Erik Jakobsen

Effect of Obesity on Prognosis After Early-Stage Breast Cancer

PURPOSE This study was performed to characterize the impact of obesity on the risk of breast cancer recurrence and death as a result of breast cancer or other causes in relation to adjuvant treatment. PATIENTS AND METHODS Information on body mass index (BMI) at diagnosis was available for 18,967 (35%) of 53,816 women treated for early-stage breast cancer in Denmark between 1977 and 2006 with complete follow-up for first events (locoregional recurrences and distant metastases) up to 10 years and for death up to 30 years. Information was available on prognostic factors and adjuvant treatment for all patients. Univariate analyses were used to compare the associations of known prognostic factors and risks of recurrence or death according to BMI categories. Cox proportional hazards regression models were used to assess the influence of BMI after adjusting for other factors. RESULTS Patients with a BMI of 30 kg/m(2) or more were older and had more advanced disease at diagnosis compared with patients with a BMI below 25 kg/m(2) (P < .001). When data were adjusted for disease characteristics, the risk of developing distant metastases after 10 years was significantly increased by 46%, and the risk of dying as a result of breast cancer after 30 years was significantly increased by 38% for patients with a BMI of 30 kg/m(2) or more. BMI had no influence on the risk of locoregional recurrences. Both chemotherapy and endocrine therapy seemed to be less effective after 10 or more years for patients with BMIs greater than 30 kg/m(2). CONCLUSION Obesity is an independent prognostic factor for developing distant metastases and for death as a result of breast cancer; the effects of adjuvant therapy seem to be lost more rapidly in patients with breast cancer and obesity.

Lung cancer survival and stage at diagnosis in Australia, Canada, Denmark, Norway, Sweden and the UK: a population-based study, 2004–2007

Background The authors consider whether differences in stage at diagnosis could explain the variation in lung cancer survival between six developed countries in 2004–2007. Methods Routinely collected population-based data were obtained on all adults (15–99 years) diagnosed with lung cancer in 2004–2007 and registered in regional and national cancer registries in Australia, Canada, Denmark, Norway, Sweden and the UK. Stage data for 57 352 patients were consolidated from various classification systems. Flexible parametric hazard models on the log cumulative scale were used to estimate net survival at 1 year and the excess hazard up to 18 months after diagnosis. Results Age-standardised 1-year net survival from non-small cell lung cancer ranged from 30% (UK) to 46% (Sweden). Patients in the UK and Denmark had lower survival than elsewhere, partly because of a more adverse stage distribution. However, there were also wide international differences in stage-specific survival. Net survival from TNM stage I non-small cell lung cancer was 16% lower in the UK than in Sweden, and for TNM stage IV disease survival was 10% lower. Similar patterns were found for small cell lung cancer. Conclusions There are comparability issues when using population-based data but, even given these constraints, this study shows that, while differences in stage at diagnosis explain some of the international variation in overall lung cancer survival, wide disparities in stage-specific survival exist, suggesting that other factors are also important such as differences in treatment. Stage should be included in international cancer survival studies and the comparability of population-based data should be improved.

Phase III Trial Comparing Three Doses of Docetaxel for Second-Line Treatment of Advanced Breast Cancer

PURPOSE To evaluate whether a relationship exists between docetaxel dose and clinical response in the treatment of patients with advanced breast cancer. PATIENTS AND METHODS Patients whose cancer had progressed after one prior chemotherapy regimen for advanced breast cancer or had recurred during or within 6 months of adjuvant chemotherapy were randomly assigned to docetaxel 60, 75, or 100 mg/m2 intravenously every 3 weeks. RESULTS Five hundred twenty-seven patients were randomly assigned (intent to treat [ITT]), and 524 were assessable for toxicity. In the population assessable for efficacy (n = 407), logistic regression analysis showed that increasing docetaxel dose was significantly associated with higher response rate (P = .007) and improved time to progression (TTP; P = .014). In the ITT analysis, a significant dose-response relationship was observed for tumor response (P = .026) but not for TTP (P = .067). The incidences of most hematologic and nonhematologic toxicities were related to increasing dose, with grade 3 to 4 neutropenia occurring in 76.4%, 83.7%, and 93.4% and febrile neutropenia occurring in 4.7%, 7.4%, and 14.1% of patients administered the 60, 75, and 100 mg/m2 doses, respectively. One death was considered treatment related. CONCLUSION A relationship between increasing dose of docetaxel and increased tumor response was observed across the dose range of 60 to 100 mg/m2 every 3 weeks. Toxicities were related to increasing dose. Depending on the therapy goal, any of the doses studied may be appropriate for second-line treatment of advanced breast cancer.

A national study of nodal upstaging after thoracoscopic versus open lobectomy for clinical stage I lung cancer.

BACKGROUND Nodal upstaging after surgical intervention for non-small cell lung cancer (NSCLC) occurs when unsuspected lymph node metastases are found during the final evaluation of surgical specimens. Recent data from The Society of Thoracic Surgery (STS) database demonstrated significantly lower nodal upstaging after thoracoscopic (VATS) lobectomy than after thoracotomy. STS data, however, may be biased from voluntary reporting, and survival was not investigated. We used a complete national registry to compare nodal upstaging and survival after lobectomy by VATS or thoracotomy. METHODS The Danish Lung Cancer Registry was used to identify patients who underwent lobectomy for clinical stage I NSCLC from 2007 to 2011. Patient demographics, comorbidity, preoperative staging, surgical approach, number of lymph nodes harvested, final pathology, and survival were evaluated. Nodal upstaging was identified by comparing cT N M with pT N M. RESULTS Lobectomy for clinical stage I NSCLC was performed in 1,513 patients: 717 (47%) by VATS and 796 (53%) by thoracotomy. Nodal upstaging occurred in 281 patients (18.6%) and was significantly higher after thoracotomy for N1 upstaging (13.1% vs 8.1%; p<0.001) and N2 upstaging (11.5% vs 3.8%; p<0.001). Overall unadjusted survival was significantly higher after VATS, but after adjusting for differences in sex, age, comorbidity, and pT N M by Cox regression analysis, we found no difference between VATS and thoracotomy (hazard ratio, 0.98; 95% confidence interval, 0.80 to 1.22, p=0.88). CONCLUSIONS National data confirm that nodal upstaging was lower after VATS than after open lobectomy for clinical stage I NSCLC. Multivariate survival analysis, however, showed no difference in survival, indicating that differences in nodal upstaging result from patient selection for reasons not captured in our registry.

High Procedure Volume Is Strongly Associated With Improved Survival After Lung Cancer Surgery

PURPOSE Studies have reported an association between hospital volume and survival for non-small-cell lung cancer (NSCLC). We explored this association in England, accounting for case mix and propensity to resect. METHODS We analyzed data on 134,293 patients with NSCLC diagnosed in England between 2004 and 2008, of whom 12,862 (9.6%) underwent surgical resection. Hospital volume was defined according to number of patients with resected lung cancer in each hospital in each year of diagnosis. We calculated hazard ratios (HRs) for death in three predefined periods according to hospital volume, sex, age, socioeconomic deprivation, comorbidity, and propensity to resect. RESULTS There was increased survival in hospitals performing > 150 surgical resections compared with those carrying out < 70 (HR, 0.78; 95% CI, 0.67 to 0.90; Ptrend < .01). The association between hospital volume and survival was present in all three periods of follow-up, but the magnitude of association was greatest in the early postoperative period. CONCLUSION High-volume hospitals have higher resection rates and perform surgery among patients who are older, have lower socioeconomic status, and have more comorbidities; despite this, they achieve better survival, most notably in the early postoperative period.

Delineation of target volumes and organs at risk in adjuvant radiotherapy of early breast cancer: National guidelines and contouring atlas by the Danish Breast Cancer Cooperative Group

Abstract During the past decade planning of adjuvant radiotherapy (RT) of early breast cancer has changed from two-dimensional (2D) to 3D conformal techniques. In the planning computerised tomography (CT) scan both the targets for RT and the organs at risk (OARs) are visualised, enabling an increased focus on target dose coverage and homogeneity with only minimal dose to the OARs. To ensure uniform RT in the national prospective trials of the Danish Breast Cancer Cooperative Group (DBCG), a national consensus for the delineation of clinical target volumes (CTVs) and OARs was required. Material and methods. A CT scan of a breast cancer patient after surgical breast conservation and axillary lymph node (LN) dissection was used for delineation. During multiple dummy-runs seven experienced radiation oncologists contoured all CTVs and OARs of interest in adjuvant breast RT. Two meetings were held in the DBCG Radiotherapy Committee to discuss the contouring and to approve a final consensus. The Dice similarity coefficient (DSC) was used to evaluate the delineation agreement before and after the consensus. Results. The consensus delineations of CTVs and OARs are available online and a table is presented with a contouring description of the individual volumes. The consensus provides recommendations for target delineation in a standard patient both in case of breast conservation or mastectomy. Before the consensus, the average value of the DSC was modest for most volumes, but high for the breast CTV and the heart. After the consensus, the DSC increased for all volumes. Conclusion. The DBCG has provided the first national guidelines and a contouring atlas of CTVs and OARs definition for RT of early breast cancer. The DSC is a useful tool in quantifying the effect of the introduction of guidelines indicating improved inter-delineator agreement. This consensus will be used by the DBCG in our prospective trials.

The effect of comorbidity on stage-specific survival in resected non-small cell lung cancer patients

AIM To quantify the effect of comorbidity on stage-specific survival in resected non-small cell lung cancer (NSCLC) patients. METHODS From the Danish Lung Cancer Registry, 20,461 patients diagnosed with lung cancer between 1st January 2005 and 31st December 2010 were identified. Among 3152 NSCLC patients who underwent surgical resection, mortality hazard ratios were calculated during three consecutive time periods following surgery (0-1 month, 1 month-1 year and >1 year) according to Charlson comorbidity score (CCS 0, 1, 2, 3+), Eastern Cooperative Oncology Group (ECOG) performance status, lung function, age, sex, pathological T (pT) and N (pN) stage using Cox proportional hazard modelling. The Kaplan Meier method was used to describe stage-specific survival according to the CCS. RESULTS Severe comorbidity (CCS 3+) was independently associated with significantly higher death rates throughout the three periods of follow-up [Hazard ratio (HR) 2.06 (1.13-3.75) for CCS 3+ in 0-1 month, 1.57 (1.17-2.12) 3+ during1 month-1 year and 1.84 (1.42-2.37) after 1 year]. Stage-specific 5-year survival in patients with severe comorbidity was significantly lower than in patients without comorbid disease [e.g. 38% (95% confidence interval (CI) 23-53%) for pT1 and CCS 3+ versus 69% (62-75%) for pT1 and CCS 0]. CONCLUSION Severe comorbidity affects survival of NSCLC patients who undergo surgical resection by as much as a single stage increment and this effect persists throughout follow-up. Further research may be necessary to help identify which patients are most likely to benefit from surgery.

Data from a national lung cancer registry contributes to improve outcome and quality of surgery: Danish results

OBJECTIVE In 1998 The Danish Lung Cancer Group published the first edition of guidelines for diagnosis and treatment of lung cancer. A national registry was implemented in the year 2000 with the primary objective to monitor the implementation of these guidelines and nationwide to secure and improve the quality of the clinical management of lung cancer. The results of this effort are reported with special focus on surgery. METHODS Through systematic nationwide registration a total of 24,153 patients have been included in the period 2000-2007. Indicators describing staging, surgical procedures, complications and survival have been registered in those 5007 patients who underwent surgery. Using an Internet based closed circle with a safe program (firewall and encryptation) more than 95% of this subgroup of patients have been notified. Each year the results have been audited locally, regionally and nationally and improvements have been proposed, implemented, monitored and consecutively evaluated by the audit-plenary. RESULTS This strategy has been a contributory factor to significantly improve the results in mortality, survival and surgical procedures. Thus, the 30-days mortality following surgery has decreased from 5.2% to 3.6% and survival has increased from an overall 1- and 2-year survival of 69% and 50% in 2000 to 77% and 60% in 2007, respectively. A number of other key indicators were also improved: the lobectomy rate has increased from 54% to 73% and the pneumonectomy rate has decreased from 23% to 11%. The proportion of patients having surgery within 14 days from referral has increased from 69% to 87%. CONCLUSIONS Establishment of a national lung cancer group with the primary tasks to implement updated national guidelines and to secure valid registration of clinical baseline data and quality parameters has been a contributory factor to significantly improve the quality of lung cancer surgery.

Suramin in Non-small Cell Lung Cancer and Advanced Breast Cancer: Two Parallel Phase II Studies

Suramin inhibits the growth of non-small cell lung cancer (NSCLC) and breast cancer in vitro by blocking the action of most known growth factors. The clinical efficacy of suramin was evaluated in patients with unresectable or relapsed NSCLC (n = 16) and advanced breast cancer (ABC) resistant to conventional therapies (n = 12). A plasma level > or = 200 micrograms/ml was maintained by three times weekly administrations using adaptive control with feedback. Treatment was continued until documented progression of disease or unacceptable toxicity. No clinical responses were observed in any patient. Median overall survival was 4.5 months in NSCLC and 9 months in ABC patients. Mean treatment duration was 6.6 weeks in NSCLC patients and 15.9 weeks in ABC patients. Treatment was discontinued due to disease progression in 14 patients, unacceptable adverse effects in 11 patients, while three patients refused to continue therapy. We cannot recommend this drug for further clinical trials in NSCLC and ABC.

Gemcitabine Plus Docetaxel Versus Docetaxel in Patients With Predominantly Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced or Metastatic Breast Cancer: A Randomized, Phase III Study by the Danish Breast Cancer Cooperative Group

PURPOSE The objective of this phase III study was to compare the efficacy of gemcitabine plus docetaxel (GD) versus docetaxel in patients with advanced breast cancer. PATIENTS AND METHODS Predominantly human epidermal growth factor receptor 2 (HER2) -negative patients were randomly assigned to gemcitabine (1,000 mg/m(2)) on days 1 and 8 plus docetaxel (75 mg/m(2)) on day 8 or to docetaxel (100 mg/m(2)) on day 1, every 21 days. Patients were untreated or had prior (neo)adjuvant chemotherapy or a single anthracycline-based chemotherapy regimen for metastatic breast cancer. The primary end point was time to progression (TTP), and secondary end points were overall survival (OS), response rate (RR), and toxicity. RESULTS A total of 170 patients were allocated to GD, and 167 were allocated to docetaxel. Median TTP on GD was 10.3 months versus 8.3 months on docetaxel (hazard ratio [HR], 0.77; 95% CI, 0.59 to 1.01; log-rank P = .06). The adjusted Cox proportional model for TTP showed a significant difference favoring the combination (HR, 0.68; 95% CI, 0.51 to 0.90; P = .007). However, RR was similar (GD, 36%; docetaxel, 34%), and OS was not different (P = .57). Grades 3 to 4 neutropenia was common (GD, 75%; docetaxel, 69%); infection was reported in 26% and 21% of patients in the GD and docetaxel groups, respectively. Grades 3 to 4 thrombocytopenia was more frequent with GD (GD, 16%; docetaxel, 0.6%), and peripheral neuropathy was higher with docetaxel (GD, 5%; docetaxel, 16%). CONCLUSION GD compared with docetaxel demonstrated increased TTP in metastatic breast cancer. However, RR and OS were similar. Thus, the addition of gemcitabine failed to demonstrate any clinically meaningful benefit when combined with docetaxel.