Prostate Surgery

Focal Therapies For Prostate Cancer

Prostate cancer is the most common malignancy in males.

Europe and the United States have similar figures, with almost 250 cases for every 1000 men. At the age of 60 years, around 40% of males have cancer cells in the prostate.

The number goes up to 70% in 80-year-old males. Still, it is sometimes slow-growing cancer, and less than 10% of cancer cases are clinically significant.

PSA screening has raised controversy because it detects nonsignificant cases. This leads to overtreatment in low-risk patients if we’re not careful.

In other words, cancer therapy sometimes affects the quality of life in males who would die from unrelated causes without developing severe symptoms. That’s why active surveillance and other treatments have been proposed for low-risk cancer. These therapies have a lower risk as compared to radical prostatectomy. They are conservative and work better in these patients.

Focal therapy is one of these innovative approaches for low-risk patients. It may be advantageous and provide new opportunities. But other issues and unexpected problems remain.

In this article, we’re exploring the topic thoroughly and show you the types of focal therapy we have in ongoing clinical trials.

What is focal therapy?

Focal therapy is a suitable alternative for localized prostate cancer. It is appropriate in cases of low-risk cancer and some intermediate-risk patients. They should all feature prostate cancer that is only confined to the prostate. This type of therapy is ruled out in cases of localized or generalized spread.

In the past, two approaches were considered in cases of localized prostate cancer:

  • Watchful waiting: This approach is useful in low-risk patients and older males that won’t likely die from prostate cancer. The patient would undergo medical tests continually to determine if the tumor is still localized. No action will be taken if cancer is still confined to the prostate or stable in size. Accelerated growth or localized spread would be treated using different methods.

  • Surgery or radiation therapy: In some cases, prostate cancer is confined to the gland but growing rapidly or diagnosed in a relatively young patient. If that’s the case, doctors would likely opt for surgery or radiation therapy. However, this approach has different side effects to consider. Even in nerve-sparing surgery, patients need to undergo rehabilitation to recover their erectile function. Urinary incontinence is another problem, as well as bleeding and pain.

Now, focal therapy offers a third alternative that works as the middle ground. What doctors achieve with focal therapy is treating low-risk cancer without as many side effects. Instead of treating the whole gland, focal therapy treats a visible tumor known as the index lesion. This may not be the only site where cancer cells are found. However, treating this area changes the way cancer progresses. Controlling growth in the index lesion can control whole-cancer growth without as many side effects.

When this method started to develop around 2007, it was recommended in a limited number of cases. Only very low-risk patients were put to the test. It was an alternative to watchful waiting or active surveillance. Nowadays, some intermediate-risk patients can also benefit from focal therapy.

The typical candidate would be a patient with a single visible tumor on magnetic resonance imaging (MRI). The typical candidate won’t have any other visible trace of cancer, as evidenced by a biopsy. The prostate gland of these patients is around 40cc or less.

Still, every case is different, and doctors need to consider many other aspects before recommending a type of treatment (1).

What are the types of focal therapy?

According to studies, around 40% of prostate cancer cases could be candidates for focal therapy.

Most of them have a Gleason score of 6 or 7. However, each one should be evaluated individually to assess the risk and other factors. Depending on each case, you could be offered one of the following alternatives (2):

High Intensity Focused Ultrasound (HIFU)

This is one of the most popular focal therapies. It uses a particular type of ultrasound and delivers these waves transrectally to the prostate. This causes coagulative necroses in guided areas of the prostate. It is crucial to prevent injury to the rectal mucosa, which is done by cooling the area. Otherwise, a urinary fistula could be developed. 

This is a popular choice because it is truly non-invasive. No incision is made, and it is administered under general anesthesia. However, it is not appropriate for all cases of prostate cancer. The range of ultrasound action is limited to 4 cm in depth. Thus, it won’t reach anterior prostate lesions if they are far from the rectal mucosa. Another option in these cases would be transurethral ablative ultrasound. However, this is not the most commonly administered procedure.

What doctors do not like about focal HIFU is the suboptimal efficacy rate. A study showed cancer persistence in 40% of patients. However, they were very low-risk patients, and only 20% of them required radical prostatectomy.

Focal Laser Ablation (FLA)

This type of focal therapy features laser technology placed into the cancer lesion. To achieve the proper position of the laser fiber, a transrectal or perineal puncture should be performed. After placing the laser fiber in the cancer lesion, energy is transmitted and causes tissue necrosis.

Compared to HIFU, FLA ablations are larger with an elliptical or circular area. However, they are minimally invasive instead of non-invasive procedures. Anesthesia is required; usually, local anesthesia. Moreover, FLA reach is not limited to 4 cm. The procedure reaches the whole prostate, and it is compatible with MRI guidance.

FLA does not have as many studies as HIFU treatment, and navigation platforms are often limited. 40% of patients can stay with residual traces of cancer, but recurrence is reported in less than 20% of cases. More studies are still required to evaluate the long-term outcomes of these patients. However, it is a very safe procedure with limited side effects.

Irreversible Electroporation (IRE)

This is one of the most recent focal therapy techniques. It uses electro-needle probes located in the target area. To place the probes, surgeons need to go through the perineum, usually through MRI guidance. Ultrasound guidance can also be used in these cases. After placing the probes, high-voltage currents are administered, triggering cell death.

Cancer persistence in these cases is around 24%, and most cases are found within the prostate. However, one of the best aspects of this technique is that it doesn’t have many side effects. No high-grade side effects have been recorded as of yet.

However, we need to remember that this is a novel technique. If FLA does not have many studies, this type of therapy has even less. It is an experimental therapy with excellent results so far. However, more safety studies are still needed with a longer follow-up.

Photodynamic therapy (PDT)

In contrast to the above, PDT is one of the most widely studied focal therapy techniques. This modality of focal therapy features the administration of an apparently inert substance. It doesn’t have significant biological effects but becomes cytotoxic when it is exposed to light. These substances are also known as photosensitizers because they raise photosensitivity. 

The substance is called padeliporfin, and it is administered intravenously. Then, a probe is placed through the perineum, directly into the prostate. This probe has infrared light that activates the photosensitizer. Padeliporfin then induces superoxide and other free radicals that destroy the area.

According to randomized controlled trials comparing PDT to active surveillance, the recurrence rate is similar to HIFU and FLA. However, since these are low-risk patients, the risk of metastasis is almost none. According to researchers, the main benefit is not destroying cancer but slowing the progression and avoiding aggressive cancer therapy. Compared to active surveillance, PDT reduced the need for aggressive therapy from 53% to 24%.

However, one of the downsides of this focal treatment option is the incidence of side effects. It is actually higher than HIFU and FLA, according to some clinical trials. However, new photosensitizers are being developed. They are targeted to the prostate membrane and may reduce the incidence of side effects.

Focal cryotherapy

Cryotherapy was initially used to destroy the whole gland, but it can also be used to destroy focal lesions. It is a widely studied method as a total gland ablation technique, and a similar procedure is followed in focal cryotherapy. It features continuous cycles of freezing and thawing until cells in the prostate tissue trigger apoptosis or start rupturing. 

The efficacy of this therapy is almost the same as the other focal therapy modalities. It is variable, and the recurrence rate can be 2-25%. People usually think about prostate cryotherapy and its side effect. They think focal cryotherapy has the same rates of fistula and erectile dysfunction. However, this is not the case.

The risk of side effects is no different from the techniques listed above. Still, there is a stigma among patients, and most of them prefer to try other methods.

Benefits

Having prostate focal therapy as an option has multiple benefits. This middle ground choice is suitable for doctors and patients alike for several reasons (3):

Focal therapies can reduce the side effects associated with prostate cancer treatment.

Whole-gland therapy causes significant and sometimes severe side effects. Despite current advancements in the field of surgery, we still have many unexpected problems. One of them is urinary incontinence. This one is widespread after radical prostatectomy and radiotherapy. It is caused by sphincter damage, detrusor overactivity, or bladder dysfunction.

Erectile dysfunction is also a possibility, especially in radiotherapy. Nerve-sparing techniques can prevent this, and erectile rehab is beneficial. However, we can still have penile hypoxia, nerve damage, or venous dysfunction after surgery.

In contrast, focal therapies reduce the rate of side effects significantly, as we will cover further in this article.

Focal therapy reduces the risk of overtreatment in low-grade cancer

The concept of overtreatment is easy to understand if we consider the side effects of cancer therapy. Chemotherapy affects many aspects of a man’s health. Radiotherapy can be very painful and cause lesions in healthy tissue. Whole-gland cryotherapy is known to cause urinary symptoms and erectile dysfunction.

Prostate cancer surgery causes damage to the urinary tract. It is associated with bleeding, pain, and urinary symptoms. Radical prostatectomy patients also need to undergo erectile function rehab after surgery.

All of these side effects would be justified in patients who would otherwise die from cancer-related causes. But prostate cancer is sometimes slow-growing. Many diagnosed and undiagnosed older adults die from unrelated causes. Some of them do not display any particular symptoms.

Overtreatment is treating these patients with mild and indolent cases, causing more harm than good. That’s why watchful waiting and active surveillance are sometimes adopted. But they have a higher risk of cancer mortality. Sometimes active surveillance would be next to do nothing about cancer. That would be undertreatment of prostate cancer.

Focal treatment is in the line between undertreatment and overtreatment. It may provide the answer to doctors and patients who want to do something about it, even when cancer is still low-risk and confined to the prostate.

Focal Therapies may promote the detection of focal prostate cancer

PSA and prostate cancer screening are very controversial topics among urologists. Some argue against overtreatment. Others point out that careful protocols can prevent side effects. As a middle ground, focal therapies may contribute to reducing the controversy.

Instead of destroying cancer and affecting nearby tissue, it provides a type of treatment that further slows down cancer. It is more appropriate than aggressive therapy and may promote the detection of this type of cancer.

Currently, we prefer not detecting low-grade cases of cancer to detecting them and start treating patients that do not require any treatment. That would be counterproductive if we trigger side effects in patients that would never experience prostate cancer symptoms in their lifetime. That’s why not all male patients are meant for screening. They need to have risk factors or at least urinary symptoms.

Having an excellent middle-ground option such as focal therapy can solve this medical dilemma. More low-risk cancer patients can be detected without risk of overtreatment, as noted above.

Focal therapy improves the patient‘s quality of life

Undertreatment and overtreatment can affect a patient’s quality of life. The former has a higher mortality risk. The latter causes significant side effects. 

Focal therapy reduces distress in patients and their partners when they’re actually doing something about cancer. The patient is more satisfied with the treatment and the outcomes. These therapies are not as invasive as whole-gland therapies. The recovery is shorter. The side effects are usually mild and transient, sometimes with no reported side effect.

All of this contributes to the patient’s quality of life instead of causing distress or uncomfortable symptoms.

Focal therapies can become a cost-saving option

Prostate cancer therapy is costly. Comparing radical prostatectomy with watchful waiting shows that surgery costs are 34% higher. Radiotherapy and laparoscopic surgery are even more expensive.

The minimally-invasive nature of these therapeutic methods makes them suitable for a more cost-effective approach. They are not as expensive as whole-gland therapy but reduce the progression of cancer as well. The risks of adverse events are lower for less money.

Side effects

As with every other surgical procedure, focal therapy for prostate cancer may also have side effects. They are almost the same in all modalities, with some variations (2, 3):

  • In high-intensity focused ultrasound, there’s a risk of rectal injury. When cooling is not appropriate in the rectal mucosa, it may lead to a urinary fistula. However, the risk is very low when expert hands perform this procedure. Urinary incontinence was only reported in 3% of patients 1-2 years after treatment. Only 8.5% of patients experience urinary infections, and the rate of erectile dysfunction is variable from 0-25%. These cases are usually mild and transient.

  • In focal laser ablation, one of the most common side effects is hematuria. This is the clinical name of blood in the urine. It was found in 15% of cases, with 8% of urinary retention cases. Studies so far do not suggest any urinary symptoms or erectile function problems after this procedure.

  • In focal cryotherapy, urinary incontinence is found in 5% of patients. Urinary retention rates are variable, from 1-17%. The same happens with erectile dysfunction, which goes between 0-31%. These cases of erectile dysfunction are limited to the first months after treatment. In most cases, it is recovered after some time.

  • In irreversible electroporation, there are not enough safety studies to provide substantial results. No high-grade adverse events are recorded as of yet. 

  • In photodynamic therapy, erectile dysfunction is the most common side effect, reaching 38%. It is followed by urinary incontinence or retention, experienced by 27% of patients. These studies are based on padeliporfin, and newer photosensitizers may lead to fewer cases.

Besides the side effects of focal therapy, doctors still need to raise a few questions before adopting this type of treatment (3):

  • Identifying the ideal patient is still a challenge. A prostate biopsy can be useful, but it has many limitations.

  • It is difficult to know when non-index cancer lesions can be significant for the progression of the disease.

  • Imaging and diagnostic tools have different challenges to face. For example, MRI accuracy is compromised in patients who had a recent biopsy. Benign prostatic hyperplasia can also overlap with cancer and makes diagnosis more difficult.

Which focal therapy is best?

As you can see, there are different types of focal therapy. Each one has its own benefits and limitations. For example, your doctor won’t likely consider High-Intensity Focused Ultrasound if you have an anteriorly located tumor.

As noted above, this type of therapy does not reach beyond 4 cm from the rectum. It is more appropriate for lesions located in the posterior portion of the prostate gland.

Similarly, you have different choices for different cases. That’s why the best focal therapy does not depend on the technique or the statistics. It depends on you and the type of lesion you have. It also depends on which procedure your doctor is more proficient at. These factors play a significant role in deciding which type of focal therapy is more appropriate in your case.

Conclusion

Treating early-stage prostate cancer with aggressive therapy can be counterproductive. It can trigger side effects and unwanted events in patients who would otherwise not experience symptoms. That’s why active surveillance became an alternative to aggressive therapy in low-risk prostate cancer. However, in some cases, active surveillance leads to undertreatment.

Focal prostate cancer therapy is becoming an alternative between two variants. It prevents overtreatment and has better functional outcomes than radical therapy. These techniques locate the prostate tumor and destroy cancer cells without affecting the rest of the gland.

Focal therapies for prostate cancer include high intensity focused ultrasound, focal ablation by laser therapy, focal cryoablation, irreversible electroporation, and photodynamic therapy. They use ultrasound, laser, cold therapy, electric impulses, or photosensitivity to destroy the tumor. Unlike radical therapy, they leave the rest of the prostate intact.

Focal therapies have many benefits. They are the dividing line between overtreatment and undertreatment. They have a lower risk of side effects and improve the quality of life and outcome of patients. They can contribute to diagnosing more cases of prostate cancer without fear of overtreatment. And they are a cost-saving option as compared to other treatments.

Sources

  1. Valerio, M., Ahmed, H. U., Emberton, M., Lawrentschuk, N., Lazzeri, M., Montironi, R., … & Polascik, T. J. (2014). The role of focal therapy in the management of localised prostate cancer: a systematic review. European urology, 66(4), 732-751.
  2. Ahdoot, M., Lebastchi, A. H., Turkbey, B., Wood, B., & Pinto, P. A. (2019). Contemporary treatments in prostate cancer focal therapy. Current opinion in oncology, 31(3), 200.
  3. Mearini, L., & Porena, M. (2011). Pros and cons of focal therapy for localised prostate cancer. Prostate Cancer, 2011.

 

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