Consensus on the Treatment and Follow-Up for the Nonmetastatic Castration-Resistant Prostate Cancer: A Report From the First Prostate Cancer Consensus Conference for Developing Countries

Abstract

PURPOSE

To present a summary of the recommendations for the treatment and follow-up for the biochemical recurrence of castration-resistant prostate cancer (PCa) as acquired through a questionnaire administered at the Prostate Cancer Consensus Conference for Developing Countries.

METHODS

A total of 27 questions were identified as relating to this topic. Responses from the clinician were tallied and are presented in percentage format. Topics included the use of imaging in staging, treatment recommendations across different patient scenarios of life expectancy and prostate-specific antigen (PSA) doubling time, and follow-up for nonmetastatic castration-resistant PCa.

RESULTS

A consensus agreed that in optimal conditions, positron emission tomography-computed tomography with prostate-specific membrane antigen would be used although in limited resource situations the combined use of CT of the abdomen and pelvic (or pelvic MRI), a bone scan, and a CT of the thorax or chest x-ray was recommended. In cases when PSA levels double in < 10 months, more than 90% of clinicians agreed on the use of apalutamide or enzalutamide, regardless of life expectancy. With a doubling time of more than 10 months, > 54% of experts recommended no treatment independent of life expectancy. More than half of the experts, regardless of resources, recommended follow-up with a physical examination and PSA levels every 3-6 months and imaging only in the case of symptoms.

CONCLUSION

The voting results and recommendations presented in this document can be used by physicians to support management for biochemical recurrence of castration-resistant PCa in areas of limited resources. Individual clinical decision making should be supported by available data.

INTRODUCTION

Fifteen percent of all men worldwide will be diagnosed with prostate cancer (PCa). Although it is the second most common cancer for men,¹ only around 3% will die from the disease and those that do often after the age of 75.² As such, there are varying degrees of risk for the disease and several factors that are considered in determining the lifetime therapy of patients. Many cases of PCa are curative; however, approximately 30%-40% of men will develop a rise in serum prostate-specific antigen (PSA) after treatment with definitive local therapies. This phenomenon is defined as a biochemical recurrence of the disease,^3,4 and even when there are no signs or symptoms of a locally recurrent or metastatic disease, it does signify a return of the cancer, but it should be noted that it does not necessarily correlate with or affect overall survival (OS).⁵

CONTEXT

• Key Objective

• The treatment of prostate cancer (PCa) is challenging in low- and middle-income countries. Limited access to several treatments is one of the mainstay problems.

• The Prostate Cancer Consensus Conference for Developing Countries was the first global effort to help physicians in these countries to guide treatment decisions with limited resources.

• Knowledge Generated

• Effective therapies for patients with nonmetastatic castration-resistant PCa were lacking until recently. New hormonal therapies (abiraterone, apalutamide, and darolutamide) changed this scenario improving survival. Molecular images for nonmetastatic castration-resistant PCa did not show the same good results as in biochemical recurrence.

• Relevance

• This article provides recommendations to manage nonmetastatic castration-resistant PCa in countries with limited resources.

Clinicians are challenged to prevent or delay the onset of metastatic disease and the resulting increased morbidity and mortality while needing to consider the negative impact on patients' quality of life and avoid overtreating PCa that is at low risk of clinical progression. When PSA levels rise following local treatment, the role of early salvage androgen deprivation therapy (ADT) is still debated^6,7; however, if salvage androgen deprivation therapy is used in men with biochemical relapse, the disease nearly always re-emerges despite castrate levels of testosterone, resulting in the biological transformation to what is known as castration-resistant prostate cancer, metastatic or nonmetastatic (CRPC).⁸ As PCa incidence and burden of disease steadily increase globally,⁹ healthcare systems especially in regions of limited resources will struggle with its management when balancing the benefits of recent advances and their cost-effectiveness for the overall healthcare system.⁹ This article summarizes the recommendations of a large panel of physicians working with PCa in developing countries for their recommended treatment and follow-up of patients presenting with nonmetastatic castration-resistant prostate cancer (nmCRPC)—with and without the consideration of limited resources to provide guidance in clinical practice and in the development of nmCRPC treatment policies.

Staging

The use of positron emission tomography-computed tomography (PET-CT) with prostate-specific membrane antigen (PSMA) imaging in patients with nmCRPC (PSA 2 ng/mL and doubling time < 10 months and/or Gleason 8 or higher) using regular images showed that 98% of these patients have spread of disease.¹⁰ Despite that the treatment strategies in nmCRPC are based on studies that used regular images, the use of PET-CT with PSMA is not compulsory in a context of limited resources.

Treatment Recommendations

In patients with nmCRPC with a rising PSA level after primary curative treatment, indicating a nonmetastatic recurrence of the disease, PSA doubling time was the stratifying factor in treatment recommendations. Short PSA doubling time showed to be prognostic in patients with nmCRPC.^11,12

Questions were posed to the panel of experts who examined scenarios with the above profile in patients with a life expectancy of more than 10-15 years and < 10-15 years, with PSA doubling time >10 months and < 10 months (Data Supplement). These results are presented in Table 1. A clear consensus was reached for patients with PSA doubling time < 10 months to use apalutamide or enzalutamide, regardless of life expectancy (for > 10-15 years 91% and for < 10-15 years 92% recommend to start either). Without access to apalutamide or enzalutamide, life expectancy played a role in treatment recommendations with 53% recommending those with > 10-15 years of life expectancy alternative treatment bicalutamide or flutamide and 33% not pursuing treatment, whereas in those with less life expectancy (< 10-15 years), almost 60% did not seek additional treatment and only 38% recommended bicalutamide or flutamide.

TABLE 1.

Treatment Recommendations for Nonmetastatic Castration-Resistant Prostate Cancer

In patients with a PSA doubling time > 10 months, treatment recommendations were seen across life expectancy although with the same trends of a greater proportion of clinicians choosing not to treat. Apalutamide or enzalutamide was only recommended by approximately 25% of the clinicians with 54% (> 10-15 years) and 66% (< 10-15 years) choosing not to treat. In limited resource settings, without the option of apalutamide or enzalutamide, the percentage of clinicians choosing not to treat rose to 70% and 81%, respectively.

The follow-up of nmCRPC was supported by more than half of the panel (56%) with primarily a physical examination and PSA measurement every 3-6 months and imaging in the case of symptoms, and 78.4% would implement in areas with limited resources. Only 30% of clinicians suggested a CT or chest x-ray of thorax, CT of the abdomen and pelvis, and bone scan every 3-6 months, and the percentage decreased to 16% for areas of limited resources. Particularly in areas of limited resources, the panelists favored a more conservative follow-up strategy to avoid an unnecessary increase in costs without a clear benefit in terms of OS.

DISCUSSION

The impact of nonmetastatic recurrence on PCa-specific mortality or OS is not clear. Rising PSA levels correlate with metastasis and PCa mortality but can predate local recurrence or metastasis by typically 7-8 years on average.^13,14 CRPC has an added layer of difficulty in treatment as these patients no longer respond to ADT or hormonal therapy. In high-risk cases where PSA levels are doubling in < 10 months, there is clear consensus by clinicians indicating treatment with apalutamide or enzalutamide; however, without access to these innovative treatments, the clinician's recommendations to not treat increased, especially in those with less life expectancy. By the time the questionnaire of this consensus was concluded, darolutamide had not yet been approved in this context.¹⁵ In lower risk cases, the decision to not further treat these patients was held by more than 50% of the clinicians participating in the questionnaire independent of limitation of resources—balancing the difficulty of treatment of these patients with the possibility for benefit for the patient. These cases must also consider the challenges for clinicians in developing countries where healthcare systems have cost containment pressures, limited or delayed access to specialists, and access barriers.

These recommendations are in concordance with the results of the trials in the nmCRPC. There is good evidence of benefit in terms of metastasis-free survival and PSA response. It is important to note that metastasis-free survival in the nmCRPC scenario is not an OS surrogate end point. These end points seem to be important to avoid symptoms and patient anxiety, respectively. The absence of OS benefit published until the date of this consensus, no major impact in quality of life, and the increase of costs are very concerning points, mainly in areas of limited resources. After the consensus, recent data showed OS benefits of new androgen blockers in nmCRPC scenario that can lead to a new discussion about cost-effectiveness of this strategy in limited resources countries.¹⁶

AUTHOR CONTRIBUTIONS

Conception and design: Felipe Moraes Toledo Pereira, Ariel Galapo Kann, Denis Leonardo Fontes Jardim, Diego Lopera, Mouna Ayadi, Sandro Roberto De Araujo Cavallero, Sergio Aguiar, Vinicius Carrera Souza, Andrey Soares

Administrative support: Andrey Soares

Provision of study materials or patients: Aldo Lourenço Abbade Dettino, Andre Deeke Sasse, Carlos Dzik, Diego Lopera, Ray Antonio Manneh Kopp

Collection and assembly of data: Felipe Moraes Toledo Pereira, Adriano Gonçalves e Silva, Aldo Lourenço Abbade Dettino, Ana Paula Garcia Cardoso, Ariel Galapo Kann, Carlos Dzik, Daniel Herchenhorn, Diego Lopera, Pamela Salman, Ray Antonio Manneh Kopp, Sandro Roberto De Araujo Cavallero, Vinicius Carrera Souza, Pedro Luiz Serrano Uson Junior, Andrey Soares

Data analysis and interpretation: Felipe Moraes Toledo Pereira, Aldo Lourenço Abbade Dettino, Ana Paula Garcia Cardoso, Andre Deeke Sasse, Ariel Galapo Kann, Diego Lopera, Pamela Salman, Ray Antonio Manneh Kopp, Ricardo Saraiva De Carvalho, Sandro Roberto De Araujo Cavallero, Vinicius Carrera Souza, Pedro Luiz Serrano Uson Junior, Andrey Soares

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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