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  • 1.
    Stenman, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University.
    Treatment selection in metastatic renal cell carcinoma: Towards an individualised approach2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Renal cell carcinoma (RCC), a common malignancy worldwide, affects 1200 new patients yearly in Sweden. Metastatic RCC (mRCC) develops in one in three and is commonly incurable. Clear cell histology dominates followed by papillary histology. The mainstay of mRCC treatment is targeted agents (TA) against aberrantly signalling pro-angiogenic tyrosine kinase receptors, and recently also immune checkpoint inhibitors. Local metastatic therapy with stereotactic radiotherapy (SRT) or surgical metastasectomy may be considered for oligometastatic disease.

    The aims of this thesis were (1) to identify clinically relevant factors useful for prognostication in real-world patients with mRCC treated in the TA era, (2) to deepen the understanding of papillary mRCC, and (3) to evaluate local metastatic therapy in mRCC. The papers of this thesis were based on retrospective data from regional databases or patient records from 2005 and onwards to reflect the contemporary therapeutic landscape.

    Paper I was a single-centre study analysing inflammatory blood and clinical parameters in relation to overall survival (OS) in mRCC (n=84). Median OS (mOS) was 20 months. Hypoalbuminemia was a negative prognostic factor (HR 2.7), independently of patient performance status (PS) or Memorial Sloan Kettering Cancer Center risk criteria.

    Paper II included solely patients with papillary mRCC (n=86) treated at three centres. mOS was 11 months. Age ≥60 years (HR 2.2), ≥3 metastatic sites (HR 2.7), and Eastern Cooperative Oncology Group (ECOG) PS ≥2 vs 1 (HR 3.0) were independently associated with worse OS.

    Paper III included mRCC patients treated with local metastatic therapy (n=117). Survival was similar irrespective of SRT or surgical metastasectomy with a mOS of 51 months. Treatment with TA in close proximity to local therapy was well tolerated. ECOG PS 1 vs 0 (HR 2.9), intracranial treatment (HR 1.8), and watchful waiting ≥18 months prior to treatment (HR 0.3) were independently prognostic.  

    Paper IV was a follow-up of patients with ccRCC brain metastases treated with single fraction gamma knife radiosurgery (sf-GKRS) at three European centres (n=43). 1- and 3-year local control rates were 97% and 90%, and mOS was 16 months. Hypoalbuminemia (HR=5.3), corticosteroids prior to sf-GKRS (HR=5.8), and Karnofsky PS <80% (HR=9.1) were independently associated with worse OS, whereas previously described prognostic scores were not. Adverse radiation effects (ARE) were uncommon and associated with large target volumes and pre-treatment oedema.

    In conclusion, this thesis identifies several factors potentially useful for prognostication in mRCC, and indicates the usefulness of local metastatic therapy, in particular SRT, in selected patients. The results should be validated prospectively.

    List of papers
    1. Prognostic significance of serum albumin in patients with metastatic renal cell carcinoma
    Open this publication in new window or tab >>Prognostic significance of serum albumin in patients with metastatic renal cell carcinoma
    2014 (English)In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 31, no 3, p. 841-Article in journal (Refereed) Published
    Abstract [en]

    Systemic inflammation has been suggested to impact on the prognosis of metastatic renal cell carcinoma (mRCC). We undertook a retrospective analysis of patients with mRCC treated at Akademiska University Hospital in Sweden during the years 2005-2012 to assess the possible prognostic significance of inflammation-related factors including serum albumin, platelet count, weight loss and C-reactive protein (CRP). The Memorial Sloan-Kettering Cancer Center (MSKCC) criteria for prognosis of mRCC and ECOG performance status were assessed for all patients. Overall survival (OS) and progression-free survival (PFS) were calculated according to Kaplan-Meier, and Cox proportional hazards regression was used for uni- and multivariate analyses. The median OS of all patients (n=84) was 20 months. Univariate analysis identified low serum albumin (HR=4.17, p<0.001), elevated platelet count (HR=2.98, p<0.001) and patient-reported weight loss prior to diagnosis of mRCC (HR=2.73, p<0.001), in addition to MSKCC (HR=3.35, p=0.0088) to be associated with shorter OS. CRP did not significantly affect OS. Serum albumin retained prognostic significance for OS in multivariate analysis (HR=2.72, p=0.015). In patients treated with an angiogenesis-targeted agent (n=47), low serum albumin level (HR=4.63, p<0.001) and elevated platelet count (HR=2.11, p=0.022) were associated with shorter PFS. In contrast, CRP, weight loss and MSKCC risk group did not significantly affect PFS. In multivariate analysis serum albumin remained associated with PFS (HR=3.92, p=0.0035). Our findings identify serum albumin as an independent prognostic factor for patients with mRCC treated with angiogenesis-targeted therapy.

    National Category
    Cancer and Oncology
    Research subject
    Oncology
    Identifiers
    urn:nbn:se:uu:diva-222546 (URN)10.1007/s12032-014-0841-7 (DOI)000337728700007 ()24477648 (PubMedID)
    Available from: 2014-04-11 Created: 2014-04-11 Last updated: 2019-08-20Bibliographically approved
    2. Metastatic papillary renal cell carcinoma in the era of targeted therapy: a retrospective study from three European academic centres
    Open this publication in new window or tab >>Metastatic papillary renal cell carcinoma in the era of targeted therapy: a retrospective study from three European academic centres
    Show others...
    2019 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 58, no 3, p. 306-312Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Metastatic papillary renal cell carcinoma (mPRCC) is understudied. The disease is often aggressive and specific treatment options are lacking.

    PATIENTS AND METHODS: mPRCC patients (n = 86) referred to three academic centres in Sweden and Germany in the years 2005-2015 were retrospectively identified from medical records. Statistical analyses included Kaplan-Meier curves and calculation of Cox proportional hazards, generating hazard ratios with 95% confidence intervals. The aim of the study was to evaluate overall survival (OS) of mPRCC patients treated outside of clinical trials in the era of targeted agents (TA) and to identify clinically useful prognostic factors.

    RESULTS: Median OS of all mPRCC patients was 11.2 months. TA were used in 77% of the patients and associated with younger age and better Eastern Cooperative Oncology Group performance status (PS). Brain metastases were common (28%). Patients with synchronous or metachronous metastases had similar OS. Variables independently associated with risk of death included age ≥60 years, worse PS and ≥3 metastatic sites. The MSKCC criteria did not provide additional prognostic information. A subgroup analysis of TA-treated patients revealed an association of lymph node metastasis with risk of death in addition to the other prognostic factors.

    CONCLUSION: OS in mPRCC remained short in the era of targeted agents. Age, PS, and number of metastatic sites provided independent prognostic information.

    Keywords
    metastatic, mRCC, non-clear cell, papillary, survival
    National Category
    Cancer and Oncology
    Research subject
    Oncology
    Identifiers
    urn:nbn:se:uu:diva-381855 (URN)10.1080/0284186X.2018.1537505 (DOI)000462947900007 ()30507262 (PubMedID)
    Available from: 2019-04-15 Created: 2019-04-15 Last updated: 2019-08-20Bibliographically approved
    3. Overall survival after stereotactic radiotherapy or surgical metastasectomy in oligometastatic renal cell carcinoma patients treated at two Swedish centres 2005-2014
    Open this publication in new window or tab >>Overall survival after stereotactic radiotherapy or surgical metastasectomy in oligometastatic renal cell carcinoma patients treated at two Swedish centres 2005-2014
    Show others...
    2018 (English)In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 127, no 3, p. 501-506Article in journal (Refereed) Published
    Abstract [en]

    Background and purpose: Investigate effects of stereotactic radiotherapy (SRT) or surgical metastasectomy (SM) on overall survival (OS) in metastatic renal cell carcinoma (mRCC) in the era of targeted agents (TA).

    Material and methods: mRCC patients (n = 117) treated with SRT (n = 57), SM (n = 30) or both modalities sequentially (n = 30) at two oncological centres in Sweden in 2005-2014 were retrospectively included. Median follow-up (mFU) was 63 months.

    Results: A majority had clear cell histology, 1-3 metastases, and ECOG performance status of 0 or 1. Two thirds had intermediate or poor risk and 44% synchronous metastases. 65% received TA. SRT patients were more likely to have adverse risk profiles. Median OS was 51 months without significant differences between SRT and SM. ECOG 1 vs 0 (HR 2.9; CI 1.6-5.2; p < 0.001), intracranial targets (HR 1.8; CI 1.1-3.2; p = 0.03) and watchful waiting >18 months prior to treatment (HR 0.3; CI 0.2-0.6; p = 0.001) were independently associated with OS. 15% of curatively treated patients (n = 60) were relapse-free with mFU of 87 months.

    Conclusions: OS after SRT was comparable to SM and longer than expected considering patients with adverse risk profiles were common. Fit patients with non-brain metastases treated after an initial period of watchful waiting had the best prognosis.

    Place, publisher, year, edition, pages
    ELSEVIER IRELAND LTD, 2018
    Keywords
    Renal cell carcinoma, Stereotactic radiotherapy, Gamma knife, Surgical metastasectomy, Overall survival, Prognostic factors
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-360494 (URN)10.1016/j.radonc.2018.04.028 (DOI)000437110000024 ()29754859 (PubMedID)
    Available from: 2018-09-17 Created: 2018-09-17 Last updated: 2019-08-20Bibliographically approved
    4. Albumin, corticosteroid use and Karnofsky performance status predict outcome of single-fraction gamma knife radiosurgery in clear cell renal cell carcinoma patients with brain metastases
    Open this publication in new window or tab >>Albumin, corticosteroid use and Karnofsky performance status predict outcome of single-fraction gamma knife radiosurgery in clear cell renal cell carcinoma patients with brain metastases
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background and Purpose: To evaluate the effects of single fraction gamma knife radiosurgery (sf-GKRS) on patients with renal cell carcinoma (RCC) brain metastases (BM) in the era of targeted agents (TA).

    Material and Methods: Clear cell metastatic RCC patients treated with sf-GKRS due to BM in 2005-2014 at three European centres were retrospectively analysed (n=43). Median follow-up was 56 months. Ninety-five percent had prior nephrectomy, 53% synchronous metastasis and 86% extracranial disease at first sf-GKRS. Karnofsky performance status (KPS) ranged from 60-100%.  Outcome measures were overall survival (OS), local control (LC) and adverse radiation effects (ARE).

    Results: One hundred and ninety-four targets were irradiated. Median number of targets at first sf-GKRS were two. The median prescription dose was 22 Gy. Thirty-seven percent had repeated sf-GKRS. Eighty-eight percent received TA. LC at 12 and 18 months were 97% and 90%. Median OS from first sf-GKRS was 15.7 months. Serum albumin (HR 5.3), corticosteroids pre sf-GKRS (HR 5.8) and KPS (HR 9.1) were independent prognostic factors. MSKCC risk group, synchronous metastasis, age, number of BM or extracranial metastases provided no additional prognostic information. Other prognostic scores for BM radiosurgery, including DS-GPA, Renal-GPA, LLV-SIR and CITV-SIR, did not add prognostic value. ARE were seldom symptomatic and were associated with tumour volume, 10-Gy volume and pre-treatment perifocal oedema. ARE were less common among patients treated with TA within one month of sf-GKRS.

    Conclusions: We identified three independent prognostic factors with potential impact on clinical decision making in patients with clear cell RCC BM.

    Keywords
    renal cell carcinoma, kidney cancer, stereotactic radiotherapy, stereotactic radiosurgery, radiosurgery, SRS, gamma knife, overall survival, prognostic factors, gkrs, rcc
    National Category
    Cancer and Oncology
    Research subject
    Oncology
    Identifiers
    urn:nbn:se:uu:diva-390135 (URN)
    Available from: 2019-08-05 Created: 2019-08-05 Last updated: 2019-08-20
  • 2.
    Stenman, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Benmakhlouf, Hamza
    Department of Medical Radiation Physics and Nuclear Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Wersäll, Peter
    Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Hatiboglu, Mustafa Aziz
    Department of Neurosurgery, Bezmialem Vakif University Medical School, Istanbul, Turkey.
    Silva, Julieta Mayer
    Centro Gamma Knife, CUF Infante Santo Hospital, Lisbon, Portugal.
    Harmenberg, Ulrika
    Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Lindskog, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sinclair, Georges
    Department of Neurosurgery, Bezmialem Vakif University Medical School, Istanbul, Turkey. Department of Neurosurgery, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden..
    Albumin, corticosteroid use and Karnofsky performance status predict outcome of single-fraction gamma knife radiosurgery in clear cell renal cell carcinoma patients with brain metastasesManuscript (preprint) (Other academic)
    Abstract [en]

    Background and Purpose: To evaluate the effects of single fraction gamma knife radiosurgery (sf-GKRS) on patients with renal cell carcinoma (RCC) brain metastases (BM) in the era of targeted agents (TA).

    Material and Methods: Clear cell metastatic RCC patients treated with sf-GKRS due to BM in 2005-2014 at three European centres were retrospectively analysed (n=43). Median follow-up was 56 months. Ninety-five percent had prior nephrectomy, 53% synchronous metastasis and 86% extracranial disease at first sf-GKRS. Karnofsky performance status (KPS) ranged from 60-100%.  Outcome measures were overall survival (OS), local control (LC) and adverse radiation effects (ARE).

    Results: One hundred and ninety-four targets were irradiated. Median number of targets at first sf-GKRS were two. The median prescription dose was 22 Gy. Thirty-seven percent had repeated sf-GKRS. Eighty-eight percent received TA. LC at 12 and 18 months were 97% and 90%. Median OS from first sf-GKRS was 15.7 months. Serum albumin (HR 5.3), corticosteroids pre sf-GKRS (HR 5.8) and KPS (HR 9.1) were independent prognostic factors. MSKCC risk group, synchronous metastasis, age, number of BM or extracranial metastases provided no additional prognostic information. Other prognostic scores for BM radiosurgery, including DS-GPA, Renal-GPA, LLV-SIR and CITV-SIR, did not add prognostic value. ARE were seldom symptomatic and were associated with tumour volume, 10-Gy volume and pre-treatment perifocal oedema. ARE were less common among patients treated with TA within one month of sf-GKRS.

    Conclusions: We identified three independent prognostic factors with potential impact on clinical decision making in patients with clear cell RCC BM.

  • 3.
    Stenman, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Laurell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Lindskog, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Prognostic significance of serum albumin in patients with metastatic renal cell carcinoma2014In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 31, no 3, p. 841-Article in journal (Refereed)
    Abstract [en]

    Systemic inflammation has been suggested to impact on the prognosis of metastatic renal cell carcinoma (mRCC). We undertook a retrospective analysis of patients with mRCC treated at Akademiska University Hospital in Sweden during the years 2005-2012 to assess the possible prognostic significance of inflammation-related factors including serum albumin, platelet count, weight loss and C-reactive protein (CRP). The Memorial Sloan-Kettering Cancer Center (MSKCC) criteria for prognosis of mRCC and ECOG performance status were assessed for all patients. Overall survival (OS) and progression-free survival (PFS) were calculated according to Kaplan-Meier, and Cox proportional hazards regression was used for uni- and multivariate analyses. The median OS of all patients (n=84) was 20 months. Univariate analysis identified low serum albumin (HR=4.17, p<0.001), elevated platelet count (HR=2.98, p<0.001) and patient-reported weight loss prior to diagnosis of mRCC (HR=2.73, p<0.001), in addition to MSKCC (HR=3.35, p=0.0088) to be associated with shorter OS. CRP did not significantly affect OS. Serum albumin retained prognostic significance for OS in multivariate analysis (HR=2.72, p=0.015). In patients treated with an angiogenesis-targeted agent (n=47), low serum albumin level (HR=4.63, p<0.001) and elevated platelet count (HR=2.11, p=0.022) were associated with shorter PFS. In contrast, CRP, weight loss and MSKCC risk group did not significantly affect PFS. In multivariate analysis serum albumin remained associated with PFS (HR=3.92, p=0.0035). Our findings identify serum albumin as an independent prognostic factor for patients with mRCC treated with angiogenesis-targeted therapy.

  • 4.
    Stenman, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Nearchou, Andreas Demetrios
    Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden.
    Sandström, Per
    Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden.
    Lindskog, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Harmenberg, Ulrika
    Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden.
    Metastatic papillary renal cell carcinoma: A retrospective study from two large academic centers in Sweden2016In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 34, no 2Article in journal (Other academic)
  • 5.
    Stenman, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sinclair, G.
    Karolinska Inst, Dept Neurosurg, S-17176 Stockholm, Sweden;Karolinska Univ Hosp, S-17176 Stockholm, Sweden.
    Paavola, P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Wersall, P.
    Karolinska Univ Hosp, S-17176 Stockholm, Sweden;Karolinska Inst, Dept Oncol Pathol, S-17176 Stockholm, Sweden.
    Harmenberg, U.
    Karolinska Univ Hosp, S-17176 Stockholm, Sweden;Karolinska Inst, Dept Oncol Pathol, S-17176 Stockholm, Sweden.
    Lindskog, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Overall survival after stereotactic radiotherapy or surgical metastasectomy in oligometastatic renal cell carcinoma patients treated at two Swedish centres 2005-20142018In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 127, no 3, p. 501-506Article in journal (Refereed)
    Abstract [en]

    Background and purpose: Investigate effects of stereotactic radiotherapy (SRT) or surgical metastasectomy (SM) on overall survival (OS) in metastatic renal cell carcinoma (mRCC) in the era of targeted agents (TA).

    Material and methods: mRCC patients (n = 117) treated with SRT (n = 57), SM (n = 30) or both modalities sequentially (n = 30) at two oncological centres in Sweden in 2005-2014 were retrospectively included. Median follow-up (mFU) was 63 months.

    Results: A majority had clear cell histology, 1-3 metastases, and ECOG performance status of 0 or 1. Two thirds had intermediate or poor risk and 44% synchronous metastases. 65% received TA. SRT patients were more likely to have adverse risk profiles. Median OS was 51 months without significant differences between SRT and SM. ECOG 1 vs 0 (HR 2.9; CI 1.6-5.2; p < 0.001), intracranial targets (HR 1.8; CI 1.1-3.2; p = 0.03) and watchful waiting >18 months prior to treatment (HR 0.3; CI 0.2-0.6; p = 0.001) were independently associated with OS. 15% of curatively treated patients (n = 60) were relapse-free with mFU of 87 months.

    Conclusions: OS after SRT was comparable to SM and longer than expected considering patients with adverse risk profiles were common. Fit patients with non-brain metastases treated after an initial period of watchful waiting had the best prognosis.

  • 6.
    Stenman, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Staehler, Michael
    Deparment of Urology, Ludwig-Maximilians University, Munich Germany.
    Szabados, Bernadett
    Deparment of Urology, Ludwig-Maximilians University, Munich Germany.
    Sandström, Per
    Department of Oncology-Pathology, Karolinska Institute, Sweden.
    Laurell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Lindskog, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Harmenberg, Ulrika
    Department of Oncology-Pathology, Karolinska Institute, Sweden.
    Metastatic papillary renal cell carcinoma in the era of targeted therapy: a retrospective study from three European academic centres2019In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 58, no 3, p. 306-312Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Metastatic papillary renal cell carcinoma (mPRCC) is understudied. The disease is often aggressive and specific treatment options are lacking.

    PATIENTS AND METHODS: mPRCC patients (n = 86) referred to three academic centres in Sweden and Germany in the years 2005-2015 were retrospectively identified from medical records. Statistical analyses included Kaplan-Meier curves and calculation of Cox proportional hazards, generating hazard ratios with 95% confidence intervals. The aim of the study was to evaluate overall survival (OS) of mPRCC patients treated outside of clinical trials in the era of targeted agents (TA) and to identify clinically useful prognostic factors.

    RESULTS: Median OS of all mPRCC patients was 11.2 months. TA were used in 77% of the patients and associated with younger age and better Eastern Cooperative Oncology Group performance status (PS). Brain metastases were common (28%). Patients with synchronous or metachronous metastases had similar OS. Variables independently associated with risk of death included age ≥60 years, worse PS and ≥3 metastatic sites. The MSKCC criteria did not provide additional prognostic information. A subgroup analysis of TA-treated patients revealed an association of lymph node metastasis with risk of death in addition to the other prognostic factors.

    CONCLUSION: OS in mPRCC remained short in the era of targeted agents. Age, PS, and number of metastatic sites provided independent prognostic information.

1 - 6 of 6
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