Jens Benn Sørensen

Brain metastases in adenocarcinoma of the lung: frequency, risk groups, and prognosis.

A consecutive group of 259 patients with inoperable adenocarcinoma of the lung (ACL) were observed to define risk groups for and frequency of brain metastases together with prognosis. All patients received chemotherapy in a three-armed randomized trial. Brain metastases were diagnosed in 25 patients before protocol entry and in 37 during treatment. Brain autopsy was performed in 87 patients and was positive in 38 (44%). Eleven of these (29%) were not diagnosed clinically. Patients younger than 60 years had a somewhat higher overall frequency of brain metastases than older patients. Patients with initial performance status above 60% and patients responding to chemotherapy had higher risk for developing brain metastasis during treatment than other patients, probably because of the increasing cumulated risk for this complication with prolonged survival. Median survival after onset of brain metastases was 73 days and survival was significantly shorter for these patients than for patients without this complication at days 0, 90, 180, and 365 after protocol entry. Thus, brain metastases is a frequent complication in ACL and the frequency increases with prolonged survival. Survival after development of brain metastases is short and it is questionable whether the inclusion of this subgroup of ACL patients into experimental cytostatic treatments is justified.

Excision repair cross-complementation group 1 (ERCC1) in platinum-based treatment of non-small cell lung cancer with special emphasis on carboplatin: A review of current literature

BACKGROUND Patients diagnosed with advanced non-small cell lung cancer have a dismal prognosis and are often relative resistant to chemotherapy. A need for markers has emerged based on tumour biology in order to predict which patients will respond to treatment. Excision repair cross-complementation group 1 (ERCC1) has shown potential as a predictive marker in patients with NSCLC treated with cisplatin-based chemotherapy. Carboplatin has gained widespread use in the treatment of advanced NSCLC and its mechanisms of action are likely similar to that of cisplatin. MATERIALS AND METHODS A literature review on ERCC1 was conducted as predictor in NSCLC patients receiving platinum-based treatment with emphasis on carboplatin. English language publications from January 1996 to February 2008 were eligible and data on methodology and outcome were recorded. RESULTS Eight preclinical articles, 25 clinical articles and 1 clinical abstract were identified. Laboratory methods were mainly RT-PCR (reverse transcriptase polymerase chain reaction) or immunohistochemistry (IHC) for expression of ERCC1. Preclinical studies pointed towards similar mechanisms of chemotherapy-resistance among platinum compounds. A statistically significant benefit in outcome was found among NSCLC patients, who received adjuvant treatment, and had low-ERCC1 expression. Advanced NSCLC patients treated with cisplatin showed improved response rates (RR) but no difference in other endpoints. Studies on advanced NSCLC patients treated with carboplatin were sparse, heterogeneous and small thus reporting varying results. CONCLUSION The literature on advanced NSCLC patients treated with carboplatin or cisplatin are dominated by small and heterogeneous patient populations and yielded different results. No firm conclusions can be drawn on carboplatin based on the current literature. Research on the development of a reliable methodology is warranted followed by validation in large, prospective, randomized trials as ERCC1 may possibly play an important role as tumour marker in tailored chemotherapy for NSCLC.

Endobronchial metastases from extrapulmonary solid tumors

Malignancy detected during endobronchial biopsies is usually regarded as proof of lung cancer. It may, however, represent endobronchial metastases from extrapulmonary primary tumors. The literature was reviewed to describe how frequent extrapulmonary tumors have been reported to metastasize to the endobronchial epithelium. English language literature was searched from 1962 through 2002. Primary lung cancer and lymphomas were excluded. Endobronchial metastases were reported in 204 patients, originating from 20 different extrapulmonary primary tumors, usually cancers of the breast, kidney, colorectal, uterine cervix, sarcoma and skin. The mean time from diagnosis of primary tumor was 50 months (range 0–300 months) and mean survival time from diagnosis of endobronchial metastasis was 15.2 months (range 0–150 months). It is important to make a distinction between endobronchial metastases from primary lung cancer, as treatment possibilities may be different. The possibility of endobronchial metastasis should be considered if the patient has a history of malignancy in other organs.

Clinical impact of ki-67 labeling index in non-small cell lung cancer

The ki-67 index is a marker of proliferation in malignant tumors. Studies from the period 2000 to 2012 on the prognostic and predictive value of ki-67 labeling index (LI) in non-small cell cancer (NSCLC) are reviewed. Twenty-eight studies reported on the prognostic value of ki-67 index with various endpoints. No consensus on the prognostic value of ki-67 LI was found among the published studies neither according to disease stage nor histological subtype. Comparison of studies is hampered by differences in patient populations, methodologies and cut-off values. Five studies explored the predictive value of ki-67 to chemotherapy and none revealed significant influence. Ki-67 index seems to be of prognostic influence in NSCLC although largely variable cut-off levels have been used in the various studies and standardization of methodology is required. The relative importance of ki-67 compared to newer biomarkers has not been explored. It is likely that a signature of several biomarkers in combination may be necessary to more sufficiently stratify patients to various treatment options than is currently possible, especially when it comes to the question of the optimal use of classical chemotherapy. A predictive impact of ki-67 to treatment in NSCLC remains unclear.

Small bowel metastases in non-small cell lung cancer.

Abstract A case report of stage I adenocarcinoma of the lung in a 43-year-old female with recurrence in the small bowel and liver 11 months after pneumonectomy is presented. In addition, a cohort of 733 patients with non-small cell lung cancer (NSCLC) in all pretreatment stages (stages I–IV) with a total of 218 autopsies are evaluated, and the literature on the topic is reviewed, in order to define the frequency of metastases from NSCLC to the small bowel. There were 10 cases with and 208 cases without small bowel involvement among 218 consecutive autopsies (autopsy rate, 30%). The frequency of small bowel involvement was 4.6% (95% confidence interval, 2.2–8.3%), and all were in patients with adenocarcinoma of the lung. All patients with small bowel involvement at autopsy had also other concurrent metastatic sites as well and the following were the most frequent: adrenals (90% of cases), mediastinal lymph nodes (80%), liver (70%), pleura (60%), contralateral lung (60%), bones (60%), and brain (50%). Significantly more metastatic sites were observed in patients with than without small bowel involvement, both totally (P=0.0001) and with respect to number of extrathoracic (P=0.0001) and intrathoracic (P=0.01) metastatic sites. In conclusion, small bowel involvement in NSCLC is relatively infrequent. As a unique finding, over-representation of patients with poorly differentiated tumors (P=0.03) and patients having solid carcinoma with mucus formation after histologic subtyping (P=0.04) among cases with small bowel involvement was observed. This indicates, that small bowel metastases is an epiphenomonen of NSCLC tumors with certain biological characteristics, although as yet undiscovered, which leads to a high metastatic potential. If such biological characteristics could be identified, they may be used in the selection of treatment options for individual patients, e.g. indicating a need for adjuvant or neoadjuvant chemotherapy in addition to surgery in resectable or marginally resectable NCSLC patients.

Metastatic spinal cord compression secondary to lung cancer.

PURPOSE Metastatic spinal cord compression (MSCC) is a disabling complication to cancer, the optimal treatment for which is not settled. An analysis was performed for all patients with MSCC secondary to lung cancer in East Denmark from 1979 to 1988. PATIENTS AND METHODS The total series included 102 cases with small-cell carcinoma (SCLC; 40%), adenocarcinoma (ACL; 26%), squamous cell carcinoma (SQLC; 18%) and large-cell carcinoma (LCC; 9%). Symptoms, clinical presentations, and therapeutic results are described. RESULTS The outcome of treatment depended fundamentally on the patients neurologic condition at the time of the diagnosis. All patients with SCLC who were able to walk at the time of MSCC remained ambulatory, whereas 15% of the nonambulatory SCLC patients regained walking ability. In non-SCLC, 95% of patients continued to be able to walk, whereas 22% regained the ability to walk. No major differences in the immediate outcome of treatment between the various histologic types of lung cancer and the different treatment modalities were observed; however, 82% of the patients with non-SCLC benefited from treatment with laminectomy followed by radiotherapy (RT) compared with either laminectomy (47%) or RT (39%) alone (P = .03, chi 2 test). The group of patients who were treated with laminectomy followed by RT had a better survival (median value, 3.5; range, 0 to 132 months) than patients who were treated with either laminectomy (median value, 1.5; range, 0 to 32 months) or RT (median value, 1; range, 0 to 59 months) alone (P = .03, log-rank test). No significant difference was observed in survival between the various histologic types of lung cancer (P = .18, log-rank test). CONCLUSION Despite a short survival, early diagnosis and immediate treatment is crucial because it may preserve the gait function in 97% of lung cancer patients who develop malignant spinal cord compression.

Fluorouracil Induces Myocardial Ischemia With Increases of Plasma Brain Natriuretic Peptide and Lactic Acid but Without Dysfunction of Left Ventricle

PURPOSE Fluorouracil (FU) is a cornerstone of colorectal cancer treatment; however, it has clinical and subclinical influence on the heart. This study aimed to clarify the pathophysiology, risk factors, and long-term effects of FU cardiotoxicity. PATIENTS AND METHODS The study prospectively accrued colorectal cancer patients (n=106) completely resected and adjuvantly treated with FU and oxaliplatin according to the FOLFOX4 regimen (infusional FU, folinic acid, and oxaliplatin). Serial measurements were made of systolic and diastolic features of the left ventricle by radionuclide ventriculography, plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), lactic acid, and ECG before chemotherapy, immediately after a treatment infusion, and at follow-up 2 weeks after cessation of the intended 12 treatment courses and were further evaluated by multivariate regression analysis that included cardiovascular history and its risk factors. RESULTS In the entire cohort, NT-proBNP significantly increased from baseline 14.5±3.2 pmol/L (mean±standard error) to 28.3±5.3 pmol/L during FU therapy (P<.001). Nine patients (8.5%) with cardiotoxicity had significantly higher NT-proBNP of 55.3±40.8 pmol/L compared with 25.4±4.1 pmol/L in those without (P<.001). In multivariate analysis, the FU-induced rise of NT-proBNP was significantly higher in females (P<.001). Plasma lactic acid significantly increased from baseline (1.3±0.1 mmol/L to 1.8±0.1 mmol/L) during FU therapy (P<.001). Left ventricular ejection fraction at baseline of 0.66±0.01 remained unchanged at 0.65±0.01 during FU therapy and 0.66±0.01 at follow-up (P=.4). CONCLUSION FU therapy generally induces myocardial neuroendocrine changes with increasing plasma NT-proBNP and lactic acid but without long-term dysfunction of the left ventricle. The usability of NT-proBNP as a predictive marker for FU cardiotoxicity remains to be clarified.

Metastatic Pattern in Non-resectable Non-small Cell Lung Cancer

This study describes the metastatic pattern at autopsy in patients with non-resectable non-small cell lung cancer (NSCLC) and evaluates the impact of various pretreatment variables and treatment outcomes on the metastatic spread. In eight phase II chemotherapy trials from 1985 through 1993, 337 patients were treated and 51 autopsies were performed (autopsy rate 15%). The male/female ratio was 31/20, median age 56 years (range 36-71), response rate to chemotherapy 8%, and median survival 88 days (range 3-899). Histologic types included adenocarcinoma, 31 cases (60%), squamous cell carcinoma, 9 cases (18%), large cell carcinoma, 9 cases (18%), and unclassified NSCLC, 2 cases (4%). Patients who were autopsied had a shorter median survival than patients without autopsy (p = 0.002, log-rank test). Most commonly involved metastatic sites found at autopsy were mediastinal lymph nodes (84%), pleura (51%), liver (47%), bone (34%), brain (32%), pericardium (29%), adrenals (29%). The median number of involved organs was 5 (range 1-16), with a median of 3 intrathoracic sites (range 1-8) and 2 extrathoracic sites (range 0-11). Patients who initially had metastatic NSCLC also had significantly more metastatic sites at autopsy both extrathoracic (p = 0.004) and totally (p = 0.03) compared to patients with locally advanced disease. No other relation to pretreatment variables was found.

Class III β-Tubulin in Advanced NSCLC of Adenocarcinoma Subtype Predicts Superior Outcome in a Randomized Trial

Purpose: Platinum-based doublets are the cornerstone of treatment in advanced non–small-cell lung cancer (NSCLC) and often include vinorelbine or taxanes. A predictive biomarker is greatly needed to select chemotherapy-sensitive patients for these microtubule-interfering agents. Class III β-tubulin (TUBB3) has been shown of value in NSCLC, but evidence is not uniform. Accordingly, we explored the predictive role of TUBB3 in advanced NSCLC. Experimental Design: Four hundred forty-three patients with advanced NSCLC were enrolled in a phase III trial and randomized to vinorelbine- or paclitaxel-containing chemotherapy. Immunohistochemical evaluation of TUBB3 status was mainly done on bioptic material and correlated to response rates, progression-free survival (PFS), overall survival (OS), quality of life (QOL), and toxicity. Results: Two hundred sixty-one (58.9%) patients had representative tissue samples for TUBB3 evaluation. Patients with TUBB3-negative adenocarcinomas had a significantly prolonged PFS and OS when compared with the opposite subgroup (7.87 vs. 6.83 months, P = 0.035 and 14.17 vs. 11.17 months, P = 0.018, respectively). Multivariate analyses revealed an HR of 1.55 (95% CI, 1.04–2.31, P = 0.032) for TUBB3-positive adenocarcinoma patients. TUBB3-negative adenocarcinoma patients showed a mean QOL decline of −18.25 points (95% CI, −4.28 to −32.22, P = 0.013) as compared with −3.86 (95% CI, −7.0 to 15.52, P = 0.5). Conclusion: TUBB3 was of predictive value in adenocarcinoma patients in the largest, randomized advanced NSCLC population published to date. It may be clinically useful in conjunction with other biomarkers, but QOL information should be recorded during validation, as prophylactic intervention may be needed in specific subgroups at risk of toxicity. Clin Cancer Res; 17(15); 5205–14. ©2011 AACR.

RT-PCR versus immunohistochemistry for correlation and quantification of ERCC1, BRCA1, TUBB3 and RRM1 in NSCLC

BACKGROUND Customized chemotherapy is increasingly used in the management of patients with advanced non-small cell lung cancer (NSCLC). However, the most reliable methodology to determine biomarker status is neither fully elucidated nor agreed upon. Accordingly, we evaluated the predictive efficiency of qRT-PCR and immunohistochemical analysis (IHC) on excision cross complementation group 1 (ERCC1), breast cancer susceptibility gene 1 (BRCA1), ribonucleotide reductase subunit M1 (RRM1) and class III β-tubulin (TUBB3). PATIENTS AND METHODS IHC and qRT-PCR on ERCC1, BRCA1, RRM1 and TUBB3 were performed on surgically resected tissue samples from NSCLC-patients included in a randomized trial. The median values of the biomarker expression dichotomized the population and were correlated to clinical endpoints. RESULTS Representative tissue samples from 33 patients showed no significant correlations between mRNA and protein expression. Predictive impact was demonstrated for all four biomarkers, when assessed by IHC, and reached significance for overall survival in patients with ERCC1-negative (14.3 vs. 8.5 months, p=0.018) and TUBB3-negative (18.5 vs. 11.10, p=0.027) tumours, while this was not the case for qRT-PCR. CONCLUSIONS IHC discriminated more effectively than qRT-PCR across four NSCLC-relevant biomarkers. The findings are further supported by the demonstrated lack of correlation between transcript and protein.