The optimal management of patients with suspected or proven residual disease following radical prostatectomy for prostate cancer remains uncertain. Controversy still exists as to whether initial or primary treatment alters the natural history of patients when compared with watchful waiting.[2,3] There is no clearer evidence regarding the value of subsequent adjuvant or therapeutic local and/or systemic therapy.[4,5]
Adjuvant systemic therapy in the form of hormones (eg, luteinizing hormone-releasing hormone [LHRH]) has improved the disease-free survival[6,7] and survival of high-risk patients following radiation therapy. High-risk patients were defined as those with locally advanced (stage T3-4) disease, poorly differentiated (Gleason score more than 8) tumors, or regional lymphatic metastases. The optimal timing of hormonal intervention would appear to be at, or before, the discovery of overt distant disease but prior to symptom development. Unfortunately, there have been no similar trials following radical prostatectomy.
Patients at risk for residual disease are advised to receive adjuvant local treatment with radiation following their surgery.[8-12] Risk factors, historically defined by reviewing the surgical pathology specimen, include positive margins, extracapsular extension, seminal vesicle and lymph node involvement, and grade (Table 1).[13-15] Other risk factors include tumor volume, DNA ploidy and the preoperative prostate specific antigen (PSA) level. Combinations of multiple risk factors (eg, stage, Gleason score, and margins) increase the predictive value for recurrence (Table 2).
Adjuvant radiation in patients at risk for recurrence appears to reduce that risk with minimal toxicity.[4,8-12] Several nonrandomized, single-institution studies have demonstrated that doses ranging from 45 to 64 Gy decrease the probability that the disease will recur. (Table 3). No survival advantage has been demonstrated thus far. However, a recent randomized trial coordinated by the Southwest Oncology Group (SWOG) that compared observation to postoperative radiation will eventually answer this question. Until this issue is resolved, however, the routine use of adjuvant irradiation is determined on a case-by-case basis.
The arguments against the use of adjuvant radiotherapy stem from its association with rectal injury or worsening incontinence. These risks are compounded by the fact that 50% to 70% of patients receiving treatment will not have local recurrences and thus are exposed to the risks of treatment without any benefit. Finally, the widespread use of neoadjuvant hormonal therapy, resulting in pathologic downstaging in up to 50% of patients, makes the assignment of a probability for recurrence based on patients' surgical pathologic specimen less accurate.[19,20]
Post-prostactectomy PSA levels have revolutionized the ability to detect treatment failures. An elevated post-operative PSA level (less than 0.4 ng/mL) is pathognomonic for residual/recurrent disease. Unlike pathologic risk factors, a rising postoperative PSA level is specific for residual disease. However, a patients elevated PSA level may indicate local disease, systemic disease, or both. A number of procedures can discern where the residual disease is.
Most patients evaluated for an elevated postoperative PSA undergo radiographic studies, including CT and/or bone scanning. However, for patients with a PSA £ 1.0 ng/mL, the yield of these studies is extremely low. Scintigraphic scans using a radiolabeled monoclonal antibody to PSA-m (Prostascint) have demonstrated residual disease in 60% of those with an elevated PSA. However, the sensitivity of this test is unknown and the specificity may be suspect due to the lack of pathologic confirmation of abnormalities in most reports.
Transrectal ultrasound (TRUS) may reveal abnormalities in the prostate bed. Pathologic correlation of these abnormalities denotes locally persistent disease in 40% to 75% of patients who are biopsied, depending on the number and location of the biopsies performed.[24,25] Hence, many patients with an elevated postoperative PSA level will not have demonstrable disease. Since serum PSA is specific for local recurrence and response to radiation is tumor-volume-dependent, treating patients early before they have overt evidence of disease should improve the probability of success.
To increase the specificity of an elevated postoperative PSA for predicting local disease, investigators have evaluated the pathologic stage, Gleason score, postoperative PSA nadir, timing and rate of PSA rise, absolute PSA level, and response to local treatment.[26-28] Patients with seminal vesicle or lymph node involvement at the time of surgery have a significantly higher rate of distant failure in conjunction with PSA elevation. However, up to 30% of those who are pathologic stage T3c,N0 can be cured with therapeutic post-prostatectomy radiation. A similar pattern of failure has been reported for patients with high Gleason scores (³ 8).
Patients who achieve an undetectable postoperative PSA that subsequently rises are more likely to harbor residual local disease than those who never achieve an undetectable level. Delayed and/or slowly rising PSA levels are also reported to favor local vs systemic recurrence. Finally, patients with a lower level of PSA at the time of therapeutic irradiation (£ 2.0 ng/mL) are more likely to respond to treatment with a further decline in PSA, suggesting a higher probability of local disease only.[29,32-33] Although, each of these factors predicts for a greater chance of local-only disease, nodal stage is the only relative contraindication to a course of curative therapeutic irradiation.
A number of factors influence the efficacy and safety of postoperative radiotherapy. These include the volume, dose, field arrangement, and level of PSA. Elective nodal irradiation has not influenced the outcome of localized prostate cancer patients treated definitively with radiotherapy. In the postoperative setting, especially in patients without pathologic nodal involvement, there is no evidence of clinical benefit from elective pelvic irradiation. However, it does significantly increase the volume of bladder and rectal irradiated. The lack of benefit, coupled with the increased volume and possible risks of irradiation, suggest that elective nodal irradiation is not an important component of postoperative radiotherapy and should be eliminated.
Field arrangements have varied from unblocked rotational or four-field box techniques to three-dimensional (3D) conformally blocked multifield plans, including axial and nonaxial beam arrangements. Target volume is defined as the prostate and seminal vesicle bed and can be recreated using either preoperative imaging studies or postoperative radiographic findings, such as clips. It is recommended that patients be treated with a full bladder, and that simulation with intravesicle and urethral contrast be done to help identify the lower border of treatment, especially in those with positive apical margins.
Although it is often assumed that the volume of normal bladder and rectum receiving full-dose radiation would be greater in the postoperative setting than in patients with an intact prostate, this assumption was recently disputed.
Sharma et al showed that the field size and volume of the rectum and bladder were identical in patients receiving conformal axial plus nonaxial fields either definitively or postoperatively. As a consequence, the risk of chronic bladder or rectal complications were equal.
The probability of complications and control correlates, most likely, with the dose given; however, not enough data have been published to support this theory. Doses ranging from 50 to 74 Gy have been reported, but no clear dose response has been identified. If doses of 60 to 64 Gy are sufficient in the adjuvant setting, doses of 66 to 70 Gy are suggested as therapeutic radiation for an elevated postoperative PSA. These doses have proven to be effective and safe.[26,29]
During therapeutic postoperative radiotherapy, we have monitored the pattern of PSA decline on a weekly basis. Ninety percent of patients experienced a decline during treatment. Those who experienced a significant increase subsequently developed evidence of failure within 18 months.
This is unlike the use of radiation therapy in patients with an intact prostate; in this situation, the PSA level may increase in 30% to 50% of patients, possibly as a result of radiation-induced prostatitis.[37,38] It is consistent with the observation that the risk of acute genitourinary toxicity is significantly lower in patients receiving postoperative vs definitive radiotherapy, however. Therefore, the symptoms often attributed to radiation cystitis may more often be due to radiation prostatitis, which does not occur in the post-prostatectomy setting.