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© 1999 American Society for Clinical Oncology Phase II Trial of Oral Estramustine, Oral Etoposide, and Intravenous Paclitaxel in Hormone-Refractory Prostate CancerFrom the Division of Hematology and Medical Oncology, Department of Internal Medicine, University of Michigan School of Medicine; and the University of Michigan Comprehensive Cancer Center, Ann Arbor, MI. Address reprint requests to David C. Smith, MD, 7-302 CCGC 0946, 1500 E. Medical Center Dr, Ann Arbor, MI 48109-0946; email dcsmith@ umich.edu
PURPOSE: To evaluate the combination of intravenous (IV) paclitaxel, oral estramustine, and oral etoposide in patients with advanced hormone-refractory prostate cancer. PATIENTS AND METHODS: Forty patients with carcinoma of the prostate that was progressing despite hormonal therapy and who had undergone antiandrogen withdrawal (if previously treated with an antiandrogen) were enrolled onto this phase II trial. Patients were treated with oral estramustine 280 mg tid and oral etoposide 100 mg/d for 7 days, with paclitaxel 135 mg/m2 IV over 1 hour on day 2 of each 21-day treatment cycle. Patients received a maximum of six cycles of therapy.
RESULTS: Thirty-seven patients were assessable for response. Twenty-two had measurable disease at baseline; response was not assessable in six of these patients. Overall response was 45% (10 of 22 patients; 95% confidence interval [CI], 24% to 68%), and response was 63% (10 of 16) in assessable patients. Twenty-six patients had a CONCLUSION: The combination of IV paclitaxel, oral estramustine, and oral etoposide is active in patients with advanced prostate cancer. The regimen is tolerable and does not have a significant impact on QOL as measured by the FACT-P in a limited sample of patients.
HORMONE-REFRACTORY adenocarcinoma of the prostate continues to be a major cause of morbidity and mortality in American men. Low response rates and significant toxicity have led to an understandable skepticism concerning the use of chemotherapy in the treatment of this disease.1,2 This skepticism has been challenged by new developments resulting from trials guided by the description of the mechanism of action of several new antineoplastic agents, the definition of appropriate study end points, and a better understanding of the biology of prostate cancer.
One major area of development has focused on agents that act at the nuclear matrix and microtubular assembly. Estramustine phosphate, an agent that combines estradiol with nitrogen mustard, acts at these sites. Estramustine is preferentially taken up by prostate epithelial cells and binds to the nuclear matrix.3 The nuclear matrix plays a critical role in DNA organization, acting as the protein framework on which DNA is organized into loop domains.4,5 The bases of these loops have been identified as the regions of active DNA transcription.6,7 The nuclear enzyme topoisomerase II, which plays a critical role in the regulation of DNA structure, has also been localized to the base of the DNA loops, where it exists in the wake of the DNA replication fork.8,9 The localization of this enzyme to this site raises the potential for synergistic effects between drugs that bind to this site and agents, such as etoposide, that inhibit topoisomerase II. Preclinical studies have explored this potential interaction. In the anaplastic Mat-Ly Lu (MLL) subline of the Dunning rat prostate adenocarcinoma, estramustine potentiates the cytotoxic effect of etoposide at relatively low levels.10 This interaction is seen at concentrations at which neither of these drugs has significant activity as a single agent.11,12 However, these low concentrations are notable because they are readily achievable in vivo. An in vivo study using Copenhagen rats treated with daily intraperitoneal injection of estramustine and intravenous (IV) injections of etoposide confirms that these agents act synergistically to inhibit the growth of anaplastic rat prostate carcinoma.10 Preliminary mechanistic evaluation suggests that estramustine increases the ability of etoposide to cause DNA strand breakage. Based on these data, three phase II trials of this combination have been conducted in patients with hormone-refractory prostate cancer.13-15 These studies have been consistent in showing a response rate of 40% to 50% according to classic response criteria in patients with soft tissue disease, and at least 50% of the patients having a Estramustine has also been shown to bind to the microtubular apparatus.16 Concurrent with the development of the strategy designed to act at the nuclear matrix, studies were undertaken to explore the activity of estramustine in combination with other antimicrotubule agents.17 The combination of estramustine and vinblastine produced significant antitumor activity in three separate clinical trials involving a total of 83 patients with metastatic hormone-refractory prostrate cancer.18-20 Approximately 30% of patients had evidence of response according to both classic and PSA criteria. With the development of paclitaxel, which acts to irreversibly stabilize microtubules, preclinical studies were conducted to assess the activity of this agent in combination with estramustine. The combination of paclitaxel and estramustine demonstrated significant antimitotic activity in prostate cancer cell lines.21 This activity occurred at levels of paclitaxel that are easily achievable with conventional doses. Initial clinical studies with paclitaxel as a single agent showed little activity in hormone-refractory prostate cancer.22 However, the combination of paclitaxel and estramustine resulted in objective response in four of nine patients with measurable soft tissue disease, and 17 of 32 patients with elevated pretreatment PSA levels had a greater than 50% decline in those levels in a recent phase II trial using a 96-hour infusion of paclitaxel.23 These preclinical and clinical studies indicate that estramustine potentiates the effects of agents that act independently at the nuclear matrix and microtubular apparatus. To assess the effect of combining these points of attack, preclinical studies were conducted using all three agents. The three-drug combination showed greater activity than either of the two-drug combinations in both cytotoxicity assays using cell lines and in-vivo models.24 Based on the documented clinical activity of these approaches and this encouraging preclinical activity for the combination of estramustine, etoposide, and paclitaxel, we conducted a phase II trial designed to assess the activity of this combination in patients with hormone-refractory prostate cancer. Recognizing the potential impact of this therapy in terms of toxicity, we also undertook to assess the effect of this treatment on patients' quality of life (QOL) using the Functional Assessment of Cancer Therapy–Prostate (FACT-P). This instrument was developed as a disease-specific QOL instrument for patients with prostate cancer and incorporates an additional subscale to address items that are specific to QOL issues in men with prostate cancer, including sexuality, elimination, and comfort.25,26
Patients Eligible patients were required to have a histologic diagnosis of adenocarcinoma of the prostate with progressive disease after standard hormonal therapy. All patients previously treated with an antiandrogen were required to undergo antiandrogen withdrawal. Patients were required to be off all antiandrogens for at least 4 weeks with further evidence of disease progression after cessation of the antiandrogen. Patients were also required to have a performance status of 0, 1, or 2 on the Zubrod scale with a life expectancy of at least 12 weeks, and adequate bone marrow (absolute neutrophil count  1500/m3 and platelet count 100,000/m3), renal (creatinine  1.5 mg/dL), and hepatic function (bilirubin 1.6 mg/dL and AST three times the upper limits of normal). Patients were required to have measurable soft tissue disease or assessable disease manifested as osseous disease with a rising PSA level or locally advanced disease with a rising PSA level. Patients with any history of recent myocardial infarction or ongoing ischemia requiring antianginal agents, arrhythmia requiring antiarrythmics, or history of ischemic disease with documented compromise of left ventricular function were excluded from this study. Similarly, patients were excluded from the study if they had uncontrolled hypertension, known brain metastases, or spinal cord compression. Patients were required to wait 4 weeks for study entry after the completion of prior chemotherapy, radiation therapy, or a change in hormonal therapy. All patients gave written informed consent in accordance with federal, state, and institutional guidelines.
Evaluations
Treatment Regimen
All subsequent cycles of therapy required that toxicity resulting from the prior cycle had resolved and that hematologic parameters had recovered to at least meet the entry criteria (ie, ANC Patients were eligible for a maximum of six cycles of therapy on this study. Patients with evidence of response were monitored after completion of the sixth cycle and were eligible for retreatment at the time of disease progression. Patients who had not undergone an orchiectomy were not maintained on a luteinizing hormone–releasing hormone analog, because estramustine reliably results in castrate levels of testosterone when given in near-continuous fashion. At the end of treatment, patients who had not undergone an orchiectomy were restarted on a luteinizing hormone–releasing hormone analog during the monitoring period.
Toxicity and Response Criteria
Statistical Considerations
Between December of 1995 and September of 1997, 40 patients were enrolled onto this phase II study. The characteristics of these patients are listed in Table 1. All patients experienced disease progression on at least one prior hormonal regimen in addition to antiandrogen withdrawal in those treated with an antiandrogen. Fourteen patients were treated with one prior hormonal therapy, with most (26 patients) having two or more. The majority (26) of patients had received prior chemotherapy; 17 had one prior regimen, whereas nine had received two regimens. The most common prior therapy was a cyclophosphamide-based regimen (14 patients). Seven patients had previously been treated with estramustine, including one patient each with estramustine/vinblastine and estramustine/etoposide. More than one half (25) of the patients had been treated with radiotherapy. Twenty-two patients (55%) had measurable soft tissue lesions, and 18 of these patients also had evidence of bone involvement, whereas one patient had disease confined to the prostate and manifested as a local mass. Nine patients had liver metastases. Seventeen patients had bone-only disease, and the remaining patient had an increasing PSA level as the only evidence of his disease.
A total of 223 cycles of therapy were delivered, with a range of one to 20 cycles. Twenty-one patients completed the six cycles of therapy initially planned. Nine of these patients received additional therapy, with the number of additional cycles ranging from one to 14 (45 total cycles). Leukopenia was the most common hematologic toxicity; nine patients developed
The presence of liver metastases was associated with a statistically significant increased risk of severe hematologic toxicity. (P = .0033, Fisher's exact test, two-sided) Of the nine patients with liver metastases, six (67%) had episodes of grade 4 hematologic toxicity, compared with four episodes in the 31 patients (13%) without evidence of liver involvement. The contribution of prior therapy to this hematologic toxicity was not as clear. Seven of the 26 patients (27%) who had received prior chemotherapy had episodes of grade 4 hematologic toxicity. Three of the 14 patients (21%) without prior chemotherapy had similar episodes. Nine of the 10 patients who had these episodes received prior radiotherapy, including both patients on the study who had previously been treated with strontium-89, suggesting that irradiation may have played a role in predisposing patients to hematologic toxicity. Thirty-seven patients were assessable for response. Response was assessed by standard criteria in the 22 patients with bidimensional measurable disease. Ten patients had at least a partial response, with one patient having complete resolution of all measurable disease, for an overall response rate of 45% (95% confidence interval [CI], 24% to 68%). The patient with complete resolution of soft tissue disease had mediastinal and retroperitoneal lymphadenopathy and a solitary lung lesion. Biopsy of the mediastinal nodes confirmed the presence of metastatic prostate cancer. Resolution of his nodal and pulmonary parenchymal mass was accompanied by a decline in his PSA level from 589 to 41 ng/mL over a 4-month period. Four patients had stable disease (three with retroperitoneal lymph nodes, one with pelvic mass), two had progressive disease, and six patients with soft tissue disease were not assessable (four received only one cycle of therapy, and two did not have repeat CT scans to assess response in retroperitoneal nodes). Ten of the 16 (63%) assessable patients had evidence of response. All patients enrolled had a measurable PSA level at baseline with values ranging from 4.5 to more than 10,000 ng/mL. Three patients (two early deaths, one withdrawal) did not have a PSA level drawn after their only cycle of therapy and were unassessable by PSA criteria. Twenty-six patients (65%; 95% CI, 48% to 79%) had greater than 50% decreases in their PSA levels while on therapy, with 16 patients having a decrease of greater than 75%. A decline in PSA of greater than 50% was associated with response by classic criteria in eight of the 10 patients who had at least a partial response. In the two patients who had partial response but did not have a 50% decline in PSA, both had significant declines in PSA levels (48% and 42%), with one having a greater than 50% decline after going off the study. One of these patients had extensive liver disease and had a transient partial response in liver disease associated with the decline in PSA. Two of the three patients with stable nodal disease had a PSA decline of at least 50%, and two patients with a significant decline in PSA had progressive soft tissue disease. One of these patients had a 98% decrease in his PSA level, but then developed increasing ureteral obstruction with an increasing PSA level and was scored as having disease progression. The second patient had poorly differentiated disease involving his liver with a baseline PSA level of only 4.5 ng/mL despite extensive liver and bone metastases. His PSA level reached a nadir value of 2.2 ng/mL after six cycles of therapy. Simultaneously, his CT showed progression of his liver disease despite an initial partial response. He developed rapidly progressive disease despite a change in therapy and died 12 weeks later. The median duration of response was 3.2 months (95% CI, 2.1 to 4.6 months), with a maximum of 8.7 months. Of the nine patients who received additional therapy, five had evidence of subsequent response by PSA criteria, and two of these patients had a third response on retreatment. Median survival was 12.8 months (95% CI, 9 to 18 months). Twenty-six patients had died at the time of the analysis. Median follow-up of the 14 surviving patients was 11.9 months, with a maximum of 25 months. At the time of the analysis, two patients were alive more than 2 years after study entry. Response duration and overall survival are shown in Figs 1 and 2.
Prior chemotherapy did not seem to influence response to this regimen as measured by PSA. Eight of 14 patients (57%) with no prior therapy had at least a 50% decline in PSA level, whereas 18 (69%) of the 26 who received prior chemotherapy (three were not assessable) had a similar decrease in PSA. The effect of prior chemotherapy on the response in measurable disease is more difficult to interpret, because all six of the patients who were not assessable were in the prior chemotherapy group. Seven of the 10 patients with soft tissue disease and no prior chemotherapy had partial responses. Three of the six assessable patients with soft tissue disease and prior therapy had responses, including the one patient with a complete response. Prior exposure to estramustine did not seem to influence response. Five of the seven patients who had prior exposure had a greater than 50% decrease in PSA level. The two nonresponders were the patients who had received prior estramustine/vinblastine and estramustine/etoposide.
QOL
Several recent trials have demonstrated that chemotherapy has substantial activity in patients with advanced hormone-refractory adenocarcinoma of the prostate.13,18,23,28 This study is a logical extension of our prior studies with estramustine and etoposide.13,14 Those studies focused on the interaction of the two agents at the nuclear matrix, whereas this combination adds the microtubule apparatus as a target. Estramustine potentiates the effect of both etoposide and paclitaxel at their respective cellular sites of action. This dual targeting strategy is based on preclinical studies that demonstrate a greater than additive effect when etoposide and paclitaxel are combined with estramustine.24 The paclitaxel, estramustine, and etoposide regimen demonstrated significant activity in this phase II trial, with a high response rate both in terms of measurable disease and by PSA criteria. It is important to note that these responses were demonstrated in patients with advanced disease, most of whom had received prior chemotherapy after experiencing disease progression while on multiple hormonal regimens. Responses were seen in patients with high- and low-grade lesions, diffuse bone metastases, and liver disease. Unfortunately, these responses were transient in nature, with patients relapsing within a few months of reaching their planned completion of treatment after the sixth cycle. The median time to disease progression as measured by an increase in PSA in the patients with response was only 3.2 months. The limited duration of therapy may have contributed to this relatively short period of response. Several of these patients went on to receive further therapy either with this combination or other agents, but it is clear that this is not a curative regimen. This regimen was generally tolerable for patients, with 21 (53%) of the 40 patients receiving all six cycles of therapy as planned. Only eight patients received fewer than three cycles of treatment, and this included the five patients who received only one cycle. In these patients, the toxicity limited therapy. Two patients died within 14 days of receiving treatment, one as a result of treatment-related toxicity and one from rapidly progressive disease. The advanced stage of the disease in most of the patients enrolled on this study is typical of patients treated with new regimens for hormone-refractory disease. This extent of disease is likely to result in a somewhat lower response rate than if patients with less extensive disease are treated. In addition, it may well have contributed to the toxicity associated with this regimen. Five of the seven patients hospitalized with febrile neutropenia had liver metastases, including three of the four patients who received only one cycle of therapy and two of the three patients who died on study. Hematologic toxicity, in the form of both neutropenia and anemia, was significantly more likely to occur in the patients with more extensive disease. Patients with liver metastases were much more likely to become neutropenic, which suggests an alteration in drug metabolism as a possible cause. Prostate cancer patients often suffer from anemia, which roughly correlates with bone and marrow involvement by tumor. As expected, patients with low baseline hemoglobin values were much more likely to develop significant anemia on this study. Chemotherapy for advanced prostate cancer has been shown to have a beneficial effect on QOL of men receiving therapy.29 The data from the 24 patients who completed sequential FACT-P surveys suggest that this regimen did not have a significant negative impact on QOL for most patients on this study. This conclusion is obviously tempered by the fact that only patients who were treated with multiple cycles of therapy were evaluated sequentially, and even some of these are not included in the analysis because of incomplete or improper data collection. There may have been a significant negative impact on the QOL of the five patients who received only one cycle of therapy, especially if therapy was halted because of toxicity. Similarly, our ability to detect a positive effect of therapy on QOL is limited by the fact that one third (eight of 24) of the patients with evidence of response did not complete sequential surveys. An improvement in QOL scores has recently been associated with PSA response,30 but the limited data do not allow us to detect any similar association on this trial. At most, we can conclude that in the patients who were able to receive multiple cycles of therapy with this regimen, there is no significant negative impact on QOL as measured by the FACT-P. This is a potentially important finding in a setting in which treatment is generally thought to be palliative. The overall response rate by PSA criteria (65%) is comparable to those seen in recently reported trials with combinations such as estramustine and paclitaxel (53%), estramustine and docetaxel (62%), and the four-drug combination of ketoconazole, doxorubicin, estramustine, and vinblastine (67%).23,28,31 It is also comparable to the response rate in our prior trials of estramustine and etoposide, in which the PSA response rate was 50%. In terms of measurable disease, the overall response rate seems somewhat lower than that reported with these other regimens. However, the response rate in the assessable patients on this trial is similar to the reported rates from the other trials, despite the enrollment of more patients with visceral disease on this trial. Compared with these regimens, which enrolled primarily previously untreated patients, hematologic toxicity in this trial was somewhat greater, although the majority of patients were able to receive all of the prescribed therapy, and several were able to tolerate additional cycles of treatment at the time of disease progression. The majority of patients enrolled on this study had received prior chemotherapy, which may have contributed to this increase in toxicity, although prior radiation therapy seems to have been a more significant predisposing factor. Alternatively, the increase may well be due to the number of patients with liver metastases enrolled on the study, because this seems to be correlated with hematologic toxicity. Nausea and vomiting were decreased in comparison to our experience with estramustine and etoposide. In terms of convenience, the 1-hour paclitaxel infusion once every 3 weeks is an improvement over the 96-hour infusion schedule for the paclitaxel/estramustine combination and the weekly infusions required for the ketoconazole/doxorubicin plus estramustine/vinblastine regimen. Thus this regimen would seem to have roughly comparable efficacy, with generally similar toxicity and more convenience than other regimens currently under development for the treatment of advanced prostate cancer. Demonstration of the activity of a chemotherapy combination in patients with advanced hormone-refractory adenocarcinoma of the prostate is the prerequisite for the development of regimens that will be used in larger trials to assess the efficacy of chemotherapy in improving survival. Although we have seen progress in the development of combinations with activity, the level of activity can still be improved, hopefully without a corresponding increase in toxicity. This trial serves as the basis for new trials designed to test the activity of chemotherapy earlier in the course of prostate cancer. Further phase II trials that incorporate additional agents in hopes of improving the activity of this multidrug regimen both in terms of response rate and duration of response are underway.
Supported in part by grants no. 1-P50-CA69568, 5-P30-CA46592-06, and RO3-CA70226 from the National Institutes of Health and the National Cancer Institute
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
