The Case for Adjuvant PCa Treatment

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Research shows it can improve survival in post-prostatectomy patients at high risk for relapse.

 

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, defined 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 combination 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 chemotherapy 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).

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