Prostate Cancer's Hidden Risk: What Is Biochemical Recurrence?

Prostate cancer, with approximately 19 thousand new diagnoses each year in Turkey, is the second most common cancer in men after lung cancer. It requires careful management because of the challenges encountered in diagnosis and treatment. This article explains a complication that occurs after treatment for early-stage prostate cancer and can often be overlooked: biochemical recurrence .

We will examine what biochemical recurrence is, how it develops, and how it affects treatment approaches.

Understanding Biochemical Recurrence

At the time prostate cancer is diagnosed, approximately 10% of patients have metastasis, meaning the cancer has spread to other organs; this cancer is most often detected at an early stage. Both prostate cancer cells and normal prostate tissue cells grow under the influence of male hormones such as testosterone. Patients with prostate cancer generally benefit greatly from treatments that suppress male hormones, a process usually termed castration in oncology. However, they may develop resistance to hormonal therapy about a year after starting treatment, requiring treatment strategies to be reassessed.

Prostate cancer generally develops over a long period and mostly affects older men. It causes many deaths, but each patient's situation differs, and a substantial proportion of patients with prostate cancer die from other causes. Consequently, prostate cancer metastases do not pose a major health problem or cause death in some patients.

This raises concerns that prostate cancer treatment, by intervening in the natural course of the cancer, could harm a group of patients whose disease might otherwise follow an indolent course (see Is Gleason 6 Prostate Cancer, and Should It Be Treated?).

In particular, biochemical recurrences indicating that prostate cancer has become active again may signal the severity and progression of the disease. Some doctors therefore try to prevent cancer progression with androgen-deprivation therapy (ADT) or next-generation androgen receptor blockers. However, obtaining clear, strong evidence that this treatment approach prolongs survival is challenging.

How Is Biochemical Recurrence Diagnosed?

Prostate-specific antigen (PSA) levels are the most important biomarker used to monitor prostate cancer. PSA levels are expected to fall to zero after treatment. However, an unexpected rise in PSA is regarded as a sign that the cancer has become active again. Diagnosing biochemical recurrence generally requires PSA to exceed a specified value.

PSA Dynamics: The rate and pattern of changes in PSA levels also matter. For example, the time it takes PSA to double (PSA doubling time), or its rate of increase over a given period, may indicate renewed cancer activity.

Prostate cancer's complex nature is an important factor that complicates treatment. Because biologically grounded predictive biomarkers are lacking, most treatments are based on clinical and pathological characteristics such as PSA doubling time. Even within these groupings, however, cancer remains highly diverse, which can affect its course and response to treatment. This underscores the need for personalized prostate cancer treatment.

Can Biochemical Recurrence Be Treated?

The following treatments have been approved by the FDA (US Food and Drug Administration) for cases with biochemical recurrence that have not yet metastasized:

These approvals represent an important step in prostate cancer treatment and broaden patients' treatment options.

On the Results of the EMBARK Study

With results published in October 2023 in NEJM, the EMBARK trial by Freedland and colleagues offers an innovative approach to the challenges of treating prostate cancer. The study selected men whose PSA values doubled within 9 months or less and who had biochemical recurrence. It also used a risk-adapted strategy intended to reduce treatment for men with androgen-sensitive tumors and identify patients requiring more aggressive therapy. This approach stands out as a method to consider in prostate cancer treatment until robust biomarkers are developed.

A second challenge associated with ADT is its potential adverse effects. ADT can cause cardiometabolic syndrome and loss of bone mineralization, which may adversely affect quality of life. In some cases, these adverse effects may shorten patients' lives. This highlights the need to carefully weigh ADT's benefits and risks.

In the EMBARK trial, 14% of patients experienced bone fractures during a median follow-up of 5 years. This was close to the proportion in whom metastases were detected (12%). Comparing the number of patients who reached the metastasis-free survival endpoint with the number who developed distant metastases also shows that 30% of deaths were due to other causes. Comparing deaths from disease progression with total deaths shows that 60% of deaths were not attributable to prostate cancer. Although the contribution of cancer treatments to deaths is uncertain, the frequency of these deaths calls the potential benefits of treatment into question.

The EMBARK trial results show that, in some men with biochemical recurrence, systemic treatment for early cancer control has benefits that outweigh its risks . These findings also confirm that androgen receptor blockers enhance ADT's efficacy in men with advanced prostate cancer.

The Role of PSMA-PET

Developing more effective drugs with fewer adverse effects is important for better predicting the risk of death from prostate cancer and the effects of treatment. In this context, detecting prostate-specific membrane antigen expression using positron emission tomography (a PSMA-PET scan) stands out as a promising development.

The usefulness of PSMA-PET in these patients has not yet been proven. This may carry a risk of overtreatment, particularly in men with biochemical recurrence. It is also important to develop objective measures, such as sarcopenia (muscle loss), and validate them prospectively to better assess frailty, comorbidities, and overall health. This could identify patients in poorer general condition and reduce treatment-related adverse effects. Supportive measures such as exercise programs and cardiovascular risk management also need to be integrated into the treatment plan.

Defining Benefit

One of the greatest obstacles in prostate cancer treatment is defining benefit. Long follow-up and continually evolving treatment approaches make prostate cancer–specific survival less useful as an endpoint. Metastasis-free survival is also complicated by the proportion of deaths unrelated to prostate cancer and by sensitive imaging methods. Early, intermittent treatment may reduce the duration of lifelong therapy, especially in patients with detected metastases, affecting total treatment duration and overall quality of life.

Patient-reported symptoms and complaints provide important information in prostate cancer treatment. However, it remains uncertain whether these measures fully reflect patients' experiences and which differences are clinically meaningful. Ultimately, the fact that there is "more to prostate cancer treatment than survival" illustrates its complexity and highlights why a single measure is insufficient. Treatment strategies must therefore be evaluated according to each individual patient's needs and the balance of risks and benefits.