In the realm of general oncology, patients who present with aggressive, poorly differentiated malignancies are usually at high risk for disseminated disease, and systemic therapy often supersedes local therapy in importance. It is not surprising, then, that a similar systemic approach to therapy is often considered for patients who present with high-risk prostate cancer. This recommendation is often supported by much of the surgical literature that cites discouraging outcomes in these patients when treated by radical prostatectomy alone.[1,2] Bittner et al make a strong argument that high-risk prostate cancer, as we currently define it, is not always systemic at diagnosis and that it is the adequacy of local prostate and periprostatic treatment that is most important for cure of these patients. Further, they articulate the underappreciated characteristics of brachytherapy that make this approach uniquely effective for the treatment of both intraprostatic and periprostatic disease in this setting.
Is Prostate Cancer Different?
Is it rational to believe that high-risk prostate cancers may be more localized and therefore more amenable to local therapy than our experience with other disease sites might indicate? It is worthwhile noting that prostate-specific antigen (PSA) is a uniquely sensitive marker for the presence of prostate cancer. Most other disease sites do not have the luxury of this early warning system. Although this is speculation, it is conceivable that due to PSA detection, even disease defined as "high risk" may be diagnosed prior to becoming systemic in a significant proportion of patients. But, because high-risk disease can exhibit a more aggressive and rapid growth pattern, it may result in earlier periprostatic extension or larger intraprostatic tumor burden at diagnosis—hence, the need for more effective treatment of periprostatic regions and higher intraprostatic doses than would be needed for low- or intermediate-risk disease.
The authors review a great deal of literature substantiating the fact that on pathologic investigation of surgical cases, disease often does not extend very far beyond the confines of the prostate even in high-risk cases. Over the past decade, the overall decline in positive lymph nodes found at the time of radical prostatectomy is further corroboration of this trend toward localized disease at diagnosis. If these concepts hold true, then intensifying local therapy may very well be an effective strategy for many patients.
Is Brachytherapy the Local Treatment of Choice?
Unfortunately, no randomized trials have compared the competing modalities of surgery, external-beam radiotherapy, and brachytherapy in this subset of patients. We are generally left with comparing single-institution results, which is hazardous because of obvious selection and endpoint biases. Nevertheless, despite this important limitation, outcomes appear to consistently favor brachytherapy. The authors point out that on theoretical grounds, surgery is limited in its ability to address periprostatic disease, while external-beam radiotherapy is limited in its ability to deliver the high doses of radiation needed for the reliable eradication of intraprostatic high-risk disease. On both counts, brachytherapy with a properly designed and executed implant is uniquely suited for the delivery of very high intraprostatic doses as well as effective treatment of periprostatic regions.
This article promotes the importance of creating generous periprostatic margins with brachytherapy for these patients. An additional important factor may be the intensity of intraprostatic dose. Recent work by Stock and Stone et al[4,5] demonstrates the importance of a high intraprostatic dose for optimum outcome. Using the concept of biologically effective dose (BED), these investigators demonstrated a dramatic improvement in the 10-year biochemical control rate with higher doses. Patients who received a low BED of < 100 Gy had only a 46% cure rate, whereas those receiving a BED > 200 Gy demonstrated a 92% success rate.
To a certain extent, higher intraprostatic doses usually mean larger margins, and larger margins usually result in higher intraprostatic doses. The concept of dose vs margin may simply be two sides of the same answer. Regardless of the mechanism, it is clear that high-risk disease requires an aggressive implant that accomplishes both substantial prostate dose and generous periprostatic margins. Because the other side of the coin in cancer treatment is morbidity avoidance, it is important that the brachytherapist performing these intense and generous implants is skilled, experienced, and able to avoid overdosage of critical normal structures.
Should Systemic Therapy Be Abandoned?
Should all high-risk patients be treated only with brachytherapy, perhaps in combination with regional external-beam radiotherapy? As the authors point out, the role of external-beam irradiation and/or androgen-deprivation therapy in addition to brachytherapy is unclear, and studies are urgently needed to address this issue.
What about the investigational use of chemotherapy? A valuable advance in urologic oncology would be the ability to identify patients whose disease is truly limited to the prostate and periprostatic region vs those whose disease has extended to the pelvic lymph nodes or beyond. In surgical series, the outcome of node-positive patients is dismal. Partin et al found that all patients who had positive nodes at the time of surgery had a PSA failure by 3 years. In these patients, it is unlikely that intensive local/regional therapy alone would be sufficient, and systemic therapy protocols should continue to be investigated. Unfortunately, with current technology there is no reliable way to easily identify this very high-risk subset of patients.
The article by Bittner and colleagues makes a strong case for intensive local therapy in the treatment of high-risk prostate cancer. It is likely that a significant proportion of these patients may actually have disease limited to the immediate periprostatic region at diagnosis. Brachytherapy appears to be ideally suited and successful in those patients with high-risk disease that is confined to the periprostatic region.
—John C. Blasko, MD
The main article can be found here:
Interstitial Brachytherapy Should Be Standard of Care for High-Risk Prostate Cancer