“Hit the primary”: A paradigm shift in the treatment of metastatic prostate cancer?

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Highlights

  • We focused on the irradiation of primary tumor in metastatic prostate cancer.

  • We analyzed preclinical data underlining the intrinsic capability of radiation therapy to act as a more general immune response modifier data.

  • We reported on clinical data mainly from retrospective surgical series, which consistently show survival benefits in metastatic prostate cancer patients following definitive therapy to the prostate.

  • We concluded that the potential and beneficial impact of local treatment of the primary tumor in metastatic prostate cancer patients is supported by a strong rationale, but requires further validation in future studies.

Abstract

Patients with metastatic prostate cancer (PC) represent a heterogeneous group with survival rates varying between 13 and 75 months. The current standard treatment in this setting is hormonal therapy, with or without docetaxel-based chemotherapy. In the era of individualized medicine, however, maximizing treatment options, especially in long-term surviving patients with limited disease burden, is of capital importance. Emerging data, mainly from retrospective surgical series, show survival benefits in men diagnosed with metastatic PC following definitive therapy for the prostate. Whether the irradiation of primary tumor in a metastatic disease might improve the therapeutic ratio in association with systemic treatments remains investigational. In this scenario, modern radiation therapy (RT) can play a significant role owing to its intrinsic capability to act as a more general immune response modifier, as well as to the potentially better toxicity profile compared to surgery. Preclinical data, clinical experience, and challenges in local treatment in de novo metastatic PC are reviewed and discussed.

Introduction

Local control of the primary tumor in the presence of metastatic disease has been associated with improved outcome in several malignancies (Flanigan et al., 2001, Mickisch et al., 2001, Temple et al., 2004). Metastatic renal cell carcinoma could be considered a paradigm in this field: indeed, two phase III trials clearly demonstrated better overall survival (OS) rates in patients treated with radical nephrectomy and interferon-alpha compared to patients receiving systemic treatment alone (Flanigan et al., 2001, Mickisch et al., 2001).

In prostate cancer (PC), evidence from three large prospective randomized phase III trials suggest that, in patients with locally advanced tumors at high risk of occult micrometastatic disease, adding radiotherapy (RT) to androgen deprivation therapy (ADT) significantly improves 10-year outcome (D’Angelillo et al., 2015, Mottet et al., 2012, Warde et al., 2011, Widmark et al., 2009). Reduction in the cancer-specific and overall mortality rates (Warde et al., 2011, Widmark et al., 2009), as well as improvements in loco-regional control and distant metastases-free progression (Mottet et al., 2012), were observed in the combined modality, starting to emerge early, 3 years after randomization.

On the other hand, in multi-metastatic PC patients (T1-4, N0-1, M1) the role of local control of the primary remains unclear, with ADT using LHRH analogues/antagonists, with or without docetaxel, representing the treatment of choice as recommended by current guidelines (Heidenreich et al., 2014). Although the scientific evidence supporting ADT in metastatic PC patients remains weak, in the case of proven metastatic disease, ADT is considered the up-front standard treatment (Heidenreich et al., 2014). ADT is not curative, but might frequently provide rapid relief of symptoms and a good rate of “temporary” biochemical control.

While the role of local RT as palliative treatment for bleeding or obstruction is well described, the benefit of associating RT to ADT as first-line treatment to improve the therapeutic ratio in metastatic PC patients remains investigational. Such an approach seems to be supported by compelling evidences indicating that patients with a limited number of PC metastases, thus entering the so-called oligometastatic state — an intermediate state of tumor spread with limited metastatic capacity (Weichselbaum and Hellman, 2011) — have a better prognosis compared with those with extensive metastatic disease (Schweizer et al., 2013, Ost et al., 2014).

The aim of the present critical review is to report and discuss available data on the role of prostate irradiation in de novo hormone-naïve metastatic PC patients. Due to the paucity and heterogeneity of data published in the recent literature, our review was not conducted according to a properly performed systematic protocol, but rather represents an overview of the body of knowledge on this topic.

Section snippets

Preclinical data

The challenging issue of local irradiation in metastatic PC is whether the natural history of disease progression might be positively influenced, once metastases have developed, by reclaiming the organ of tumor origin.

An answer comes from the experimental demonstration of a process called ‘tumor self-seeding’ (Kim et al., 2009), during which circulating tumor cells (CTCs) — usually seeding distant organs — have the potential to reinfiltrate an established tumor at the primary site. Under these

Clinical data

Mechanisms underlying the benefit of definitive treatments of the primary in metastatic PC patients are not fully understood. Improvement in the local control and reduction in the need of palliative treatment, removal of a tumor with persistent capability to produce future metastases as well as improved response to ADT might constitute the rationale for definitive treatment of the primary tumor (Ost et al., 2014). As observed by Tzelepi et al. (2011), a persistent network of molecular pathways

Treatment options

Despite the inherent biases due to their retrospective nature of many of the studies acknowledged in the previous paragraph, which lay the groundwork for a role of definitive treatment of the primary tumor in the context of metastatic PC, a confirmation in a prospective fashion is warranted. The choice of local therapy, either RP or RT, in this setting remains challenging.

Potential benefits of RP consist in the removal of the malignant prostate, thus avoiding the complications of local tumor

Ongoing trials

Despite the promising results of retrospective and cohort studies published so far, the real benefit of definitive local treatment in de novo metastatic PC remains unknown at this writing. Hopefully, many open questions concerning the potential role of local RT in the management of these patients will be probably answered in the coming years by three phase III trials.

Results obtained through a phase II ongoing multidisciplinary clinical trial intended to assess the role of systemic therapy

Conclusions

The potential and beneficial impact of local treatment of the primary tumor in men with de novo metastatic PC is supported by a strong rationale, but requires further validation in future studies. In this emerging scenario, modern RT can play a significant role owing to its intrinsic capability to act as a more general immune response modifier, as well as to the potentially better toxicity profile compared to the surgery. Accurate selection of the optimal candidates is mandatory in maximizing

Conflicts of interest

All authors declare no financial and personal relationships with other people or organisations that could inappropriately influence their work.

Stefano Arcangeli, Radiation Oncologist and Clinical Researcher. He has published more than 50 articles (indexed/peer-reviewed journals) and several book chapters. Main topics of his activity are: radiation oncology and prostate cancer, SBRT. Peer-Reviewer for: Reports of Practical Oncology and Radiotherapy, Radiotherapy Oncology, Tumori and Editorial Board Member of the World Journal of Radiology. He’s an ESTRO (European Society of Radiation Oncology) and AIRO (Italian Society of Radiation

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  • Cited by (0)

    Stefano Arcangeli, Radiation Oncologist and Clinical Researcher. He has published more than 50 articles (indexed/peer-reviewed journals) and several book chapters. Main topics of his activity are: radiation oncology and prostate cancer, SBRT. Peer-Reviewer for: Reports of Practical Oncology and Radiotherapy, Radiotherapy Oncology, Tumori and Editorial Board Member of the World Journal of Radiology. He’s an ESTRO (European Society of Radiation Oncology) and AIRO (Italian Society of Radiation Oncology) member. His h-index is 15.

    Thomas Zilli, Radiation Oncologist and Senior Clinical Associate at the University Hospital of Geneva (Switzerland). He is author of more than 30 publications in the major indexed/peer-reviewed journals. Main topics of his activity are: GU and GI cancers, molecular imaging applied to Radiation Oncology and modern techniques of RT delivery. He is an ESTRO (European Society of Radiation Oncology) and EORTC (European Organisation for Research and Treatment of Cancer) member.

    Berardino De Bari, Radiation Oncologist and clinical investigator. He published more than 50 articles (indexed/Peer reviewed Journals), one book chapter and more than 100 abstracts presented as oral presentations or posters at national and international scientific congress. Main topics of his activity are: prostate cancer, GI cancer, imaging in radiotherapy and IGRT. He is an ESTRO (European Society of Radiation Oncology) fellow and a coordinator of the ESTRO contouring workshops in the context of the FALCON Project, including prostate cancer. He speaks regularly at international conferences and teaching events. He has been member of the board of the AIRO prostate working group. His h-index is 10.

    Filippo Alongi, Radiation Oncologist and clinical investigator. He is chief of the Radiotherapy department in the Hospital of Negrar-Verona. He published more than 60 articles (indexed/Peer reviewed Journals), 3 book chapters and more than 150 abstracts presented as oral presentations or posters at national and international scientific congress. His main topics of activity are: SBRT, hypofractionation, IGRT, molecular imaging in Radiation Oncology, prostate cancer. Since 2012, he is the national coordinator of the young group of AIRO (Italian society of Radiation Oncology) and he is on the board of AIRO prostate working group. He is member of the Editorial board of “Tumori” and “Technology in Cancer Research and Treatment”. His h-index is 17.

    1

    These authors contributed equally as last co-authors.

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