Cancer progresses in a stepwise fashion. Oligometastatic cancer is an intermediate stage of tumor spread between localized disease and disseminated metastases. Oligometastatic prostate cancer is defined as up to five extrapelvic lesions on conventional imaging. There are controversies surrounding the management of this malignancy, but retrospective and population-based studies suggest a role for radical prostatectomy. Despite insufficient data to draw conclusions regarding the effectiveness of aggressive therapies on overall or cancer-specific survival of patients with oligometastatic prostate cancer, current studies suggest that surgery decreases tumor burden, disease-related morbidity, and the need for palliative surgical intervention, while increasing the period of time to development of castration-resistant disease.
The dramatic stage migration of prostate cancer toward earlier-stage, lower-grade disease at diagnosis is due to the widespread use of prostate-specific antigen (PSA) screening. In the pre-PSA era, regional or distant metastatic disease was seen in 25% of patients at diagnosis; since the introduction of PSA screening, however, fewer than 5% of men with prostate cancer are diagnosed with synchronous metastatic disease. The US Preventive Services Task Force recommendation against PSA-based prostate cancer screening has resulted in an increased incidence of patients with metastatic prostate cancer at diagnosis.[2-4]
The current standard of care for men with metastatic prostate cancer targets the androgen axis (by testosterone suppression using surgical or hormonal castration). The treatment of the primary tumor in the metastatic setting is limited to patients with significant local symptoms secondary to the primary tumor, and is undertaken only as a palliative measure.
Men with metastatic hormone-sensitive prostate cancer are typically treated with immediate or deferred systemic androgen deprivation therapy (ADT), with or without antiandrogen agents.[6-9] The addition of chemotherapy to hormonal therapy in the management of metastatic hormone-sensitive prostate cancer has been shown to improve survival and highlights the potential benefit of a multimodal approach in treating men with metastatic disease.[10,11] The broad, nontargeted systemic treatment of metastatic prostate cancer patients irrespective of disease burden was challenged by findings from the CHAARTED, STAMPEDE, and GETUG-AFU 15 trials.[10-12] Furthermore, recently reported results of the LATITUDE trial demonstrated improvements in both overall survival (OS) and radiographic progression-free survival (PFS) following treatment with abiraterone (plus prednisone and ADT) across all subgroups of patients with metastatic prostate cancer—including those with visceral metastasis and more than 10 bone lesions—compared with men randomized to ADT plus placebo. The findings of these trials suggest that chemohormonal therapy improved survival in men with high-volume disease, whereas this treatment failed to yield a survival benefit with long-term follow-up in men with low-volume or oligometastatic disease.[10-13]
Despite the benefits observed with some of the previously mentioned therapies, metastatic prostate cancer is associated with a 5-year survival rate of only 28%, and carries a large economic burden.[14,15] This suggests the existence of a distinct phenotype of metastatic disease that may warrant distinct treatment strategies compared with the approaches used for nonmetastatic disease. Historically, radical prostatectomy (RP) and radiation therapy (RT) have been offered only to men with localized prostate cancer, and recent studies indicate that these modalities demonstrate sustained oncologic benefits in the setting of locally advanced disease.[16-21] In contrast, very few data exist to support treatment of primary prostate cancer in the metastatic setting. While the body of evidence in support of achieving local disease control to improve both the rate of response to systemic therapy and survival is well established in other malignancies (including metastatic renal cell, colon, breast, and ovarian cancers, and glioblastoma), similar evidence is lacking in the medical literature on prostate cancer.[22-28]
Extrapolating from other malignancies to metastatic prostate cancer, there is growing interest in elucidating the role of cytoreductive prostatectomy in management of low-volume metastatic or oligometastatic prostate cancer. Many theories have been proposed in support of local disease control; the leading theory is that, despite systemic therapy, the primary tumor may continue to harbor viable tumor cells with lethal molecular features and serve as a source for the seeding of new metastatic foci.[29,30]
Despite a paucity of level 1 evidence to support treatment of the primary tumor in metastatic prostate cancer, emerging data suggest improved survival with this approach in men with metastatic prostate cancer and locally advanced prostate cancer (ie, lymph node–positive disease).[20,21,31-36] The management of oligometastatic prostate cancer is complex owing to variation in the definition of oligometastatic prostate cancer and inconsistency among published data in the literature. In this review, we will examine the theories supporting treatment to achieve local disease control in oligometastatic prostate cancer, analyze the evidence supporting cytoreductive prostatectomy, and review selected relevant ongoing clinical trials.
Definition and Diagnosis of Oligometastatic Prostate Cancer
Metastatic cancer is synonymous with advanced-stage disease, where malignant cells are disseminated through the systemic circulation. Cancers are, and this dissemination is, believed to occur in a stepwise fashion. In their 1995 article, Hellman and Weichselbaum postulated an oligometastatic state with limited metastasis burden as an intermediate state in the malignancy spectrum prior to widespread metastases. In their opinion, oligometastatic disease may reflect a time point in the malignant process when local therapies can potentially achieve a durable response to treatment—or even cure.[37,38]
The rise in the diagnosis of oligometastatic prostate cancer is likely multifactorial, and may result from closer monitoring of patients, improved diagnosis of low-burden disease due to advances in imaging techniques, and improved survival secondary to the use of emerging new therapies.[39,40]
Currently, the European Association of Urology and the National Comprehensive Cancer Network suggest cross-sectional studies (such as CT scan or MRI) and 99mTc-methylene diphosphonate planar or single photon emission tomography bone scan as the standard of care to evaluate for presence of metastases to lymph nodes, bone, or viscera.[7-9] The number of metastases is the most commonly used criterion to distinguish between oligometastatic and widely metastatic disease. Some clinicians additionally emphasize the anatomic location of metastasis in determining the existence of an oligometastatic state. A review of the medical literature suggests wide variability in the criteria used to define oligometastatic prostate cancer, with different levels of evidence. In most studies and ongoing trials, oligometastasis is defined as the presence of disease in five or fewer sites. Tables 1 and 2 summarize selected ongoing trials and previously published studies defining oligometastatic prostate cancer.
1. Ryan CJ, Elkin EP, Small EJ, et al. Reduced incidence of bony metastasis at initial prostate cancer diagnosis: data from CaPSURE. Urol Oncol. 2006;24:396-402.
2. Banerji JS, Wolff EM, Massman JD 3rd, et al. Prostate needle biopsy outcomes in the era of the U.S. Preventive Services Task Force recommendation against prostate specific antigen based screening. J Urol. 2016;195:66-73.
3. Barocas DA, Mallin K, Graves AJ, et al. Effect of the USPSTF grade D recommendation against screening for prostate cancer on incident prostate cancer diagnoses in the United States. J Urol. 2015;194:1587-93.
4. Weiner AB, Matulewicz RS, Eggener SE, Schaeffer EM. Increasing incidence of metastatic prostate cancer in the United States (2004-2013). Prostate Cancer Prostatic Dis. 2016;19:395-7.
5. Mathieu R, Korn SM, Bensalah K, et al. Cytoreductive radical prostatectomy in metastatic prostate cancer: does it really make sense? World J Urol. 2017;35:567-77.
6. Crawford ED, Higano CS, Shore ND, et al. Treating patients with metastatic castration resistant prostate cancer: a comprehensive review of available therapies. J Urol. 2015;194:1537-47.
7. Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and local treatment with curative intent-update 2013. Eur Urol. 2014;65:124-37.
8. Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2014;65:467-79.
9. Mohler JL, Armstrong AJ, Bahnson RR, et al. Prostate cancer. Version 1.2016. J Natl Compr Canc Netw. 2016;14:19-30.
10. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373:737-46.
11. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387:1163-77.
12. Gravis G, Fizazi K, Joly F, et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14:149-58.
13. Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377:352-60.
14. Wu JN, Fish KM, Evans CP, et al. No improvement noted in overall or cause-specific survival for men presenting with metastatic prostate cancer over a 20-year period. Cancer. 2014;120:818-23.
15. James ND, Spears MR, Clarke NW, et al. Survival with newly diagnosed metastatic prostate cancer in the “docetaxel era”: data from 917 patients in the control arm of the STAMPEDE trial (MRC PR08, CRUK/06/019). Eur Urol. 2015;67:1028-38.
16. Gandaglia G, Sun M, Trinh QD, et al. Survival benefit of definitive therapy in patients with clinically advanced prostate cancer: estimations of the number needed to treat based on competing-risks analysis. BJU Int. 2014;114:E62-E69.
17. Bastian PJ, Boorjian SA, Bossi A, et al. High-risk prostate cancer: from definition to contemporary management. Eur Urol. 2012;61:1096-106.
18. Touijer KA, Mazzola CR, Sjoberg DD, et al. Long-term outcomes of patients with lymph node metastasis treated with radical prostatectomy without adjuvant androgen-deprivation therapy. Eur Urol. 2014;65:20-5.
19. Bekelman JE, Mitra N, Handorf EA, et al. Effectiveness of androgen-deprivation therapy and radiotherapy for older men with locally advanced prostate cancer. J Clin Oncol. 2015;33:716-22.
20. Warde P, Mason M, Ding K, et al. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet. 2011;378:2104-11.
21. Widmark A, Klepp O, Solberg A, et al. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet. 2009;373:301-8.
22. Polychemotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1998;352:930-42.
23. Bristow RE, Tomacruz RS, Armstrong DK, et al. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol. 2002;20:1248-59.
24. Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001;345:1655-9.
25. Glehen O, Mohamed F, Gilly FN. Peritoneal carcinomatosis from digestive tract cancer: new management by cytoreductive surgery and intraperitoneal chemohyperthermia. Lancet Oncol. 2004;5:219-28.
26. Mickisch GH, Garin A, van Poppel H, et al. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001;358:966-70.
27. Nitta T, Sato K. Prognostic implications of the extent of surgical resection in patients with intracranial malignant gliomas. Cancer. 1995;75:2727-31.
28. Temple LK, Hsieh L, Wong WD, et al. Use of surgery among elderly patients with stage IV colorectal cancer. J Clin Oncol. 2004;22:3475-84.
29. Resel Folkersma L, San José Manso L, Galante Romo I, et al. Prognostic significance of circulating tumor cell count in patients with metastatic hormone-sensitive prostate cancer. Urology. 2012;80:1328-32.
30. Tzelepi V, Efstathiou E, Wen S, et al. Persistent, biologically meaningful prostate cancer after 1 year of androgen ablation and docetaxel treatment. J Clin Oncol. 2011;29:2574-81.
31. Thompson IM, Tangen C, Basler J, Crawford ED. Impact of previous local treatment for prostate cancer on subsequent metastatic disease. J Urol. 2002;168:1008-12.
32. Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J Urol. 2009;181:956-62.
33. James ND, Spears MR, Clarke NW, et al. Failure-free survival and radiotherapy in patients with newly diagnosed nonmetastatic prostate cancer: data from patients in the control arm of the STAMPEDE trial. JAMA Oncol. 2016;2:348-57.
34. Lin CC, Gray PJ, Jemal A, Efstathiou JA. Androgen deprivation with or without radiation therapy for clinically node-positive prostate cancer. J Natl Cancer Inst. 2015;107(7).
35. Rusthoven CG, Carlson JA, Waxweiler TV, et al. The impact of definitive local therapy for lymph node-positive prostate cancer: a population-based study. Int J Radiat Oncol Biol Phys. 2014;88:1064-73.
36. Tward JD, Kokeny KE, Shrieve DC. Radiation therapy for clinically node-positive prostate adenocarcinoma is correlated with improved overall and prostate cancer-specific survival. Pract Radiat Oncol. 2013;3:234-40.
37. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol. 1995;13:8-10.
38. Weichselbaum RR, Hellman S. Oligometastases revisited. Nat Rev Clin Oncol. 2011;8:378-82.
39. Evangelista L, Briganti A, Fanti S, et al. New clinical indications for (18)F/(11)C-choline, new tracers for positron emission tomography and a promising hybrid device for prostate cancer staging: a systematic review of the literature. Eur Urol. 2016;70:161-75.
40. Khoo V. Is there another bite of the cherry? The case for radical local therapy for oligometastatic disease in prostate cancer. Eur Urol. 2016;69:13-4.
41. Tosoian JJ, Gorin MA, Ross AE, et al. Oligometastatic prostate cancer: definitions, clinical outcomes, and treatment considerations. Nat Rev Urol. 2017;14:15-25.
42. Apolo AB, Lindenberg L, Shih JH, et al. Prospective study evaluating Na18F PET/CT in predicting clinical outcomes and survival in advanced prostate cancer. J Nucl Med. 2016;57:886-92.
43. Poulsen MH, Petersen H, Hoilund-Carlsen PF, et al. Spine metastases in prostate cancer: comparison of technetium-99m-MDP whole-body bone scintigraphy, [(18) F]choline positron emission tomography(PET)/computed tomography (CT) and [(18) F]NaF PET/CT. BJU Int. 2014;114:818-23.
44. Schirrmeister H, Guhlmann A, Elsner K, et al. Sensitivity in detecting osseous lesions depends on anatomic localization: planar bone scintigraphy versus 18F PET. J Nucl Med. 1999;40:1623-9.
45. Cho SY, Szabo Z. Molecular imaging of urogenital diseases. Semin Nucl Med. 2014;44:93-109.
46. van Leeuwen PJ, Stricker P, Hruby G, et al. (68) Ga-PSMA has a high detection rate of prostate cancer recurrence outside the prostatic fossa in patients being considered for salvage radiation treatment. BJU Int. 2016;117:732-9.
47. Maurer T, Eiber M, Schwaiger M, Gschwend JE. Current use of PSMA-PET in prostate cancer management. Nat Rev Urol. 2016;13:226-35.
48. Perera M, Papa N, Christidis D, et al. Sensitivity, specificity, and predictors of positive 68Ga-prostate-specific membrane antigen positron emission tomography in advanced prostate cancer: a systematic review and meta-analysis. Eur Urol. 2016;70:926-37.
49. O’Shaughnessy MJ, McBride SM, Vargas HA, et al. A pilot study of a multimodal treatment paradigm to accelerate drug evaluations in early-stage metastatic prostate cancer. Urology. 2017;102:164-72.
50. Woodhouse EC, Chuaqui RF, Liotta LA. General mechanisms of metastasis. Cancer. 1997;80:1529-37.
51. Kim MY, Oskarsson T, Acharyya S, et al. Tumor self-seeding by circulating cancer cells. Cell. 2009;139:1315-26.
52. Miyamoto DT, Sequist LV, Lee RJ. Circulating tumour cells—monitoring treatment response in prostate cancer. Nat Rev Clin Oncol. 2014;11:401-12.
53. Nguyen DX. Tracing the origins of metastasis. J Pathol. 2011;223:195-204.
54. Sceneay J, Smyth MJ, Möller A. The pre-metastatic niche: finding common ground. Cancer Metastasis Rev. 2013;32:449-64.
55. Taplin ME, Montgomery B, Logothetis CJ, et al. Intense androgen-deprivation therapy with abiraterone acetate plus leuprolide acetate in patients with localized high-risk prostate cancer: results of a randomized phase II neoadjuvant study. J Clin Oncol. 2014;32:3705-15.
56. Gupta GP, Massague J. Cancer metastasis: building a framework. Cell. 2006;127:679-95.
57. Kaplan RN, Rafii S, Lyden D. Preparing the “soil”: the premetastatic niche. Cancer Res. 2006;66:11089-93.
58. Campbell PJ, Yachida S, Mudie LJ, et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature. 2010;467:1109-13.
59. Gundem G, Van Loo P, Kremeyer B, et al. The evolutionary history of lethal metastatic prostate cancer. Nature. 2015;520:353-7.
60. Hong MK, Macintyre G, Wedge DC, et al. Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer. Nat Commun. 2015;6:6605.
61. Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010;467:1114-7.
62. Cifuentes FF, Valenzuela RH, Contreras HR, Castellon EA. Development of an orthotopic model of human metastatic prostate cancer in the NOD-SCIDgamma mouse (Mus musculus) anterior prostate. Oncol Lett. 2015;10:2142-8.
63. Cifuentes FF, Valenzuela RH, Contreras HR, Castellon EA. Surgical cytoreduction of the primary tumor reduces metastatic progression in a mouse model of prostate cancer. Oncol Rep. 2015;34:2837-44.
64. Kadmon D, Heston WD, Fair WR. Treatment of a metastatic prostate derived tumor with surgery and chemotherapy. J Urol. 1982;127:1238-42.
65. Schweizer MT, Zhou XC, Wang H, et al. Metastasis-free survival is associated with overall survival in men with PSA-recurrent prostate cancer treated with deferred androgen deprivation therapy. Ann Oncol. 2013;24:2881-6.
66. Ost P, Decaestecker K, Lambert B, et al. Prognostic factors influencing prostate cancer-specific survival in non-castrate patients with metastatic prostate cancer. Prostate. 2014;74:297-305.
67. Wiegand LR, Hernandez M, Pisters LL, Spiess PE. Surgical management of lymph-node-positive prostate cancer: improves symptomatic control. BJU Int. 2011;107:1238-42.
68. Won AC, Gurney H, Marx G, et al. Primary treatment of the prostate improves local palliation in men who ultimately develop castrate-resistant prostate cancer. BJU Int. 2013;112:E250-E255.
69. Ghavamian R, Bergstralh EJ, Blute M, et al. Radical retropubic prostatectomy plus orchiectomy versus orchiectomy alone for pTxN+ prostate cancer: a matched comparison. J Urol. 1999;161:1223-7.
70. Steuber T, Budaus L, Walz J, et al. Radical prostatectomy improves progression-free and cancer-specific survival in men with lymph node positive prostate cancer in the prostate-specific antigen era: a confirmatory study. BJU Int. 2011;107:1755-61.
71. Messing EM, Manola J, Yao J, et al. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol. 2006;7:472-9.
72. Schroder FH, Kurth KH, Fossa SD, et al. Early versus delayed endocrine treatment of pN1-3 M0 prostate cancer without local treatment of the primary tumor: results of European Organisation for the Research and Treatment of Cancer 30846—a phase III study. J Urol. 2004;172:923-7.
73. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-22.
74. 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.
75. Antwi S, Everson TM. Prognostic impact of definitive local therapy of the primary tumor in men with metastatic prostate cancer at diagnosis: a population-based, propensity score analysis. Cancer Epidemiol. 2014;38:435-41.
76. Fossati N, Trinh QD, Sammon J, et al. Identifying optimal candidates for local treatment of the primary tumor among patients diagnosed with metastatic prostate cancer: a SEER-based study. Eur Urol. 2015;67:3-6.
77. Leyh-Bannurah SR, Gazdovich S, Budaus L, et al. Local therapy improves survival in metastatic prostate cancer. Eur Urol. 2017;72:118-24.
78. Heidenreich A, Pfister D, Porres D. Cytoreductive radical prostatectomy in patients with prostate cancer and low volume skeletal metastases: results of a feasibility and case-control study. J Urol. 2015;193:832-8.
79. Gandaglia G, Fossati N, Stabile A, et al. Radical prostatectomy in men with oligometastatic prostate cancer: results of a single-institution series with long-term follow-up. Eur Urol. 2017;72:289-92.
80. Sooriakumaran P, Karnes J, Stief C, et al. A multi-institutional analysis of perioperative outcomes in 106 men who underwent radical prostatectomy for distant metastatic prostate cancer at presentation. Eur Urol. 2016;69:788-94.
81. Tabata K, Niibe Y, Satoh T, et al. Radiotherapy for oligometastases and oligo-recurrence of bone in prostate cancer. Pulm Med. 2012;2012:541656.
82. Ahmed KA, Barney BM, Davis BJ, et al. Stereotactic body radiation therapy in the treatment of oligometastatic prostate cancer. Front Oncol. 2013;2:215.
83. Berkovic P, De Meerleer G, Delrue L, et al. Salvage stereotactic body radiotherapy for patients with limited prostate cancer metastases: deferring androgen deprivation therapy. Clin Genitourin Cancer. 2013;11:27-32.
84. Schick U, Jorcano S, Nouet P, et al. Androgen deprivation and high-dose radiotherapy for oligometastatic prostate cancer patients with less than five regional and/or distant metastases. Acta Oncol. 2013;52:1622-8.
85. Decaestecker K, De Meerleer G, Lambert B, et al. Repeated stereotactic body radiotherapy for oligometastatic prostate cancer recurrence. Radiat Oncol. 2014;9:135.