancer.

AIM: To evaluate weekly induction chemotherapy followed by weekly concomitant chemoradiotherapy in a multicentre phase II study of patients with unresectable stage III non-small cell lung cancer (NSCLC; stage wet IIIB excluded). PATIENTS AND METHODS: Eligible patients received three weekly cycles of paclitaxel 100 mg/m2 and carboplatin AUC2 followed by six weekly cycles of paclitaxel 60 mg/m2 and carboplatin AUC2 in combination with thoracic radiotherapy (2 Gy per fraction and day to a total dose of 60 Gy). RESULTS: Sixty-four patients (40 males and 24 females) with a median age of 63 years (range, 43-79 years) entered the study. T and N stage were distributed as follows: T1 2 patients (3.2%), T2 10 patients (15.6%), T3 15 patients (23.4%), T4 37 patients (57.8%); N0 10 patients (15.6%), N1 1 patient (1.6%), N2 26 patients (40.6%), N3 26 patients (40.6%), and N missing 1 patient (1.6%). Seven patients (10.9%) suffered from grade 3/4 oesophagitis. Grade 1/2 oesophagitis occurred in 36 patients (56.3%) and pneumonitis grade 1/2 occurred in 10 patients (15.6%). Sixty-three patients were evaluated on an intent-to-treat basis. The overall response rate was 74.6%. The median time to progression was 247 days and median overall survival was 461 days. According to subgroup analyses, no statistically significant differences were noted according to gender, age (<65 vs. > or =65 years), performance status, histology, or study centre. CONCLUSION: Induction chemotherapy followed by concurrent chemoradiotherapy with weekly cycles of paclitaxel and carboplatin is feasible and generates moderate toxicity. Efficacy is comparable to other recently published regimens. However, prognosis remains, in general, poor for this group of patients and further work to develop better therapy is required.

NTCP modelling and pulmonary function tests evaluation for the prediction of radiation induced pneumonitis in non-small-cell lung cancer radiotherapy.

This work aims to evaluate the predictive strength of the relative seriality, parallel and Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP) models regarding the incidence of radiation pneumonitis (RP), in a group of patients following lung cancer radiotherapy and also to examine their correlation with pulmonary function tests (PFTs). The study was based on 47 patients who received radiation therapy for stage III non-small-cell lung cancer. For each patient, lung dose volume histograms (DVHs) and the clinical treatment outcome were available. Clinical symptoms, radiological findings and pulmonary function tests incorporated in a post-treatment follow-up period of 18 months were used to assess the manifestation of radiation induced complications. Thirteen of the 47 patients were scored as having radiation induced pneumonitis, with RTOG criteria grade 3 and 28 of the 47 with RTOG criteria grade 2. Using this material, different methods of estimating the likelihood of radiation effects were evaluated, by analysing patient data based on their full dose distributions and associating the calculated complication rates with the clinical follow-up records. Lungs were evaluated as a paired organ as well as individual lungs. Of the NTCP models examined in the overall group considering the dose distribution in the ipsilateral lung, all models were able to predict radiation induced pneumonitis only in the case of grade 2 radiation pneumonitis score, with the LKB model giving the best results (chi2-test: probability of agreement between the observed and predicted results Pchi(chi2)=0.524 using the 0.05 significance level). The NTCP modelling considering lungs as a paired organ did not give statistically acceptable results. In the case of lung cancer radiotherapy, the application of different published radiobiological parameters alters the NTCP results, but not excessively as in the case of breast cancer radiotherapy. In this relatively small group of lung cancer patients, no positive statistical correlation could be established between the incidence of radiation pneumonitis as estimated by NTCP models and the pulmonary function test evaluation. However, the use of PFTs as markers or predictors for the incidence or severity of radiation induced pneumonitis must be investigated further.

Intraoperative radiotherapy for patients with carcinoma of the pancreas.

BACKGROUND/AIMS: Local recurrence is one of the most common sites of failure after resection of exocrine pancreatic adenocarcinoma. Intraoperative radiotherapy (IORT) involves delivery of high doses of irradiation to the pancreas in patients with locally advanced disease, and to the surgical bed following pancreatic resection while uninvolved and dose-limiting tissues are displaced. Here we report our current experience with IORT in patients with pancreatic cancer. METHODS: IORT was given as adjuvant treatment in 18 and palliatively in 37 patients. External beam radiotherapy (EBRT) was in addition delivered to 10 patients in the resection group and 29 in the palliation group. The cancer diagnosis was verified histologically and/or cytologically in all patients. RESULTS: There was no hospital mortality. Among the resected patients the postoperative complication rate was 44% (8/18). The corresponding figure after palliative operation was 14% (5/37). None of the postoperative complications were regarded as a consequence of IORT. Symptoms and complaints were observed after EBRT in 70 and 90%, respectively, in the two groups. However, no symptom was serious in nature. After resection the median survival time was 9 months (range 3-58) and local recurrence was diagnosed in 33% (6/18). In the palliatively treated patients the median survival was 7 months (range 2-30) and pain requiring opioids was present in 89% (24/27) of the patients within 6 months. CONCLUSION: In this nonrandomized study no apparent beneficial effects were seen after IORT in patients with pancreatic cancer, neither adjuvantly nor palliatively. However, radiotherapy did not lead to any major complications.

Extended operation with or without intraoperative (IORT) and external (EBRT) radiotherapy for gallbladder carcinoma.

BACKGROUND/AIMS: Gallbladder carcinoma is a rare disease with dismal prognosis. However, lately improved survival has been reported after extended operation including liver resection and lymphadenectomy in addition to cholecystectomy. The aim of this study was to evaluate such a surgical strategy with and without adjuvant intra- and postoperative radiotherapy (IORT/EBRT). METHODOLOGY: 20 patients underwent extended operation and the last 10 of them IORT/EBRT in addition. Tumor staging was done using the TNM system, determination of histological tumor differentiation and immunohistochemical assessment of p53, Ki67, metallothionein, deleted in colorectal cancer and carcinoembryogenic antigen in tumor tissue. RESULTS: There was no hospital mortality. Postoperative complications occurred in 3 patients (15%). Actuarial 5-year survival was 47% in the radiotherapy group and 13% after operation only (NS). The corresponding figures for median survival are 28.8 and 20.2 months, respectively. Five patients are still alive in the radiotherapy group. There was no difference in tumour stages of the two groups irrespective of the way of evaluation. CONCLUSIONS: The results suggest that extended operation for gallbladder carcinoma +/- IORT/EBRT can be done safely. The tendency to longer survival after adjuvant radiotherapy was not statistically significant.