Neoadjuvant PCa Therapy: An Update

Men with localized high-risk tumors are at significant relapse risk after surgery or radiotherapy

In the PSA era, most men with newly diagnosed prostate cancer present with clinically localized disease and are curable with surgery or radiation. Among patients with no evidence of metastasis at presentation, radical prostatectomy alone is associated with 10- and 15-year cancer-specific survival rates of 96% and 93%, respectively, and post-operative periods of biochemical progression-free survival of 77% and 75%, respectively. Approximately 25%-35% of men believed to have localized cancer fail to be cured following definitive local therapy, most of whom require some form of systemic therapy.

Predicting which patients with localized disease are at risk for failing localized therapy can be done with some accuracy by evaluating several important clinical factors. Prior to surgery, prostate cancer is characterized ac-cording to three main factors: extent of disease (clinical by digital rectal examination), tumor grade (biopsy-based Gleason patterns) and serum PSA level. For greater predictive value, tables and nomograms that combine these three variables—such as the Partin table and the Kattan nomogram—are used to crunch these numbers and stratify patients according to risk. Following surgery, additional information is available, including surgical margins, level of prostatic capsular invasion, and involvement of seminal vesicles, and lymph nodes. Using these additional data and methods, patients who might have occult metastatic disease that could lead to a recurrence after surgery can be identified, and enrollment in a trial of systemic therapy should be offered.

For patients categorized as high risk for recurrence after local therapy, the timing and type of systemic therapies must be considered. Optimal timing remains unclear and is under investigation. Neoadjuvant therapy (preceding surgery or radiation) allows for earlier exposure of any micro-metastases to treatment. Since surgical pathology specimens are garnered after neoadjuvant therapy, pre- and post-treatment specimens can be compared, and mechanisms of drug action and resistance potentially elucidated. In contrast, adjuvant therapy (administered after primary localized treatment) targets the primary cancer first. Advocates claim that with the adjuvant course, early prostate removal provides important pathologic information sooner and allows for better staging and patient selection. Patients may also receive systemic therapy concurrent with radiation treatments.

Experience in other cancers demonstrates that multimodal strategies improve patient outcomes. For prostate cancer, various types and combinations of systemic therapies are under investigation. The most commonly used systemic therapies include androgen deprivation therapy (ADT) and chemotherapy.

In a study by Bolla et al, patients who chose external beam radiation as their local modality had improved disease-free and overall survival with the addition of adjuvant androgen deprivation treatment (N Engl J Med. 1997;337:295-300). In an effort to improve outcomes even more for this population, ongoing and future studies will investigate higher radiation doses, whole pelvis irradiation, the addition of chemotherapy to hormonal therapy, and other treatments.

At present, neoadjuvant hormonal therapy in conjunction with radical prostatectomy for locally advanced disease is not advisable. Studies show it can reduce the incidence of positive margins, but this effect has not correlated with reduced likelihood

of biochemical recurrence.

Based on data from the 1970s and '80s, chemotherapy was not thought to benefit men with prostate cancer. Research in Canada and the United States in the 1990s revealed a palliative benefit—but not a survival benefit—among patients with hormone-resistant prostate cancer (HRPC) treated with prednisone and mitoxantrone (J Clin Oncol. 1996;14:1756-1764; J Clin Oncol. 1999;17:2506-2513). In recent years, the taxane class of anti-neoplastics has become the focus of research for patients with advanced androgen-independent prostate cancer. Based on laboratory studies, taxoids appear to have significant activity against prostate cancer in vitro and in vivo. Docetaxel (Taxotere; Sanofi-Aventis Pharmaceuticals), a semisynthetic toxoid, induces apoptotic cell death through inhibition of microtubule depolymerization and through effects on bcl-2 and bcl-xL gene expression. In 2004, two separate randomized phase III trials were published showing a significant survival advantage among men treated with neoadjuvant docetaxel plus either prednisone or estramustine compared with mitoxantrone plus prednisone (N Engl J Med. 2004;351:1502-1520).

Several phase II trials of regimens containing a taxane plus other potent hemotherapeutic agents administered prior to radical prostatectomy have been completed. In one study, neoadjuvant paclitaxel was given in combination with estramustine and carboplatin in 36 patients with high-risk prostate cancer (J Urol. 2004;171:709-713). Thirty-four patients completed four cycles of chemotherapy, one patient completed two cycles, and one completed six cycles. Significant adverse effects included deep venous thrombosis in 22% of patients and immediate perioperative complications in 17%. All prostate specimens had evidence of pathology and positive surgical margins were found in 22%. Half of these patients remained free of biochemical recurrence at a median follow-up of 20 months.

In a separate trial, researchers looked at the feasibility of short-course high-dose docetaxel as a single neoadjuvant agent in men with locally advanced prostate cancer, establishing the baseline effect of this agent (Urology. 2004;63:1138-1142). The study enrolled 29 men with clinical stage T2b malignancy, a PSA level of 15 ng/mL or greater, or a Gleason sum 8 or greater, with no evidence of metastatic disease. The men were given docetaxel (40 mg/m2 IV) weekly for six weeks. Eighty percent of the patients completed all six weeks of therapy and 97% underwent RP. Docetaxel induced a significant drop in serum PSA pre- and post-treatment (from 12.0 to 8.42 ng/mL). Twenty-four percent of participants experienced a greater than 50% reduction in PSA level in response to docetaxel alone. There were no unexpected toxicities or intraoperative complications. All patients had residual carcinoma of the prostate at surgery. After a median follow-up of 23 months, more than two thirds of patients were alive and disease free.

These trials have laid the foundation for a paradigm shift in the treatment of high-risk but localized prostate cancer, and important studies are underway and being planned to evaluate neoadjuvant and adjuvant chemotherapy strategies. A neoadjuvant study currently enrolling patients is CALGB 90203, which is examining neoadjuvant chemotherapy (docetaxel) plus hormonal therapy (a luteinizing hormone-releasing hormone agonist) prior to radical prostatectomy. Eligibility criteria are detailed at www.clinicaltrials.gov.

The many treatment questions surrounding locally advanced prostate cancer will remain unanswered unless there is a boost in recruitment into clinical trials, especially multicenter phase III studies. Data show that subject accrual in prostate cancer trials lags far behind that for breast cancer, despite similar numbers of new patients and opportunities for enrollment (Urology. 2004;63:1138-1142).