Research shows it can improve survival in post-prostatectomy patients at high risk for relapse
By Mario A. Eisenberger, MD
WITH WIDESPREAD screening now the norm, prostate cancer is being detected with increasing frequency and at earlier stages than in previous years. At least 90% of cases are metastasis-free at diagnosis and most patients undergo local treatment. Patients with locally advanced disease, however, are at high risk of recurrence and thus are more challenging to manage.
Consideration of systemic therapy, including adjuvant therapy, is warranted, researchers say.
Adjuvant chemotherapy has been shown to improve survival in patients with breast, colorectal, and lung cancers, and is being studied in prostate cancer patients. Compared with neoadjuvant therapy, the timing of adjuvant therapy after prostatectomy carries several advantages, including improved staging and the availability of more information with which to select candidate patients. There are also clinical and biologic benefits. The tumor burden that remains after surgery might be more sensitive to chemotherapy because of its lower volume, reduced heterogeneity, and higher growth fraction, i.e., a shorter cell cycle. Additionally, the vascular supply is preserved, reducing hypoxia to the region.
A recently completed review of 379 men who underwent radical prostatectomy between 1982 and 2000 revealed that patients were more likely to die from their disease if a recurrence occurred within three years compared with later recurrence (J Urol. 2006;176:1404-1408). This may be due to a more rapid doubling time with some tumors, and supports the need to seriously consider adjuvant chemo in high-risk patients. This review highlights several recent important studies examining post- operative adjuvant therapy given as either hormonal (androgen deprivation therapy [ADT]) or chemotherapy. (Some of the trials are still seeking patient participants.)
Adjuvant chemotherapy
Docetaxel (Taxotere), a broadly active taxane, is the most active compound for patients with hormone refractory disease and the only treatment shown to prolong survival in these patients. A multi-institutional pilot study (TAX-2501) demon-strated the feasibility of adjuvant docetaxel in patients at high risk for relapse after radical prostatectomy. Subjects were given docetaxel 35mg/m2 once weekly for three weeks per month over a six-month period. The main study end point was time to biochemical relapse, de-fined as PSA level greater than 0.2 ng/mL and rising. Outcomes were compared against a matched group of historical controls.
At a median follow-up of 28 months, 46 of 76 evaluable patients (60%) had disease progression. Median progression-free survival (PFS) was nearly 16 months in adjuvant treated patients, which was superior to a predicted median Kaplan-Meier PFS of 10 months using the Kattan nomogram. The most common adverse event was hyperglycemia, experienced by six patients (7.8%) with grade III and two (2.6%) with grade IV tumors. Other significant toxicities included dyspnea in four (5.2%), fatigue in three (3.9%), leukopenia in three (3.9%), and nausea, diarrhea, dizziness, and edema.
To further evaluate the role of adjuvant systemic treatments with hormones and or chemotherapy a multi-institutional, global phase III study (TAX-3501) is currently actively accruing patients. The specific aims of this study are to test whether immediate systemic treatment with either androgen deprivation treatment alone or in combin-ation with docetaxel is more effective than deferred (at the time of PSA relapse defined as 0.4 ng/mL or greater) with the same treatment regimens. The basis for this design is that the post-surgical cancer-cell burden is sufficiently small to succumb to immediate adjuvant chemotherapy. If left untreated, however, these residual cells would potentially have multiplied several times by the time recurrence is detected, rendering deferred che-motherapy less effective against such a high tumor burden. Furthermore, dual therapy with hormonal and chemotherapeutic components would potentially enhance the effects of systemic treatment by targeting both tumor cell populations of hormone-sensitive and hormone-independent cells.
A 2 x 2 factorial design will allow for assessment of both aspects of adjuvant therapy described above. Patients at high risk for relapse following prostatectomy for localized disease will be randomized into one of four groups: immediate adjuvant therapy with androgen deprivation treatment (leuprolide) alone; immediate adjuvant therapy with leuprolide plus docetaxel combined; deferred treatment with leuprolide alone; and deferred combined therapy. Leuprolide will be given every three months for a total of 18 months and docetaxel will be administered every three weeks for six doses. To qualify for this study, patients must have a post-surgical PSA level below 0.2 ng/mL and at least one of the following risk factors: seminal vesicle invasion, positive lymph nodes, or Gleason grade of 7 or higher, and either positive margins or cancer outside the gland (pT3).
SWOG-9921 is another study addressing whether adjuvant hormonal therapy alone is sufficient to prevent relapse or whether combined chemotherapy and hormonal therapy is more effective. The trial, which recently stopped enrolling patients, randomized patients with cT1-T2b disease treated locally with radical retropubic prostatectomy (RRP) into one of two treatment arms: hormonal therapy consisting of subcutaneous goserelin once every 13 weeks and oral bicalutamide once daily for two years, or the same hormonal regimen plus IV mitoxantrone once every three weeks for six cycles and oral prednisone twice daily.
In a separate randomized phase III trial, the VA Cooperative Study #553, adjuvant chemotherapy with docetaxel and prednisone will be compared with active surveillance for recurrence in a cohort of high-risk post-RRP patients. If PSA progression is detected, patients will receive treatment with radiation therapy or ADT.
Conclusion
Many questions regarding the management of locally advanced prostate cancer remain unanswered. Further research is needed to determine the best candidates for treatment, optimal types of combinations, and durations of treatment. Adjuvant therapy has many valid theoretical benefits to patients and early research supports its feasibility in post-prostatectomy patients who are at high risk for relapse.
The clinical paradigms in prostate cancer have shifted considerably to earlier phases of the disease over the past several years. Most patients have no evidence of metastasis today and consequently the role of our systemic modalities of treatment, hormonal therapy and chemotherapy, is much less well defined. Clinical trials represent the appropriate way of defining new standards of care and provide the opportunity to evaluate new approaches that may enhance the quality and quantity of life of our patients. Clearly the benefits from treatment in the early disease (non-metastatic) paradigm are most likely much more consequential to our patients than the primarily palliative effects in the end-stage metastatic stage of the disease. As a medical community, we need to encourage more patients to participate in clinical trials. Of the 20,000 high-risk patients who undergo prostatectomy annually, a mere 1% are en-rolled, a clear sign that greater awareness and recruitment is needed.
Dr. Eisenberger is the R. Dale Hughes professor of oncology and urology at Johns Hopkins Univer-sity in Baltimore.