Publications by authors named "Bjørn Henning Grønberg"

27 Publications

  • Page 1 of 1

High-dose versus standard-dose twice-daily thoracic radiotherapy for patients with limited stage small-cell lung cancer: an open-label, randomised, phase 2 trial.

Lancet Oncol 2021 03;22(3):321-331

Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway; Department of Oncology, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.

Background: Concurrent chemoradiotherapy is standard treatment for limited stage small-cell lung cancer (SCLC). Twice-daily thoracic radiotherapy of 45 Gy in 30 fractions is considered to be the most effective schedule. The aim of this study was to investigate whether high-dose, twice-daily thoracic radiotherapy of 60 Gy in 40 fractions improves survival.

Methods: This open-label, randomised, phase 2 trial was done at 22 public hospitals in Norway, Denmark, and Sweden. Patients aged 18 years and older with treatment-naive confirmed limited stage SCLC, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, and measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1 were eligible. All participants received four courses of intravenous cisplatin 75 mg/m or carboplatin (area under the curve 5-6 mg/mL × min, Calvert's formula) on day 1 and intravenous etoposide 100 mg/m on days 1-3 every 3 weeks. Participants were randomly assigned (1:1) in permuted blocks (sized between 4 and 10) stratifying for ECOG performance status, disease stage, and presence of pleural effusion to receive thoracic radiotherapy of 45 Gy in 30 fractions or 60 Gy in 40 fractions to the primary lung tumour and PET-CT positive lymph node metastases starting 20-28 days after the first chemotherapy course. Patients in both groups received two fractions per day, ten fractions per week. Responders were offered prophylactic cranial irradiation of 25-30 Gy. The primary endpoint, 2-year overall survival, was assessed after all patients had been followed up for a minimum of 2 years. All randomly assigned patients were included in the efficacy analyses, patients commencing thoracic radiotherapy were included in the safety analyses. Follow-up is ongoing. This trial is registered at ClinicalTrials.gov, NCT02041845.

Findings: Between July 8, 2014, and June 6, 2018, 176 patients were enrolled, 170 of whom were randomly assigned to 60 Gy (n=89) or 45 Gy (n=81). Median follow-up for the primary analysis was 49 months (IQR 38-56). At 2 years, 66 (74·2% [95% CI 63·8-82·9]) patients in the 60 Gy group were alive, compared with 39 (48·1% [36·9-59·5]) patients in the 45 Gy group (odds ratio 3·09 [95% CI 1·62-5·89]; p=0·0005). The most common grade 3-4 adverse events were neutropenia (72 [81%] of 89 patients in the 60 Gy group vs 62 [81%] of 77 patients in the 45 Gy group), neutropenic infections (24 [27%] vs 30 [39%]), thrombocytopenia (21 [24%] vs 19 [25%]), anaemia (14 [16%] vs 15 [20%]), and oesophagitis (19 [21%] vs 14 [18%]). There were 55 serious adverse events in 38 patients in the 60 Gy group and 56 serious adverse events in 44 patients in the 45 Gy group. There were three treatment-related deaths in each group (one neutropenic fever, one aortic dissection, and one pneumonitis in the 60 Gy group; one thrombocytic bleeding, one cerebral infarction, and one myocardial infarction in the 45 Gy group).

Interpretation: The higher radiotherapy dose of 60 Gy resulted in a substantial survival improvement compared with 45 Gy, without increased toxicity, suggesting that twice-daily thoracic radiotherapy of 60 Gy is an alternative to existing schedules.

Funding: The Norwegian Cancer Society, The Liaison Committee for Education, Research and Innovation in Central Norway, the Nordic Cancer Union, and the Norwegian University of Science and Technology.
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http://dx.doi.org/10.1016/S1470-2045(20)30742-7DOI Listing
March 2021

Prognostic value of absolute quantification of mutated KRAS in circulating tumour DNA in lung adenocarcinoma patients prior to therapy.

J Pathol Clin Res 2021 Jan 27. Epub 2021 Jan 27.

Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Technology and Science, Trondheim, Norway.

Droplet digital polymerase chain reaction (ddPCR) is a highly sensitive and accurate method for quantification of nucleic acid sequences. We used absolute quantification of mutated v-Ki-ras2 Kirsten rat sarcoma viral oncogene homology gene (KRAS) by ddPCR to investigate the prognostic role of mutated KRAS in patients with KRAS-mutated lung adenocarcinomas. Pre-treatment plasma samples from 60 patients with stages I-IV KRAS-mutated lung adenocarcinomas were analysed for KRAS mutations. The associations between survival, detectable KRAS mutations in plasma, and the plasma concentration of mutated KRAS were assessed. Overall, 23 of 60 (38%) patients had detectable KRAS mutation in plasma. The percentage of patients with detectable mutation was 8% in stage I, 30% in stage II, 71% in stage III, and 73% in stage IV. Estimated overall median progression-free survival (PFS) and overall survival (OS) were 26.2 months [95% confidence interval (CI) 12.5-39.9] and 50.8 months (95% CI 0-107.3), respectively. Patients with detectable mutations in plasma had significantly worse median PFS compared to patients with undetectable mutation (13.1 versus 70.1 months) and shorter median OS (20.7 versus not reached). High circulating tumour DNA (ctDNA) concentrations of mutated KRAS were significantly associated with shorter PFS [hazard ratio (HR) 1.008, 95% CI 1.004-1.012] and OS (HR 1.007, 95% CI 1.003-1.011). All associations remained statistically significant in multivariable analyses. In conclusion, ddPCR is an accurate and easily feasible technique for quantification of KRAS mutations in ctDNA. The presence of detectable KRAS mutation in plasma at baseline was associated with worse PFS and OS. High concentration of mutated KRAS in ctDNA was an independent negative prognostic factor for both PFS and OS.
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http://dx.doi.org/10.1002/cjp2.200DOI Listing
January 2021

CT Derived Muscle Measures, Inflammation, and Frailty in a Cohort of Older Cancer Patients.

In Vivo 2020 Nov-Dec;34(6):3565-3572

The Research Centre for Age Related Functional Decline and Diseases, Innlandet Hospital Trust, Ottestad, Norway.

Background/aim: Muscle loss, inflammation, and frailty are prevalent among older cancer patients. We aimed to evaluate whether inflammatory markers could identify muscle loss, and if muscle measures differed between frail and non-frail patients.

Patients And Methods: A total of 115 patients ≥70 years old with solid tumors were included. Inflammation was measured using the Glasgow Prognostic Score (GPS), which is based on C-reactive protein (CRP) and albumin levels, and CRP alone. Frailty was evaluated using a modified geriatric assessment (mGA) of eight domains affecting older patients' health status. Computed tomography-derived muscle measures were collected at the level of the third lumbar vertebra.

Results: Patients with GPS=2 and CRP>27 mg/l exhibited poorer muscle measures compared to patients with lower levels. No associations between mGA-based frailty and muscle mass were found.

Conclusion: Inflammation has detrimental effects on muscle mass. However, GPS or CRP alone cannot be used to identify muscle loss, and muscle measures were not associated with frailty in this series.
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http://dx.doi.org/10.21873/invivo.12200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811618PMC
August 2020

Timing of Severe Toxicity from Chemotherapy in Patients With Lung Cancer.

Anticancer Res 2020 Nov;40(11):6399-6406

Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Trondheim, Norway

Background/aim: The aim of this study was to investigate the timing of severe toxicity in lung cancer patients receiving chemotherapy.

Patients And Methods: Patients with advanced non-small cell lung cancer or limited disease small cell lung cancer included in two randomized controlled trials were analysed. Severe toxicity was defined as grade 3-5 toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) v3.0.

Results: We analysed 569 patients and 433 (76.1%) experienced severe toxicity. Of these, 249 (57.5%) experienced the first episode of severe toxicity after the first, 109 (25.2%) after the second, 54 (12.5%) after the third and 18 (4.2%) after the fourth course of chemotherapy. Performance status (PS 2 vs. 0-1; p=0.046) and treatment arm were independent predictive factors for severe toxicity.

Conclusion: Severe toxicity was most frequent after the first chemotherapy course, but some patients did not experience severe toxicity until after the fourth course. Accounting for timing might be important when studying factors predicting severe toxicity.
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http://dx.doi.org/10.21873/anticanres.14661DOI Listing
November 2020

Associations between muscle measures, survival, and toxicity in patients with limited stage small cell lung cancer.

J Cachexia Sarcopenia Muscle 2020 10 28;11(5):1283-1290. Epub 2020 Jul 28.

Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, 7491, Norway.

Background: Standard treatment for patients with limited stage small cell lung cancer (LS SCLC) is concurrent platinum-etoposide chemotherapy and thoracic radiotherapy (TRT). Up to 30% of patients are cured, but severe toxicity is common, and we are not able to identify those who are cured or those who experience severe toxicity before chemoradiotherapy commences. Studies of other cancer patients show that low muscle mass and muscle radiodensity are associated with inferior survival and that a high drug dose per kilogram lean body mass (LBM) is associated with more toxicity, but this has not been investigated in LS SCLC. We analysed patients from a randomized trial comparing two schedules of TRT (n = 157) to investigate the prognostic and predictive role of these muscle measures in LS SCLC.

Methods: Patients from a trial comparing once daily hypofractionated with twice daily hyperfractionated TRT were analysed. The skeletal muscle index (SMI), skeletal muscle radiodensity (SMD), and LBM were assessed from baseline computed tomography scans at the L3 level using the SliceOMatic software.

Results: Images at the L3 level were available for 122 patients (77.7%). Median age was 64 years, 18% had performance status 2, and 38% had stage III. Grade 3-4 toxicity was observed in 89%, and 5% died from treatment-related side effects. Overall, the median overall survival was 23 months, and the 5 year survival was 25%. Median LBM was 45.2 (range: 16-65) kg, the median SMI 44.8 (range: 29-77) cm /m , and the median SMD 39.3 (range 16-62) HU. There were no significant associations between survival and any of the muscle measures in the univariable analyses (SMI: P = 0.906, SMD: P = 0.829) or in multivariable analyses adjusting for baseline characteristics (SMI: P = 0.836, SMD: P = 0.260). A higher cisplatin dose per kilogram LBM in the first course significantly increased the risk of grade 3-4 haematological toxicity (P = 0.011) and neutropenic infections (P = 0.012).

Conclusions: Patients who received a high dose of cisplatin per kilogram LBM had more haematological toxicity and neutropenic infections than other patients. None of the muscle measures were independent prognostic factors for survival in our cohort of LS SCLC patients who underwent standard chemoradiotherapy.
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http://dx.doi.org/10.1002/jcsm.12583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567150PMC
October 2020

Randomized phase III trial comparing switch-maintenance pemetrexed with observation followed by pemetrexed at progression in advanced NSCLC.

Acta Oncol 2020 Sep 16;59(9):1051-1057. Epub 2020 Jun 16.

Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.

Two phase III trials show that maintenance pemetrexed therapy after platinum-doublet chemotherapy prolongs overall survival (OS) and progression free survival (PFS) in advanced non-squamous non-small-cell lung cancer (NSCLC). However, few patients in the control arms received pemetrexed at progression in these trials, performance status (PS) two patients were ineligible and few of the participants were elderly. Thus, we designed this study comparing immediate switchmaintenance pemetrexed therapy with pemetrexed at progression after platinum-doublet chemotherapy. Patients with stage IIIB/IV non-squamous NSCLC, ≥18 years, PS 0-2, and non-progression after four courses of carboplatin/vinorelbine were randomized to receive immediate maintenance pemetrexed therapy or observation followed by pemetrexed at progression. The primary endpoint was OS, secondary endpoints were PFS, toxicity and health related quality of life (HRQoL). 105 patients were randomized between May 2014 and September 2017. Median age was 67 years, 36% were >70 years, 9% had PS 2, 91% stage IV and 47% were women. In the observation arm, 73% received pemetrexed at progression. Patients in the maintenance arm had a numerically longer OS (median 12.0 vs. 10.0 months;  = .10) and a statistically significant longer PFS (median 3.1 vs. 1.9 months;  < .01). In multivariable analyses adjusting for baseline characteristics, there was a trend toward improved OS (HR 0.65, 95% CI 0.42-1.01);  = .05), and a significantly improved PFS (HR 0.53, 95% CI 0.35-0.80;  < .01). There were no significant differences in toxicity or HRQoL between the treatment arms. There was a trend toward prolonged OS and significantly longer PFS from switch maintenance pemetrexed therapy when 73% of patients in the control arm received pemetrexed at progression. NCT02004184.
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http://dx.doi.org/10.1080/0284186X.2020.1778179DOI Listing
September 2020

Osimertinib in T790M-positive and -negative patients with EGFR-mutated advanced non-small cell lung cancer (the TREM-study).

Lung Cancer 2020 05 12;143:27-35. Epub 2020 Mar 12.

Vestre Viken Hospital Trust, Drammen, Norway; Department of Cancer Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Objectives: In non-small cell lung cancer patients with acquired resistance to first- or second-generation EGFR-TKIs, osimertinib is approved in the presence of the T790 M resistance mutation. We assessed the efficacy of osimertinib in both T790M-positive and T790M-negative patients.

Materials And Methods: The TREM-study is an investigator-initiated, multi-centre, single-arm, phase 2 clinical trial conducted in five Northern European countries. Patients with progression on at least one previous EGFR-TKI were assigned to treatment with 80 mg of osimertinib daily until radiological progression or death. Patients were included regardless of the presence of T790 M. The primary endpoint was objective response rate (ORR).

Results: Of 199 included patients, 120 (60 %) were T790M-positive, 52 (26 %) were T790M-negative and 27 (14 %) had unknown T790M-status. 24 % had brain metastases and 15 % had an ECOG performance status of 2. Overall ORR was 48 % (95 % CI, 41 %-55 %), 60 % (51 %-69 %) for T790M-positive patients and 28 % (15 %-41 %) for T790M-negative patients, p < 0.001. ORR for patients with co-occurring del19 vs L858R was 61 % vs 32 %, p = 0.001. Duration of response was similar between the T790M-positive and -negative groups (11.8 vs 10.7 months, p = 0.229). Overall median progression-free survival (PFS) was 8.9 months (95 % CI, 7.4-10.5), and 10.8 vs 5.1 months for T790M-positive vs -negative patients (HR 0.62, p = 0.007). Median overall survival (OS) was 17.9 months (95 % CI, 14.4-21.3). For T790M-positive vs -negative median OS was 22.5 vs 13.4 months, (HR 0.55, p = 0.002).

Conclusions: This study confirms the efficacy of osimertinib for T790M-positive patients. There was also clinically significant activity of osimertinib in a proportion of T790M-negative patients.

Clinical Trial Registration: This trial is registered with ClinicalTrials.gov (NCT02504346).
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http://dx.doi.org/10.1016/j.lungcan.2020.03.009DOI Listing
May 2020

The relevance of tumor mutation profiling in interpretation of NGS data from cell-free DNA in non-small cell lung cancer patients.

Exp Mol Pathol 2020 02 21;112:104347. Epub 2019 Nov 21.

Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; Department of Pathology, Clinic of Laboratory Medicine, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.

Studies have indicated that detection of circulating tumor DNA (ctDNA) prior to treatment is a negative prognostic marker in non-small cell lung cancer (NSCLC). ctDNA is currently identified by detection of tumor mutations. Commercial next-generation sequencing (NGS) assays for mutation analysis of ctDNA for routine practice usually include small gene panels and are not suitable for general mutation analysis. In this study, we investigated whether mutation analysis of cfDNA could be performed using a commercially available comprehensive NGS gene panel and bioinformatics workflow. Tumor DNA, plasma DNA and peripheral blood leukocyte DNA from 30 NSCLC patients were sequenced. In two patients (7%), tumor mutations in cfDNA were immediately called by the bioinformatic workflow. In 13 patients (43%), tumor mutations were not called, but were present in ctDNA and were identified based on the known tumor mutation profile. In the remaining 15 patients (50%), no concordant mutations were detected. In conclusion, we were able to identify tumor mutations in ctDNA from 57% of NSCLC patients using a comprehensive gene panel. We demonstrated that sequencing paired tumor DNA was helpful to interpret data and confirm ctDNA, and thus increased the ratio of patients with detectable ctDNA. This approach might be feasible for mutation analysis of ctDNA in routine diagnostic practice, especially in case of suboptimal plasma quality and quantity.
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http://dx.doi.org/10.1016/j.yexmp.2019.104347DOI Listing
February 2020

Modifiable factors affecting older patients' quality of life and physical function during cancer treatment.

J Geriatr Oncol 2019 11 21;10(6):904-912. Epub 2019 Aug 21.

The Research Centre for Age Related Functional Decline and Diseases, Innlandet Hospital Trust, P.O. box 68, 2313 Ottestad, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, P.O. box 4956, Nydalen, 0424 Oslo, Norway; The Cancer Unit, Innlandet Hospital Trust, Hamar Hospital, Skolegata 32, 2326 Hamar, Norway.

Background: Maintaining physical function and quality of life (QoL) are prioritized outcomes among older adults. We aimed to identify potentially modifiable factors affecting older patients' physical function and QoL during cancer treatment.

Methods: Prospective, multicenter study of 307 patients with cancer ≥70 years, referred for systemic treatment. Pre-treatment, a modified geriatric assessment (mGA) was performed, including registration of comorbidities, medications, nutritional status, cognitive function, depressive symptoms (Geriatric Depression Scale-15 [GDS]), and mobility (Timed Up and Go [TUG]). Patient-reported physical function (PF)-, global QoL-, and symptom scores were assessed at baseline, two, four, and six months by the EORTC Quality of Life Core Questionnaire-C30. The impact of mGA components and symptoms on patients' PF and global QoL scores during six months was investigated by linear mixed models. To identify groups following distinct PF trajectories, a growth mixture model was estimated.

Results: 288 patients were eligible, mean age was 76.9 years, 68% received palliative treatment. Higher GDS-scores and poorer TUG were independently associated with an overall level of poorer PF and global QoL throughout follow-up, as were more pain, dyspnea, and appetite loss, and sleep disturbance. Three groups with distinct PF trajectories were identified: a poor group exhibiting a non-linear statistically (p < .001) and clinically significant decline (≥10 points), an intermediate group with a statistically (p = .003), but not clinically significant linear decline, and a good group with a stable trajectory. Higher GDS-scores and poorer TUG, more pre-treatment pain and dyspnea were associated with higher odds of belonging to the poor compared to the good PF group.

Conclusion: Depressive symptoms, reduced mobility, and more physical symptoms increased the risk of decrements in older patients' PF and global QoL scores during cancer treatment, and represent potential targets for interventions aiming at improving these outcomes.
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http://dx.doi.org/10.1016/j.jgo.2019.08.001DOI Listing
November 2019

Autocrine activin A signalling in ovarian cancer cells regulates secretion of interleukin 6, autophagy, and cachexia.

J Cachexia Sarcopenia Muscle 2020 02 21;11(1):195-207. Epub 2019 Aug 21.

Department of Biomedical Laboratory Science, Faculty of Natural Sciences, NTNU-Norwegian University of Science and Technology, Trondheim, Norway.

Background: The majority of patients with advanced cancer develop cachexia, a weight loss syndrome that severely reduces quality of life and limits survival. Our understanding of the underlying mechanisms that cause the condition is limited, and there are currently no treatment options that can completely reverse cachexia. Several tumour-derived factors and inflammatory mediators have been suggested to contribute to weight loss in cachectic patients. However, inconsistencies between studies are recurrent. Activin A and interleukin 6 (IL-6) are among the best studied factors that seem to be important, and several studies support their individual role in cachexia development.

Methods: We investigated the interplay between activin A and IL-6 in the cachexia-inducing TOV21G cell line, both in culture and in tumours in mice. We previously found that the human TOV21G cells secrete IL-6 that induces autophagy in reporter cells and cachexia in mice. Using this established cachexia cell model, we targeted autocrine activin A by genetic, chemical, and biological approaches. The secretion of IL-6 from the cancer cells was determined in both culture and tumour-bearing mice by a species-specific ELISA. Autophagy reporter cells were used to monitor the culture medium for autophagy-inducing activities, and muscle mass changes were evaluated in tumour-bearing mice.

Results: We show that activin A acts in an autocrine manner to promote the synthesis and secretion of IL-6 from cancer cells. By inhibiting activin A signalling, the production of IL-6 from the cancer cells is reduced by 40-50% (up to 42% reduction on protein level, P = 0.0048, and 48% reduction on mRNA level, P = 0.0308). Significantly reduced IL-6 secretion (P < 0.05) from the cancer cells is consistently observed when using biological, chemical, and genetic approaches to interfere with the autocrine activin A loop. Inhibiting activin signalling also reduces the ability of the cancer cells to accelerate autophagy in non-cancerous cells (up to 43% reduced autophagy flux, P = 0.0006). Coherent to the in vitro data, the use of an anti-activin receptor 2 antibody in cachectic tumour-bearing mice reduces serum levels of cancer cell-derived IL-6 by 62% (from 417 to 159 pg/mL, P = 0.03), and, importantly, it reverses cachexia and counteracts loss of all measured muscle groups (P < 0.0005).

Conclusions: Our data support a functional link between activin A and IL-6 signalling pathways and indicate that interference with activin A-induced IL-6 secretion from the tumour has therapeutic potential for cancer-induced cachexia.
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http://dx.doi.org/10.1002/jcsm.12489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015233PMC
February 2020

Associations between hematologic toxicity and health-related quality of life during first-line chemotherapy in advanced non-small-cell lung cancer: a pooled analysis of two randomized trials.

Acta Oncol 2018 Nov 3;57(11):1574-1579. Epub 2018 Aug 3.

a European Palliative Care Research Centre (PRC), Department of Clinical and Molecular Medicine , Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology , Trondheim , Norway.

Background: Many patients experience toxicity from chemotherapy that may negatively impact their health-related quality of life (HRQoL), but side effects often go undetected by health care personnel. Our aim was to investigate whether hematologic toxicity (HT) was associated with HRQoL impairment, and, consequently, if blood counts could be used to identify patients with the highest need for supportive care during chemotherapy.

Material And Methods: Data from two phase III trials of first-line chemotherapy in advanced non-small-cell lung cancer (NSCLC) were analyzed (n = 873). Blood counts were measured weekly in the treatment period. We categorized patients as having severe (CTCAE grade 3-4) or non-severe (grade 0-2) HT during the first chemotherapy cycle. HRQoL was reported on the EORTC QLQ-C30 and LC13 before and at the end of the cycle. The primary endpoints were changes in global quality of life, fatigue, nausea/vomiting and dyspnea (LC13).

Results: Of the 766 patients with complete data set, 177 (23%) developed severe HT during the first chemotherapy cycle. Changes in fatigue and nausea/vomiting were significantly worse for patients experiencing severe compared to patients with non-severe HT (difference in mean change of 4.9 points; p = .01, and 6.4 points; p = .01, respectively), but this association was limited to neutropenia, not thrombocytopenia or anemia. There were no significant associations between HT and global quality of life or dyspnea (difference in mean change of 2.1 points; p = .28, and 3.3 points; p = .053, respectively).

Conclusions: Patients developing severe HT had worse changes in two out of four of the primary HRQoL endpoints, but the association was not strong enough to use blood counts to identify patients who need more clinical attention and supportive care during chemotherapy.
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http://dx.doi.org/10.1080/0284186X.2018.1492151DOI Listing
November 2018

Screening for frailty among older patients with cancer using blood biomarkers of inflammation.

J Geriatr Oncol 2019 03 23;10(2):272-278. Epub 2018 Jul 23.

Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, P.O. Box 4956, Nydalen, 0424 Oslo, Norway; The Cancer Unit, Innlandet Hospital Trust, Hamar Hospital, Skolegata 32, 2326 Hamar, Norway.

Introduction: As frailty is associated with inflammation, biomarkers of inflammation may represent objective measures that could facilitate the identification of frailty. Glasgow prognostic score (GPS), combines C-reactive protein (CRP) and albumin, and is scored from 0 to 2 points. Higher score indicates a higher degree of inflammation.

Objectives: To investigate whether (1) GPS is associated with frailty, (2) GPS could be used to screen for frailty, (3) IL-6 and TNF-α add to the accuracy of GPS as a screening tool, and (4) GPS adds prognostic information in frail older patients with cancer.

Methods: Prospective, observational study of 255 patients ≥70 years with solid malignant tumours referred for medical cancer treatment. At baseline, frail patients were identified by a modified Geriatric Assessment (mGA), and blood samples were collected.

Results: Mean age was 76.7 years, 49.8% were frail, and 56.1% had distant metastases. The proportion of frail patients increased with higher GPS (GPS zero: 43.2%, GPS one: 52.7%, GPS two: 94.7%). GPS two was significantly associated with frailty (OR 18.5), independent of cancer type, stage, BMI and the use of anti-inflammatory drugs. The specificity of GPS was high (99%), but the sensitivity was low (14%). Frail patients with GPS two had poorer survival than patients with GPS zero-one. TNF-α and IL-6 did not improve the accuracy of GPS when screening for frailty.

Conclusion: Frailty and GPS two are strongly associated, and GPS two is a significant prognostic factor in frail, older patients with cancer. The inflammatory biomarkers investigated are not suitable screening tools for frailty.
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http://dx.doi.org/10.1016/j.jgo.2018.07.003DOI Listing
March 2019

Substantial nation-wide improvement in lung cancer relative survival in Norway from 2000 to 2016.

Lung Cancer 2018 08 6;122:138-145. Epub 2018 Jun 6.

Department of Thoracic Surgery, Oslo University Hospital, Oslo, Norway.

Introduction: There have been significant changes in both diagnostic procedures and therapy for lung cancer since the beginning of the millennium. National incidence and survival data from 2000 through 2016 are studied.

Methods: National data on cancer incidence and vital status are virtually complete. Changes in incidence and survival are described by absolute numbers, percentages, and calculation of relative survival (period analysis).

Results: A total of 44,825 individuals were diagnosed with lung cancer in Norway in the study period. The number of incident cases increased with 49% whereas the prevalence increased with 136% from 2000 to 2016. Age-standardised rates rose markedly for women and levelled off for men. In 2016, adenocarcinoma accounted for about 50% of all lung cancers, slightly more for women than for men. The entity "NSCLC not otherwise specified" declined from 24% to 13%, and the fraction of patients with metastatic disease decreased from 54% to 46% during the period, for both sexes combined. The overall median survival time doubled for women and men, reaching 14.3 months and 11.4 months, respectively. For patients with metastatic disease, median survival time showed a small increase but remained less than 6 months. The overall 5-year relative survival increased from 16% to 26% in women and from 16% to 22% in men. The corresponding improvements for the subgroup of non-surgically treated cases with localised disease, were up from 25% to more than 40% in females, and from 10% to almost 40% in males.

Conclusion: There have been notable changes in incidence patterns and a remarkable improvement in survival for lung cancer over the last 17 years, most markedly for patients without distant metastases at the time of diagnosis. Hopefully, survival will improve even more when immunotherapy is implemented.
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http://dx.doi.org/10.1016/j.lungcan.2018.06.003DOI Listing
August 2018

Cancer patients' knowledge about their disease and treatment before, during and after treatment: a prospective, longitudinal study.

BMC Cancer 2018 04 3;18(1):381. Epub 2018 Apr 3.

Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology, N-7491, Trondheim, Norway.

Background: Knowledge about disease and treatment is necessary before patients can consent to treatment. One of the few established instruments for evaluating whether sufficient information has been provided, is the EORTC QLQ-INFO25 questionnaire which was developed to measure how patients perceive information. The aim of this study was to investigate whether cancer patients' level of knowledge about their disease and treatment was associated with their perception of and satisfaction with the information.

Methods: Breast cancer patients referred for adjuvant chemotherapy and prostate cancer patients referred for curative radiotherapy were included. Level of knowledge about their disease and treatment was measured using study-specific questionnaires. Patients' perception of and satisfaction with the received information was assessed using EORTC QLQ-INFO25. Assessments were done before the first consultation with an oncologist (T1), after the consultation (T2) and 8 weeks after start of treatment (T3).

Results: Ninety eight patients were enrolled. Patients with higher education, daily Internet access and in paid employment had the highest baseline knowledge scores. The mean knowledge score increased significantly (T1: 16.4; T2: 20.8; T3: 21.3; p < 0.001.). During the same period, the patients reported on the INFO25 a significant, positive increase in how much information they had received, and that they were more satisfied with the information.

Conclusions: Patients' knowledge increased significantly during the study period, and they reported that they felt better informed and were more satisfied with the information, suggesting that EORTC QLQ-INFO25 might be used to evaluate cancer patients' level of knowledge about their disease and treatment.

Trial Registration: ClinicalTrials.gov identifier: NCT01699672 . Date of registration: September 21, 2012.
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http://dx.doi.org/10.1186/s12885-018-4164-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5883273PMC
April 2018

Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial.

Acta Oncol 2017 Dec 4;56(12):1776-1785. Epub 2017 Jul 4.

l Department of Radiation Sciences & Oncology , Umeå University , Umeå , Sweden.

Introduction: A pilot study of temozolomide (TMZ) given before radiotherapy (RT) for anaplastic astrocytoma (AA) and glioblastoma (GBM) resulted in prolonged survival compared to historical controls receiving RT alone. We therefore investigated neoadjuvant TMZ (NeoTMZ) in a randomized trial. During enrollment, concomitant and adjuvant radio-chemotherapy with TMZ became standard treatment. The trial was amended to include concurrent TMZ.

Patients And Methods: Patients, after surgery for GBM or AA, age ≤60 years and performance status (PS) 0-2, were randomized to either 2-3 cycles of TMZ, 200 mg/m days 1-5 every 28 days, followed by RT 60 Gy in 30 fractions or RT only. Patients without progressive disease after two TMZ cycles, received the third cycle. From March 2005, TMZ 75 mg/m was administered daily concomitant with RT. TMZ was recommended first-line treatment at progression. Primary endpoint was overall survival and secondary safety.

Results: The study closed prematurely after enrolling 144 patients, 103 with GBM and 41 with AA. Median age was 53 years (range 24-60) and 89 (62%) were male. PS was 0-1 for 133 (92%) patients, 53 (37%) had complete surgical resection and 18 (12%) biopsy. Ninety-two (64%) received TMZ concomitant with RT. Seventy-two (50%) were randomized to neoadjuvant treatment. For the overall study population survival was 20.3 months for RT and 17.7 months for NeoTMZ (p = .76), this not reaching the primary objective. For the preplanned subgroup analysis, we found that NeoTMZ AA patients had a median survival of 95.1 months compared to 35.2 months for RT (p = .022). For patients with GBM, no difference in survival was observed (p = .10). MGMT and IDH status affected outcome.

Conclusions: No advantage of NeoTMZ was noted for the overall study population or subgroup of GBM, while NeoTMZ resulted in 5 years longer median survival for patients diagnosed as AA.
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http://dx.doi.org/10.1080/0284186X.2017.1332780DOI Listing
December 2017

Geriatric assessment is superior to oncologists' clinical judgement in identifying frailty.

Br J Cancer 2017 Aug 29;117(4):470-477. Epub 2017 Jun 29.

Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, PO box 4956 Nydalen, Oslo 0424, Norway.

Background: Frailty is a syndrome associated with increased vulnerability and an important predictor of outcomes in older cancer patients. Systematic assessments to identify frailty are seldom applied, and oncologists' ability to identify frailty is scarcely investigated.

Methods: We compared oncologists' classification of frailty (onc-frail) based on clinical judgement with a modified geriatric assessment (mGA), and investigated associations between frailty and overall survival. Patients ⩾70 years referred for medical cancer treatment were eligible. mGA-frailty was defined as impairment in at least one of the following: daily activities, comorbidity, polypharmacy, physical function or at least one geriatric syndrome (cognitive impairment, depression, malnutrition, falls).

Results: Three hundred and seven patients were enroled, 288 (94%) completed the mGA, 286 (93%) were rated by oncologists. Median age was 77 years, 56% had metastases, 85% performance status (PS) 0-1. Overall, 104/286 (36%) were onc-frail and 140/288 (49%) mGA-frail, the agreement was fair (kappa value 0.30 (95% CI 0.19; 0.41)), and 67 mGA-frail patients who frequently had localised disease, good PS and received curative treatment, were missed by the oncologists. Only mGA-frailty was independently prognostic for survival (HR 1.61, 95% CI 1.14; 2.27; P=0.007).

Conclusions: Systematic assessment of geriatric domains is needed to aid oncologists in identifying frail patients with poor survival.
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http://dx.doi.org/10.1038/bjc.2017.202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5558687PMC
August 2017

Corrigendum to "Prognosis in advanced lung cancer - A prospective study examining key clinicopathological factors" [Lung Cancer 88 (2015) 304-309].

Lung Cancer 2017 06 28;108:256. Epub 2017 Apr 28.

Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK; European Palliative Care Research Centre, Norwegian University of Science and Technology, Trondheim, Norway. Electronic address:

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http://dx.doi.org/10.1016/j.lungcan.2017.04.015DOI Listing
June 2017

Prognosis in advanced lung cancer--A prospective study examining key clinicopathological factors.

Lung Cancer 2015 06 28;88(3):304-9. Epub 2015 Mar 28.

Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK; European Palliative Care Research Centre, Norwegian University of Science and Technology, Trondheim, Norway. Electronic address:

Objectives: In patients with advanced incurable lung cancer deciding as to the most appropriate treatment (e.g., chemotherapy or supportive care only) is challenging. In such patients the TNM classification system has reached its ceiling therefore other factors are used to assess prognosis and as such, guide treatment. Performance status (PS), weight loss and inflammatory biomarkers (Glasgow Prognostic Score (mGPS)) predict survival in advanced lung cancer however these have not been compared. This study compares key prognostic factors in advanced lung cancer.

Materials And Methods: Patients with newly diagnosed advanced lung cancer were recruited and demographics, weight loss, other prognostic factors (mGPS, PS) were collected. Kaplan-Meier and Cox regression methods were used to compare these prognostic factors.

Results: 390 patients with advanced incurable lung cancer were recruited; 341 were male, median age was 66 years (IQR 59-73) and patients had stage IV non-small cell (n=288) (73.8%) or extensive stage small cell lung cancer (n=102) (26.2%). The median survival was 7.8 months. On multivariate analysis only performance status (HR 1.74 CI 1.50-2.02) and mGPS (HR 1.67, CI 1.40-2.00) predicted survival (p<0.001). Survival at 3 months ranged from 99% (ECOG 0-1) to 74% (ECOG 2) and using mGPS, from 99% (mGPS0) to 71% (mGPS2). In combination, survival ranged from 99% (mGPS 0, ECOG 0-1) to 33% (mGPS2, ECOG 3).

Conclusion: Performance status and the mGPS are superior prognostic factors in advanced lung cancer. In combination, these improved survival prediction compared with either alone.
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http://dx.doi.org/10.1016/j.lungcan.2015.03.020DOI Listing
June 2015

[Occupational lung cancer in Sør-Trøndelag county].

Tidsskr Nor Laegeforen 2014 Oct 28;134(20):1943-7. Epub 2014 Oct 28.

Arbeidsmedisinsk avdeling St. Olavs hospital og Institutt for samfunnsmedisin Det medisinske fakultet Norges teknisk-naturvitenskapelige universitet.

Background: Lung cancer can be caused by occupational exposure. This is not always recognised or reported, and not all patients receive the benefits to which they are entitled.

Material And Method: We collected occupational case histories for patients from Sør-Trøndelag county with a first-time diagnosis of lung cancer. The number of reported cases of occupationally related lung cancer was collected from the Norwegian Labour Inspection Authority, and information on approval of occupational illness was collected from the Norwegian Labour and Welfare Authority (NAV).

Results: 105 patients with lung cancer took part in the study, 73 men and 32 women. Among the men, altogether 12 cases (16%) were assessed as likely and 16 (22%) as possibly occupationally related. Among the women, none of the cases were assessed as occupationally related. The reporting frequency from the health regions to the Norwegian Labour Inspection Authority varied from 1.7% to 5.1%. Altogether 9 out of 11 likely cases and 5 out of 12 possible cases of occupationally related lung cancer were granted injury compensation by the Norwegian Labour and Welfare Authority.

Interpretation: In this study, we found that approximately 20% of the cases of lung cancer in men are occupationally related, and that the underreporting of occupationally related lung cancer appears to be considerable. The obligation of doctors to report to the Norwegian Labour Inspection Authority should be made better known. Most likely, more patients would have had their lung cancer verified as an occupational illness and could have received injury compensation if they had been aware of the opportunity to apply for this.
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http://dx.doi.org/10.4045/tidsskr.13.0900DOI Listing
October 2014

Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial.

Lancet Oncol 2012 Sep 8;13(9):916-26. Epub 2012 Aug 8.

Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Unit of Advanced Palliative Home Care, County Council of Östergötland, Linköping, Sweden.

Background: Most patients with glioblastoma are older than 60 years, but treatment guidelines are based on trials in patients aged only up to 70 years. We did a randomised trial to assess the optimum palliative treatment in patients aged 60 years and older with glioblastoma.

Methods: Patients with newly diagnosed glioblastoma were recruited from Austria, Denmark, France, Norway, Sweden, Switzerland, and Turkey. They were assigned by a computer-generated randomisation schedule, stratified by centre, to receive temozolomide (200 mg/m(2) on days 1-5 of every 28 days for up to six cycles), hypofractionated radiotherapy (34·0 Gy administered in 3·4 Gy fractions over 2 weeks), or standard radiotherapy (60·0 Gy administered in 2·0 Gy fractions over 6 weeks). Patients and study staff were aware of treatment assignment. The primary endpoint was overall survival. Analyses were done by intention to treat. This trial is registered, number ISRCTN81470623.

Findings: 342 patients were enrolled, of whom 291 were randomised across three treatment groups (temozolomide n=93, hypofractionated radiotherapy n=98, standard radiotherapy n=100) and 51 of whom were randomised across only two groups (temozolomide n=26, hypofractionated radiotherapy n=25). In the three-group randomisation, in comparison with standard radiotherapy, median overall survival was significantly longer with temozolomide (8·3 months [95% CI 7·1-9·5; n=93] vs 6·0 months [95% CI 5·1-6·8; n=100], hazard ratio [HR] 0·70; 95% CI 0·52-0·93, p=0·01), but not with hypofractionated radiotherapy (7·5 months [6·5-8·6; n=98], HR 0·85 [0·64-1·12], p=0·24). For all patients who received temozolomide or hypofractionated radiotherapy (n=242) overall survival was similar (8·4 months [7·3-9·4; n=119] vs 7·4 months [6·4-8·4; n=123]; HR 0·82, 95% CI 0·63-1·06; p=0·12). For age older than 70 years, survival was better with temozolomide and with hypofractionated radiotherapy than with standard radiotherapy (HR for temozolomide vs standard radiotherapy 0·35 [0·21-0·56], p<0·0001; HR for hypofractionated vs standard radiotherapy 0·59 [95% CI 0·37-0·93], p=0·02). Patients treated with temozolomide who had tumour MGMT promoter methylation had significantly longer survival than those without MGMT promoter methylation (9·7 months [95% CI 8·0-11·4] vs 6·8 months [5·9-7·7]; HR 0·56 [95% CI 0·34-0·93], p=0·02), but no difference was noted between those with methylated and unmethylated MGMT promoter treated with radiotherapy (HR 0·97 [95% CI 0·69-1·38]; p=0·81). As expected, the most common grade 3-4 adverse events in the temozolomide group were neutropenia (n=12) and thrombocytopenia (n=18). Grade 3-5 infections in all randomisation groups were reported in 18 patients. Two patients had fatal infections (one in the temozolomide group and one in the standard radiotherapy group) and one in the temozolomide group with grade 2 thrombocytopenia died from complications after surgery for a gastrointestinal bleed.

Interpretation: Standard radiotherapy was associated with poor outcomes, especially in patients older than 70 years. Both temozolomide and hypofractionated radiotherapy should be considered as standard treatment options in elderly patients with glioblastoma. MGMT promoter methylation status might be a useful predictive marker for benefit from temozolomide.

Funding: Merck, Lion's Cancer Research Foundation, University of Umeå, and the Swedish Cancer Society.
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http://dx.doi.org/10.1016/S1470-2045(12)70265-6DOI Listing
September 2012

[Mutation testing for non-small-cell lung cancer].

Tidsskr Nor Laegeforen 2012 Apr;132(8):952-5

Avdeling for kreftbehandling, Oslo universitetssykehus, Radiumhospitalet, Norway.

Background: Epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI) are a relatively new class of drugs for treatment of non-small-cell lung cancer. The national professional group for lung cancer, The Norwegian Lung Cancer Group, recommends that patients with non-small-cell lung cancer are tested for mutations in the EGFR gene. Here, we report the experience collected after the introduction of such testing in Norway in 2010.

Material And Method: Information on the number of patients tested, gender distribution, histopathological data and analysis results have been collected from the molecular-pathology laboratories at the university hospitals in Tromsø, Trondheim, Bergen and Oslo for the period from May 2010 to May 2011.

Results: During this period, altogether 1,058 patients with lung cancer were tested for mutations in the EGFR gene, equal to approximately half of all those who were diagnosed with non-small-cell lung cancer. A mutation was detected in 123 patients (11.6 per cent). There was a higher proportion of mutation-positive women than men (17.6 per cent, compared to 6.3 per cent, p < 0.001), and a lower proportion with squamous cell carcinoma than for other histopathological subtypes (3.0 per cent, compared to 12.9 per cent, p < 0.001). Of a total of 80 cytological tests, nine (11.3 per cent) were positive.

Interpretation: In light of the relatively high mutation frequency and a considerable number of positives in the group with squamous cell carcinoma, we recommend to continue the practice of mutation-testing all patients with non-small-cell lung cancer.
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http://dx.doi.org/10.4045/tidsskr.11.1017DOI Listing
April 2012

Prolonged survival in patients with lung cancer with diabetes mellitus.

J Thorac Oncol 2011 Nov;6(11):1810-7

Department of Thoracic Medicine, St. Olavs Hospital HF, Trondheim University Hospital, Trondheim, Norway.

Introduction: Patients with lung cancer have a high frequency of comorbidity. Data on the impact of diabetes mellitus, the most frequent endocrine disorder, on the prognosis of lung cancer are conflicting. The aim was to investigate the impact of diabetes mellitus on survival in lung cancer.

Method: We analyzed data from a cohort, the Nord-Trøndelag Health Study (HUNT study) linked to the Norwegian Cancer Registry and controlled the results using two lung cancer studies, the Pemetrexed Gemcitabine study and the Norwegian Lung Cancer Biobank. Survival in lung cancer with and without diabetes mellitus was compared using the Kaplan-Meier method and Cox regression model for each study and the studies combined.

Results: One thousand six hundred seventy-seven cases of lung cancer were included, 1031 from HUNT study, 436 from the Pemetrexed Gemcitabine study, and 210 from the Norwegian Lung Cancer Biobank registry, and among these 77 patients had diabetes mellitus. In the combined analysis, patients with lung cancer with diabetes mellitus had increased survival compared with those without (p = 0.005). The 1-, 2-, and 3-year survival in patients with lung cancer with and without diabetes mellitus were 43% versus 28%, 19% versus 11%, and 3% versus 1%, respectively. Adjusting for age, gender, histology, and stage of disease in the Cox regression model, the hazard ratio for survival in patients with lung cancer with diabetes mellitus was 0.55 (95% CI, 0.41-0.75) as compared with without.

Conclusion: Patients with lung cancer with diabetes mellitus have an increased survival compared with those without diabetes mellitus.
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http://dx.doi.org/10.1097/JTO.0b013e31822a75beDOI Listing
November 2011

Lung cancer patients' perceptions of informed consent documents.

Patient Educ Couns 2008 Nov;73(2):313-7

Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, St. Olavs Hospital, NO-7006 Trondheim, Norway.

Objective: To compare patients' perceptions and preferences of two different versions of informed consent documents.

Methods: Patients eligible for a trial of palliative chemotherapy for lung cancer (N = 22) were randomly assigned to receive either an original consent document or a shortened version written for the present study. Semi-structured interviews were conducted after the patients had read the consent documents. The interviews were transcribed verbatim and analysed using qualitative content analysis.

Results: Few differences between the two groups were found with respect to patients' assessment of the amount of content and the most important information in the documents. Information about disease and treatment seemed to be of most interest for the patients, while information about research aspects of the study such as financing, confidentiality and publishing (formalities) was judged to be of lesser relevance. Two patients who read the original document indicated that they treated the formalities as secondary.

Conclusion: Patients seemed to pay little attention to the research aspects, and thus risked to misunderstand the main point of the consent document.

Practice Implications: The structure of consent documents should clarify for the readers that they are asked to take part in research, and that participation is voluntary.
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http://dx.doi.org/10.1016/j.pec.2008.06.011DOI Listing
November 2008

[Investigation in suspected pulmonary tumor].

Tidsskr Nor Laegeforen 2005 Nov;125(21):2958

Kreftavdelingen, St. Olavs Hospital, 7006 Trondheim.

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November 2005