Kelly L. Stratton, MD

Prostate cancer detection using transrectal ultrasound-guided biopsy provided the necessary diagnosis to recommend radical treatment. Until recently, patients had a limited number of treatments for localized prostate cancer. These limitations exacerbated the overtreatment of prostate cancer and caused concern that overdiagnosis should be prevented to limit unnecessary treatments and comorbidities. However, in other cancers facing similar concerns, attempts were made to reduce the treatment field and preserve the patient’s quality of life while still receiving adequate treatment. Partial nephrectomy, lumpectomy, and other organ-preserving operations quickly gained momentum and were supported by studies showing the potential benefits.

Yet, prostate cancer largely remained hindered by concerns that cancer detection was not sufficient to focally treat the prostate. This Achilles heel was finally remedied with the introduction of multiparametric MRI of the prostate. There is now a constant stream of reports supporting the use of focal therapy for prostate cancer. In the European Union, padeliporfin (Tookad) and vascular targeted photodynamic therapy has been approved for the treatment of low-risk prostate cancer. The rising popularity of focal therapy has raised concern from urologists on how to appropriately manage patients who have recurrent prostate cancer following focal therapy.

After undergoing focal therapy, patients typically undergo a posttreatment biopsy and are subsequently monitored with serial prostate-specific antigen (PSA) tests and MRI exams. Prostate cancer recurrence may be identified at any point during the follow-up after treatment. Similar to patients who are being followed on active surveillance, there are challenges classifying cancer that is detected during follow-up. Based on our experience from patients undergoing radical prostatectomy, recurrence is frequently attributed to cancers growing in the resection bed or as newly detected areas of previously occult metastases. However, from the perspective of patients undergoing focal therapy, a recurrence could be either in the previously treated area or a newly identified foci in an untreated segment of the prostate. During the posttreatment biopsy, cores are obtained from the treatment zone in addition to the remaining prostate. 

 illustrates a patient who underwent focal therapy of the left lateral peripheral zone, with persistent cancer identified on the 6-month biopsy. One of the most frequently proposed criticisms of focal therapy is the potential for untreated occult cancers. Although this is a valid concern, there are several treatment options for these patients and for those who have residual cancer in the focal therapy treatment zone. 

 demonstrates a patient with successful ablation of a right-sided lesion but with newly discovered occult contralateral cancer identified on the systematic biopsies. Classifying the cancer recurrence can help guide recommendations for salvage treatments.

Patients with recurrent prostate cancer following focal therapy are offered many of the same treatment choices that they considered at the time of their initial diagnosis. To help determine the appropriate treatment choice, a risk-based approach, similar to that described by Aminsharifi et al, could be considered 

 Options range from active surveillance to radical prostatectomy. For many patients, their preference to select focal therapy suggests a desire to avoid jeopardizing their quality of life. Regardless of their prior preference, a thorough discussion of all treatment options and the potential risk for adverse effects is important to selecting the best treatment.

Posttreatment identification of low-risk prostate cancer is common in patients undergoing focal therapy. To date, there are no published series of post focal-therapy active surveillance cohorts.

 However, there is no reason to believe these patients experience a higher likelihood of disease progression or spread. Importantly, many patients may have been on active surveillance before electing to undergo focal therapy. Regardless of their history, patients with low-risk cancer remain good candidates for active surveillance. Patients with low-volume, intermediate-risk prostate cancer may also consider active surveillance. For these patients, concordance with PSA levels and MRI can be reassuring as they avoid additional treatment. However, patients with a new MRI lesion corresponding to the foci of cancer recurrence, or with a PSA that continues to increase over, may benefit from definitive local therapy.

Patients who are particularly satisfied with their initial focal therapy experience may be inclined to request a retreatment with additional focal therapy. Retreatment with ablative treatments such as cryotherapy or high-intensity focused ultrasound (HIFU) varies by location and provider preference, with some studies showing a high rate of secondary treatment. For patients with newly discovered contralateral disease, ablation of the new foci may provide oncologic control with similar preservation of urinary and sexual function. Lovegrove et al evaluated the functional outcomes of patients undergoing repeat HIFU and compared them with patients who underwent a single treatment.

 They found that men undergoing a single HIFU procedure generally experienced improvement in urinary symptoms with some decline in erectile function. When looking at men who underwent a second HIFU treatment, they had a worsening of both their urinary function and erectile function. There was no significant impact in continence with repeat HIFU therapy. Their results support a gradual decline in quality of life with an increase in treatment burden. Importantly, patients who are considering repeat focal therapy should know that some recommend against salvage prostatectomy after repetitive ablative procedures. Treatment failure rates after repeat ablation vary by study and selection of treatment candidates but can be as high as 26%.

 For patients who fail repeat ablation, the potential for additional impacts on quality of life are expected to increase but are not particularly well characterized.

Patients who considered radical prostatectomy or radiation therapy prior to focal therapy may reconsider this treatment choice at the time of recurrence. Patients with high-risk prostate cancer are not typically offered focal therapy up front but may have occult high-risk/high-grade cancer found on subsequent biopsy. For these patients, radical prostatectomy or radiation therapy are the best treatments to provide definitive local therapy. Given the concern that prostatectomy may be more challenging after focal therapy, there are several prostatectomy series evaluating focal therapy patients. Most of these studies have found that post focal-therapy prostatectomy is safe and provides good function outcomes. However, recently Marconi et al showed that patients with recurrence in the previously treated field may experience worse oncologic outcomes.

 This is an important factor to consider, but prostatectomy may still avoid the impact of androgen deprivation therapy associated with radiation therapy and allows for additional salvage treatment if needed.

Focal therapy continues to gain popularity for select patients who desire preservation of function while effectively treating localized prostate cancer. However, with this growth, more patients have experienced recurrence after focal therapy. This creates a new group of patients who need secondary local therapy. They also may have heightened expectations given their prior treatment experience. Careful consideration of treatment options is important to match the best treatment with the patient’s preferences. Fortunately, patients who have received focal therapy appear to be candidates for all the typical prostate cancer treatments. With continued improvements in prostate cancer imaging and new ablative treatment options, we can expect continued growth in focal therapy procedures. Post focal-therapy salvage therapies will play an important part in assuring the success of a new treatment paradigm. We can look to other cancers to be reassured that patients will desire to continue exploring focal therapy and that clinicians will find a way to make it increasingly beneficial.

Stratton is an associate professor of urologic oncology at the University of Oklahoma, Oklahoma City and Patel is a resident urologist at the University of Oklahoma, Oklahoma City.

1. Aminsharifi A, Polascik TJ. Diagnosis and management of local recurrence after prostate focal therapy: challenges and solutions. 

. 2019;2(5):539-540. doi:10.1016/j.euo.2019.07.008

2. Marra G, Valerio M, Emberton M, et al. Salvage local treatments after focal therapy for prostate cancer. 

. 2019;2(5):526-538. doi:10.1016/j.euo.2019.03.008

3. Lovegrove CE, Peters M, Guillaumier S, et al. Evaluation of functional outcomes after a second focal high-intensity focused ultrasonography (HIFU) procedure in men with primary localized, non-metastatic prostate cancer: results from the HIFU Evaluation and Assessment of Treatment (HEAT) registry. 

. 2020;125(6):853-860. doi:10.1111/bju.15004

4. Stabile A, Orczyk C, Hosking-Jervis F, et al. Medium-term oncological outcomes in a large cohort of men treated with either focal or hemi-ablation using high-intensity focused ultrasonography for primary localized prostate cancer. 

. 2019;124(3):431-440. doi:10.1111/bju.14710

5. Marconi L, Stonier T, Tourinho-Barbosa R, et al: Robot-assisted radical prostatectomy after focal therapy: oncological, functional outcomes and predictors of recurrence. 

. 2019;76(1): 27-30. doi:10.1016/j.eururo.2019.03.007

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Providers must carefully consider treatment options to align with patient preference.

Management of recurrent prostate cancer after focal therapy

Over the past 10 years, there has been a rapid evolution in the evaluation and diagnosis of prostate cancer. Previously, prostate cancer detection relied on a digital rectal exam and systematic biopsy using transrectal ultrasound guidance. Improved prostate cancer detection was obtained by increasing the number of cores taken during the biopsy. However, advancements in prostate imaging with multiparametric magnetic resonance imaging (mpMRI) has changed the prostate imaging paradigm. Tumors that were previously only detected microscopically can be detected radiographically prior to biopsy. This has resulted in the adoption of image fusion technology to combine the MRI imaging with real-time ultrasound imaging during the prostate biopsy procedure.

Acknowledging the expanded role of prostate mpMRI in the detection and treatment of prostate cancer, the American Urological Association (AUA) provided a policy statement in 2017 regarding mpMRI.

 At the time the statement was published, there were sufficient data to support prostate MRI in patients with a prior negative biopsy and an ongoing concern for cancer. However, insufficient data were available to support routine prostate MRIs as preparation for a patient’s initial biopsy. New data evaluating mpMRI prior to biopsy have shown a potential benefit for patients undergoing their first biopsy. The AUA recently released an updated standard operating procedure (SOP) with a recommendation to consider mpMRI for all men with no prior biopsy who are considering a prostate biopsy.

 In this article, we will discuss the updated SOP for prostate imaging and consider additional recent reports on prostate biopsy in light of this rapidly changing field.

The added value of prostate imaging is dependent on the combination of image quality, reader experience, and engagement from the urologist performing the biopsy. The AUA SOP suggests that optimal imaging is provided by a 3.0 Tesla (T) magnet with a surface coil. Some centers with older 1.5 T machines may obtain acceptable imaging using an endorectal coil, whereas those with newer 1.5 T scanners obtain adequate images without the coil. Both anatomical and functional images should be acquired, with target lesions identified and marked by the radiologist using the PI-RADS v2.1 criteria.

After identification of the potential target lesion, the urologist can determine the best approach to obtain adequate samples for diagnosis. Having the capability to conduct both transrectal and transperineal biopsy provides the best opportunity to sample the target regardless of location 

. Samples obtained during transrectal biopsy typically include a portion of both the peripheral zone and the transition zone. However, sampling apical areas of the prostate is more difficult from the transrectal approach, given the needle angle and potential for patient discomfort. Conversely, the transperineal biopsy provides cores with varying amounts of peripheral and transition zone, depending on the location of the biopsy. The needle orientation gives the advantage of obtaining cores from the apex of the prostate. In patients with a prior negative biopsy, apical lesions identified on mpMRI may be sampled using the transperineal approach to diagnose occult cancer that may have been missed on a prior transrectal biopsy 

Advancements in prostate cancer detection and opportunities for image-guided biopsy have resulted in some clinicians advocating against systematic biopsies as an unnecessary addition to the fusion-guided targeted biopsy. Arguments for avoiding systematic biopsy include a reduction in detecting clinically insignificant cancer and lessening the risk for adverse effects such as infection or bleeding. There might even be the potential to avoid biopsy altogether in patients who have no target lesion on the MRI.

However, a recent report from the TRIO study group cautioned against the omission of systematic biopsies.

 In this study, which included men who were biopsy naive, had a prior negative biopsy, and were on active surveillance, 2103 participants with an MRI-visible lesion underwent both systematic and targeted biopsy. Of those, 408 underwent prostatectomy. The investigators found that the combination of systematic and targeted biopsy resulted in the highest detection of clinically significant prostate cancer and prevented the misclassification of 8.8% of significant cancers missed on targeted biopsy alone. Further, when considering patients who went on to radical prostatectomy, the investigators found that the combination of systematic and targeted biopsy reduced pathologic upgrading to only 3.5% of patients.

Findings from additional retrospective studies have confirmed that detection of clinically significant cancer is optimized by the combination of systematic and targeted biopsies. In a study of over 500 patients with targetable lesions undergoing fusion biopsy, the detection of prostate cancer was significantly higher when combining systematic and fusion biopsy.

 When considering only those in whom clinically significant cancer was identified, the authors found that the combination of systematic and targeted biopsy resulted in a 6% improvement in cancer detection. Had the systematic biopsy been omitted, 29 of 185 patients (16%) with clinically significant cancer would have been misclassified. The authors concluded that standard systematic biopsy should be routinely included at the time of fusion biopsy to avoid missing a significant number of patients harboring occult clinically significant prostate cancer.

Although MRI fusion biopsy has clearly been shown to improve prostate cancer detection, in some areas the implementation of prostate mpMRI has been hampered by the high costs of imaging systems and fusion devices. Many urologists can defray the financial burden by partnering with a hospital or imaging center. However, even when adequate imaging systems are in place, some urologists face a reluctance by radiologists to read mpMRI images and mark potential target lesions. The cost and complexities of mpMRI and fusion biopsy systems has led to the increased consideration of alternative imaging modalities. Advances in ultrasound technology have produced new, high-resolution micro-ultrasound devices capable of operating at much higher frequencies (29MHz) than standard ultrasound devices. This higher frequency provides significant improvement in ultrasound image resolution, with some devices achieving a resolution of up to 70 μm. The improved resolution means that micro-ultrasound is better able to visualize the ductal anatomy and cell density, which, like mpMRI, could represent changes associated with prostate cancer.

A recent study compared the accuracy of micro-ultrasound directed prostate biopsy to MRI-fusion prostate biopsy.

 The study included 104 patients with known lesions on mpMRI who underwent a micro-ultrasound targeted biopsy followed by an MRI-fusion targeted and 12-core systematic biopsy. The micro-ultrasound targeted biopsy was found to have a sensitivity of 94% for the detection of clinically significant prostate cancer, with 33/35 cases successfully identified. The specificity of micro-ultrasound was 28% with a positive predictive value of 40%. There was general concordance of targets between micro-ultrasound and mpMRI lesions. However, micro-ultrasound detected clinically significant cancer in 3 discordant cases whereas mpMRI detected clinically significant cancer in 4 discordant cases. The authors concluded that advanced prostate ultrasound may provide a new option for the detection of clinically significant prostate cancer.

The last decade has seen a back-and-forth swing in enthusiasm for prostate cancer screening and diagnosis. The era of early detection with prostate-specific antigen (PSA) screening and aggressive treatment of low-risk disease ended with a movement recommending against PSA testing. However, some believe that the resulting wave of high-risk and advanced prostate cancer could be attributed to delays in diagnosis that developed from these recommendations. Advances in prostate imaging have provided a new opportunity to identify prostate cancer early on and provide effective treatment.

A fear that we may be repeating the past sins of overdiagnosis has started to gain momentum, but it is important to consider the alternative perspective. We know that, historically, prostate cancer was a frequent cause of cancer mortality in men. Although recent advances in the treatment of advanced prostate cancer have produced significant survival gains, improved detection could prevent the development of advanced disease while allowing for treatments that preserve quality of life. Advances in prostate imaging have led to the consideration of focal therapy for men with identifiable lesions who are willing to consider novel treatments that are less likely to cause changes in urinary and sexual function.

Advanced prostate imaging and improvements in prostate biopsy techniques have resulted in a new paradigm of prostate cancer screening and diagnosis. Men with elevated PSA are now considered for up-front prostate imaging with mpMRI. Those with no lesion undergo a 12-core systematic biopsy whereas those with a lesion undergo targeted sampling of the index lesion. Men with a negative biopsy have the assurance that occult clinically cancer is not present. Additional genomic testing is available based on the urologist’s preference. Men with low-risk disease can be offered active surveillance with a future confirmatory biopsy following a repeat MRI. The era of repeat serial biopsy has been replaced by prostate imaging. It is true that although image-guided prostate biopsy may increase the diagnosis of some low-risk cancers, it also provides improved opportunities for surveillance.

Unfortunately, some men will be diagnosed with clinically significant prostate cancer. For those with intermediate- and high-risk disease, prostate imaging can be useful for staging and treatment planning. This can be particularly helpful for the evaluation of nerve sparing and bladder neck anatomy. Although the potential impact of micro-ultrasound remains unknown, continued improvements in prostate imaging should further optimize prostate cancer detection, reduce treatment morbidity, and improve outcomes of prostate cancer treatment.

is assistant professor of urologic oncology at the University of Oklahoma, Oklahoma City.

1. Fulgham PF, Rukstalis DB, Turkbey IB, et al. AUA policy statement on the use of multiparametric magnetic resonance imaging in the diagnosis, staging and management of prostate cancer.

 2017;198(4):832-838. doi:10.1016/j.juro.2017.04.101

2. Bjurlin MA, Carroll PR, Eggener S, et al. Update of the standard operating procedure on the use of multiparametric magnetic resonance imaging for the diagnosis, staging and management of prostate cancer.

 2020;203(4):706-712. doi:10.1097/JU.0000000000000617

3. Ahdoot M, Wilbur AR, Reese SE, et al. MRI-targeted, systematic, and combined biopsy for prostate cancer diagnosis. 

. 2020;382(10):917-928. doi:10.1056/NEJMoa1910038

4. Hanna N, Wszolek MF, Mojtahed A, et al. Multiparametric magnetic resonance imaging-ultrasound fusion biopsy improves but does not replace standard template biopsy for the detection of prostate cancer. 

 2019;202(5):944-951. doi:10.1097/JU.0000000000000359

5. Laurence Klotz CM. Can high resolution micro-ultrasound replace MRI in the diagnosis of prostate cancer? 

 2020;6(2):419-423. doi:10.1016/j.euf.2019.11.006

6. Lughezzani G, Saita A, Lazzeri M, et al. Comparison of the diagnostic accuracy of micro-ultrasound and magnetic resonance imaging/ultrasound fusion targeted biopsies for the diagnosis of clinically significant prostate cancer. 

 2019;2(3):329-332. doi:10.1016/j.euo.2018.10.001

Advanced imaging and improvements in biopsy techniques usher in a new paradigm for screening and diagnosis.

Kelly L. Stratton, MD

Articles

Management of recurrent prostate cancer after focal therapy

Rapid advances propel prostate biopsy forward