Eulau and Corn provide an excellent review of the current status of neoadjuvant androgen deprivation therapy combined with radiation therapy or surgery in the management of locally advanced prostatic cancer. They comprehensively describe the published literature on neoadjuvant androgen deprivation plus surgery or radiation and correctly conclude that, despite apparent advantages, such combinations have yet to be shown to increase patient survival. Overall survival must be the ultimate end point in determining the benefit of any therapy in advanced prostatic cancer.
As the authors point out, the majority of studies dealing with the problem have involved both stage T2 and T3 patients. Although it is generally recognized that approximately 50% of tumors thought to be confined to the prostate extend beyond the prostatic capsule, it is difficult to compare studies that lump together T2 and T3 disease, given the observation that 40% to 50% of patients with clinical stage C (T3) disease already have positive pelvic lymph nodes and are unlikely to be cured by any known therapy.
Meaning of PSA Levels Following Radiation Therapy
Despite the general optimism shown by the authors for the use of radiation therapy and androgen deprivation therapy in locally advanced carcinoma, the only data showing that combination therapy may be beneficial are based on prostate-specific antigen (PSA) values following the completion of treatment. Although there is little doubt that a detectable PSA following radical prostatectomy represents recurrent disease (in the absence of the prostate, the PSA should be 0 ng/mL), the same confidence cannot be applied to serum PSA levels in the determination of recurrent disease following radiation therapy.
In our studies of neoadjuvant androgen deprivation prior to radical prostatectomy, more than 80% of patients had a serum PSA level of 0 ng/mL following 3 months of goserelin(Drug information on goserelin) (Zoladex) plus flutamide(Drug information on flutamide) (Eulexin). However, when the radical prostatectomy specimen was stained with monoclonal and polyclonal antibodies for PSA, staining of the malignant glands was found in more than 80% of cases despite a serum level of 0 ng/mL. Most interestingly, normal prostate glands or those consistent with benign prostatic hyperplasia were devoid of PSA in the luminal cells, but copious quantities were found in the malignant cells, implying that interference with secretion of PSA from the malignant cells or interference with the measurement of PSA in the serum following androgen deprivation therapy is involved.
In recent experiments, Thalmann and colleagues implanted the LNCaP cell line (a standard prostate cancer cell line-isolated from a human lymph node) in mice and treated the mice with suramin . Although serum PSA levels in the animals dropped precipitously, there was no appreciable effect on tumor growth. That this is so should not be surprising, as the ability of the malignant cell to manufacture the PSA protein is likely to be quite separate from functions necessary for cell viability. Hence, studies using only PSA values to determine response to radiation treatment or chemotherapy must be viewed with caution.
Although PSA is the most valuable marker currently available for assessing the results of therapy in patients with prostate cancer, we must appreciate that therapeutic interventions may alter PSA levels without affecting
cell growth. The fact that Radiation Therapy Oncology Group (RTOG) study 86-10, which randomized patients to either 2 months of neoadjuvant androgen deprivation plus radiation therapy or radiation therapy alone, showed that only 46% of patients treated with combined therapy (vs 26% of those who received radiation alone) had a PSA level below 4 ng/mL during the 3 years of follow-up is somewhat discouraging. This finding suggests that more stringent PSA values would have reduced the disease-free survival rate in the combination-therapy group to close to the rate in the group treated with radiation alone.
As a surgeon with a strong interest in the use of androgen deprivation plus definitive local therapy, I am encouraged to see my colleagues in radiation oncology proceeding with randomized control studies to answer these very important questions. However, as was pointed out by Dr. Hanks (reference 3 in the article), the ultimate results of any randomized trial can be correctly interpreted only in light of comparisons with similar patient groups. Thus, given the high percentage of pelvic lymph nodes that may be involved with microscopic disease, I would strongly encourage any radiation therapy studies involving stage C patients to include surgical evaluation of the pelvic nodes. In this age of minimally invasive laparoscopic surgery, the "mini-lap" surgical evaluation of the nodes can be done with minimal morbidity and should be a prerequisite for all studies in locally advanced disease, especially those designed to assess the efficacy of whole-pelvic irradiation.
Repeat Prostate Biopsies Plus PSA Needed to Assess Results
Speaking as a surgeon, and while recognizing that the ultimate end point of any therapeutic manipulation has to be based on a comparison of survival in randomized populations, I would call on my radiation oncology colleagues to encourage the use of repeat prostate biopsies as well as serum PSA to assess the results of radiation studies either alone or in combination with androgen deprivation or chemotherapy. At Memorial Sloan-Kettering, Dr. Zvi Fuks and colleagues are to be congratulated for embarking on a systematic evaluation of all patients who have received three-dimensional conformal therapy for prostate cancer. In order to avoid the difficulties inherent in interpreting biopsies done too soon after radiation therapy, we are selecting only those patients who have been treated more than 2-1/2 years prior to the biopsy regardless of serum PSA results. We believe that this will be a landmark study for assessing the effectiveness of serum PSA levels in the follow-up of patients treated with radiation therapy and will encourage our colleagues in urology, radiation oncology, and medical oncology to do other studies.
Clearly, the purpose of any local therapy, such as surgery or radiation, is the elimination of all local disease. In the case of radiation therapy, I do not believe that serum PSA is an adequate surrogate end point to replace carefully performed sextant biopsies at an appropriate time period following radiation therapy. Repeat biopsies are needed to: (1) judge the effectiveness of such treatment and (2) show the correlation between serum PSA levels and the presence or absence of residual disease. By using this strategy, it may also be possible to identify patients in whom radiation therapy is ineffective at a time when salvage prostatectomy may be considered appropriate, at least in a subset of patients.