Locoregional Therapies for Early-Stage Prostate Cancer

Introduction

Use of prostate-specific antigen (PSA) as a screening tool has increased the incidence of biopsy-proven prostate cancer, as well as shifted the stage of presentation increasingly to early-stage disease. Of the estimated 244,00 patients with newly diagnosed prostate cancer in 1995 [1], approximately 75% will have disease clinically confined to the prostate gland (stage T1 to T2). The treatment of these patients with early-stage prostate cancer is highly controversial. The controversy centers around two general issues: (1) Which patients require treatment for their prostate cancer and which only need to be observed? (2) Once the decision for treatment has been made, which therapeutic modality is optimal?

Traditionally, the two modalities used to treat early-stage prostate cancer have been radical prostatectomy and external-beam radiation therapy. Recent technical advances in both modalities have led to decreased morbidity with the promise of improved results. In addition, new treatment approaches, such as brachytherapy and cryosurgery, are now being used for early-stage prostate cancer.

This review describes the various treatment options for early-stage prostate cancer and their technical refinements. It also analyzes treatment end points, compares results, and explores treatment-related morbidity.

Treatment Modalities

Radical Prostatectomy

Radical prostatectomy is the standard surgical treatment for prostate cancer. Using a retropubic or perineal approach, the prostate and seminal vesicles are removed and the bladder is reanastomosed with the urethra. In addition, a bilateral pelvic lymph node dissection is usually performed to identify patients who have lymph node metastases.

In 1982, Walsh and Donker introduced a modification of the standard retropubic prostatectomy, the nerve-sparing radical prostatectomy [2]. The major change came from a more precise anatomic identification of the prostate gland, which permitted excision of the prostate without injuring the neurovascular bundles containing the cavernous nerves and vessels that preserve sexual potency. In addition, Walsh demonstrated that, in patients with extracapsular tumor extension, these bundles could be sacrificed to obtain wider margins than are usually achieved with a standard retropubic or perineal prostatectomy [3].

External-Beam Radiation Therapy

Beginning in the 1970s, external-beam radiation techniques for treating prostate cancer were refined. These refinements included irradiation of the pelvis to treat the prostate, seminal vesicles, and primary draining lymph nodes, accomplished with the use of a four-field pelvic box technique. Following pelvic irradiation, a radiation boost to the prostate alone or prostate and seminal vesicles was delivered via a four-field technique or arcing beams.

Over time, the concept of treating the whole pelvis for early-stage prostate cancer fell out of favor. A Radiation Therapy Oncology Group (RTOG) randomized trial failed to show any benefit of irradiation of the whole pelvis plus prostate over irradiation of the prostate alone for stages A and B disease [4]. In addition, data from surgical series helped distinguish patients at low risk for pelvic lymph node metastases from those at high risk [5]. High-risk patients could then be selected for less invasive surgical procedures, such as laparoscopic pelvic lymph node dissection, to identify those with negative nodes for curative therapy.

These findings supported the concept of radiation treatment of the prostate and seminal vesicles alone. With advances in CT imaging and computer programming technology, three-dimensional conformal external-beam therapy was developed [6]. This new technique enables the prostate and seminal vesicles to be treated with a high degree of accuracy while greatly decreasing the dose delivered to surrounding normal structures, such as the bladder and rectum.

Brachytherapy

The use of brachytherapy with permanent radioactive seed implants to treat early-stage prostate cancer gained popularity in the 1970s and '80s. Based on work done by Whitemore and Hilaris, an open laparotomy exposed the prostate gland, calipers measured the prostate volume, and freehand placement of needles guided seed placement into the gland [7]. Improved dosimetric evaluation and long-term follow-up often revealed a poor distribution of seeds with a corresponding inadequate radiation dose coverage. Also, patients with inadequate im- plants had high local recurrence rates based on digital rectal examination [8]. Due to these findings, brachytherapy fell out of favor as a treatment for prostate cancer.

Recent refinements in ultrasound and CT imaging led to the development of a transperineal implantation technique and spurred a renewed interest in this procedure [9-11]. The new technique achieves accurate seed placement within the gland and improved dose coverage.

Cryosurgery

Cryosurgery was pioneered as a treatment for prostate cancer in the early 1960s but was abandoned due to a high rate of complications stemming from an inability to adequately control the freezing technique [12]. Transrectal ultrasound and percutaneous tissue accessing techniques subsequently enabled the accurate placement of cryoprobes and, thus, an enhanced ability to control freezing.

Radical cryosurgical ablation is currently defined as the freezing of the entire prostate gland, periprostatic tissue, neurovascular pedicles, and proximal seminal vesicles [13]. Current cryosurgery involves a transperineal technique with placement of cryoprobes into the gland under ultrasound guidance. A urethral warming device is used to prevent freezing of the urethra, and formation of an ice ball is monitored by ultrasound imaging.

Comparing Treatment Results

It is difficult to compare results of the two most common treatment modalities, external-beam radiation therapy and radical prostatectomy. In a randomized trial comparing the two modalities conducted by the Uro-Oncology Research Group [14], radical prostatectomy was superior in terms of time to treatment failure, but the trial was faulty in many respects, including small numbers of patients and inherent methodologic problems. In addition, outcomes in the radiation therapy arm were inferior to results reported in other large single- and multi-institutional radiation oncology studies for T1 to T2 cancers, and were more consistent with results for stage T3 to T4 cancers reported by the same group [15]. Further attempts to run a comparison trial failed due to poor patient accrual [16].

Selection Bias

Difficulties in comparing the results of radical prostatectomy and radiotherapy stem, in part, from biases in selecting patients for the two modalities. In general, patients with higher PSA levels, grade, and stage are referred for radiation therapy. Emerging data suggest that pretreatment PSA is one of the most important determinants of outcome [17-19].

Recent radiation oncology series from both Massachusetts General Hospital and the Mayo Clinic show the typical PSA ranges of patients referred for radiation therapy. In the series by Zeitman et al, 53% of patients had PSA levels 10 ng/mL or less[19]. The series by Pisansky et al revealed that 50% of patients receiving radiation therapy had PSA levels < 13 ng/mL [20]. Of the patients selected for radical prostatectomy by Catalona and Smith [21] and Partin et al [22], 67% and 75%, respectively, had PSA levels 10 ng/mL or less. Within one institution, a selection bias has been demonstrated, with a larger percentage of patients with advanced-stage and higher PSA being selected for radiation therapy than for surgery [19].

In addition, patients with positive pelvic lymph nodes are thought by many to be destined to develop distant metastases [23,24].Radical prostatectomy is often abandoned if positive nodes are found, and therefore, prostatectomy series often do not include node-positive patients in treatment reports. In contrast, since patients receiving radiation do not benefit from surgical staging of their lymph nodes, radiation therapy series more often include node-positive patients. In a Stanford study, patients undergoing radiation therapy were staged surgically; 19% of patients with T1 or T2 disease had positive nodes [25].

Different End Points

Another obstacle to comparing studies stems from the different end points used to define outcome. There are methodologic differences in the detection of local recurrence following radiation therapy and radical prostatectomy. Some reports require biopsy-proven recurrence to signify local failure, whereas others use only the digital rectal examination.

Historically, most radiation therapy series have reported local failure based on digital rectal findings, which can be unreliable, rather than the more accurate method of post-treatment ultrasound-guided prostate biopsies. Post-treatment prostate biopsies have only recently been used routinely to assess local control [26].

In addition, local failure following radical prostatectomy is often difficult to detect by digital rectal examination, and prostate bed biopsies are not routinely performed. In a series by Lightner et al, 42% of patients with an elevated PSA and a normal digital rectal examination had biopsy-proven local recurrence at the site of anastomosis [27].For this reason, disease-free survival, which is also affected by local recurrence, is not the optimal end point for use in comparing treatment modalities.