Helena Fohlin

Swedish Two-County Trial: Impact of Mammographic Screening on Breast Cancer Mortality during 3 Decades

PURPOSE To estimate the long-term (29-year) effect of mammographic screening on breast cancer mortality in terms of both relative and absolute effects. MATERIALS AND METHODS This study was carried out under the auspices of the Swedish National Board of Health and Welfare. The board determined that, because randomization was at a community level and was to invitation to screening, informed verbal consent could be given by the participants when they attended the screening examination. A total of 133 065 women aged 40-74 years residing in two Swedish counties were randomized into a group invited to mammographic screening and a control group receiving usual care. Case status and cause of death were determined by the local trial end point committees and, independently, by an external committee. Mortality analysis was performed by using negative binomial regression. RESULTS There was a highly significant reduction in breast cancer mortality in women invited to screening according to both local end point committee data (relative risk [RR] = 0.69; 95% confidence interval: 0.56, 0.84; P < .0001) and consensus data (RR = 0.73; 95% confidence interval: 0.59, 0.89; P = .002). At 29 years of follow-up, the number of women needed to undergo screening for 7 years to prevent one breast cancer death was 414 according to local data and 519 according to consensus data. Most prevented breast cancer deaths would have occurred (in the absence of screening) after the first 10 years of follow-up. CONCLUSION Invitation to mammographic screening results in a highly significant decrease in breast cancer-specific mortality. Evaluation of the full impact of screening, in particular estimates of absolute benefit and number needed to screen, requires follow-up times exceeding 20 years because the observed number of breast cancer deaths prevented increases with increasing time of follow-up.

Prognostic Significance of C-Reactive Protein and Smoking in Patients with Advanced Non-small Cell Lung Cancer Treated with First-Line Palliative Chemotherapy

Hypothesis: The objective of the study was to analyze if C-reactive protein (CRP) and smoking status provide prognostic information in patients with advanced non-small cell lung cancer (NSCLC) receiving palliative first-line chemotherapy. Methods: Retrospective, single-institutional study, comprising all patients with NSCLC stage IIIB/IV and World Health Organization performance status (PS) 0–2 who started palliative first-line chemotherapy between January 1, 2002, and January 31, 2007. Patient records were reviewed. Cox’s proportional hazards model was used to identify prognostic factors. Results: Two hundred eight-nine consecutive patients were evaluable. Sixty-eight percent had stage IV disease and 67% had PS 0 or 1. Median survival was 7.4 months. At onset of chemotherapy, 206 patients (71%) had elevated CRP values (≥10 mg/liter). One-hundred-forty-four patients (50%) were current smokers. On univariate analysis, patients with elevated CRP levels had inferior survival (hazard ratio [HR] = 1.67, 95% confidence interval [CI], 1.28–2.19, p < 0.001). Smoking at onset of treatment was associated with shorter survival (HR 1.56, 95% CI, 1.22–1.98, p < 0.001). Ever smokers had shorter survival than never smokers (HR 1.80, 95% CI, 1.25–2.59, p = 0.001). On multivariate analysis, with stage, PS, albumin, and gender as covariates, both smoking at start of chemotherapy and CRP elevation were independent negative prognostic factors for survival. Conclusions: CRP and smoking status are independent prognostic factors for survival in patients with advanced NSCLC receiving palliative first-line chemotherapy and provide additional information to established prognostic factors such as stage of disease and performance status.

Long-term Effectiveness of Adjuvant Goserelin in Premenopausal Women With Early Breast Cancer

Background Systematic reviews have found that luteinizing hormone–releasing hormone (LHRH) agonists are effective in treating premenopausal women with early breast cancer. Methods We conducted long-term follow-up (median 12 years) of 2706 women in the Zoladex In Premenopausal Patients (ZIPP), which evaluated the LHRH agonist goserelin (3.6 mg injection every 4 weeks) and tamoxifen (20 or 40 mg daily), given for 2 years. Women were randomly assigned to receive each therapy alone, both, or neither, after primary therapy (surgery with or without radiotherapy/chemotherapy). Hazard ratios and absolute risk differences were used to assess the effect of goserelin treatment on event-free survival (breast cancer recurrence, new tumor or death), overall survival, risk of recurrence of breast cancer, and risk of dying from breast cancer, in the presence or absence of tamoxifen. Results Fifteen years after the initiation of treatment, for every 100 women not given tamoxifen, there were 13.9 (95% confidence interval [CI] = 17.5 to 19.4) fewer events among those who were treated with goserelin compared with those who were not treated with goserelin. However, among women who did take tamoxifen, there were 2.8 fewer events (95% CI = 7.7 fewer to 2.0 more) per 100 women treated with goserelin compared with those not treated with goserelin. The risk of dying from breast cancer was also reduced at 15 years: For every 100 women given goserelin, the number of breast cancer deaths was lower by 2.6 (95% CI = 6.6 fewer to 2.1 more) and 8.5 (95% CI = 2.2 to 13.7) in those who did and did not take tamoxifen, respectively, although in the former group the difference was not statistically significant. Conclusions Two years of goserelin treatment was as effective as 2 years of tamoxifen treatment 15 years after starting therapy. In women who did not take tamoxifen, there was a large benefit of goserelin treatment on survival and recurrence, and in women who did take tamoxifen, there was a marginal potential benefit on these outcomes when goserelin was added.

Predictive role of plasma vascular endothelial growth factor for the effect of celecoxib in advanced non-small cell lung cancer treated with chemotherapy

AIM OF THE STUDY The primary purpose of this study is to investigate if pretreatment plasma levels of vascular endothelial growth factor (VEGF) are predictive of the effect of celecoxib on survival in advanced non-small cell lung cancer (NSCLC) treated with palliative chemotherapy. A secondary objective is to describe the course of plasma VEGF levels during and after treatment with cytotoxic chemotherapy combined with celecoxib or placebo. METHODS In a previously published double-blind multicenter phase III trial, 316 patients with NSCLC stage IIIB or IV and World Health Organisation (WHO) performance status 0-2 were randomised to receive celecoxib 400mg b.i.d. or placebo in combination with two-drug platinum-based chemotherapy. Chemotherapy cycle length was three weeks and planned duration of chemotherapy was four cycles. Celecoxib was given for a maximum of one year but was stopped earlier in case of disease progression or prohibitive toxicity. In a subset of patients, plasma VEGF levels were examined at onset of treatment and at 6, 12 and 20 weeks. RESULTS VEGF levels at start of treatment were obtained in 107 patients at four study sites. The median value was 70 pg/ml. Mean values declined during the first 12 weeks and then increased at 20 weeks. A subpopulation treatment effect pattern plot (STEPP) analysis showed an inverse relationship between initial plasma VEGF and the impact of celecoxib on survival with zero effect at 200 pg/ml. The effect on survival by celecoxib in the whole subset of patients was positive (hazard ratio (HR)=0.64 [confidence interval (CI) 0.43-0.95], p=0.028). CONCLUSION Low pretreatment plasma levels of VEGF appear to be predictive of a positive effect of celecoxib on survival.

Prolonged tamoxifen treatment increases relapse-free survival for patients with primary breast cancer expressing high levels of VEGF

Previous retrospective studies have shown that high intratumoural levels of vascular endothelial growth factor (VEGF) correlate with an inferior outcome for patients treated with adjuvant tamoxifen. Our objectives were to validate the impact of VEGF on survival after adjuvant tamoxifen and to investigate the interaction between VEGF and treatment duration. For this purpose tumour homogenates from 402 patients with operable oestrogen receptor positive breast cancer (BC), treated with tamoxifen for 2 (n=149) or 5 years (n=253) as the only systemic adjuvant therapy were included. The median follow-up time for surviving patients was 9.8 years (range 0.5-14.8 years). Expression of VEGF was assessed by an enzyme-linked immunosorbent assay and investigated in relation to the standard BC parameters and survival. In the total population, higher VEGF was significantly correlated with shorter recurrence-free survival (RFS) (HR=1.63, 95%CI=1.11-2.39, p=0.010), breast cancer corrected survival (BCCS) (HR=1.82, 95%CI=1.13-2.93, p=0.014) and overall survival (OS) (HR=1.51, 95%CI=1.11-2.05, p=0.009). High VEGF was significantly associated with reduced RFS (HR=2.61, 95%CI=1.45-4.70, p=0.001) after two years of tamoxifen, whilst no difference was seen in patients treated for five years (HR=1.09, 95%CI=0.64-1.84, p=0.760). A statistically significant interaction was observed between high VEGF expression and improved RFS after 5-year tamoxifen (p=0.034). In concordance with previous studies, high VEGF was significantly correlated with shorter survival. We present data not reported previously revealing that patients expressing high levels of VEGF display a better outcome provided that tamoxifen is given for five years. Further studies on the impact of VEGF on a 5-year regimen are motivated.

Three‐dimensional reconstruction of seed implants by randomized rounding and visual evaluation

The development of efficient 3D seed reconstruction algorithms is an ongoing and vivid research topic. Since the 1980s many publications about seed assignment were published. In this paper a novel mathematical approach is described to solve the 3D assignment problem for the reconstruction of seeds with radiographs: we present a fast linear programming approach together with afterwards applying the so-called randomized rounding scheme to compute good (possibly partial) assignments. We apply a visualization software that allows user interaction to check the solution given by the algorithm and to augment partial assignments. The second step is justified as the randomized algorithm already returns optimal solutions is many cases, and in cases with partial assignments it fails to match only a very small number of seed images. Our algorithm transfers ideas from recent breakthrough research work on the design of efficient randomized algorithms in discrete optimization and computer science to the seed reconstruction problem.

No clear effect of postoperative radiotherapy on survival of breast cancer patients with one to three positive nodes: a population-based study

BACKGROUND In published radiotherapy trials, the failure rate in the control arm among patients with one to three positive nodes is high compared with that seen with modern adjuvant treatments. Therefore, the generalizability of the results has been questioned. The aim of the present study was to compare relative survival in breast cancer patients between two Swedish regions with screening mammography programs and adjuvant treatment guidelines similar with the exception of the indication of radiotherapy for patients with one to three positive nodes. PATIENTS AND METHODS Between 1989 and 2006, breast cancer patients were managed very similarly in the west and southeast regions, except for indication for postoperative radiotherapy. In patients with one to three positive nodes, postmastectomy radiotherapy was generally given in the southeast region (89% of all cases) and generally not given in the west region (15% of all cases). For patients with one to three positive nodes who underwent breast-conserving surgery, patients in the west region had breast radiotherapy only, while patients in the southeast region had both breast and lymph nodes irradiated. RESULTS The 10-year relative survival for patients with one to three positive lymph nodes was 78% in the west region and 77% in the southeast region (P = 0.12). Separate analyses depending on type of surgery, as well as number of examined nodes, also revealed similar relative survival. CONCLUSION Locoregional postoperative radiotherapy has well-known side-effects, but in this population-based study, there was little or no influence of this type of radiotherapy on survival when one to three lymph nodes were involved.BACKGROUND In published radiotherapy trials, the failure rate in the control arm among patients with one to three positive nodes is high compared with that seen with modern adjuvant treatments. Therefore, the generalizability of the results has been questioned. The aim of the present study was to compare relative survival in breast cancer patients between two Swedish regions with screening mammography programs and adjuvant treatment guidelines similar with the exception of the indication of radiotherapy for patients with one to three positive nodes. PATIENTS AND METHODS Between 1989 and 2006, breast cancer patients were managed very similarly in the west and southeast regions, except for indication for postoperative radiotherapy. In patients with one to three positive nodes, postmastectomy radiotherapy was generally given in the southeast region (89% of all cases) and generally not given in the west region (15% of all cases). For patients with one to three positive nodes who underwent breast-conserving surgery, patients in the west region had breast radiotherapy only, while patients in the southeast region had both breast and lymph nodes irradiated. RESULTS The 10-year relative survival for patients with one to three positive lymph nodes was 78% in the west region and 77% in the southeast region (P = 0.12). Separate analyses depending on type of surgery, as well as number of examined nodes, also revealed similar relative survival. CONCLUSION Locoregional postoperative radiotherapy has well-known side-effects, but in this population-based study, there was little or no influence of this type of radiotherapy on survival when one to three lymph nodes were involved.

Akt2 expression is associated with good long-term prognosis in oestrogen receptor positive breast cancer

INTRODUCTION Akt is a signalling modulator for many cellular processes, including metabolism, cell proliferation, cell survival and cell growth. Three isoforms of Akt have been identified, but only a few studies have concerned the isoform-specific roles in the prognosis of breast cancer patients. The aim of this study was to investigate the prognostic value of v-akt murine thymoma viral oncogene homologue 1 (Akt1) and v-akt murine thymoma viral oncogene homologue 2 (Akt2) in oestrogen receptor positive (ER+) and oestrogen receptor negative (ER-) breast cancer with long-term follow-up. MATERIAL AND METHODS The expression of Akt in tumour tissue was analysed with immunohistochemistry in a cohort of 272 postmenopausal patients with stage II breast cancer. The median follow-up time was 19 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Coxs proportional hazards model. RESULTS The risk of distant recurrence was reduced for patients with ER+ tumours expressing Akt2 compared to patients with no Akt2 expression (HR=0.49, 95% CI 0.29-0.82, p=0.007). When adjusting for important clinical tumour characteristics and treatment, Akt2 was still an independent prognostic factor (HR=0.38, 95% CI 0.21-0.68, p=0.001) and the association remained long-term. The prognostic value of Akt2 increased with higher oestrogen receptor levels from no effect among patients with ER- tumours to 68% risk reduction for the group with high ER-levels (P for trend=0.042). Akt1 showed no significant prognostic information. CONCLUSION Our results indicate that Akt2 expression is associated with a lower distant recurrence rate for patients with ER+ tumours and that this association remains long-term. The prognostic value of Akt2 increases with higher oestrogen receptor expression, motivating further mechanistic studies on the role of Akt2 in ER+ breast cancer.

Cyclooxygenase-2 expression in lung cancer cells evaluated by immunocytochemistry†

Cyclooxygenase‐2 (COX‐2) expression may be a prognostic factor in lung cancer. In previous studies, COX‐2 expression has almost exclusively been evaluated with immunohistochemical methods performed on histology sections of tissue biopsies. However, in clinical practice, lung cancer is often diagnosed with cytological techniques only. We present methodology and results from analysis of COX‐2 expression with immunochemistry on cytological material in 53 patients with lung cancer. Preparation and staining with the method established at our laboratory were easy to perform and resulted in good quality slides. The percentage COX‐2‐stained cells and the intensity of staining varied widely between and within the different cases. The proportion of positively stained tumor cells was as follows: <1% in 20 patients, 1–10% in 7 patients, 11–50% in 17 patients, and more than 50% in 9 patients. In 17 cases, groups of cells with different intensity of COX‐2 staining were found in the same slide. In conclusion, immunocytochemical analysis of COX‐2 expression is technically easy to perform with routine diagnostic procedures. There is a great variation in the proportion of COX‐2‐positive cells among patients and in the intensity of staining among individual cells in many single cases. Diagn. Cytopathol.2011;39:188–193.

Randomized algorithms for mixed matching and covering in hypergraphs in 3D seed reconstruction in brachytherapy

Brachytherapy is a radiotherapy method for cancer. In its low dose radiation (LDR) variant a number of radioactive implants, so-called seeds, are inserted into the affected organ through an operation. After the implantation, it is essential to determine the locations of the seeds in the organ. A common method is to take three X-ray photographs from different angles; the seeds show up on the X-ray photos as small white lines. In order to reconstruct the three-dimensional configuration from these X-ray photos, one has to determine which of these white lines belong to the same seed. We model the problem as a mixed packing and covering hypergraph optimization problem and present a randomized approximation algorithm based on linear programming. We analyse the worst-case performance of the algorithm by discrete probabilistic methods and present results for data of patients with prostate cancer from the university clinic of Schleswig-Holstein, Campus Kiel. These examples show an almost optimal performance of the algorithm which presently cannot be matched by the theoretical analysis.