Optimal Treatment Sequence for Metastatic Castration-resistant Prostate Cancer

BackgroundProstate cancer (PCa) accounts for 20% of all cancers in subjects over 50 years in Italy. The majority of patients with PCa present with localized disease at the time of diagnosis, but many patients develop recurrent metastatic disease after treatment with curative intent. Androgen deprivation therapy is the standard of care for metastatic PCa patients; unfortunately, most of them progress to castrate-resistant prostate cancer (CRPC) within 5 years. Metastatic CRPC (mCRPC) heavily affects patients in terms of quality of life, side effects, and survival, and greatly impacts economic costs. The approval of new effective agents in recent years, including cabazitaxel, abiraterone acetate, enzalutamide, and radium-223, has dramatically changed patient management.Materials and methodsHere, we aimed to estimate the current costs of illness of mCRPC in Italy. All patients affected by mCRPC and treated with a single agent in an annual time horizon were considered. Therefore, the analysis was not focused on the management pathway of single patients through different lines of treatment. Direct medical costs referred to therapy, adverse event management, and skeletal-related event management were analyzed. A bottom-up approach was used to estimate the resource consumption: through national guidelines and expert opinions, the mean cost per patient was estimated and then multiplied by the total number of patients diagnosed with mCRPC.ResultsDirect medical costs ranged from €196.5 million to €228.0 million, representing ~0.2% of the financing of the Italian National Health Service in 2016. The main cost driver was the cost of treatment, which represented more than 77% of the overall economic burden.ConclusionOur analysis, reflective of real clinical practice, shows for the first time the high economic cost of mCRPC in Italy.

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“…Nonetheless, despite the numerous treatment options, there are limited data on appropriate sequencing of available drugs. 9 …”

Section: Introductionmentioning

confidence: 99%

Economic burden of the management of metastatic castrate-resistant prostate cancer in Italy: a cost of illness study

Restelli

Ceresoli

Croce

et al. 2017

CMAR

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“…This reduces bone pain and temporarily retards metastatic growth, but, after some time, the disease relapses to castration-resistant prostate cancer (CRPC). New treatments for CRPC have become available in the clinic, including more efficient blockage of androgen synthesis and androgen receptor (AR) signaling, novel chemotherapies, immunotherapies, and bone-targeting treatments that all temporarily retard disease progression, although with different efficiency in different patients [ 2 ]. Recent studies have suggested the existence of molecularly diverse subtypes of prostate cancer [ 3 , 4 ] and our own studies have shown similar molecular diversities among bone metastases [ 5 , 6 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Bone Cell Activity in Clinical Prostate Cancer Bone Metastasis and Its Inverse Relation to Tumor Cell Androgen Receptor Activity

Nordstrand

Ylitalo

Thysell

et al. 2018

IJMS

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Advanced prostate cancer frequently metastasizes to bone and induces a mixed osteoblastic/osteolytic bone response. Standard treatment for metastatic prostate cancer is androgen-deprivation therapy (ADT) that also affects bone biology. Treatment options for patients relapsing after ADT are limited, particularly in cases where castration-resistance does not depend on androgen receptor (AR) activity. Patients with non-AR driven metastases may, however, benefit from therapies targeting the tumor microenvironment. Therefore, the current study specifically investigated bone cell activity in clinical bone metastases in relation to tumor cell AR activity, in order to gain novel insight into biological heterogeneities of possible importance for patient stratification into bone-targeting therapies. Metastasis tissue obtained from treatment-naïve (n = 11) and castration-resistant (n = 28) patients was characterized using whole-genome expression analysis followed by multivariate modeling, functional enrichment analysis, and histological evaluation. Bone cell activity was analyzed by measuring expression levels of predefined marker genes representing osteoclasts (ACP5, CTSK, MMP9), osteoblasts (ALPL, BGLAP, RUNX2) and osteocytes (SOST). Principal component analysis indicated a positive correlation between osteoblast and osteoclast activity and a high variability in bone cell activity between different metastases. Immunohistochemistry verified a positive correlation between runt-related transcription factor 2 (RUNX2) positive osteoblasts and tartrate-resistant acid phosphatase (TRAP, encoded by ACP5) positive osteoclasts lining the metastatic bone surface. No difference in bone cell activity was seen between treatment-naïve and castration-resistant patients. Importantly, bone cell activity was inversely correlated to tumor cell AR activity (measured as AR, FOXA1, HOXB13, KLK2, KLK3, NKX3-1, STEAP2, and TMPRSS2 expression) and to patient serum prostate-specific antigen (PSA) levels. Functional enrichment analysis indicated high bone morphogenetic protein (BMP) signaling in metastases with high bone cell activity and low tumor cell AR activity. This was confirmed by BMP4 immunoreactivity in tumor cells of metastases with ongoing bone formation, as determined by histological evaluation of van Gieson-stained sections. In conclusion, the inverse relation observed between bone cell activity and tumor cell AR activity in prostate cancer bone metastasis may be of importance for patient response to AR and/or bone targeting therapies, but needs to be evaluated in clinical settings in relation to serum markers for bone remodeling, radiography and patient response to therapy. The importance of BMP signaling in the development of sclerotic metastasis lesions deserves further exploration.

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“…4 Men with localized or metastatic high-risk disease will typically be treated with RT with or without hormonal therapy, while patients with recurrent or metastatic, castratesensitive or -resistant disease can be offered chemotherapy. [5][6][7][8] The potential of targeted therapies based on leveraging of the patient's immune system to treat the cancer is currently being actively evaluated. 9,10 Most of the aforementioned nonsurgical treatments can have marked effects on the histological appearance of tumor and non-tumor prostate tissue, which have been well described.…”

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confidence: 99%

Treatment effects in prostate cancer

Evans

2018

Modern Pathology

120

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Nonsurgical treatments for prostate cancer include androgen-deprivation therapy (ADT), radiation therapy (RT), ablative therapies, chemotherapy, and newly emerging immunotherapies. These approaches can be used alone or in combination depending on the clinical scenario. ADT is typically reserved for high-risk locally or systemically advanced disease that is not amenable to curative surgery. Radiation therapy can be used instead of surgery as primary therapy with curative intent for low-intermediate-risk disease as well as for control of locally advanced disease not suitable for surgery. Ablative therapies can be used as primary therapy for low-intermediate-risk disease or as salvage therapy for clinically localized disease where RT has failed. Chemotherapy and immune-based therapies are currently used for androgen-independent disease, although the indications for these approaches may well change as new data from clinical trials accrue. Pathologists should be able to recognize tissue changes associated with these treatments to provide information that will optimize patient management. This is particularly true in situations where clinical history of recent or remote nonsurgical treatment is not provided with the specimen. In the absence of this information, pathologists encountering the features described herein are encouraged to review patient records or communicate directly with clinical colleagues to determine how a given patient was treated and when.

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Optimal Treatment Sequence for Metastatic Castration-resistant Prostate Cancer

Cited by 43 publications

References 60 publications

Economic burden of the management of metastatic castrate-resistant prostate cancer in Italy: a cost of illness study

Economic burden of the management of metastatic castrate-resistant prostate cancer in Italy: a cost of illness study

Bone Cell Activity in Clinical Prostate Cancer Bone Metastasis and Its Inverse Relation to Tumor Cell Androgen Receptor Activity

Treatment effects in prostate cancer

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