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Treatment of high-risk localized prostate cancer remains inadequate. We performed a phase II multicenter trial of neoadjuvant docetaxel plus bevacizumab prior to radical prostatectomy.
Eligibility included any of the following: PSA > 20 ng/ml or PSA velocity > 2 ng/ml/yr, cT3 disease, any biopsy Gleason 8–10, Gleason 7 with T3 disease by endorectal (er) MRI. Also, ≥50% biopsy cores involved and either Gleason 7 or PSA >10 or cT2 disease were eligible. Patients were treated with docetaxel 70 mg/m2 q 3weeks × 6 cycles and bevacizumab 15 mg/m2 q 3 weeks × 5 cycles. The primary endpoint was partial response by erMRI.
41 patients were treated. Median age was 55 yrs (range, 40–66 yrs). Baseline characteristics included: median PSA 10.1 ng/mL, cT2 49%, cT3 32%, and Gleason 8–10 73%. Thirty-eight of 41 (93%) patients completed all 6 cycles. Grade ≥ 3 adverse events were rare, though 3/41 (7%) experienced febrile neutropenia. Twelve patients (29%; 95% CI 16%, 45%) achieved a > 50% reduction in tumor volume and 22% (95% CI 11%, 38%) achieved a >50% post-treatment decline in PSA. Thirty-seven of the 41 pts underwent radical prostatectomy; there were no complete pathologic responses.
Neoadjuvant docetaxel and bevacizumab is safe, and demonstrates clinical activity, in men with high-risk localized prostate cancer. The role of neoadjuvant chemotherapy in prostate cancer, and perioperative antiangiogenic therapy in solid tumors in general, requires further elucidation through ongoing and planned randomized trials.
Prostate cancer is the second leading cause of cancer death in men in the United States.1 While radical prostatectomy is curative in the majority of patients with clinically localized prostate cancer, 30–40% of men will develop prostate-specific antigen (PSA) recurrence, many of whom will ultimately succumb to their disease.2 As has been demonstrated in other solid tumors, the integration of perioperative systemic treatment may be necessary to increase the likelihood of cure in this high-risk subset of patients.
The successful development and implementation of perioperative systemic therapeutic strategies for the treatment of clinically localized solid tumors requires both an accurate means to risk stratify patients and the availability of active systemic therapy. Furthermore, intermediate endpoints that can be utilized in the phase II setting to help guide decisions regarding the initiation of large and lengthy definitive phase III trials are desirable. In patients with prostate cancer, pre-treatment clinical and pathologic variables, including Gleason score, PSA, and clinical stage, have been shown to accurately predict PSA recurrence and cancer-related death after radical prostatectomy.3–4 Both androgen deprivation therapy (ADT) and docetaxel are active in the majority of patients with advanced disease as measured by post-treatment declines in PSA, symptomatic improvements, and prolonged survival. Finally, delivery of systemic therapy in the neoadjuvant setting affords the ability to assess response in the primary tumor, which has correlated with survival in many other solid tumors.
Several historical randomized trials exploring neoadjuvant androgen deprivation therapy prior to prostatectomy in patients with high risk localized prostate cancer failed to demonstrate an improvement in clinical outcomes. However, these trials were generally underpowered, suffered from short durations of treatment and follow-up, and did not employ optimal risk stratification.5–9 The approval of docetaxel for the treatment of advanced prostate cancer led to a renewed interest in the evaluation of neoadjuvant therapy in high-risk localized disease.10–12 We previously reported a phase II study of neoadjuvant docetaxel prior to radical prostatectomy in 19 men with high-risk localized prostate cancer, demonstrating that treatment was well tolerated and associated with PSA declines of ≥50% in 58% of patients and tumor volume reductions of ≥50% by endorectal MRI (erMRI) in 21% of patients.12 Based on the results of our study and others, a phase III study of neoadjuvant chemotherapy followed by prostatectomy versus prostatectomy alone in patients with high risk localized prostate cancer was initiated by the Cancer and Leukemia Group B (CALGB 90203) and is ongoing.
Bevacizumab is a humanized monoclonal antibody that binds to and neutralizes serum vascular endothelial growth factor (VEGF), a major mediator of tumor angiogenesis. The addition of bevacizumab to chemotherapy has led to improved clinical outcomes in patients with diverse solid tumors.13–14 Phase II studies of docetaxel plus bevacizumab in castration resistant prostate cancer15–17 have demonstrated significant activity leading to a phase III CALGB trial in patients with metastatic disease.18 Recently, this study was reported to not demonstrate a survival advantage to the combination, but did show biological activity with a longer progression-free survival in the group receiving bevacizumab. Given that tumors generally cannot grow beyond 1–2 mm3 without recruitment of the neovasculature, the benefits of inhibiting VEGF may be more substantial in the setting of micrometastatic disease.19 Therefore, we initiated a phase II multicenter trial to evaluate the safety and efficacy of the combination of docetaxel and bevacizumab in men with high-risk localized prostate cancer prior to radical prostatectomy.
This study was designed as a single-arm, 3-site (Dana Farber Cancer Institute, Beth Israel Deaconess Medical Center, Duke Comprehensive Cancer Center) phase II trial as part of the Prostate Cancer Clinical Trials Consortium.20 Eligible patients had histologic documentation of adenocarcinoma of the prostate and were candidates for radical prostatectomy. Patients were considered high risk for recurrence as defined by one or more of the following characteristics: Gleason score ≥8, Gleason score 7 and erMRI T3 disease, clinical T stage of T3a or T3b, serum PSA ≥20 ng/mL, and PSA velocity of ≥2 ng/mL/yr in the year prior to diagnosis. In addition, patients with ≥50% of the total number of biopsy cores positive for prostate cancer were eligible provided that one of the following characteristics were also present: Gleason score of 7, clinical T stage of T2a, T2b, or T2c, and/or serum PSA ≥10 ng/mL. All patients were required to be free from evidence of metatstatic disease, have an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and have a serum testerosterone of > 100 ng/dL. Patients with a history of unstable angina, symptomatic peripheral vascular disease, New York Heart Association grade ≥ heart failure, uncontrolled hypertension, myocardial infarction or stroke during the 12 months prior to enrollment, history of deep venous thrombosis or pulmonary embolism, known coagulopathy or bleeding diathesis, ongoing use of anticoagulant therapy, abdominal fistulas, gastrointestinal perforation, nonhealing ulcer or fracture, or spot urine protein:creatinine ratio > 1.0 were excluded. Other eligibility criteria included adequate hematologic, hepatic, and renal function. The protocol was approved by the Institutional Review Boards at each participating institution. Informed consent was obtained from all patients prior to enrollment.
The pretreatment evaluation included a complete medical history and physical examination including a digital rectal examination (DRE). Baseline studies included a spot urine protein:creatinine ratio, complete blood count with differential (CBC), serum chemistries including creatinine and liver function tests (LFTs), PSA, testosterone, and an electrocardiogram. All patients underwent a baseline erMRI.
The treatment plan is outlined in Figure 1. Docetaxel was administered on day 1 at a dose of 70 mg/m2 intravenously every 21-days with standard dexamethasone premedications and antiemetics. Bevacizumab was administered on day 1 at a dose of 15 mg/kg intravenously every 21-days. Combination treatment with docetaxel plus bevacizumab was administered during cycles 1–5 and docetaxel alone was administered during cycle 6. Prior to each treatment, patients underwent an evaluation including an assessment of adverse events, CBC, and chemistry panel including LFTs, PSA, and testosterone. Patients underwent a repeat DRE on Cycle 2, Day 1, and on Cycle 4, Day 1. Patients with disease progression by DRE underwent an early restaging erMRI. Toxicity assessments were performed on the day of each treatment using the Common Toxicity Criteria (CTC) of the National Cancer Institute version 3.0. The dose of docetaxel and/or bevacizumab was held and/or decreased as per an algorithm based on the specific toxicity.
Patients continued to receive therapy until completion of 6 cycles. Treatment was discontinued early in the event of progressive disease defined as at least one of the following: appearance of metastatic disease; serum PSA ≥ 150% of Cycle 1 Day 1 value, confirmed with another serum PSA taken at least 2 weeks later; increase in tumor volume by at least 50% from baseline, as measured by eMRI.
All patients were reevaluated by participating urologists for consideration of radical prostatectomy once chemotherapy was completed. The surgical approach, including decisions regarding lymphadenectomy and nerve-sparing techniques, were left to the discretion of the surgeon. The surgery was to take place between 5–8 weeks after completion of neoadjuvant therapy (Week 23–26), allowing for full recovery from the last cycle of chemotherapy.
Anti-tumor response was assessed with an erMRI repeated after completion of 6 cycles of neoadjuvant therapy (week 18). A response was defined as a decrease in tumor size of >50% for the largest lesion in the prostate by erMRI using methodology as previously described12 and as noted in the statistical design section. Serum PSA levels were checked at baseline, with each cycle of therapy, 4–6 weeks after radical prostatectomy, then at least every 6 months during the 5 year follow-up period. All radical prostatectomy specimens were submitted to a reference pathologist (M.B.) for central review.
The primary objective of this study was to determine the response rate to neoadjuvant docetaxel plus bevacizumab as defined by a decrease in tumor size of >50% of the largest prostatic lesion by erMRI. Secondary objectives included evaluation of safety, pathologic complete response rate, post-treatment PSA changes, post-surgical PSA recurrence-free survival, and surgical results associated with improved outcome (margin negativity, lack of lymph node involvement).
This trial was designed as a Simon two-stage single arm phase II trial with a target alpha of ≤ 0.06 and a target beta of ≤ 0.20. Response was defined as a decrease in tumor size by >50% by erMRI from baseline to week 18. For this primary endpoint, tumor size was calculated as follows: On the baseline erMRI, one target prostate cancer lesion was identified. This lesion was identified on T2 weighted non-contrast imaging. The target lesion was identified as the largest of the lesions in the prostate and was ideally > 0.5 mm3. The target lesion was measured and recorded by its longest diameter in 3 dimensions to derive a volumetric measurement. This measurement required a >50% reduction in size for the patient to be considered a responder.
Our previous data suggested that an erMRI response rate of <18% would not be of interest (similar to docetaxel alone)12, while an erMRI response rate of ≥ 35% would be worthy of further investigation. In the first stage, 17 patients were accrued. If < 4 responses were observed, the study would stop. If ≥ 4 responses were observed, an additional 25 patients would be accrued in stage 2. If at the completion of enrollment, ≥ 12 responses were observed, the regimen would be deemed worthy of further study.
An early stopping rule for toxicity was also employed. After 17 patients were discharged from the hospital following their radical prostatectomy, their hospital course, including their surgery and time in the hospital after surgery, were reviewed by a team of physicians including at least one urologist and one medical oncologist for toxicities that occurred during the hospitalization that were both serious and unexpected (including, but not limited to, Grade 3 or 4 bleeding events, Grade 3 or 4 venous or arterial thromboembolic events, and wound dehiscence). If three or more such unexpected Grade 3 or 4 adverse events occurred, plans were to close the study to further enrollment. With this rule, the probability of detecting a true unexpected serious toxicity rate of 30% was 92.3%.
Between July 2006 and November 2008, 42 patients were enrolled on study; however, one patient withdrew from the study prior to receiving any treatment. Therefore, a total of 41 patients were included in the analysis. The baseline patient characteristics are presented in Table 1. The median age of enrolled patients was 55 years (range, 41–67). The majority of patients had cT2 (49%) or cT3 (32%) disease and a Gleason score of 8–10 (73%). The median baseline PSA was 10.5 (range, 2.1–62.5).
Three of the 41 patients discontinued neoadjuvant therapy prior to completion of all 6 cycles (docetaxel-related allergic reaction = 1, patella fracture = 1, rising PSA = 1). The treatment delivery is outlined in Table 2. The median duration of protocol therapy (from day 1 cycle 1 until the date of radical prostatectomy) was 5.3 months (range, 1.4–6.3 months). Thirty-seven of the 41 patients underwent radical prostatectomy. The reasons for not proceeding with surgery in the remaining 4 patients included: a Foley catheter-related puncture of the bladder neck and rectum prior to surgery, surgeon’s decision based on results of lymphadenectomy, and withdrawal of consent in 2 patients. The median time from completion of chemotherapy to radical prostatectomy was 1.2 months (maximum, 1.8 months).
The treatment-related adverse events experienced by > 10% of patient are outlined in Table 3. The vast majority of adverse events were low grade and consistent with previously described side effects of docetaxel and bevacizumab. Notably, there were no episodes of Grade 3 or 4 hypertension, bleeding, gastrointestinal perforation, or thromboembolic events. There were 3 episodes of febrile neutropenia.
The median procedural time for the 37 patients undergoing radical prostatectomy was 240 minutes (range, 119–308) and median blood loss was 500 mL (range, 75–1700). Two patients experienced Grade 2–4 adverse events that extended hospitalization, both were Grade 3 intraoperative rectal injuries (one of these related to the Foley catheter placement noted above). The median number of hospital days during admission for radical prostatectomy was 3 days (range, 2–11).
Endorectal MRI responses were evaluable in 38 patients. Reasons for the lack of erMRI response data in the remaining 3 patients included: discontinuation of treatment after cycle 3 (n=1) and lack of measurable target lesions (n=2). A waterfall plot detailing the post-treatment changes in tumor volume by erMRI is shown in Figure 2. Twelve of 41 patients (29%; 95% CI 16%, 45%) achieved a > 50% reduction in tumor volume.
A waterfall plot demonstrating the post-treatment changes in PSA is shown in Figure 2. Any degree of PSA decline was noted in 76% (95% CI 60%, 88%) of patients while 22% (95% CI 11%, 38%) achieved a > 50% post-treatment decline in PSA. Several patients achieving a post-treatment decline in PSA experienced an increase in tumor volume on erMRI and vice versa (Figure 2).
Of the 37 patients who underwent radical prostatectomy, 24 (65%, 95% CI 47%, 80%) achieved a nadir <0.1 ng/mL post-surgery. Eighteen of the 37 (49%) patients have developed recurrence post-prostatectomy as defined by a PSA ≥ 0.2ng/mL (confirmed by subsequent PSA ≥0.2) or initiation of additional therapy. The median time to recurrence from the date of prostatectomy was 13.0 months (range 1.2–41.5+ months). The results of the central pathologic review are presented in presented in Table 4. No patients achieved a pathologic complete response.
The median testosterone level after completing chemotherapy was 382 ng/ml (range, 164–909). No patients experienced a decline in testosterone level to < 50 ng/ml during treatment with docetaxel plus bevacizumab.
The current study demonstrates the safety and anti-tumor activity of neoadjuvant docetaxel plus bevacizumab in patients with high-risk localized prostate cancer. Specifically, this study shows that this combination can be administered with rare grade > 2 toxicities and uncommon intra-operative or peri-operative complications. Furthermore, the majority of patients achieved a reduction in tumor volume by erMRI (with 29% patients achieving a reduction of > 50%, meeting the study’s primary endpoint) and decrease PSA (with 22% patients achieving a reduction of 50%). Unfortunately, similar to other reported neoadjuvant studies, no complete pathologic responses were observed.
The role of neoadjuvant single-agent docetaxel in high-risk localized prostate cancer is in evolution and a large randomized phase III trial (CALGB 90203) is ongoing.21 We previously demonstrated that single-agent docetaxel was associated with a reduction of tumor volume of >50% in 21% of patients12 compared with 29% of patients in the current study of docetaxel plus bevacizumab. However, the small sample sizes of these studies and problems inherent in cross-study comparisons make conclusions regarding incremental improvements problematic. Furthermore, while tumor down-staging by MRI represents a non-invasive intermediate endpoint obtainable in the vast majority of patients on the current study, whether or not erMRI response correlates with progression-free survival or overall survival has not yet been established and is the subject of ongoing work. Also of note, in the current study, erMRI responses did not directly correlate with post-treatment declines in PSA, a finding that also warrant further evaluation, and correlation with long-term clinical outcomes, in an effort to define an optimal intermediate endpoint for neoadjuvant prostate studies. Though complete pathologic responses to neoadjuvant therapy have been associated with improved long term outcomes in other solid tumors, complete pathologic responses have been an extremely rare event in neoadjuvant prostate cancer studies. Ultimately, the results of CALGB 90203 will be required to determine if the responses achieved with docetaxel-based neoadjuvant therapy in prostate cancer are sufficient to improve clinical outcomes.
The results of the current study must be interpreted in the context of additional clinical data regarding the use of bevacizumab that has emerged since the conduct of this trial. CALGB 90401 was a randomized phase III trial of docetaxel versus docetaxel plus bevacizumab in patients with castration-resistant metastatic prostate cancer.18 While CALGB 90401 demonstrated that the combination regimen was associated with a statistically significant improvement in response rate and progression-free survival, there was no significant improvement in overall survival with the addition of bevacizumab. Despite these findings, the mechanism of action of antiangiogenic therapy in patients with bulky established metastatic disease (e.g., vascular normalization and improved chemotherapy delivery) may be quite different than the mechanism in patients at high risk for micrometastatic disease (e.g., preventing metastases through inhibition of recruitment of the neovasculature). In this regard, the results of National Surgical Adjuvant Breast and Bowel Project (NSABP) C-08 and the AVANT study are more concerning. Both of these randomized phase III trials, exploring the use of adjuvant chemotherapy plus bevacizumab in high-risk localized colon cancer, failed to demonstrate an improvement in relapse-free survival with the addition of adjuvant anti-angiogenic therapy.22 The results of ongoing randomized studies exploring perioperative bevacizumab in other solid tumors will be helpful in determining if docetaxel plus bevacizumab warrants further evaluation as neoadjuvant therapy in prostate cancer.
The role of integration of ADT into neoadjuvant regimens is also worthy of discussion. Several randomized trials have explored varying durations of neoadjuvant androgen-deprivation therapy prior to prostatectomy.5–9 These trials have generally revealed improved tumor down-staging and a lower rate of positive surgical margins with the use of neoadjuvant hormonal therapy, though no significant impact on long-term clinical outcomes. Prostate cancer xenograft studies have demonstrated conflicting findings regarding the impact of treatment sequence on combination chemotherapy plus hormonal therapy with one study suggesting improved activity with simultaneous administration and another demonstrating optimal growth inhibition with docetaxel followed by ADT.23–24 Phase II studies have demonstrated the feasibility and activity of docetaxel plus ADT as neoadjuvant therapy prior to prostatectomy with one study demonstrating 2 complete pathologic responses.10 The combined chemohormonal approach is being explored in the ongoing CALGB 90203.
In summary, the current study demonstrates the safety and activity of docetaxel plus bevacizumab as neoadjuvant therapy prior to prostatectomy in patients with high-risk localized prostate cancer. Given that subsets of patients will likely benefit preferentially from both docetaxel and bevacizumab, molecular correlates of response to treatment on the current trial are being analyzed and will be reported separately. The role of neoadjuvant chemotherapy in prostate cancer, and perioperative antiangiogenic therapy in solid tumors, requires further elucidation through the results of ongoing randomized clinical trials.
Support: Genentech, Sanofi-Aventis
Presented in part at the 2009 and 2011 American Society of Clinical Oncology Annual Meeting