- Email: [email protected]
Treatment of the Primary Tumour in the Presence of Metastases: Lessons from Breast Cancer
EURURO-6271; No. of Pages 3 EUROPEAN UROLOGY XXX (2015) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial and Reply from Authors Referring to the articles published on pp. a–b and on pp. x–y of this issue
Treatment of the Primary Tumour in the Presence of Metastases: Lessons from Breast Cancer Adri C. Voogd a,b,*, Rob H.A. Verhoeven b a
Department of Epidemiology and Department of Medical Oncology, School of Oncology and Developmental Biology (GROW), Maastricht University Medical
Centre, Maastricht, The Netherlands; b Department of Research, Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, The Netherlands
Except for the gender difference, important similarities exist between prostate cancer and breast cancer when looking at the epidemiology of M1 disease, in which the patients present with de novo metastatic cancer. For both breast and prostate cancer, patients with M1 disease represent only a small part of all cancer cases, and the bones are the most likely site to be affected. Data from the Netherlands Cancer Registry [1] show that for prostate cancer, the proportion has decreased from 26% in 1989 to 11% in 2006 (Fig. 1). The sharp increase in the incidence of localised prostate cancer, caused by the widespread use of prostate-specific antigen (PSA) testing, is mentioned as the most likely explanation for the decreasing percentage of patients with M1 disease. In more recent years, the percentage tends to rise again, which may reflect more restrictive PSA testing. In breast cancer patients, the proportion of M1 disease is even lower. Since 1989, the proportion has varied between 4% and 6%, again, referring to Dutch data [1] (Fig. 1). In this case, the increased use of mammography, following the introduction of populationbased mammography screening for women aged 50–70 yr, did not result in a lower percentage of M1 breast cancer, despite the increasing incidence of early stage cancers. This might be explained by the introduction and more widespread use of more sensitive imaging techniques to detect metastatic disease, such as 18 F-fluorodeoxyglucose positron emission tomography/computed tomography. Another similarity between breast and prostate cancer is the relatively long life expectancy of patients diagnosed with M1 disease. For breast cancer, median survival is currently >24 mo, with an increasing proportion of women
surviving >5 yr [1,2]. For prostate cancer, median survival is approximately 30 mo, according to the Netherlands Cancer Registry [1]. Figures are gradually improving as a result of the introduction of more effective drugs, such as docetaxel, cabazitaxel, and new antiandrogens (enzalutamide and abiraterone) for prostate cancer; trastuzumab for HER2 receptor–positive breast cancer; and aromatase inhibitors for hormone-sensitive breast tumours. The success of systemic treatment in prolonging survival explains why local tumour control is becoming an increasingly important treatment goal in M1 breast and prostate cancer. In this issue of European Urology, Bayne et al give a balanced overview of the literature on the treatment of the primary tumour in men with metastatic prostate cancer, covering external radiation therapy, brachytherapy, and radical prostatectomy [3]. Of special interest are the population-based studies demonstrating a survival benefit conferred by radical prostatectomy (in absolute numbers) in the order of 35–45% for 5-yr overall survival and between 25% and 30% for 5-yr disease-specific survival [4,5]. A systematic review of patients presenting with M1 breast cancer showed that surgical resection of the primary tumour was associated with a 35% reduction of the hazard for mortality. Of the 10 studies analysed, 7 reported significantly better survival for the patients who underwent surgery, and the other 3 studies observed a trend towards better survival [6]. Nonetheless, it should be noted that, similar to the situation for M1 prostate cancer, all studies were nonrandomised and conducted retrospectively. Without evidence from randomised trials, the question will remain unanswered regarding whether the observed
DOIs of original articles: http://dx.doi.org/10.1016/j.eururo.2015.04.036, http://dx.doi.org/10.1016/j.eururo.2015.05.023. * Corresponding author. Department of Epidemiology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands. Tel. +31 43 3882387; Fax: +31 43 3884128. E-mail address: [email protected] (A.C. Voogd). http://dx.doi.org/10.1016/j.eururo.2015.06.024 0302-2838/# 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Voogd AC, Verhoeven RHA. Treatment of the Primary Tumour in the Presence of Metastases: Lessons from Breast Cancer. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.06.024
EURURO-6271; No. of Pages 3 2
EUROPEAN UROLOGY XXX (2015) XXX–XXX
Fig. 1 – Percentage of patients with de novo metastatic (M1) breast cancer and M1 prostate cancer diagnosed between 1989 and 2013 [1].
survival benefit reflects a true impact of the resection of the primary tumour or whether it can be attributed to imbalances between the patients groups with respect to important prognostic factors that have not been measured or taken into account properly in the multivariate analysis. Potential confounders are age; comorbidity; performance status; the site, number, and volume of the metastatic deposits; presence and extent of nodal disease; tumour grade; and timing and dosages of the systemic treatment modalities used. Even if information on these factors were available and of sufficient quality, residual confounding by unknown or unmeasured confounders cannot be ruled out. In prostate cancer, trials are currently being established in which surgery is part of the multimodal treatment of M1 disease. Details of these initiatives are given in the overview by Bayne et al [3]. In breast cancer, similar trials are ongoing or have already completed patient accrual [7]. Preliminary results from a Turkish trial show that the effect of surgery is probably smaller than suggested by the results of the observational studies (ClinicalTrials.gov identifier NCT00557986). An important ongoing study is the Eastern Cooperative Oncology Group EA2108 trial, which is being performed in Canada and the Unites States (ClinicalTrials.gov identifier NCT01242800). Unfortunately, the accrual in this trial was much poorer than expected, and the original sample size was adjusted from 880 to 368 patients. Other trials are ongoing in Japan and Austria. In the Netherlands, a trial was started in 2013 but was terminated early because of poor accrual (ClinicalTrials.gov identifier NCT01392586). What can be learned from the trials in M1 breast cancer to improve the chances of success of future prostate cancer trials? Poor accrual can have many causes. In general, trials with widely diverging treatment options are difficult to explain to patients, especially shortly after cancer has been diagnosed. In the breast cancer trials, many oncologists
seemed reluctant to randomise patients before the start of systemic treatment because removal of the primary tumour meant that an important marker for response was no longer available. Accrual can be improved by increasing the time window during which prostatectomy may be considered. This means that not only patients presenting with a resectable tumour but also those with a tumour that becomes resectable after an adequate response to systemic treatment would be candidates for the trial. Urologists are not familiar with radical prostatectomy in patients with M1 disease. Currently, it is used only for highly selected patients. In the population-based studies by Culp et al and Gratzke et al, only 3–5% of all patients with de novo metastatic disease underwent radical prostatectomy [4,5]. This restrictive use makes it difficult to estimate how many patients will be candidates for a trial in which prostatectomy is offered. What is clear is that thousands of patients need to be screened for eligibility to guarantee that enough patients can be randomised. If possible, trials should be set up on an international scale. In contrast, one should realise that it is often difficult to find funding for cross-border studies that do not involve drugs. If international initiatives turn out not to be feasible, a meta-analysis of individual trials should be considered. Pooling of data is possible only if the trial designs have sufficient elements in common. Efforts should be taken to reach consensus worldwide on the inclusion criteria, the timing of the local treatment, and the end points. Pooling of data may also allow subgroup analyses to identify which M1 patients are likely to benefit from local treatment and which are not. A study by Fossati et al indicated that the largest benefit from local therapy may be obtained by patients with low-volume metastatic disease [8]; however, because their findings are also based on nonrandomised studies and thus are potentially biased, there seems to be no reason to exclude patients with extensive metastatic disease from trials,
Please cite this article in press as: Voogd AC, Verhoeven RHA. Treatment of the Primary Tumour in the Presence of Metastases: Lessons from Breast Cancer. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.06.024
EURURO-6271; No. of Pages 3 EUROPEAN UROLOGY XXX (2015) XXX–XXX
provided that they are fit enough to undergo surgery and have a sufficiently long life expectancy. The study by Sooriakumaran et al, also published in this issue of European Urology, shows that radical prostatectomy appears to be safe when performed by experts and when used in carefully selected patients with stage M1 disease [9]. In their retrospective, international, and multicentre series of 106 patients, 80% suffered no complications, and only 1 patient had an intraoperative injury. These risks of prostatectomy should be weighed against the potentially life-prolonging effect and the complications resulting from local progression if the tumour is left in situ. Consequently, quality of life will be an important secondary end point in each trial. Finally, collection of blood and tumour tissue is indispensable for testing the different hypotheses of how treatment of the primary tumour may affect the growth of metastatic deposits, including the role of circulating tumour cells.
3
[2] Ruiterkamp j, Ernst MF, de Munck L, et al. Improved survival of patients with primary distant metastatic breast cancer in the period 1995–2008. A nationwide population-based study in the Netherlands. Breast Cancer Res Treat 2011;128:495–503. [3] Bayne CE, Williams SB, Cooperberg MR, et al. Treatment of the primary tumor in metastatic prostate cancer: current concepts and future perspectives. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo. 2015.04.036 [4] Culp SH, Schellhammer PF, Williams MB. Might men diagnosed with metastatic prostate cancer benefit from definitive treatment of the primary tumor? A SEER-based study. Eur Urol 2014;65:1058–66. [5] Gratzke C, Engel J, Stief CG. Role of radical prostatectomy in metastatic prostate cancer: data from the Munich Cancer registry. Eur Urol 2014;66:602–3. [6] Ruiterkamp J, Voogd AC, Bosscha K, Tjan-Heijnen VCG, Ernst MF. Impact of breast surgery on survival in patients with distant metastases. A systematic review of the literature. Breast Cancer Res Treat 2010;120:9–16. [7] Patrick J, Khan SA. Surgical management of de novo stage IV breast cancer. J Compr Canc Netw 2015;13:487–93. [8] Fossati N, Trinh QD, Sammon J, et al. Identifying optimal candidates for
Conflicts of interest: The authors have nothing to disclose.
local treatment of the primary tumor among patients diagnosed with metastatic prostate cancer: a SEER-based study. Eur Urol 2015;67:3–6.
References
[9] Sooriakumaran P, Karnes J, Stief C, et al. A multi-institutional analysis of perioperative outcomes in 106 men who underwent radical pros-
[1] The Netherlands Cancer Registry. Netherlands Comprehensive Cancer Organisation Web site. http://www.cijfersoverkanker.nl.
tatectomy for distant metastatic prostate cancer at presentation. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2015.05.023
Please cite this article in press as: Voogd AC, Verhoeven RHA. Treatment of the Primary Tumour in the Presence of Metastases: Lessons from Breast Cancer. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.06.024
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial and Reply from Authors Referring to the articles published on pp. a–b and on pp. x–y of this issue
Treatment of the Primary Tumour in the Presence of Metastases: Lessons from Breast Cancer Adri C. Voogd a,b,*, Rob H.A. Verhoeven b a
Department of Epidemiology and Department of Medical Oncology, School of Oncology and Developmental Biology (GROW), Maastricht University Medical
Centre, Maastricht, The Netherlands; b Department of Research, Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, The Netherlands
Except for the gender difference, important similarities exist between prostate cancer and breast cancer when looking at the epidemiology of M1 disease, in which the patients present with de novo metastatic cancer. For both breast and prostate cancer, patients with M1 disease represent only a small part of all cancer cases, and the bones are the most likely site to be affected. Data from the Netherlands Cancer Registry [1] show that for prostate cancer, the proportion has decreased from 26% in 1989 to 11% in 2006 (Fig. 1). The sharp increase in the incidence of localised prostate cancer, caused by the widespread use of prostate-specific antigen (PSA) testing, is mentioned as the most likely explanation for the decreasing percentage of patients with M1 disease. In more recent years, the percentage tends to rise again, which may reflect more restrictive PSA testing. In breast cancer patients, the proportion of M1 disease is even lower. Since 1989, the proportion has varied between 4% and 6%, again, referring to Dutch data [1] (Fig. 1). In this case, the increased use of mammography, following the introduction of populationbased mammography screening for women aged 50–70 yr, did not result in a lower percentage of M1 breast cancer, despite the increasing incidence of early stage cancers. This might be explained by the introduction and more widespread use of more sensitive imaging techniques to detect metastatic disease, such as 18 F-fluorodeoxyglucose positron emission tomography/computed tomography. Another similarity between breast and prostate cancer is the relatively long life expectancy of patients diagnosed with M1 disease. For breast cancer, median survival is currently >24 mo, with an increasing proportion of women
surviving >5 yr [1,2]. For prostate cancer, median survival is approximately 30 mo, according to the Netherlands Cancer Registry [1]. Figures are gradually improving as a result of the introduction of more effective drugs, such as docetaxel, cabazitaxel, and new antiandrogens (enzalutamide and abiraterone) for prostate cancer; trastuzumab for HER2 receptor–positive breast cancer; and aromatase inhibitors for hormone-sensitive breast tumours. The success of systemic treatment in prolonging survival explains why local tumour control is becoming an increasingly important treatment goal in M1 breast and prostate cancer. In this issue of European Urology, Bayne et al give a balanced overview of the literature on the treatment of the primary tumour in men with metastatic prostate cancer, covering external radiation therapy, brachytherapy, and radical prostatectomy [3]. Of special interest are the population-based studies demonstrating a survival benefit conferred by radical prostatectomy (in absolute numbers) in the order of 35–45% for 5-yr overall survival and between 25% and 30% for 5-yr disease-specific survival [4,5]. A systematic review of patients presenting with M1 breast cancer showed that surgical resection of the primary tumour was associated with a 35% reduction of the hazard for mortality. Of the 10 studies analysed, 7 reported significantly better survival for the patients who underwent surgery, and the other 3 studies observed a trend towards better survival [6]. Nonetheless, it should be noted that, similar to the situation for M1 prostate cancer, all studies were nonrandomised and conducted retrospectively. Without evidence from randomised trials, the question will remain unanswered regarding whether the observed
DOIs of original articles: http://dx.doi.org/10.1016/j.eururo.2015.04.036, http://dx.doi.org/10.1016/j.eururo.2015.05.023. * Corresponding author. Department of Epidemiology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands. Tel. +31 43 3882387; Fax: +31 43 3884128. E-mail address: [email protected] (A.C. Voogd). http://dx.doi.org/10.1016/j.eururo.2015.06.024 0302-2838/# 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Voogd AC, Verhoeven RHA. Treatment of the Primary Tumour in the Presence of Metastases: Lessons from Breast Cancer. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.06.024
EURURO-6271; No. of Pages 3 2
EUROPEAN UROLOGY XXX (2015) XXX–XXX
Fig. 1 – Percentage of patients with de novo metastatic (M1) breast cancer and M1 prostate cancer diagnosed between 1989 and 2013 [1].
survival benefit reflects a true impact of the resection of the primary tumour or whether it can be attributed to imbalances between the patients groups with respect to important prognostic factors that have not been measured or taken into account properly in the multivariate analysis. Potential confounders are age; comorbidity; performance status; the site, number, and volume of the metastatic deposits; presence and extent of nodal disease; tumour grade; and timing and dosages of the systemic treatment modalities used. Even if information on these factors were available and of sufficient quality, residual confounding by unknown or unmeasured confounders cannot be ruled out. In prostate cancer, trials are currently being established in which surgery is part of the multimodal treatment of M1 disease. Details of these initiatives are given in the overview by Bayne et al [3]. In breast cancer, similar trials are ongoing or have already completed patient accrual [7]. Preliminary results from a Turkish trial show that the effect of surgery is probably smaller than suggested by the results of the observational studies (ClinicalTrials.gov identifier NCT00557986). An important ongoing study is the Eastern Cooperative Oncology Group EA2108 trial, which is being performed in Canada and the Unites States (ClinicalTrials.gov identifier NCT01242800). Unfortunately, the accrual in this trial was much poorer than expected, and the original sample size was adjusted from 880 to 368 patients. Other trials are ongoing in Japan and Austria. In the Netherlands, a trial was started in 2013 but was terminated early because of poor accrual (ClinicalTrials.gov identifier NCT01392586). What can be learned from the trials in M1 breast cancer to improve the chances of success of future prostate cancer trials? Poor accrual can have many causes. In general, trials with widely diverging treatment options are difficult to explain to patients, especially shortly after cancer has been diagnosed. In the breast cancer trials, many oncologists
seemed reluctant to randomise patients before the start of systemic treatment because removal of the primary tumour meant that an important marker for response was no longer available. Accrual can be improved by increasing the time window during which prostatectomy may be considered. This means that not only patients presenting with a resectable tumour but also those with a tumour that becomes resectable after an adequate response to systemic treatment would be candidates for the trial. Urologists are not familiar with radical prostatectomy in patients with M1 disease. Currently, it is used only for highly selected patients. In the population-based studies by Culp et al and Gratzke et al, only 3–5% of all patients with de novo metastatic disease underwent radical prostatectomy [4,5]. This restrictive use makes it difficult to estimate how many patients will be candidates for a trial in which prostatectomy is offered. What is clear is that thousands of patients need to be screened for eligibility to guarantee that enough patients can be randomised. If possible, trials should be set up on an international scale. In contrast, one should realise that it is often difficult to find funding for cross-border studies that do not involve drugs. If international initiatives turn out not to be feasible, a meta-analysis of individual trials should be considered. Pooling of data is possible only if the trial designs have sufficient elements in common. Efforts should be taken to reach consensus worldwide on the inclusion criteria, the timing of the local treatment, and the end points. Pooling of data may also allow subgroup analyses to identify which M1 patients are likely to benefit from local treatment and which are not. A study by Fossati et al indicated that the largest benefit from local therapy may be obtained by patients with low-volume metastatic disease [8]; however, because their findings are also based on nonrandomised studies and thus are potentially biased, there seems to be no reason to exclude patients with extensive metastatic disease from trials,
Please cite this article in press as: Voogd AC, Verhoeven RHA. Treatment of the Primary Tumour in the Presence of Metastases: Lessons from Breast Cancer. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.06.024
EURURO-6271; No. of Pages 3 EUROPEAN UROLOGY XXX (2015) XXX–XXX
provided that they are fit enough to undergo surgery and have a sufficiently long life expectancy. The study by Sooriakumaran et al, also published in this issue of European Urology, shows that radical prostatectomy appears to be safe when performed by experts and when used in carefully selected patients with stage M1 disease [9]. In their retrospective, international, and multicentre series of 106 patients, 80% suffered no complications, and only 1 patient had an intraoperative injury. These risks of prostatectomy should be weighed against the potentially life-prolonging effect and the complications resulting from local progression if the tumour is left in situ. Consequently, quality of life will be an important secondary end point in each trial. Finally, collection of blood and tumour tissue is indispensable for testing the different hypotheses of how treatment of the primary tumour may affect the growth of metastatic deposits, including the role of circulating tumour cells.
3
[2] Ruiterkamp j, Ernst MF, de Munck L, et al. Improved survival of patients with primary distant metastatic breast cancer in the period 1995–2008. A nationwide population-based study in the Netherlands. Breast Cancer Res Treat 2011;128:495–503. [3] Bayne CE, Williams SB, Cooperberg MR, et al. Treatment of the primary tumor in metastatic prostate cancer: current concepts and future perspectives. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo. 2015.04.036 [4] Culp SH, Schellhammer PF, Williams MB. Might men diagnosed with metastatic prostate cancer benefit from definitive treatment of the primary tumor? A SEER-based study. Eur Urol 2014;65:1058–66. [5] Gratzke C, Engel J, Stief CG. Role of radical prostatectomy in metastatic prostate cancer: data from the Munich Cancer registry. Eur Urol 2014;66:602–3. [6] Ruiterkamp J, Voogd AC, Bosscha K, Tjan-Heijnen VCG, Ernst MF. Impact of breast surgery on survival in patients with distant metastases. A systematic review of the literature. Breast Cancer Res Treat 2010;120:9–16. [7] Patrick J, Khan SA. Surgical management of de novo stage IV breast cancer. J Compr Canc Netw 2015;13:487–93. [8] Fossati N, Trinh QD, Sammon J, et al. Identifying optimal candidates for
Conflicts of interest: The authors have nothing to disclose.
local treatment of the primary tumor among patients diagnosed with metastatic prostate cancer: a SEER-based study. Eur Urol 2015;67:3–6.
References
[9] Sooriakumaran P, Karnes J, Stief C, et al. A multi-institutional analysis of perioperative outcomes in 106 men who underwent radical pros-
[1] The Netherlands Cancer Registry. Netherlands Comprehensive Cancer Organisation Web site. http://www.cijfersoverkanker.nl.
tatectomy for distant metastatic prostate cancer at presentation. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2015.05.023
Please cite this article in press as: Voogd AC, Verhoeven RHA. Treatment of the Primary Tumour in the Presence of Metastases: Lessons from Breast Cancer. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.06.024