Niels Viggo Jensen

The influence of chemotherapy on survival after recurrence in breast cancer-a population-based study of patients treated in the 1950s, 1960s and 1970s

In a population-based study survival after recurrence was compared in three cohorts of patients with a primary diagnosis of breast cancer in 1959, 1969 and 1979, respectively. The use of chemotherapy after recurrence in these cohorts was either none, sporadic or widespread. This allowed a retrospective analysis of the survival impact of chemotherapy. Given the basic assumption that the natural history of breast cancer and the influence of endocrine therapy have not changed significantly during the 20-year period covered by the study, our data suggest that chemotherapy in recurrent breast cancer prolongs survival by 9.5 months in patients who survive more than 2 weeks from the start of treatment for this recurrence.

Improved overall survival after implementation of targeted therapy for patients with metastatic renal cell carcinoma: Results from the Danish Renal Cancer Group (DARENCA) study-2

AIM To evaluate the implementation of targeted therapy on overall survival (OS) in a complete national cohort of patients with metastatic renal cell carcinoma (mRCC). METHODS All Danish patients with mRCC referred for first line treatment with immunotherapy, TKIs or mTOR-inhibitors between 2006 and 2010 were included. Baseline and outcome data were collected retrospectively. Prognostics factors were identified using log-rank tests and Cox proportional hazard model. Differences in distributions were tested with the Chi-square test. RESULTS 1049 patients were referred; 744 patients received first line treatment. From 2006 to 2010 we observed a significant increase in the number of referred patients; a significant increase in treated patients (64% versus 75%, P=0.0188); a significant increase in first line targeted therapy (22% versus 75%, P<0.0001); a significant increase in second line treatment (20% versus 40%, P=0.0104), a significant increased median OS (11.5 versus 17.2 months, P=0.0435) whereas survival for untreated patients remained unchanged. Multivariate analysis validated known prognostic factors. Moreover, treatment start years 2008 (HR 0.74, 95% CI, 0.55-0.99; P=0.0415), 2009 (HR 0.72, 95% CI, 0.54-0.96; P=0.0277) and 2010 (HR 0.63, 95% CI, 0.47-0.86; P=0.0035) compared to 2006, and more than two treatment lines received for patients with performance status 0-1 (HR 0.76, 95% CI, 0.58-0.99; P=0.0397) and performance status 2-3 (HR 0.19, 95% CI, 0.06-0.60; P=0.0051) were significantly associated with longer OS. CONCLUSION This retrospective study documents that the implementation of targeted therapy has resulted in significantly improved treatment rates and overall survival in a complete national cohort of treated mRCC patients.

A five-factor biomarker profile obtained week 4-12 of treatment for improved prognostication in metastatic renal cell carcinoma: Results from DARENCA study 2

Abstract Background: Several biomarkers of treatment efficacy have been associated with a better prognosis in patients with metastatic renal cell carcinoma (mRCC). The prognostic significance of biomarkers in the early treatment phase is unclear. Material and methods: In a complete national cohort of mRCC patients receiving first-line tyrosine kinase inhibitors (TKI) or interleukin-2 based immunotherapy (IT) from 2006 to 2010, overall survival (OS) was analysed for baseline International mRCC Database Consortium (IMDC) classification factors and on-treatment time-dependent biomarkers obtained day 1 each cycle week 4–12 after treatment initiation with multivariate analysis and bootstrap validation. Results: A total of 735 patients received first-line TKI (59%) or IT (41%). Median OS was overall 14.0 months and 33.4, 18.5, and 5.8 months for baseline IMDC favourable, intermediate, and poor risk groups, respectively (p < 0.0001). Systolic blood pressure ≥140 mmHg, neutrophils < lower level of normal (LLN), platelets < LLN, sodium ≥ LLN, and LDH ≤1.5 times upper level of normal after treatment initiation were significantly associated with favourable OS independent of baseline IMDC risk group in multivariate analyses stratified for TKI and IT (p ≤ 0.04). Concordance (C)-index for IMDC classification alone was 0.625 (95% CI 0.59–0.66) and combined with the five-factor biomarker profile 0.683 (95% CI 0.64–0.72). For patients with good (3–5 factors) and poor (0–2 factors) biomarker profile median OS were 23.5 and 9.6 months, respectively (p < 0.0001). Adding the five-factor biomarker profile significantly improved prognostication in IMDC intermediate (25.7 vs. 12.0 months, p < 0.0001) and poor (12.8 vs. 6.4 months, p < 0.0001) risk groups. A trend was seen in IMDC favourable risk group (38.9 vs. 28.7 months, p = 0.112). Conclusion: On-treatment hypertension, neutropenia, thrombocytopenia, LDH below 1.5 times upper level of normal, and normal sodium, obtained week 4–12 of treatment, are independent biomarkers of favourable outcome in mRCC, independent of treatment type.

Vinflunine treatment in patients with metastatic urothelial cancer: A Nordic retrospective multicenter analysis.

In 2009, vinflunine was introduced as a second-line treatment to be used after the failure of platinum therapy in patients with metastatic urothelial carcinoma (mUC). The present study investigated the administered vinflunine to patients with mUC in standard clinical practice with the aim of evaluating treatment patterns, response, survival parameters and side-effects. Data were collected retrospectively from the first 100 mUC patients treated with vinflunine at three Nordic cancer centers associated with the Nordic Urothelial Cancer Oncology Group. The overall response rate was 23% and complete response was observed in one patient. The median progression-free survival (mPFS) and median overall survival (mOS) were 2.8 (range, 0.5–34.3) and 6.3 (range, 0.3–39.7) months, respectively. An Eastern Cooperative Oncology Group performance status (ECOG PS) of 2 was present in 20% of the patients, and those patients exhibited significantly shorter mOS (4.1 vs. 7.0 months, P=0.001) and a significantly higher degree of grade 3/4 toxicity (P=0.026) compared with ECOG PS 0–1 patients. Furthermore, patients without visceral metastases had significantly longer mOS than patients with visceral metastases (10.6 vs. 6.0 months, P=0.008). The median number of cycles of vinflunine was 3 (range, 1–28). The current data confirms that vinflunine is an active agent for second-line treatment in an unselected clinical cohort of patients with mUC. ECOG PS and presence of visceral metastases were significant prognostic parameters. In particular, patients with ECOG PS 2 receiving vinflunine had a shorter mOS and a higher frequency of severe toxicity, and, thus, should be treated with caution. Furthermore, the present study observed large inter-individual differences in radiological response and OS, indicating the need for further development of improved patient selection tools to optimize vinflunine treatment in platinum-refractory mUC patients.

Phase I study of tauromustine administered in a weekly schedule

Tauromustine was administered orally in weekly doses with interindividual dose escalation to patients with disseminated malignant melanoma. The dose in the first cohort of 6 patients was 20 mg/m2/week. The dose escalation was 5 mg/m2/week. The limit of tolerance was 55 mg/m2/week. 99 patients completed at least 8 weeks of treatment and eight dose levels were evaluated for toxicity. Reversible thrombocytopenia, and to a lesser degree leukopenia, were dose limiting. From a starting dose of 40 mg/m2/week, the long-term tolerated dose was 35 mg/m2/week, thus achieving a considerable increase of dose intensity without a significant increase of toxicity by employing this weekly schedule of tauromustine.

Trends in kidney cancer among the elderly in Denmark, 1980–2012

Abstract Background The purpose of this study is to elucidate incidence, mortality, survival, and prevalence of kidney cancer in elderly persons compared with younger persons in Denmark. Material and methods Cancer of the kidney was defined as ICD-10 code DC 64. Data derived from the NORDCAN database with comparable data on cancer incidence, mortality, prevalence and relative survival in the Nordic countries, where the Danish data were delivered from the Danish Cancer Registry and the Danish Cause of Death Registry with follow-up for death or emigration until the end of 2013. Results The proportion of patients diagnosed with kidney cancer over the age of 70 years has decreased from 43% in 1980 to 32% in 2012 in men and remained almost constant in women, around 50%. Incidence rates were at least five times higher in men aged 70 years more but there was no particular trend with time. In men aged less than 70 years, the incidence rates started increasing around 2000. The incidence rates were lower in women but with a similar pattern as in men. Mortality rates remained stable over time in persons aged 70 years or more while they decreased with time in younger women. Both the one- and the five-year relative survival increased steadily over time for all age groups but the survival was lower for patients aged 70 years or more than for younger patients. The prevalence increased three times from 1559 patients being alive after kidney cancer in1980 to 4713 in 2012. Conclusion A challenge in managing kidney cancer in the elderly is to establish interdisciplinary collaborations between different specialties, such as surgeons, clinical oncologists, and geriatricians to be able to deliver the best possible care in the future.

Trends in cancer of the urinary bladder and urinary tract in elderly in Denmark, 2008–2012

Abstract Background The aim of this study was to examine the trends in incidence, mortality, survival, and prevalence of cancers of the urinary bladder and urinary tract in Denmark from 1980 to 2012 with particular focus on elderly patients over age 70 years. Design Cancer of the urinary bladder and urinary tract was defined as ICD-10 codes C67.9, D09.0, D41.4. Data were derived from the NORDCAN database with comparable data on cancer incidence, mortality, prevalence and relative survival in the Nordic countries, where the Danish data were delivered from the Danish Cancer Registry and the Danish Cause of Death Registry. Results The average annual number of bladder cancers increased from 1478 to 1810 (22%) from 1980 to 2012, with close to 60% occurring in the elderly population. The incidence rates were 7–10 times higher in persons aged 70 years or more compared with younger persons. Mortality rates were decreasing with time in all age groups but 90+-year-old men. The one- and five-year relative survival improved significantly with time for all age groups both in men and women. The prevalence increased two times from 6014 in 1980 to 12 359 in 2012 among men and from 1974 to 4454 among women. There was a relatively higher proportional increase in prevalence among elderly men compared to younger patients. Conclusion More prospective data are needed, preferably as randomized clinical trials, for determining the influence of age on the decisions of the surgical approach as well as chemo/radiotherapy for the elderly patients with urothelial cancers compared to younger patients.

Pazopanib-Induced Hypertension in Patients With Renal Cell Carcinoma Is Associated With Low Urine Excretion of NO Metabolites

Drugs targeting VEGF (vascular endothelial growth factor) are often associated with rapid development of hypertension by a yet not fully understood mechanism. VEGF is expressed in renal epithelial cells and stimulates NO production. In the renal medulla, inhibition of NO formation by local L-NAME or by impaired endothelin-1 leads to hypertension. The present study was designed to test the hypothesis that VEGF receptor inhibitor treatment leads to hypertension through decreased renal medullary formation of NO and endothelin-1. With a single-center prospective observational design, patients with metastatic renal cell carcinoma (n=27) treated with the receptor tyrosine kinase inhibitor pazopanib were included in the study. Home blood pressure was measured, and plasma and urine samples were collected at baseline and after 4 and 8 weeks of treatment. After 4 weeks, systolic and diastolic blood pressures increased, whereas heart rate decreased significantly; urine protein/creatinine ratio increased significantly, whereas estimated glomerular filtration rate was unchanged. Urine nitrite/nitrate (NOx) and cGMP/creatinine ratios decreased significantly, whereas urine endothelin-1/creatinine ratio and FENa+ were unchanged. In plasma, NOx, cGMP, and brain natriuretic peptide decreased significantly, whereas endothelin-1 was significantly elevated. Blood leukocyte count decreased significantly with unchanged CRP (C-reactive protein). In summary, pazopanib treatment of patients with advanced renal cell carcinoma is associated with hypertension, proteinuria, myelosuppression, and decreased urine and plasma NO metabolites. Results are compatible with a significant role of reduced renal medullary NO bioavailability in VEGF inhibitor–induced hypertension.

A randomized phase II trial of interleukin-2 and interferon-α plus bevacizumab versus interleukin-2 and interferon-α in metastatic renal-cell carcinoma (mRCC): results from the Danish Renal Cancer Group (DaRenCa) study-1

Abstract Background: Interleukin-2 (IL2)-based immunotherapy is curative for a small subset of patients with metastatic renal-cell carcinoma (mRCC). Preclinical data suggests that bevacizumab (BEV), a humanized anti-VEGF monoclonal antibody, has potential immunomodulatory effects by permitting efficient natural killer (NK) cell-mediated killing and by reverting immune suppression. Patient and methods: We performed a randomized phase II study comparing IL2/IFN (interferon)/BEV with IL2/IFN in favourable/intermediate-risk mRCC patients. One hundred and eighteen patients received IFN 3 MIU subcutaneously (sc) daily and IL2 2.4 MIU/m2 sc twice daily, 5 days per week for two consecutive weeks every 28-day-cycle, for 9 months; or supplemented with BEV 10 mg/kg, every 2 weeks intravenously (iv) until progression, unacceptable toxicity, or 1 year following no evidence of disease (NED). Primary end point was progression-free survival (PFS). Results: Baseline characteristics were well-balanced between the two arms; metastasis-free interval <1 year (75 versus 76%); prior nephrectomy (85 versus 86%); MSKCC favourable/intermediate-risk group (51/49 versus 52%/48%); three or more disease sites (41 versus 44%), respectively. The median PFS was 8.0 mo (95% CI, 4.2–11.9) with IL2/IFN/BEV and 8.1 mo (95% CI, 5.1–11.0) with IL2/IFN, p = .73. There was no difference in secondary endpoints, IL2/IFN/BEV versus IL2/IFN; median time-to-treatment failure (7.4 versus 5.6 mo, p = .54), response rate (44.1 versus 28.8%, p = .13), surgery of residual disease (17.0 versus 17.0%, p = 1.0), patients achieving NED (3.4 versus 8.5%, p = .44), and median overall survival (30.3 versus 34.1 mo, p = .39), respectively. TKI post progression was well-balanced (85 versus 78%). No new/unexpected toxicity was observed. Most common Grade 3/4 adverse events for IL2/IFN/BEV and IL2/IFN were fatigue (64 versus 61%), flu-like symptoms (37 versus 41%) and thrombosis (6.8 versus 18.6%, p = .01), respectively. Conclusions: The addition of BEV to IL-2/IFN did not add efficacy in mRCC. (ClinicalTrials.gov, NCT01274273.).