Prostate Cancer

Prostate cancer has a highly variable natural history, presenting a bewildering variety of treatment management options to the clinician and patient alike, ranging all the way from radical surgery, to many different forms of radiotherapy, to medical therapy, to no active therapy at all. Each of these treatments has proponents and opponents, and the “perfect” treatment method for prostate cancer remains elusive.

EARLY STAGE DISEASE

For early stage tumors in healthy patients (T1-2, N0, M0), surgical resection, permanent source brachytherapy (seed implant), high dose rate (HDR) brachytherapy, 3D conformal radiotherapy (3DCRT), intensity modulated radiotherapy (IMRT), combined radiotherapy modalities such as 3DCRT plus HDR brachytherapy, or combined androgen suppressive therapy (“hormone therapy”) plus radiotherapy are all accepted as reasonable therapeutic alternatives(1 -15).

BENEFITS AND DRAWBACKS OF SPECIFIC APPROACHES

Radical prostatectomy

Radical prostatectomy is the only method to date with a proven survival advantage compared with active surveilance in early stage prostate cancer patients (2), causing many practitioners to consider it the “gold standard,” against which other treatments are compared. To complicate the analysis though, other studies have found no significant difference in disease-free survival between radical prostatectomy, high dose external beam radiotherapy (EBRT), or permanent source brachytherapy (16,17). Yet another study has proven PSA-disease free survival equivalence between HDR brachytherapy and permanent source brachytherapy (9).

In other words, a number of treatment approaches appear to have similar curative potential against localized disease, with no single modality clearly proven superior to the others.

Anatomic radical prostatectomy, as described by Walsh, et al, defines the standard approach to the management of localized prostate cancer, due to its published effectiveness with long-term follow-up (1). In addition to its cancer curative potential, anatomic prostatectomy carries has a reasonable quality of life outcome, with full return of urinary continence representing the norm (3). In young men with early stage lesions, where bilateral nerve sparing is possible, sexual potency preservation with this method is likely (5). Laparoscopic, robotically-assisted radical prostatectomy may have additional advantages, including better identification of the neurovascular bundles and dorsal venous plexus vasculature through direct visualization, potentially leading to less blood loss and better potency preservation compared with the classic technique (4).

Radical prostatectomy also has potential drawbacks, including all the risks that go with a major operation, as well as the need for hospitalization, and the need for a urinary catheter for several weeks following the procedure. Potency preservation is not guaranteed, particularly for patients with non-favorable tumor presentations, where sacrifice of one or both neurovascular bundles may still be required to adequately remove all of the tumor. Older patients also have lower potency preservation rates, even if both neurovascular bundles are spared (5). The laparoscopic robotically-assisted prostatectomy method has a substantial learning curve and expertise in its application remains rare (6).

Intensity modulated Radiotherapy (IMRT)

IMRT has emerged as the preferred external beam radiotherapy (EBRT) method, superior to standard three-dimentional conformal radiotherapy (3DCRT), due to its spatially superior dose conforming capability, translating to an improved ability to deliver a very high dose of radiotherapy to the prostate, while better sparing the encroaching rectum from the high dose region, significantly reducing the incidence of delayed rectal toxicity, particularly when a dose of greater than 75Gy is delivered (10, 11).

Compared with lower dose EBRT methods, high dose IMRT has produced improved disease-free survival (10, 11). Another randomized radiation dose escalation trial demonstrated the superiority of high dose EBRT (79.2Gy) compared with “conventional dose” EBRT (70.2Gy), using proton beam therapy as the prostate dose escalation method (12). Proton beam therapy conforms the high dose volume comparably to IMRT. These two trials have established high-dose radiation therapy, preferably delivered by IMRT or proton beam, as the preferred EBRT method.

Against the benefit of IMRT, as with all treatments, there are drawbacks, primarily including a two month time frame to deliver a full therapeutic course, plus a symptomatic recovery period that follows over the next several months. Although rectal injury is less frequent with IMRT, relative to the radiotherapeutic approaches of its predecessors, it is still possible. There is also a substantially higher cost of IMRT compared with standard 3DCRT.

Permanent source prostate brachytherapy (seed implant)

Permanent source prostate brachytherapy (prostate seed implant) represents another powerful radiation dose escalation method, which has also produced impressive long-term disease-free survival (7, 8). Another huge advantage of this method is its ability to be delivered in a single outpatient procedure.

The major drawback of permanent source prostate brachytherapy is the potential for long-term morbidity, particularly affecting the urinary tract, with at least one study identifying brachytherapy as having inferior long-term urinary and sexual quality of life outcomes compared with 3DCRT or RP (18), though other studies have not found this to be the case (19).

Although most permanent source brachytherapy patients do not experience permanent urinary tract toxicity, it is not uncommon for them to be symptomatic for a year or more, before their final recovery (20).

High dose rate prostate brachytherapy (HDR brachytherapy)

High dose rate brachytherapy entails the placement of hollow tubes into the prostate, through the skin behind the scrotum, through which a high intensity radiation source is delivered and precisely moved through up to several hundred computer controlled “dwell positions,” allowing very precise radiation dose sculpting in and around the prostate. Due to the precision of the radiation dosimetry allowed by this method, a short course of radiotherapy, using large doses per treatment, may be effectively delivered (9).

This approach is known as hypofractionated radiotherapy, and appears well suited to treat prostate malignancy, which appears particularly radiobiologically sensitive to hypofractionation (21). In a prospective comparitive study, HDR brachytherapy provided a 98% 3-year PSA disease-free survival rate, comparable to that seen with Palladium-103 permanent source prostate brachytherapy in the same series, but with significantly decreased urinary tract and sexual symptoms (9).

The major drawback of HDR brachytherapy includes the necessity of a hospital admission for HDR tube placement and maintenance, which increases the expense significantly. Pain control is also challenging, due to the obvious discomfort created by the indwelling tubes themselves. Finally, the tubes may move over time, potentially degrading the accuracy of the radiation delivery by this method (22).

Combined EBRT/Brachytherapy

External beam radiotherapy (EBRT) and brachytherapy have complimentary strengths, such that applying  them together theoretically improves the outcome, by combining the central power of brachytherapy, with the better margin coverage of EBRT. Very high disease-free survival results have been published with combined modality therapy (13), even in patients with more advanced disease (14).

Against the demonstrated high efficacy of this approach are several drawbacks. First, studies that have compared the outcome of combined therapy versus brachytherapy monotherapy in early to intermediate prognosis patients have failed to demonstrate superiority in the combined therapy arm (23).

Combined therapy regimens may also be more toxic than monotherapy approaches (24). Finally, combined therapy is expensive.

Androgen suppressive therapy plus radiotherapy

The combination of androgen suppressive therapy (medical suppression of the male hormone testosterone – also known as “hormone therapy”) and radiotherapy has been shown to improve the disease-free survival, and in some studies, overall survival, compared with radiotherapy alone (15, 25). Prostate cancer cells are usually stimulated to grow by testosterone, and suppressing it leads to the death of cancer cells, reducing the cell burden to be controlled with radiation.

To cloud the issue though, studies showing benefit to added androgen suppressive therapy tend to have in common the use of low dose and/or outdated radiotherapy technology as the control arm. Studies using high dose, contemporary radiotherapy have not routinely demonstrated added benefit from androgen suppressive therapy, presumably reflecting more complete prostate cancer cell eradication by the more contemporary radiotherapy methods and doses. (10, 11, 17, 26)

For patients with very advanced disease, whose clinical course is more likely characterized by early development of metastatic disease (spread of their tumor to different parts of the body), long-term androgen suppressive therapy added to the regimen may extend disease-free and overall survival even if optimal local therapy techniques are applied, likely reflecting direct suppression of metastatic deposits. For patients with early stage disease though, the added cost and side effects of added androgen suppressive therapy do not appear justified, as the disease-free survival result with local therapy alone is excellent.

Learn more about our comprehensive approach to prostate cancer treatment: Genesis Prostate Cancer Center.

BIBLIOGRAPHY

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