Management of Locally Advanced Prostate Cancer

Introduction

Prostate cancer has overtaken lung cancer as the most prevalent malignancy in males, and is now the second most common cause of cancer death in men. As the proportion of elderly males in the population has grown, so too has the incidence of prostate cancer. Improved screening programs, utilization of the prostate-specific antigen (PSA) blood assay, and a greater awareness of prostate cancer as a disease entity have resulted in a dramatically increased overall detection rate, particularly for organ-confined tumors.

Up to two-thirds of newly diagnosed cases of prostate cancer are clinically confined to the gland at presentation. Therapeutic intervention, including surgery or radiation, will be recommended for many of these patients. Those men with distant metastatic disease at initial diagnosis will likely receive hormonal therapy. Finally, a subset of patients will present with locally advanced disease. Therapeutic alternatives for this last group of patients are quite varied, and there is no clear consensus as to which alternative is most appropriate.

Natural History

The choice among the different management options for prostate cancer patients, particularly those with locally advanced lesions, is made more difficult by the complex natural history of the disease. Similar to other malignancies, progression of prostate cancer is related to both disease stage and tumor grade at the time of diagnosis. The rate and severity of progression, however, often are much slower with prostate cancer than normally seen with other common tumors.

In a study by Johansson et al, patients who presented with low-stage prostate cancers did not receive treatment until the time of disease progression. Only 8.5% of these patients ultimately succumbed to prostate carcinoma, and the 10-year disease-free survival rate was 86.8%. The same study emphasized the importance of tumor grade. Patients initially diagnosed with grade 3 (poorly differentiated) tumors had a relative risk of dying from their prostate cancer 58.4 times that of patients with grade 1 (well-differentiated) tumors.[1]

Research by Stamey et al demonstrated the effect of prostate cancer volume on disease progression. Most tumors with volumes moer than 12 cm³ are associated with adverse pathologic features, including nodal disease and seminal vesicle invasion. Larger tumors, therefore, are more likely to metastasize,[2] while prostate cancer lesions with volumes less than 4 cm³ rarely spread.[3]

Prostatic capsular penetration by tumor cells, also has prognostic significance, particularly important are the location and amount of capsular violation. Epstein et al reported a higher rate of tumor progression in the presence of established penetration of the capsule, as compared with focal involvement.[4]

Staging

Prostate cancer has traditionally been staged according to the American Urological Association (AUA) classification as stage A, B, C, or D; more recently, the tumor, node, metastasis (TNM) system has gained popularity (Table 1). The term "clinically locally advanced prostate cancer" refers to lesions defined as clinical stage C or T3-T4, N0 disease. These cancers have penetrated through the prostatic capsule, often invading the seminal vesicles.

Clinical staging of prostate cancer can be imprecise. In a review of 703 men with clinically localized prostate cancer, Partin et al found that as many as 38% had established capsular penetration during pathologic examination following radical prostatectomy.[5] Nodal metastasis varies in frequency according to tumor grade and stage, and is seen more often in the setting of seminal vesicle involvement than gross capsular penetration.[6]

Staging Modalities

Digital rectal examination (DRE) is the oldest staging modality, but is limited in its inability to give precise estimates of tumor volume and in the differentiation of stage B from early stage C lesions.[7] Phillips and Thompson found that only 39% of their clinical B1 patients had pathologically confined tumors at the time of prostatectomy.[8] Digital rectal examination is unlikely to overstage, however, and patients with evidence of locally advanced disease on physical examination will usually have extraprostatic tumor extension on pathologic evaluation.

Prostate-specific antigen has gained widespread use in the detection and monitoring of prostate carcinoma. Although PSA levels can be suggestive of tumor volume and stage, categorical values for determining various stages do not exist currently.

Transrectal ultrasound (TRUS) is an imaging tool utilized primarily to guide needle biopsy of the prostate. Estimates of TRUS staging accuracy vary, with a sensitivity of 35% to 85% for extracapsular extension.[9-16] Tranrectal ultrasound-guided needle biopsy of suspicious periprostatic regions can confirm the presence of non-organ-confined disease.

Tranrectal ultrasound has been shown to be a more accurate staging tool than DRE. In one study, TRUS correctly predicted the local extent of disease in 84% of patients, whereas DRE understaged 64% of patients.[17]

Computed Tomography (CT) has been insufficiently accurate for preoperative staging of prostate cancer and fails to demonstrate the needed precision to evaluate for local extent of this disease.[18-22]

Magnetic Resonance Imaging (MRI)--The staging efficacy of MRI has improved with the introduction of endorectal coil techniques; sensitivity ranges from 37% to 80% for body coil MRI vs 63% to 91% for endorectal coil MRI).[13,23-29] Studies comparing the staging efficacy of TRUS and MRI have shown a sensitivity for advanced disease from 35% to 66% for TRUS, 47% to 76% for body coil MRI, and 91% for endorectal coil MRI.[13,14,16]

Relative to body coil imaging, endorectal coil MRI provides higher contrast and better spatial resolution when imaging the prostate, capsule, and perioprostatic tissues, including the neurovascular bundles and seminal vesicles (Figures 1 and 2).[30-33] Fast-spin echo-pulse sequences, as well as the use of glucagon(Drug information on glucagon), can further improve image quality while decreasing examination time and motion artifact.[28,34] The multicoil array technique offers more uniform signal-to-noise ratios and better image resolution for the evaluation of extracapsular disease and visualization of the anterior aspect of the gland.[20,27,32,34] Post-biopsy hemorrhage can be misinterpreted as extracapsular tumor extension, and staging accuracy improves significantly when MRI of the prostate is deferred for at least 21 days after biopsy.[35]

D'Amico et al recently demonstrated that endorectal coil MRI improved the detection of clinically unsuspected seminal vesicle involvement and extracapsular extension in a heterogeneous subgroup of patients with moderately elevated PSA (more than 10 to 20 ng/mL) and a Gleason score of 5 to 7.[36] A limiting factor with present imaging techniques is the inability to detect microscopic capsular penetration. However, endorectal coil MRI is the standard to which all imaging is compared for staging efficacy analysis.[27,36] It is the imaging modality of choice when assistance with clinical staging is required.