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© 2000 American Society for Clinical Oncology Neoadjuvant Chemotherapy and Hormonal Therapy Followed by Radical Prostatectomy: Feasibility and Preliminary ResultsFrom the Departments of Urology, Pathology, and Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX. Address reprint requests to Curtis A. Pettaway, MD, Department of Urology, Box 110, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; email cpettawa@ mdanderson.org.
PURPOSE: We assessed the feasibility and efficacy of integrating chemotherapy and androgen ablation with radical prostatectomy in patients with locally advanced prostate cancer. The neoadjuvant approach was adopted because it allows an in situ assessment of antitumoral activity.
PATIENTS AND METHODS: Thirty-three patients were enrolled who met the clinical criteria of stage T1–2, Gleason score of RESULTS: Chemotherapy complications were comparable to those reported with this regimen previously. No major intraoperative complications occurred. Postoperative complications occurred in 10 (33%) of 30 patients. One patient died at home after discharge (postoperative day 17; no autopsy was performed). Ten (33%) of the 30 patients had organ-confined disease, and 20 (70%) of 30 had extraprostatic extension; 11 (37%) of the 30 had positive lymph nodes. Only five (17%) of 30 exhibited positive surgical margins. All patients achieved an undetectable PSA level postoperatively, and 20 of the surviving 29 patients remain without disease recurrence with a median follow-up of 13 months (range, 9 to 18 months). CONCLUSION: Chemotherapy and androgen ablation followed by radical prostatectomy was feasible in patients with locally advanced prostate cancer. Although the goal of achieving a 20% rate for pT0 status was not achieved, we believe this type of integrated therapeutic strategy should be investigated further for its ability to alter the course of regionally advanced prostate cancer.
THE WIDESPREAD use of prostate-specific antigen (PSA) testing for the early detection of prostate cancer has resulted in a stage migration away from gross distant disease at presentation to clinically localized disease at presentation.1 However, because of the constraints of anatomic staging modalities, we continue to understage prostate cancer that is thought to be clinically organ-confined in 35% to 50% of cases.2,3 Several recent studies suggest that the criteria for successfully delivering curative therapy in prostate cancer patients using single-treatment modalities (ie, radical prostatectomy, external-beam radiation therapy, or interstitial brachytherapy) include clinically organ-confined prostate cancer, a PSA level of less than 10 ng/mL, and the absence of poorly differentiated components within the cancer (ie, Gleason score of < 7).4-8 For patients who exhibit adverse prognostic factors, a significant risk for treatment failure exists because of the volume of local tumor, the presence of extraprostatic extension, or the presence of occult metastases. A potential solution for patients who desire radical prostatectomy (RP) has been to combine either preoperative hormonal therapy or postoperative adjuvant radiation therapy with surgery. However, preoperative hormonal therapy has failed to benefit patients with clinical stage T3 disease.9-11 Furthermore, the decrease in positive surgical margins noted in patients with stage T2 prostate cancer has failed to decrease the rate of biochemical failure with up to 3 years of follow-up.10-14 Neoadjuvant hormonal therapy clearly affects a population of prostate cancer cells; however, relatively androgen-insensitive cells remain within the prostate, extraprostatic tissue, seminal vesicles, and lymph nodes. This is evidenced by the fact that a pT0 status within the prostate is rarely attained, and the incidence of seminal vesicle involvement and positive lymph nodes remains largely unaffected by preoperative hormonal therapy.10-14 In a contemporary series of 507 men who underwent radical prostatectomy (and were lymph-node negative), the sites of relapse were distant (20%), local (10%), and both distant and local (9%), and PSA elevation alone in 61%.15 Adjuvant radiation therapy in this setting would theoretically benefit only a subset of such patients and would not address systemic micrometastases that could contribute to biochemical failure. In fact, in two recent studies of patients undergoing adjuvant radiation therapy after prostatectomy in the setting of positive seminal vesicles or high-grade disease, only 37% to 45% of patients did not have relapse at 5 years.16,17 One could interpret this data to indicate that micrometastatic and androgen-independent clones are established in patients with regionally advanced prostate cancers. Thus neoadjuvant androgen ablation or adjuvant radiotherapy when combined with surgery could still be theoretically ineffective. The impetus to consider the early use of chemotherapy for prostate cancer is the evidence that it possesses antitumor activity in patients with significantly advanced cancer. Recent data suggests that combination chemotherapy is active in patients with metastatic androgen-insensitive prostate cancer, with response rates in the 30% to 67% range.18-21 In a series of clinical trials at The University of Texas M.D. Anderson Cancer Center (Houston, TX), a high PSA response rate was noted.18,20 As with other combination chemotherapy regimens, the PSA responses were reflected in parallel decreases in the size of soft tissue masses when present.18 Other investigators have reported similar experiences.19,21 The rationale for the four-drug combination regimen (ketoconazole, doxorubicin, vinblastine, and estramustine) that we used in this study has been previously reported.18 Given our experience and the relative efficacy and toxicity profile of this combination, we hypothesized that this regimen could be combined with surgery. Thus if chemotherapy and androgen ablation were additive (or synergistic) therapeutic modalities, a dual therapeutic advantage could be achieved in eradicating extraprostatic and distant androgen-sensitive and resistant cell populations. Specifically, both an increased rate of local control and control of micrometastasis could be achieved. Furthermore, utilizing such a strategy in the neoadjuvant setting before surgery would allow for a rapid in vivo assessment of therapeutic response. The assumption that formed the basis of this trial was that chemotherapy combined with androgen ablation would both increase resectability and control the micrometastasis in select patients with advanced prostate cancer. As an initial step, we explored the feasibility of combining chemotherapy and androgen ablation with surgery as initial therapy for patients with locally advanced prostate cancer.
Patients Between April 23, 1997, and January 15, 1998, 33 patients were enrolled on an institutionally approved phase I/II protocol to assess the feasibility and efficacy of delivering 3 months of combined androgen blockade and systemic chemotherapy before RP. Eligibility criteria are listed in Table 1, and surgical candidates included men at risk for adverse pathologic features (and disease relapse) after prostatectomy as defined by digital rectal examination (DRE), pretherapy PSA, and Gleason score characteristics.22 Criteria for acceptable hematologic, renal, and hepatobiliary function are also listed in Table 1. Patients were excluded from participation for the following reasons: (1) androgen ablation or corticosteroid use of greater than 2 months’ duration, (2) documented metastases subsequent to clinical staging, (3) an elevated serum enzymatic acid phosphatase test (method of Roy et al23 ), (4) life expectancy of less than 10 years due to comorbid illness, and (5) infection with human immunodeficiency virus or chronic hepatitis B or C.
Staging Evaluation The tumor-node-metastasis staging system was used.24 To assign local stage, patients underwent DRE and transrectal ultrasound (TRUS). TRUS was performed with the Bruel and Kjaer 1846 ultrasound machine (Bruel and Kjaer, Marlboro, MA) using a 7.0-MHz transducer. Total prostate volume was measured using a planimetric step section method at 2-mm intervals before and after systemic therapy. However, individual tumor volumes were not routinely calculated. Confirmation of extraprostatic extension of cancer on the basis of equivocal DRE results was obtained in some cases with biopsies of extraprostatic fat or seminal vesicles. Clinical stage T3 was not assigned on the basis of TRUS findings alone. Chest x-ray, computed tomography of the abdomen and pelvis, and radioscintigraphic bone scans were required of all participants before study entry to rule out the existence of obvious metastatic disease.
Treatment
The end point of the clinical trial required 30 patients to complete systemic therapy and undergo prostatectomy. Thirty-three patients were placed on trial (three declined prostatectomy after initial treatment). No maintenance androgen ablation was planned after surgery. Toxicity effects were assessed via the National Cancer Institute common toxicity scale (grades 1 through 5) during therapy. RP was to be performed according to protocol within 1 month of systemic therapy completion as long as granulocytic and coagulation variables had normalized. A standard anatomic dissection was performed as described by Walsh25 using a non–nerve-sparing technique. Because the patients were at risk for extraprostatic extension of cancer and positive surgical margins, techniques to widely excise periprostatic tissue along the rectum were used.26 If a lymph node was considered to be grossly positive at the time of pelvic lymphadenectomy, frozen section confirmation was obtained; if the node was confirmed to be positive, then the prostatectomy was not performed. Because of the potential for thromboembolic phenomena, sequential compression devices were used intraoperatively and discontinued on ambulation (postoperative day 1). In addition, aspirin (80 to 325 mg/d) was given postoperatively when oral intake was resumed and continued for a 1-month period. Operative reports were dictated immediately within 24 hours after the procedure by the staff surgeon (using an agreed-upon template) and included an assessment of the difficulty of various components of the operative procedure (eg, pelvic lymphadenectomy, apical and rectal dissection), operative time, and estimated blood loss. Perioperative transfusion requirements and early postoperative complications (within 30 days) were assessed by chart review and telephone calls to the patients.
Pathology
Statistical Considerations
Follow-Up
For the purposes of defining disease recurrence, an undetectable PSA level was defined as either
Clinical Characteristics The clinical characteristics of the study population are listed in Table 3. Approximately one half of the patients were younger than 60 years. Clinical or pathologic stage T3 prostate cancer was found in 18 (55%) of 33 patients before treatment. Twenty (61%) of 33 patients had prostate cancer with a Gleason score of  8. One patient with a Gleason score of 6 was admitted to the study with multiple bilateral positive biopsies and repeated PSA levels of greater than 45 ng/mL. Twenty (61%) of 33 patients had a serum PSA level of greater than 10 ng/mL, with 36% of patients having serum PSA levels of greater than 20 ng/mL.
Toxicity Thirty-three patients received at least one of two planned courses of chemotherapy and could be evaluated for toxic effects. Thirty-one (94%) of 33 patients completed both courses. The incidence rates of adverse events ranged from 3% to 36%. The most common adverse events (occurring in 15% of patients) were grade 1-2 hematologic laboratory abnormalities (granulocytopenia, leukopenia, anemia), elevated liver transaminases, nausea, stomatitis, headache, peripheral edema, local skin reactions, and fatigue. Potentially significant hematologic toxic effects (grade 3-4) were noted in four (12%) of the 33 patients; however, no infectious complications were associated with these events. Two patients with fever and normal WBC counts were treated with oral antibiotics; in retrospect, they were found to have positive blood cultures. Repeat cultures were negative and no sequelae were noted. Three patients (9%) required hospitalization during systemic therapy. One of these patients developed a transient ileus requiring nasogastric decompression. The second patient developed a severe headache that was associated with anxiety and hypertension. Both findings resolved after anxiolytic therapy, and a computed tomography scan of the brain was normal. These two patients refused further systemic therapy. The third patient who required hospitalization developed a central vein thrombosis in association with an upper-extremity long-line catheter as he completed the second course of therapy. The patient received anticoagulation therapy and had the catheter removed. This patient subsequently proceeded with RP (deep venous thrombosis prophylaxis was administered) without incident. A fourth patient requiring hospitalization developed biliary colic and jaundice after chemotherapy and underwent laparoscopic cholecystectomy. RP was delayed 10 days for this patient. Four patients had hyperglycemia at least once during therapy; however, only one patient required treatment (blood glucose > 400 mg/dL). Grade 3 elevation of liver transaminases occurred in one patient; levels returned to normal after antiandrogen therapy was discontinued. Overall, 30 (91%) of 33 patients completed systemic therapy and underwent RP at approximately the scheduled time point. Two patients refused further chemotherapy, and a third patient refused surgery after completing the systemic regimen.
RP The median operative time (from Foley catheter placement to skin closure) was 300 minutes (range, 195 to 527 minutes), with a median operative blood loss of 1,100 mL (range, 500 to 5,200 mL). Nine of thirty patients (30%) required at least one unit of homologous blood. The median hospital stay was 4 days (range, 2 to 6 days). Complications occurring within 30 days of radical prostatectomy are listed in Table 4. Three patients were sent home (postoperative days 5, 3, 5) with closed suction drains. The first patient of these was readmitted with a soft tissue infection involving the drain tract. This resolved with intravenous antibiotics and drain removal. The other two patients had initial high drain outputs that were determined to be urine. Both urine leaks stopped by postoperative day 7, and the drains were removed without sequelae. Two patients had leg edema during perioperative period; deep venous thrombosis was ruled out with Doppler ultrasonography and the edema resolved. One of two patients with vomiting required readmission to the hospital for 3 days for treatment of dehydration. Serum electrolyte and cortisol levels were determined to rule out an addisonian-like state, and results were normal.
One patient died at home unexpectedly on postoperative day 17. This patient had been discharged home on postoperative day 5 after an unremarkable hospital course. Although no autopsy was performed, it is likely that the patient died from a massive pulmonary embolus, which is a known complication of RP.
Pathology
PSA and TRUS Sequential Measurements Sequential PSA levels were obtained in all patients undergoing RP. Fifteen (50%) of 30 patients achieved an undetectable serum PSA level (< 0.1 ng/mL) before surgery. Six of these patients had received up to 2 months of therapy before referral. The distribution of RP findings with respect to the status of organ confinement, seminal vesicle or lymph node invasion, and surgical margins was similar regardless of whether an undetectable (< 0.1 ng/mL) serum PSA level was reached before surgery. Twenty-five patients underwent TRUS examination immediately before and after systemic therapy. Eighteen (72%) of 25 patients who underwent TRUS exhibited at least a 20% decrease in prostate volume after therapy, with 13 (52%) of 25 achieving a 30% decrease. However, ultrasound-detected prostate volume changes were unrelated to pathologic stage.
Follow-Up
The results of this trial indicate that the combined use of chemotherapy and androgen ablation followed by surgery in patients at high risk for disease relapse is feasible. The toxicity seen with KAVE chemotherapy was similar to that which we previously reported and did not affect the patient’s ability to undergo surgery.18 By using a vinblastine dose of 4 mg/m2 of body-surface area, we avoided some of the acute gastrointestinal side effects that we previously reported. Of greatest concern to the development of this combination regimen was the high rate of thromboembolic phenomena reported with vinblastine and estramustine-based therapy, with deep venous thrombosis and peripheral edema noted in 18% and 49% of patients, respectively.18 In the current series, only one patient developed an upper extremity central vein thrombosis in association with an intravenous catheter, with six patients (18%) having mild edema during chemotherapy. These latter events may be due to the estrogenic effects of estramustine being exacerbated by hydrocortisone. The lower incidence of these events in the present series of patients may be due to the relatively short duration of therapy. In addition, the daily hydrocortisone dose was decreased from 35 mg in our previous study18 to 30 mg. Overall, the systemic regimen was well tolerated in this otherwise healthy surgical population. No studies have reported on the feasibility of combining contemporary combination chemotherapy and androgen ablation with surgery, although previous reports suggest that the concept is feasible.10,32 In the study by Von Poppell et al,10 the use of neoadjuvant estramustine did not substantially increase the surgical complications of RP. Androgen ablation alone also did not increase surgical complications of RP in two other studies.12,13 We found that dissecting the prostate off the rectum was the most difficult part of the procedure because of a desmoplastic reaction that we attributed to the KAVE regimen and AA. This was reflected in a longer than usual operative time (median, 300 minutes). Because the incidence of positive surgical margins was only 17%, we believe that these reactive changes represented fibrosis that was possibly related to therapy. Previously, Van de Voorde et al33 described an increased incidence of fibrosis and lymphocytic infiltration in the prostates of patients treated with estramustine rather than flutamide before prostatectomy. An in-depth histologic assessment of RP specimens in the present study to assess therapy-related changes is currently in progress. Although the rectal dissection was more difficult, there were no rectal injuries, and the operative blood loss and length of hospital stay are consistent with those reported in a series of patients undergoing RP after neoadjuvant therapy or for stage T3 prostate cancer.12,13,34 The incidence of early postoperative complications (within 30 days of surgery) was also consistent with those reported in other recent reports. We were concerned that the combination of chemotherapy and corticosteroid replacement might predispose patients to wound-healing problems. The incidence of wound-related problems (infection, hernia, and hematoma) ranges from 4% to 18% in patients undergoing RP for stage T2b-T3 prostate cancer with or without neoadjuvant therapy.12,34 Two (7%) of 30 patients in the current series had wound problems that resolved with conservative management. Furthermore, no fascial dehiscences occurred. Prolonged drainage because of either lymphatic fluid or urine occurs in 4% to 6% of similarly staged patients,12,34 and results were not significantly different for the present series. All drains were removed by postoperative day 7. Postoperative thromboembolic events are a potentially devastating complication and were of considerable concern in the present trial because of the administration of estramustine in combination with RP. The incidence of thromboembolic events (deep venous thrombosis, pulmonary embolus) was 5.5% in a series reported from the Mayo Clinic that consisted of 232 patients undergoing RP for stage T3 cancer.34 In the Canadian Neoadjuvant Therapy Trial,13 thromboembolic events occurred in 4% and 8.7% of patients treated with surgery alone or with neoadjuvant cyproterone acetate, respectively (one death occurred in the latter group). In the present study, all patients received sequential compression devices at surgery and were ambulated on postoperative day 1. In addition, aspirin therapy was begun by postoperative day 3 and continued for a month. Although no documented thromboembolic events occurred, we believe that the only death in the trial was probably related to a pulmonary embolus (one of 30 patients, 3.3%), as the patient had no history of coronary artery disease and his death at home was sudden (postoperative day 17). Long-term follow-up will be necessary to evaluate the effects of the combined regimen on urinary continence, bladder neck strictures, and sexual quality of life. However, because non–nerve-sparing RP was performed in all cases, it is anticipated that spontaneous erections will be rare.35 The results of our trial do not establish the efficacy of neoadjuvant chemotherapy and androgen ablation. In the absence of any reliable surrogates to assess the effect of therapy on the androgen-independent clones, our only definitive measure of antitumoral activity was the total disappearance of cancer. We hypothesized that a 20% rate of total disappearance of cancer would be sufficient evidence to justify a phase III trial if no excess toxicity occurred. This calculation was based on reported rates of achieving such pT0 status of 0% to 4% with neoadjuvant androgen ablation alone.9-14,30 Subsequent to pathologic evaluation, however, variable amounts of cancer persisted within the prostate, periprostatic tissues, seminal vesicles, and/or the regional lymph nodes in all patients. Thus we did not achieve one of our objectives. Approximately 50% of patients with clinically confined high-grade cancer actually had organ-confined disease. In contrast, only 18% of patients with clinical T3 cancer were downstaged after surgery. Considering errors in clinical staging, it is difficult to assess the significance of these findings without a control group. However, data obtained with respect to surgical margin status strongly suggest that the current regimen had a therapeutic effect. In four contemporary series, the incidence of positive surgical margins in patients with locally advanced prostate cancer ranged from 46% to 65% without neoadjuvant androgen ablation, compared with 18% to 28% when such ablation was given.11-14 In the present series, the 17% rate (five of 30 patients) for positive surgical margins compares favorably with the latter group and suggests that improved resectability may have been achieved in most of these patients with high-grade advanced cancers. Clearly, early follow-up indicates that a positive surgical margin is synonymous with biochemical failure (five of five patients). This may be due to the aggressive phenotype of residual therapy-resistant cells at the margin of resection. At present, nine patients (31%) have developed a detectable serum PSA level, and the treatment is considered a failure in these patients. Follow-up in the remaining 20 patients (13 months) is too short to determine the ultimate relapse-free survival rate. It is our view that this trial will serve as the basis of future trials. The molecular and cellular characterization of posttreatment prostatectomy specimens may allow us to develop intermediate end points that will serve as surrogates of efficacy. In addition, defining markers of resistance to therapy may assist in developing novel therapeutic targets. Such studies may lead to the development of clinical trials that will allow us to improve therapies for patients with locally advanced prostate cancer at an accelerated pace. In conclusion, the combined use of neoadjuvant chemotherapy and androgen ablation with RP was feasible, and we did not detect an increased incidence of complications associated with RP compared with similarly staged patients reported in the literature. Although the goal of achieving a 20% rate for pT0 status was not achieved, we believe that a favorable surgical outcome with respect to surgical margin status was achieved. Studies to define the molecular mechanisms of drug resistance in resected surgical specimens are in progress. This concept of multimodal integrated therapy should be investigated further for its ability to alter the course of regionally advanced prostate cancer.
Sponsored in part by the Robert Wood Johnson Foundation, Princeton, NJ (C.A.P.), and TAP Pharmaceuticals, Deerfield, IL (L.F. and C.J.L.)
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
0.1 ng/mL on the Tosoh assay (Tosoh Inc, San Francisco, CA) or, for patients seen by referring physicians, values less than the biologic limit of detection for the PSA assay used. Treatment failure was defined as (1) failure to achieve an undetectable PSA level, (2) two subsequent increases above the biologic limit of detection (ie, PSA value of 
