Docetaxel Followed by Hormone Therapy in Men Experiencing Increasing Prostate-Specific Antigen After Primary Local Treatments for Prostate C
http://www.100md.com
《临床肿瘤学》
the Greenebaum Cancer Center and Department of Radiology, University of Maryland School of Medicine and the Baltimore VA Medical Center
Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD
ABSTRACT
PURPOSE: Prostatectomy or radiation for localized prostate cancer (PC) can fail in up to 15% to 30% of patients. The purpose of this study was to determine feasibility, tolerability, and outcome of docetaxel followed by hormone therapy in men experiencing an increasing prostate-specific antigen (PSA) after their primary local treatments for PC.
PATIENTS AND METHODS: Men with increasing serum PSA after prostatectomy or/and radiation were eligible. Serum PSA had to be 4 ng/mL and serum testosterone had to be in the noncastrate range. Treatment included docetaxel 70 mg/m2 every 3 weeks for up to six cycles, followed by total androgen suppression (luteinizing hormone-releasing hormone agonist plus bicalutamide) and peripheral androgen blockade (finasteride plus bicalutamide) for 12 to 20 months.
RESULTS: Thirty-nine men were enrolled; 32 had PSA-only failure, seven also had clinical metastasis. Baseline median PSA was 13.7 ng/mL. Serum PSA decreased 50% in 17 of 35 patients (48.5%) and 75% in seven of 35 patients (20%) with docetaxel. The PSA decreased to a median of 0.1 ng/mL with subsequent hormone therapy. In 28 of 33 patients the PSA increased (median, 0.41 ng/mL) at a median follow-up of 2.3 months after treatment. In contrast, in five of 33 men the PSA remains at 0.1 ng/mL at a median of 18.9 months after therapy; three of these five men had soft tissue metastasis at entry but remain in complete remission. The most common grade 3 to 4 toxicity was neutropenia (61.5%).
CONCLUSION: Docetaxel followed by hormone therapy of limited duration may provide disease control in subgroups of men experiencing failure after local treatments for PC.
INTRODUCTION
Currently, no specific consensus exists regarding management of patients who develop an increasing serum prostate-specific antigen (PSA) after initial local therapies (surgery or/and radiation) for localized prostate cancer (PC). 1- 6 Although an increasing PSA after surgery or radiation likely reflects the presence of residual or recurrent PC, the risks for subsequent clinical metastasis in these patients vary. 7- 11
One approach in such patients who exhibit an increasing PSA has been to institute hormone therapy such as gonadal or total androgen suppression (TAS), antiandrogen monotherapy, or peripheral androgen blockade (PAB). Androgen deprivation (AD) can provide control of the increasing PSA and the underlying disease. However, as in metastatic PC, over time AD can fail in men experiencing PSA-only failure after their local therapies despite a possible lead-time bias that may occur because of the earlier institution of hormone therapy.
Chemotherapy traditionally has been used in metastatic hormone-resistant PC (HRPC). However, clinical hormone resistance may be associated with a relatively chemotherapy-resistant state. 12- 14 In addition, preclinical models demonstrate that although AD is cytocidal for a majority of the androgen-sensitive prostate cells, a subpopulation of cells with altered bax-to-bcl2 ratios emerges within weeks of the hormone ablation (which can make prostate cells resistant to apoptosis). 15 Thus, cytotoxic drugs identified to have activity in HRPC may also be active, and perhaps more so, in hormone-sensitive/naive PC (HSPC). Given that hormone ablation by itself is unlikely to be curative, and if chemotherapy is to be integrated with hormone therapy for a potentially better therapeutic effect, then a reasonable approach would be to treat PC patients with chemotherapy first, followed then by hormone ablation, with the latter aimed at the androgen-sensitive components of the disease.
With this rationale in mind, we treated men with PC who developed an increasing PSA after radical prostatectomy (RP) or/and radiation with single-agent docetaxel because of its demonstrated activity in advanced HRPC. 16- 24 The docetaxel was followed by hormone therapy, with both treatments given for a defined period. The aims of the study were to determine the response to chemotherapy and hormone therapy of hormone-sensitive patients with PC who exhibit an increasing PSA, as well as to determine outcome of the overall treatment in this patient population.
PATIENTS AND METHODS
Eligibility
Before enrollment, all patients gave written informed consent. Patients with histologically documented prostate adenocarcinoma who initially underwent local therapies for localized/locally advanced disease but then experienced disease relapse with an increasing PSA were eligible. Patients could have received a short duration ( 6 months) of prior hormone ablation, given in the neoadjuvant/adjuvant setting with the local therapies, provided their serum testosterone was not in the castrate range at trial entry (men were required to have serum testosterone levels 50 ng/dL). Serum PSA had to be 4 ng/mL, documented on three separate occasions measured at least 2 weeks apart.
Positive findings on baseline computed tomography (CT) scans and/or technetium-99m bone scintigraphy (bone scans) were not necessarily an exclusion criteria. Patients had to have Eastern Cooperative Group performance status of 0 to 2, life expectancy more than 24 months, and no other serious medical or psychiatric illness. Prior exposure to chemotherapy was not allowed. Required baseline laboratory parameters were WBC 2,500 cells/μL, granulocyte count 1,500 cells/μL, platelets 100,000/μL, hepatic aminotransferase levels 2.5x institutional upper limits of normal, and bilirubin no more than the institutional upper limits of normal.
Treatment
Patients were given docetaxel 70 mg/m2 intravenously during 1 hour every 21 days for up to six cycles. They were premedicated with dexamethasone 8 mg orally given twice a day for 3 days starting the day before each docetaxel dose. TAS was instituted 3 weeks after the last docetaxel treatment. TAS consisted of luteinizing hormone releasing hormone agonist (leuprolide acetate 30 mg intramuscularly or goserelin acetate 10.8 mg subcutaneously) plus bicalutamide 50 mg/d orally. Patients were treated with 4 or 12 months of TAS; 12 months of TAS was given if there were any positive findings on CT and/or bone scans or to patients whose serum PSA remained more than 4 ng/dL after the first 4 months of TAS. In general, maximal responses to hormone ablation are achieved in a majority of patients within the first several months of instituting gonadal androgen suppression or TAS therapy. Therefore, after a defined period of treatment with TAS, additional hormone therapy in the form of PAB was used, again for a limited duration, because of the relative testosterone-sparing properties and likelihood of fewer, lower-intensity adverse effects of the latter treatment. After TAS, PAB was continued for another 8 months. PAB consisted of bicalutamide 50 mg/d orally plus finasteride 5 mg/d orally. Overall, patients received 12 to 20 months of hormonal therapy (TAS plus PAB) after the initial docetaxel.
Outcome Assessments
The main end points were to determine PSA response (and objective response in those men with measurable disease) to the chemotherapy and hormone therapy components of the treatment regimen, as well as duration of response after completing treatment. Secondary end points included assessment of toxicity of the treatment, impact on quality of life (QOL), and effects on serum testosterone levels.
For toxicity assessment, the National Cancer Institute Common Toxicity Criteria (version 2.0) was used. PSA was measured at the beginning of each docetaxel cycle and monthly during hormonal therapy. Post-treatment follow-up was every 2 months for the first year and every 3 months thereafter. Radiographic studies were obtained at baseline and at completion of the treatment. In patients with positive imaging studies, these were also repeated on completion of chemotherapy (ie, before hormone therapy). Radiographic studies were obtained during follow-up if there was progression by PSA criteria. Guidelines using PSA criteria for response and progression have been established by the PSA Working Group for androgen-independent PC. 25 No such guidelines exist for patients such as those treated in the present trial. PSA response in this trial was defined as 50% reduction in serum PSA of the pretreatment value, confirmed with a second PSA at least 2 weeks apart. PSA progression was defined as more than 50% increase of the nadir PSA, measured on two consecutive occasions, and an increase in the absolute PSA by at least 5 ng/mL. Progression on imaging studies was defined as appearance of new bone lesions and/or 25% increase in the sum of the products of the perpendicular diameters of measurable lesions on CT scans.
There is a paucity of data regarding response to single-agent docetaxel administered every 3 weeks in HRPC (PSA decline 50% has been reported in 38% to 46% in small series 16, 17), and essentially no such data exist in HSPC. Although it was likely that responses to the chemotherapy and hormone therapy components of the treatment regimen would be different in the enrolled patient population, in this trial response (PSA response or/and objective response) to the chemotherapy component was used for an optimal two-stage design; the statistical power of the study was at least 90%, with type I error of 10%.
Serum testosterone levels were measured before and after docetaxel, during and at completion of hormone therapy, and during subsequent follow-ups until recovery to noncastrate levels. For QOL, the Functional Assessment of Cancer Therapy–General (FACT-G) questionnaire and the Functional Assessment of Cancer Therapy–Prostate (FACT-P) scale (version 3) were used. 26- 28 Patients were asked to complete the questionnaires before and after chemotherapy, and at the completion of TAS and PAB therapy. Wilcoxon signed rank sum test was used to compare the QOL measures at each time point during treatment.
RESULTS
Patients
Between September 2, 1999, and September 17, 2001, 39 men (19 white, 20 African American) entered onto the trial. Baseline characteristics are listed in Table 1: median age, 66 years; median Gleason score, 7 of original PC; median serum PSA at entry, 13.7 ng/mL; and median serum testosterone, 338.5 ng/dL. Initial local therapies included RP in 25 men (64%), with 16 also receiving external radiation (seven patients receiving adjuvant radiation, nine patients receiving salvage radiation). Fourteen patients (36%) received radiation as their primary local therapy (11 patients receiving external-beam radiation therapy, three patients receiving brachytherapy). Five men had 4 to 6 months of AD with their local treatments. Baseline imaging studies demonstrated that seven of the 39 patients had positive CT (n = 3) or bone scans (n = 4) but not both (Table 1). Two of the three men with positive CT scans had multiple bilateral pulmonary nodules (biopsy-confirmed PC in one), whereas one patient had intra-abdominal adenopathy.
Treatment Outcome
Thirty-five men received four (n = 3; docetaxel was limited to four cycles in three men because of neutropenic infection or polyneuropathy) or six (n = 32) cycles of docetaxel. The other four men received only one dose of docetaxel before being taken off study (one withdrew consent, three had unanticipated toxicities; see Toxicity). After chemotherapy, 33 men received hormone therapy; 27 had 4 months and six 12 months of TAS. Thirty-two men completed PAB after TAS; one patient became noncompliant after TAS and did not keep follow-up appointments, although he was alive at the time of this report. There were four deaths among the original 39 patients; two men completing chemotherapy died before initiating or completing TAS from myocardial infarction/cardiac arrest, one patient who had been taken off study after one cycle of docetaxel also died from myocardial infarction (all three deaths were believed to be unrelated to docetaxel), whereas the fourth patient died as a result of prostate cancer progression.
PSA responses to docetaxel are listed in Table 2. A 50% decline in serum PSA occurred in 17 of 35 patients (48.5%) with the docetaxel. In seven of the 35 men, a 75% decrease in serum PSA occurred with chemotherapy. Included in the latter group are three men who received only four doses of docetaxel but their PSA declined by 99.5%, 99%, and 91%, respectively. Only in one patient did the PSA actually increase at the completion of docetaxel by 28% of baseline value. In none of the 35 men treated with docetaxel were the testosterone levels altered significantly, despite dexamethasone premedication with each docetaxel infusion (Table 3).
Table 4 lists the PSA response to hormone therapy. As listed in Table 3, all men achieved castrate serum testosterone levels after 4 months of taking TAS, and as expected, serum PSA declined further (Table 4). The median PSA at completion of 4 months of TAS was 0.1 ng/mL (range, 0.1 to 7.5 ng/mL) compared with the post-docetaxel/pre-TAS median of 5.7 ng/mL (range, 0.1 to 90 ng/mL). At completion of PAB, the median PSA remained 0.1 ng/mL (range, 0.1 to 3.2 ng/mL), whereas serum testosterone recovered to noncastrate levels in all but one patient (Table 3).
The majority of men entering the trial had PSA-only failure. However, seven also had metastasis at enrollment; six patients completed the entire treatment. Three patients had soft-tissue–only disease (pulmonary nodules in two patients, intra-abdominal adenopathy in one patient). Both patients with the pulmonary nodules had a 78% decrease in serum PSA and more than 50% decrease of the pulmonary nodules after six cycles of docetaxel (Table 5). The residual pulmonary lesions disappeared after patients took TAS for 4 months. For the patient with intra-abdominal adenopathy, a 99.5% decrease in serum PSA occurred after only four doses of docetaxel. Although imaging studies were not obtained after chemotherapy in this patient, no residual adenopathy was found in the abdomen after he had been taking TAS for 4 months (Table 5). In the three men with positive bone scans at baseline, although the serum PSA decreased with chemotherapy and hormone therapy, essentially no changes occurred on serial bone imaging (Table 5).
Median time from end of treatment to last follow-up for the 33 patients completing treatment is 26 months (range, 5 to 39.8 months). An increase in serum PSA occurred in 28 men at a median of 2.3 months after treatment (the median PSA at first increase was 0.41 ng/mL). In 20 of these patients, the PSA reached 5 ng/mL or greater at a median of 7 months from the time PAB was completed to last follow-up. In contrast, in five patients the PSA has remained 0.1 ng/mL at a median follow-up of 18.9 months after treatment. Included in this group are the three men who also had soft-tissue disease at study entry. All three men have remained disease free on repeat imaging 11 to 19 months from the time they completed their therapy. In three of the 33 men who received both chemotherapy and hormone therapy, clinical progression has occurred despite reinstitution of hormonal therapy. Of the four deaths among the original 39 patients, only one was due to progression of the prostate cancer.
FACT-P evaluations were available for 32 patients (Table 6). There was no significant change in QOL on the FACT-G (which assesses global QOL) from baseline through treatment to post-treatment. On total FACT-P, which incorporates both FACT-G and the prostate-specific subscale, a significant difference was noted from baseline to after docetaxel therapy (P = .02), but not from baseline to after TAS or after PAB. Significant differences were noted in scores on the prostate subscale from baseline to after chemotherapy (P = .05), from baseline to after TAS (P = .03), and from baseline to after PAB (P = .01). Data from the FACT-P surveys suggest that chemotherapy had a negative impact, consistent with the toxicities from chemotherapy, whereas adverse effects of androgen suppression would most likely account for the decline in mean scores on the prostate subscales. Overall, the FACT-G and FACT-P instruments demonstrate that the treatment regimens did not significantly influence QOL in most patients on this study.
Toxicity
Toxicity data are presented in Tables 7 and 8. A total of 208 doses of docetaxel at 70 mg/m2 were given among the 39 enrolled patients. Four patients were taken off study after only one dose of docetaxel; one withdrew consent and the other three had unexpected grade 3 or 4 toxicities. One patient fell and fractured both ankles. The second patient developed grade 3 pancreatitis within 48 hours of docetaxel infusion. This patient had a prior history of alcoholism; apparently the alcohol-based solvent used to reconstitute the docetaxel triggered the pancreatitis. In the third patient, grade 3 gastrointestinal bleeding of diverticular origin occurred.
The most common grade 3 to 4 toxicity with chemotherapy was neutropenia, with five episodes of febrile neutropenia (three had documented infections). Twenty-seven separate episodes of grade 3 or 4 neutropenia were observed among the 208 doses of docetaxel given (13% incidence). In total, grade 3 and/or 4 neutropenia occurred in 24 of the 39 enrolled patients (61.5%). No patient had grade 3 anemia or thrombocytopenia. In the two patients with grade 3 elevations in serum aminotransferases, the abnormal liver function tests returned to baseline values over time. Grades 3 and 4 nonhematologic toxicities were infrequent (Tables 7 and 8). Whether the one episode of grade 3 polyneuropathy was due to the docetaxel or some other process is difficult to ascertain. Overall, the incidence of chemotherapy-related adverse events in this trial is similar to that observed with docetaxel in advanced HRPC. During the hormonal phase, most of the adverse effects that occurred during docetaxel treatments resolved, although as expected, low-grade fatigue persisted, and nondebilitating episodes of hot flashes were noted (Table 9).
DISCUSSION
It is apparent that men with HSPC are sensitive to single-agent docetaxel; there was either stabilization or decline of the increasing serum PSA with only a short duration of docetaxel treatment (Table 2). In HRPC, single-agent docetaxel (75 mg/m2 every 3 weeks) has shown response rates (defined as 50% decline in serum PSA) of 38% to 46%. 16, 17 By these criteria, docetaxel is at least as effective in our HSPC patient population, with 48.5% of the patients showing 50% decline in serum PSA (Table 2). A subgroup of HSPC patients exists who appear to be particularly sensitive to docetaxel; 20% of the patients had 75% decrease in serum PSA, with three experiencing 91% to 99.5% decrease with only four doses of docetaxel. In two of the three patients with documented soft-tissue disease, a 78% decrease in serum PSA was accompanied by a concomitant decrease of the pulmonary lesions with docetaxel therapy (Table 5). In the one patient with intra-abdominal adenopathy, a 99.5% decrease in serum PSA occurred with the docetaxel (because repeat CTs were not obtained before TAS, we cannot determine whether any associated decrease in the lymph nodes also occurred). Given that serum testosterone levels were not affected during chemotherapy (Table 3), the antitumor effects were due to the docetaxel and not any modulation of testosterone levels.
Patients retain sensitivity to hormone ablation after the initial chemotherapy, with the PSA nadir at a median of 0.1 ng/mL from the pre-TAS median of 5.7 ng/mL after 4 months of TAS (Table 4). Hormone sensitivity is further demonstrated by the disappearance of soft-tissue disease in the patients after 4 months of TAS (Table 5). The optimum duration of hormone ablation in patients such as those enrolled onto this trial is not known. In general, androgen-sensitive cancer cells undergo apoptosis within a short period of time after androgen withdrawal. Although limited AD may not provide long-term disease control, it should still be able to target a major proportion of the androgen-sensitive cancer cells. Following the initial chemotherapy, we therefore limited the duration of hormone therapy in an effort to determine whether such a limited chemotherapy plus hormonal therapy approach is beneficial in patients experiencing an increase in PSA.
All patients completing TAS achieved castrate levels of serum testosterone (Table 3). With the exception of one patient, at the completion of PAB serum testosterone recovered to noncastrate levels (Table 3). Although the median PSA was 0.1 ng/mL at the end of PAB treatment, biochemical progression occurred in the majority (28 of 33 patients) within a short period of follow-up (median, 2.3 months after PAB), and in 20 such patients the PSA progressed to 5 ng/mL at a median of 7 months after PAB. In five of the 33 patients receiving the chemotherapy plus hormones, serum PSA has remained 0.1 ng/mL at a median of 18.9 months after PAB despite recovery of serum testosterone to the noncastrate range in all five men.
Several aspects related to these five men with long-term disease control are noteworthy (Table 10). Their median serum testosterone level of 254 ng/dL before trial entry was not significantly different from that of the entire group (338.5 ng/dL), and if anything, their PSA doubling time before study entry was shorter (3.5 months) compared with the group as a whole (6.6 months). Although all five men experienced a decrease in PSA with docetaxel, the extent of PSA response to the chemotherapy may not necessarily predict for long-term outcome; in two men only a 28% and 37% decrease in PSA occurred with chemotherapy, but their PSA has remained at 0.1 ng/mL 22 and 37.4 months after the time PAB was stopped, respectively (Table 10). These two men also received only 4 months of TAS followed by PAB. The other three men who remain biochemically (PSA 0.1 ng/mL) and clinically with no evidence of disease (NED) 11 to 19 months after end of treatment actually had soft-tissue metastasis at the time of trial entry. Thus, among men who experience failure after initial local treatments for PC, a subgroup exists that can perhaps benefit from a limited chemotherapy plus hormonal treatment approach. All five men with NED had prostatectomy as the primary local treatment, whereas all 14 men who had external-beam radiation therapy and/or brachytherapy as their primary treatment have experienced failure after the subsequent treatment with chemotherapy plus hormones (Table 10).
Conceivably, patients in whom the primary tumor sites are surgically removed initially (via RP) might be more amenable to disease control at the time of recurrence with systemically directed salvage treatments (such as chemotherapy plus hormonal treatment). None of the enrolled African American patients completing therapy (ie, 0 of 17) had any long-term disease control after the chemotherapy plus hormonal treatments were stopped. In contrast, of the 16 white patients completing the trial, five men have NED 11 to 37.4 months after PAB. These results could be skewed because of the limited numbers of patients enrolled, or may in fact reflect inherent differences in prostate tumor biology between African Americans and white patients.
Preliminary results of another study employing chemotherapy plus hormonal treatment in patients with increasing PSA have been presented. 29, 30 In this trial, estramustine (EMP)/docetaxel for four cycles is followed by 15 months of TAS. The overall treatment design is similar to that presented above; however, several differences are noteworthy. In this second study no minimum PSA values were required and no patient had metastasis at entry. Because of the estrogenic properties of EMP, low levels of serum testosterone occurred during the chemotherapy phase. It is likely that the high PSA responses reported with EMP/docetaxel are in part due to the effects of EMP on serum testosterone. Recent data suggest that in HRPC, outcome of EMP/docetaxel versus docetaxel may be similar. 31, 32 An intriguing question is whether docetaxel followed by AD would provide similar outcome as EMP/docetaxel followed by AD in HSPC patients with increasing PSA after local therapies.
In conclusion, although optimization of both chemotherapy and hormone therapy needs to be achieved, and the observed toxicities need to be put in context with respect to treatment outcomes, this trial demonstrates feasibility and activity of sequential chemotherapy and hormone therapy of limited duration in HSPC patients experiencing failure after primary local treatments for prostate cancer.
Authors' Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Honoraria: Arif Hussain, Aventis, Cytogen, Novartis; Nancy Dawson, AstraZenenca, Aventis. Research Funding: Arif Hussain, Aventis, Cytogen, Novartis. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
Acknowledgment
We thank Florence Wade for typing the manuscript.
NOTES
Supported in part by a Merit Review Award from the Department of Veterans Affairs (A.H.) and Aventis Pharmaceuticals (A.H.).
Presented at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001; American Urologic Association, Anaheim, CA, June 2-7, 2001; and Chemotherapy Foundation Symposium XX, New York, NY, November 13, 2003, as preliminary data.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD
ABSTRACT
PURPOSE: Prostatectomy or radiation for localized prostate cancer (PC) can fail in up to 15% to 30% of patients. The purpose of this study was to determine feasibility, tolerability, and outcome of docetaxel followed by hormone therapy in men experiencing an increasing prostate-specific antigen (PSA) after their primary local treatments for PC.
PATIENTS AND METHODS: Men with increasing serum PSA after prostatectomy or/and radiation were eligible. Serum PSA had to be 4 ng/mL and serum testosterone had to be in the noncastrate range. Treatment included docetaxel 70 mg/m2 every 3 weeks for up to six cycles, followed by total androgen suppression (luteinizing hormone-releasing hormone agonist plus bicalutamide) and peripheral androgen blockade (finasteride plus bicalutamide) for 12 to 20 months.
RESULTS: Thirty-nine men were enrolled; 32 had PSA-only failure, seven also had clinical metastasis. Baseline median PSA was 13.7 ng/mL. Serum PSA decreased 50% in 17 of 35 patients (48.5%) and 75% in seven of 35 patients (20%) with docetaxel. The PSA decreased to a median of 0.1 ng/mL with subsequent hormone therapy. In 28 of 33 patients the PSA increased (median, 0.41 ng/mL) at a median follow-up of 2.3 months after treatment. In contrast, in five of 33 men the PSA remains at 0.1 ng/mL at a median of 18.9 months after therapy; three of these five men had soft tissue metastasis at entry but remain in complete remission. The most common grade 3 to 4 toxicity was neutropenia (61.5%).
CONCLUSION: Docetaxel followed by hormone therapy of limited duration may provide disease control in subgroups of men experiencing failure after local treatments for PC.
INTRODUCTION
Currently, no specific consensus exists regarding management of patients who develop an increasing serum prostate-specific antigen (PSA) after initial local therapies (surgery or/and radiation) for localized prostate cancer (PC). 1- 6 Although an increasing PSA after surgery or radiation likely reflects the presence of residual or recurrent PC, the risks for subsequent clinical metastasis in these patients vary. 7- 11
One approach in such patients who exhibit an increasing PSA has been to institute hormone therapy such as gonadal or total androgen suppression (TAS), antiandrogen monotherapy, or peripheral androgen blockade (PAB). Androgen deprivation (AD) can provide control of the increasing PSA and the underlying disease. However, as in metastatic PC, over time AD can fail in men experiencing PSA-only failure after their local therapies despite a possible lead-time bias that may occur because of the earlier institution of hormone therapy.
Chemotherapy traditionally has been used in metastatic hormone-resistant PC (HRPC). However, clinical hormone resistance may be associated with a relatively chemotherapy-resistant state. 12- 14 In addition, preclinical models demonstrate that although AD is cytocidal for a majority of the androgen-sensitive prostate cells, a subpopulation of cells with altered bax-to-bcl2 ratios emerges within weeks of the hormone ablation (which can make prostate cells resistant to apoptosis). 15 Thus, cytotoxic drugs identified to have activity in HRPC may also be active, and perhaps more so, in hormone-sensitive/naive PC (HSPC). Given that hormone ablation by itself is unlikely to be curative, and if chemotherapy is to be integrated with hormone therapy for a potentially better therapeutic effect, then a reasonable approach would be to treat PC patients with chemotherapy first, followed then by hormone ablation, with the latter aimed at the androgen-sensitive components of the disease.
With this rationale in mind, we treated men with PC who developed an increasing PSA after radical prostatectomy (RP) or/and radiation with single-agent docetaxel because of its demonstrated activity in advanced HRPC. 16- 24 The docetaxel was followed by hormone therapy, with both treatments given for a defined period. The aims of the study were to determine the response to chemotherapy and hormone therapy of hormone-sensitive patients with PC who exhibit an increasing PSA, as well as to determine outcome of the overall treatment in this patient population.
PATIENTS AND METHODS
Eligibility
Before enrollment, all patients gave written informed consent. Patients with histologically documented prostate adenocarcinoma who initially underwent local therapies for localized/locally advanced disease but then experienced disease relapse with an increasing PSA were eligible. Patients could have received a short duration ( 6 months) of prior hormone ablation, given in the neoadjuvant/adjuvant setting with the local therapies, provided their serum testosterone was not in the castrate range at trial entry (men were required to have serum testosterone levels 50 ng/dL). Serum PSA had to be 4 ng/mL, documented on three separate occasions measured at least 2 weeks apart.
Positive findings on baseline computed tomography (CT) scans and/or technetium-99m bone scintigraphy (bone scans) were not necessarily an exclusion criteria. Patients had to have Eastern Cooperative Group performance status of 0 to 2, life expectancy more than 24 months, and no other serious medical or psychiatric illness. Prior exposure to chemotherapy was not allowed. Required baseline laboratory parameters were WBC 2,500 cells/μL, granulocyte count 1,500 cells/μL, platelets 100,000/μL, hepatic aminotransferase levels 2.5x institutional upper limits of normal, and bilirubin no more than the institutional upper limits of normal.
Treatment
Patients were given docetaxel 70 mg/m2 intravenously during 1 hour every 21 days for up to six cycles. They were premedicated with dexamethasone 8 mg orally given twice a day for 3 days starting the day before each docetaxel dose. TAS was instituted 3 weeks after the last docetaxel treatment. TAS consisted of luteinizing hormone releasing hormone agonist (leuprolide acetate 30 mg intramuscularly or goserelin acetate 10.8 mg subcutaneously) plus bicalutamide 50 mg/d orally. Patients were treated with 4 or 12 months of TAS; 12 months of TAS was given if there were any positive findings on CT and/or bone scans or to patients whose serum PSA remained more than 4 ng/dL after the first 4 months of TAS. In general, maximal responses to hormone ablation are achieved in a majority of patients within the first several months of instituting gonadal androgen suppression or TAS therapy. Therefore, after a defined period of treatment with TAS, additional hormone therapy in the form of PAB was used, again for a limited duration, because of the relative testosterone-sparing properties and likelihood of fewer, lower-intensity adverse effects of the latter treatment. After TAS, PAB was continued for another 8 months. PAB consisted of bicalutamide 50 mg/d orally plus finasteride 5 mg/d orally. Overall, patients received 12 to 20 months of hormonal therapy (TAS plus PAB) after the initial docetaxel.
Outcome Assessments
The main end points were to determine PSA response (and objective response in those men with measurable disease) to the chemotherapy and hormone therapy components of the treatment regimen, as well as duration of response after completing treatment. Secondary end points included assessment of toxicity of the treatment, impact on quality of life (QOL), and effects on serum testosterone levels.
For toxicity assessment, the National Cancer Institute Common Toxicity Criteria (version 2.0) was used. PSA was measured at the beginning of each docetaxel cycle and monthly during hormonal therapy. Post-treatment follow-up was every 2 months for the first year and every 3 months thereafter. Radiographic studies were obtained at baseline and at completion of the treatment. In patients with positive imaging studies, these were also repeated on completion of chemotherapy (ie, before hormone therapy). Radiographic studies were obtained during follow-up if there was progression by PSA criteria. Guidelines using PSA criteria for response and progression have been established by the PSA Working Group for androgen-independent PC. 25 No such guidelines exist for patients such as those treated in the present trial. PSA response in this trial was defined as 50% reduction in serum PSA of the pretreatment value, confirmed with a second PSA at least 2 weeks apart. PSA progression was defined as more than 50% increase of the nadir PSA, measured on two consecutive occasions, and an increase in the absolute PSA by at least 5 ng/mL. Progression on imaging studies was defined as appearance of new bone lesions and/or 25% increase in the sum of the products of the perpendicular diameters of measurable lesions on CT scans.
There is a paucity of data regarding response to single-agent docetaxel administered every 3 weeks in HRPC (PSA decline 50% has been reported in 38% to 46% in small series 16, 17), and essentially no such data exist in HSPC. Although it was likely that responses to the chemotherapy and hormone therapy components of the treatment regimen would be different in the enrolled patient population, in this trial response (PSA response or/and objective response) to the chemotherapy component was used for an optimal two-stage design; the statistical power of the study was at least 90%, with type I error of 10%.
Serum testosterone levels were measured before and after docetaxel, during and at completion of hormone therapy, and during subsequent follow-ups until recovery to noncastrate levels. For QOL, the Functional Assessment of Cancer Therapy–General (FACT-G) questionnaire and the Functional Assessment of Cancer Therapy–Prostate (FACT-P) scale (version 3) were used. 26- 28 Patients were asked to complete the questionnaires before and after chemotherapy, and at the completion of TAS and PAB therapy. Wilcoxon signed rank sum test was used to compare the QOL measures at each time point during treatment.
RESULTS
Patients
Between September 2, 1999, and September 17, 2001, 39 men (19 white, 20 African American) entered onto the trial. Baseline characteristics are listed in Table 1: median age, 66 years; median Gleason score, 7 of original PC; median serum PSA at entry, 13.7 ng/mL; and median serum testosterone, 338.5 ng/dL. Initial local therapies included RP in 25 men (64%), with 16 also receiving external radiation (seven patients receiving adjuvant radiation, nine patients receiving salvage radiation). Fourteen patients (36%) received radiation as their primary local therapy (11 patients receiving external-beam radiation therapy, three patients receiving brachytherapy). Five men had 4 to 6 months of AD with their local treatments. Baseline imaging studies demonstrated that seven of the 39 patients had positive CT (n = 3) or bone scans (n = 4) but not both (Table 1). Two of the three men with positive CT scans had multiple bilateral pulmonary nodules (biopsy-confirmed PC in one), whereas one patient had intra-abdominal adenopathy.
Treatment Outcome
Thirty-five men received four (n = 3; docetaxel was limited to four cycles in three men because of neutropenic infection or polyneuropathy) or six (n = 32) cycles of docetaxel. The other four men received only one dose of docetaxel before being taken off study (one withdrew consent, three had unanticipated toxicities; see Toxicity). After chemotherapy, 33 men received hormone therapy; 27 had 4 months and six 12 months of TAS. Thirty-two men completed PAB after TAS; one patient became noncompliant after TAS and did not keep follow-up appointments, although he was alive at the time of this report. There were four deaths among the original 39 patients; two men completing chemotherapy died before initiating or completing TAS from myocardial infarction/cardiac arrest, one patient who had been taken off study after one cycle of docetaxel also died from myocardial infarction (all three deaths were believed to be unrelated to docetaxel), whereas the fourth patient died as a result of prostate cancer progression.
PSA responses to docetaxel are listed in Table 2. A 50% decline in serum PSA occurred in 17 of 35 patients (48.5%) with the docetaxel. In seven of the 35 men, a 75% decrease in serum PSA occurred with chemotherapy. Included in the latter group are three men who received only four doses of docetaxel but their PSA declined by 99.5%, 99%, and 91%, respectively. Only in one patient did the PSA actually increase at the completion of docetaxel by 28% of baseline value. In none of the 35 men treated with docetaxel were the testosterone levels altered significantly, despite dexamethasone premedication with each docetaxel infusion (Table 3).
Table 4 lists the PSA response to hormone therapy. As listed in Table 3, all men achieved castrate serum testosterone levels after 4 months of taking TAS, and as expected, serum PSA declined further (Table 4). The median PSA at completion of 4 months of TAS was 0.1 ng/mL (range, 0.1 to 7.5 ng/mL) compared with the post-docetaxel/pre-TAS median of 5.7 ng/mL (range, 0.1 to 90 ng/mL). At completion of PAB, the median PSA remained 0.1 ng/mL (range, 0.1 to 3.2 ng/mL), whereas serum testosterone recovered to noncastrate levels in all but one patient (Table 3).
The majority of men entering the trial had PSA-only failure. However, seven also had metastasis at enrollment; six patients completed the entire treatment. Three patients had soft-tissue–only disease (pulmonary nodules in two patients, intra-abdominal adenopathy in one patient). Both patients with the pulmonary nodules had a 78% decrease in serum PSA and more than 50% decrease of the pulmonary nodules after six cycles of docetaxel (Table 5). The residual pulmonary lesions disappeared after patients took TAS for 4 months. For the patient with intra-abdominal adenopathy, a 99.5% decrease in serum PSA occurred after only four doses of docetaxel. Although imaging studies were not obtained after chemotherapy in this patient, no residual adenopathy was found in the abdomen after he had been taking TAS for 4 months (Table 5). In the three men with positive bone scans at baseline, although the serum PSA decreased with chemotherapy and hormone therapy, essentially no changes occurred on serial bone imaging (Table 5).
Median time from end of treatment to last follow-up for the 33 patients completing treatment is 26 months (range, 5 to 39.8 months). An increase in serum PSA occurred in 28 men at a median of 2.3 months after treatment (the median PSA at first increase was 0.41 ng/mL). In 20 of these patients, the PSA reached 5 ng/mL or greater at a median of 7 months from the time PAB was completed to last follow-up. In contrast, in five patients the PSA has remained 0.1 ng/mL at a median follow-up of 18.9 months after treatment. Included in this group are the three men who also had soft-tissue disease at study entry. All three men have remained disease free on repeat imaging 11 to 19 months from the time they completed their therapy. In three of the 33 men who received both chemotherapy and hormone therapy, clinical progression has occurred despite reinstitution of hormonal therapy. Of the four deaths among the original 39 patients, only one was due to progression of the prostate cancer.
FACT-P evaluations were available for 32 patients (Table 6). There was no significant change in QOL on the FACT-G (which assesses global QOL) from baseline through treatment to post-treatment. On total FACT-P, which incorporates both FACT-G and the prostate-specific subscale, a significant difference was noted from baseline to after docetaxel therapy (P = .02), but not from baseline to after TAS or after PAB. Significant differences were noted in scores on the prostate subscale from baseline to after chemotherapy (P = .05), from baseline to after TAS (P = .03), and from baseline to after PAB (P = .01). Data from the FACT-P surveys suggest that chemotherapy had a negative impact, consistent with the toxicities from chemotherapy, whereas adverse effects of androgen suppression would most likely account for the decline in mean scores on the prostate subscales. Overall, the FACT-G and FACT-P instruments demonstrate that the treatment regimens did not significantly influence QOL in most patients on this study.
Toxicity
Toxicity data are presented in Tables 7 and 8. A total of 208 doses of docetaxel at 70 mg/m2 were given among the 39 enrolled patients. Four patients were taken off study after only one dose of docetaxel; one withdrew consent and the other three had unexpected grade 3 or 4 toxicities. One patient fell and fractured both ankles. The second patient developed grade 3 pancreatitis within 48 hours of docetaxel infusion. This patient had a prior history of alcoholism; apparently the alcohol-based solvent used to reconstitute the docetaxel triggered the pancreatitis. In the third patient, grade 3 gastrointestinal bleeding of diverticular origin occurred.
The most common grade 3 to 4 toxicity with chemotherapy was neutropenia, with five episodes of febrile neutropenia (three had documented infections). Twenty-seven separate episodes of grade 3 or 4 neutropenia were observed among the 208 doses of docetaxel given (13% incidence). In total, grade 3 and/or 4 neutropenia occurred in 24 of the 39 enrolled patients (61.5%). No patient had grade 3 anemia or thrombocytopenia. In the two patients with grade 3 elevations in serum aminotransferases, the abnormal liver function tests returned to baseline values over time. Grades 3 and 4 nonhematologic toxicities were infrequent (Tables 7 and 8). Whether the one episode of grade 3 polyneuropathy was due to the docetaxel or some other process is difficult to ascertain. Overall, the incidence of chemotherapy-related adverse events in this trial is similar to that observed with docetaxel in advanced HRPC. During the hormonal phase, most of the adverse effects that occurred during docetaxel treatments resolved, although as expected, low-grade fatigue persisted, and nondebilitating episodes of hot flashes were noted (Table 9).
DISCUSSION
It is apparent that men with HSPC are sensitive to single-agent docetaxel; there was either stabilization or decline of the increasing serum PSA with only a short duration of docetaxel treatment (Table 2). In HRPC, single-agent docetaxel (75 mg/m2 every 3 weeks) has shown response rates (defined as 50% decline in serum PSA) of 38% to 46%. 16, 17 By these criteria, docetaxel is at least as effective in our HSPC patient population, with 48.5% of the patients showing 50% decline in serum PSA (Table 2). A subgroup of HSPC patients exists who appear to be particularly sensitive to docetaxel; 20% of the patients had 75% decrease in serum PSA, with three experiencing 91% to 99.5% decrease with only four doses of docetaxel. In two of the three patients with documented soft-tissue disease, a 78% decrease in serum PSA was accompanied by a concomitant decrease of the pulmonary lesions with docetaxel therapy (Table 5). In the one patient with intra-abdominal adenopathy, a 99.5% decrease in serum PSA occurred with the docetaxel (because repeat CTs were not obtained before TAS, we cannot determine whether any associated decrease in the lymph nodes also occurred). Given that serum testosterone levels were not affected during chemotherapy (Table 3), the antitumor effects were due to the docetaxel and not any modulation of testosterone levels.
Patients retain sensitivity to hormone ablation after the initial chemotherapy, with the PSA nadir at a median of 0.1 ng/mL from the pre-TAS median of 5.7 ng/mL after 4 months of TAS (Table 4). Hormone sensitivity is further demonstrated by the disappearance of soft-tissue disease in the patients after 4 months of TAS (Table 5). The optimum duration of hormone ablation in patients such as those enrolled onto this trial is not known. In general, androgen-sensitive cancer cells undergo apoptosis within a short period of time after androgen withdrawal. Although limited AD may not provide long-term disease control, it should still be able to target a major proportion of the androgen-sensitive cancer cells. Following the initial chemotherapy, we therefore limited the duration of hormone therapy in an effort to determine whether such a limited chemotherapy plus hormonal therapy approach is beneficial in patients experiencing an increase in PSA.
All patients completing TAS achieved castrate levels of serum testosterone (Table 3). With the exception of one patient, at the completion of PAB serum testosterone recovered to noncastrate levels (Table 3). Although the median PSA was 0.1 ng/mL at the end of PAB treatment, biochemical progression occurred in the majority (28 of 33 patients) within a short period of follow-up (median, 2.3 months after PAB), and in 20 such patients the PSA progressed to 5 ng/mL at a median of 7 months after PAB. In five of the 33 patients receiving the chemotherapy plus hormones, serum PSA has remained 0.1 ng/mL at a median of 18.9 months after PAB despite recovery of serum testosterone to the noncastrate range in all five men.
Several aspects related to these five men with long-term disease control are noteworthy (Table 10). Their median serum testosterone level of 254 ng/dL before trial entry was not significantly different from that of the entire group (338.5 ng/dL), and if anything, their PSA doubling time before study entry was shorter (3.5 months) compared with the group as a whole (6.6 months). Although all five men experienced a decrease in PSA with docetaxel, the extent of PSA response to the chemotherapy may not necessarily predict for long-term outcome; in two men only a 28% and 37% decrease in PSA occurred with chemotherapy, but their PSA has remained at 0.1 ng/mL 22 and 37.4 months after the time PAB was stopped, respectively (Table 10). These two men also received only 4 months of TAS followed by PAB. The other three men who remain biochemically (PSA 0.1 ng/mL) and clinically with no evidence of disease (NED) 11 to 19 months after end of treatment actually had soft-tissue metastasis at the time of trial entry. Thus, among men who experience failure after initial local treatments for PC, a subgroup exists that can perhaps benefit from a limited chemotherapy plus hormonal treatment approach. All five men with NED had prostatectomy as the primary local treatment, whereas all 14 men who had external-beam radiation therapy and/or brachytherapy as their primary treatment have experienced failure after the subsequent treatment with chemotherapy plus hormones (Table 10).
Conceivably, patients in whom the primary tumor sites are surgically removed initially (via RP) might be more amenable to disease control at the time of recurrence with systemically directed salvage treatments (such as chemotherapy plus hormonal treatment). None of the enrolled African American patients completing therapy (ie, 0 of 17) had any long-term disease control after the chemotherapy plus hormonal treatments were stopped. In contrast, of the 16 white patients completing the trial, five men have NED 11 to 37.4 months after PAB. These results could be skewed because of the limited numbers of patients enrolled, or may in fact reflect inherent differences in prostate tumor biology between African Americans and white patients.
Preliminary results of another study employing chemotherapy plus hormonal treatment in patients with increasing PSA have been presented. 29, 30 In this trial, estramustine (EMP)/docetaxel for four cycles is followed by 15 months of TAS. The overall treatment design is similar to that presented above; however, several differences are noteworthy. In this second study no minimum PSA values were required and no patient had metastasis at entry. Because of the estrogenic properties of EMP, low levels of serum testosterone occurred during the chemotherapy phase. It is likely that the high PSA responses reported with EMP/docetaxel are in part due to the effects of EMP on serum testosterone. Recent data suggest that in HRPC, outcome of EMP/docetaxel versus docetaxel may be similar. 31, 32 An intriguing question is whether docetaxel followed by AD would provide similar outcome as EMP/docetaxel followed by AD in HSPC patients with increasing PSA after local therapies.
In conclusion, although optimization of both chemotherapy and hormone therapy needs to be achieved, and the observed toxicities need to be put in context with respect to treatment outcomes, this trial demonstrates feasibility and activity of sequential chemotherapy and hormone therapy of limited duration in HSPC patients experiencing failure after primary local treatments for prostate cancer.
Authors' Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Honoraria: Arif Hussain, Aventis, Cytogen, Novartis; Nancy Dawson, AstraZenenca, Aventis. Research Funding: Arif Hussain, Aventis, Cytogen, Novartis. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
Acknowledgment
We thank Florence Wade for typing the manuscript.
NOTES
Supported in part by a Merit Review Award from the Department of Veterans Affairs (A.H.) and Aventis Pharmaceuticals (A.H.).
Presented at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001; American Urologic Association, Anaheim, CA, June 2-7, 2001; and Chemotherapy Foundation Symposium XX, New York, NY, November 13, 2003, as preliminary data.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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