Prostate cancer is the second most common cancer in men globally, with an annual incidence of over 1 million (Bray et al., 2018). Its associated mortality accounts for approximately 3.8% of all cancer deaths in men (Bray et al., 2018).
In most cases, prostate cancer recurrence serves as the primary driver of mortality. This link relates to the clinical features of recurrence, including an increased risk of incurable metastasis and reduced therapeutic options.
Radical treatment can be curative for localized prostate cancer, but some patients present with more advanced diseases and a significant proportion of those who die from it.
The introduction of salvage therapies such as hormone therapy, radiation therapy, surgery, and chemotherapy in such situations can improve clinical outcomes (Miura and Horie, 2019; Pezaro et al., 2014). However, resistance and inadequacy of predictive biomarkers highlight the need for novel therapeutic approaches for recurrent prostate cancers.
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What Is Prostate Cancer Recurrence?
Prostate cancer recurrence is the return of cancer after treatment and a period when no cancer activity could be detected. Local therapies with radical prostatectomy or radiation therapy are the two main ways to eliminate localized prostate cancer.
Both options are definitive treatments because they can cure prostate cancer altogether. However, local treatments are ineffective if cancer has spread outside the prostate gland. Here, other types of treatment (systemic chemotherapy) are needed to target cancer cells located in other parts of the body.
Cancer cells remain after curative treatments because of positive surgical margins or metastasis if the disease is more advanced than initially thought. Prostate cancer cells can start to grow again from these sites.
Treatment relapse increases the possibility of developing advanced incurable disease that needs complex treatment decisions to manage. However, current clinical methods for treating recurred prostate cancer can result in both over-treatment and under-treatment due to a lack of adequate biomarkers to predict response.
How Common Is Recurrence of Prostate Cancer?
Early diagnosis and treatment can cure localized prostate cancer, and most men will remain free of cancer for many years, potentially the rest of their life. Despite these favorable statistics and improvements in the available local therapies, up to 40% of men treated for prostate cancer will experience a recurrence.
Since the majority of these patients are already elderly, they are more likely to die from causes other than prostate cancer. This age-dependent effect reduces the need for immediate clinical intervention following recurrence.
It is noteworthy that more than 90% of prostate cancer cases present while the cancer is either localized in the prostate gland or has spread to areas around the gland (local spread).
Therefore, these men can expect to live at least five years after diagnosis, which is a much better outcome than other cancers. Among the 10% with advanced disease, about 30% can expect to reach the five-year survival mark.
How Is a Recurrence Detected?
After local treatment for prostate cancer, patients usually undergo routine blood tests to measure the levels of specific biomarkers in their blood. One such biomarker is the prostate-specific antigen (PSA) used for both diagnosis and prognosis.
PSA defined biochemical recurrence is the primary method for reporting the outcome of definitive prostate cancer treatments. PSA levels in the blood are an indicator of cancer activity that decreases after treatment but increases during local or distant recurrence.
When PSA levels suggest that prostate cancer has come back or continues to grow, imaging-based tests are performed to detect and localize any recurrent cancer. The following imaging techniques are commonly utilized for this task:
- Bone scan – identify the involvement of the bones, typical site of prostate cancer metastasis.
- Computed tomography (CT-scan) produces cross-sectional images of the body to detect cancer in any part of the body.
- Positron emission tomography (PET-scan) produces a metabolic map of the body to identify cancer activity in any part of the body.
- Magnetic resonance imaging (MRI) – produce cross-sectional images of the organs in the body to identify invasion.
Additionally, a prostate biopsy can help characterize the recurrent tumor and make informed treatment decisions.
What Factors Determine the Likelihood of Recurrence?
Several clinicopathological factors influence the risk of treatment relapse and how fast it occurs after treatment.
Especially, tumor characteristics observed at diagnoses, such as tumor stage and size, play essential roles in selecting treatment methods and predicting long-term treatment outcomes. Studies have consistently linked the following factors with an increased risk of recurrence:
- PSA value during initial diagnosis: The higher the tumor activity measured by PSA, the greater the chance of recurrence. Many authors demonstrated that PSA is a reliable preoperative indicator of feature recurrence (D’Amico et al., 1998). However, rising PSA levels may occur through cancer-independent mechanisms.
- Prostate-specific membrane antigen (PSMA) expression: PSMA is an independent predictor of PSA recurrence and is used to guide adjuvant therapy for prostate cancer (Perner et al., 2007).
- Tumour stage at diagnosis: Advanced disease is challenging to treat and has an increased risk of treatment relapse. Indeed, those who present with more advanced disease are likely to experience prostate cancer recurrence compared to those presenting at the early slow-growing stages of the disease.
- Tumour size at diagnosis: Like disease stage, larger tumors have a higher chance of recurrence.
- Gleason score: High Gleason score and aggressive phenotype predict future prostate cancer recurrence. Gleason is now routinely used to guide treatment selection for prostate cancer.
- Lymph node involvement: Prostate cancer cells that have spread into lymph nodes near the pelvic region are more likely to survive treatment and spread to other parts of the body. Patients who present with locally advanced have increased risk of lymph node involvement.
- Age: Disease recurrence exhibits significant variations among age groups. Older men have a higher risk of prostate cancer and are likely to experience recurrence after treatment (Parker et al., 2011).
- Positive surgical margins: Men with positive surgical margins are significantly more likely to experience PSA recurrence than those without (Grossfled et al., 2000). Tumour stage and volume influence the positivity of surgical margins after surgery for prostate cancer (Ahyai et al., 2010).
- Specific genetic alterations: Mutations in certain genes like PTEN and expression of specific receptors like CXCR4 correlates with the rate of recurrence (Bedolla et al., 2007; Jung et al., 2011).
What Type of Follow-Up Treatments Are Recommended?
Like the initial treatment, secondary treatment (also called salvage therapy) depends on the type and stage of prostate cancer, possible side effects, and patient’s overall health. Further, salvage therapy highly depends on the first method of treatment.
Patients may receive the same treatment, like surgery, to remove additional cancer tissues or adjusted radiation doses to destroy leftover cancer cells. The following sections discuss the recommended follow-up treatment based on the initial treatment.
Salvage therapy after initial radical prostatectomy: Salvage therapy after initial radical prostatectomy: Doctors use various clinical and pathological factors to gauge the rate of progression and guide treatment after relapse. Watchful waiting is recommended for low-risk patients and early salvage radiation therapy for more aggressive types. This therapy can be supplemented with androgen deprivation therapy (ADT) for the highest-risk patients. Further, patients with lymph node recurrence require ADT with or without salvage lymph node dissection (Suardi et al., 2015).
Salvage therapy after initial radiation therapy: The second treatment option for localized prostate cancer is radiation therapy. It is either given as brachytherapy or external beam radiation therapy with or without androgen deprivation. Like radical prostatectomy, prostate cancer can recur after radiation therapy. Salvage radical prostatectomy is recommended, but the risk of complications caused by initial radiation (fibrosis and altered wound healing) remains a source of severe concern. Other treatments include salvage brachytherapy or cryoablation. However, the best option for prostate cancer recurrence after radiation therapy depends on your clinical and pathological presentation.
How to lower the risk of prostate cancer recurrence
Lifestyle changes can help reduce your risk of prostate cancer recurrence. They range from engaging in regular physical exercise to taking nutritional supplements.
However, further research studies are needed to confirm the actions of many preventative strategies for prostate cancer recurrence. We discuss some of these approaches below.
- Undertake regular physical activity. Research suggests that regular exercise after treatment significantly reduces the risk of prostate cancer mortality compared to control groups who do not exercise.
- Maintain a healthy weight. Men who are overweight or obese at diagnosis tend to have worse treatment outcomes than those at a healthy weight.
- Quit smoking. Smoking increases the rate of prostate cancer recurrence and mortality.
- Nutrition and supplements. A healthy diet rich in vegetables and low in animal fat promotes overall health. The benefits of a healthy diet go beyond the prostate and other cancers. Some dietary supplements may help reduce the risk of prostate cancer recurrence, but further research is needed.
Modern prostate cancer treatments have resulted in improved cancer survival, but with the risk of the disease recurrence.
The natural history of prostate cancer treatment outcome is heterogeneous; some men remain cancer-free while others progress and require salvage local or systemic treatment.
Salvage therapy with radiation therapy, surgery, hormone therapy, or chemotherapy offered based on specific clinicopathological features has shown reasonable cancer control. This treatment benefit is enhanced when salvage therapy is administered early before developing an incurable metastatic disease.
Depending on the first method of treatment, some salvage therapies can cause significant adverse effects and amplify the primary treatment’s side effects.
Current methods for staging and assessing recurrent prostate cancer remains limited in distinguishing between different levels of recurrence. Thus, better risk prediction and prognostic biomarkers are needed to guide treatment decisions.