- Email: [email protected]
ORAL CHEMOTHERAPY FOR HORMONE REFRACTORY PROSTATE CANCER
0094-0143/99 $8.00
HORMONE REFRACTORY PROSTATE CANCER
+
.OO
ORAL CHEMOTHERAPY FOR HORMONE REFRACTORY PROSTATE CANCER The University of Michigan Experience Jeffrey M. Kamradt, MD, David C. Smith, MD, and Kenneth J. Pienta, MD
Traditionally, chemotherapy for malignant disease has been administered as a bolus intravenous dose. The patient receives a large dose of a drug at the beginning of a treatment cycle, followed by a lag period until normal tissues, such as myeloid elements and mucosa, can recover prior to receiving the next dose. Oral chemotherapy offers an alternative to this approach. The agents can be delivered at lower doses over an extended period of time. This has a number of benefits. First, toxicity is generally decreased. The circulating level of the drug does not cross a threshold above which damage to normal tissues occur. Because of this, the agent can be given over an extended period of time. This is important in tumors such as prostate cancer that have a low proliferative rate.’ Patients can assume an active role in their daily treatment, and compliance is enhanced. The cost of oral chemotherapy is less than that of traditionally administered agents.4 Regimens using prolonged doses of oral chemotherapy for hormone-refractory prostate cancer have been developed at the au-
thors’ center over the past 5 years (Table 1). The combination of estramustine and etoposide has been tested in two separate trials for patients with advanced symptomatic disease. Also, the combination of cyclophosphamide, diethylstilbestrol, and prednisone has been investigated as a first-line treatment for patients with early asymptomatic hormone-refractory disease. Similarly, diethylstilbestrol has been used alone as a single agent. The authors’ experience with these agents has been positive; good responses are achieved with a minimum of toxicity. Additional trials using other novel oral agents are being conducted. It is hoped that these studies will yield new well-tolerated regimens for the treatment of hormone-refractory prostate cancer. ESTRAMUSTINE AND ETOPOSIDE Methods
The combination of oral estramustine and etoposide has been the cornerstone of recent
From the Division of Hematology and Oncology, Department of Internal Medicine (JMK, DCS), and the Department of Genitourinary Oncology (KJP), University of Michigan Cancer Center, AM Arbor, Michigan
UROLOGIC CLINICS OF NORTH AMERICA VOLUME 26 * NUMBER 2 * MAY 1999
333
334
KAMRADT et a1
Table 1. ORAL CHEMOTHERAPY REGIMENS AT THE UNIVERSITY OF MICHIGAN
Regimen
Method of Administration
Estrnmustine and etoposide Cytoxan, DES, and prednisone Single-agent DES DES
=
diethylstilbestrol; EMP
=
EMP, 280 mg, tid on days 1 to 21 ETP, 50 mg, bid on days 1 to 21 Cytoxan, 100 mg, on days 1 to 20 DES, 1 mg, qd Prednisone, 10 mg, qd DES, 1 mg, qd
estramustine phosphate; ETP
chemotherapy trials at the University of Michigan. The combination (at two different dose levels) has been tested in two separate phase I1 trials as well as combined with intravenous chemotherapy agents. Prior to its use in the clinic, the two-drug combination underwent extensive preclinical testing. In vitro, the drugs demonstrated enhanced cytotoxicity as well as an ability to impair DNA synthesis at the level of the nuclear matrix.s In vivo, the combination of the two drugs was more effective at suppressing tumor growth in an animal model of prostate cancer. This preclinical synergy provided the rationale for combining the two agents in clinical trials. Two separate trials of the combination have been performed in patients with hormonerefractory prostate cancer. The first study enrolled 42 patients from November 1991 through June 1993.xThe dose of estramustine was 15 mg/kg/day and the dose of etoposide, 50 mg/m2. The second trial enrolled 62 patients from July 1993 through March 1996.' The dose of etoposide was the same as that used in the earlier trial; however, the dose of estramustine was decreased to 10 mg/kg/ day. The treatment regimen was given for 21 days of a 28-day cycle. Patients were eligible for the study if they had a Zubrod performance status of at least 3 and demonstrated histologically proven adenocarcinoma of the prostate with distant metastasis that had become refractory to androgen deprivation. All prior therapy was completed at least 4 weeks prior to enrollment. This is particularly important in regards to therapy with the antiandrogen flutamide. The first trial enrolled patients before recognition of the "flutamide withdrawal" response; however, the enrollees all demonstrated a rise in prostate-specific
=
PSA Response
SoftTissue Response
Reference
39% to 52%,
50% to 53%
7, 8
36%
43%
6
43%"
NA
12
etoposide.
antigen (PSA) following discontinuation of the antiandrogen. For the second trial, this phenomenon was described and accounted for appropriately. In each of the trials, disease response was assessed after the first two cycles and then every 8 weeks. A complete response required the resolution of all measurable soft-tissue lesions. A partial response required a decrease of at least 50% for measurable lesions. A partial response by PSA required that the marker drop by more than 50% of the baseline value for two consecutive determinations.
Results
Pretreatment characteristics for the two trials demonstrated that the patients had a median age of 67 to 69 years, with approximately 60% having a performance score of 0 or 1. Nearly all of the patients had evidence of bone metastasis. In the first and second trial, 43% and 24% of patients exhibited a measurable soft-tissue lesion, respectively. Prior chemotherapy disqualified patients from the first study; however, 62% of patients in the second study were previously treated with chemotherapy. The estramustine-etoposide combination was tolerated reasonably well by patients. Most patients who worked before enrolling in the study continued to do so during treatment. Hematologic toxicity was manifested mainly as leukopenia and thrombocytopenia. In the initial trial, 25% of patients required a dose reduction of the etoposide because of leukopenia, thrombocytopenia, or both. There were five episodes of neutropenic fever in
ORAL CHEMOTHERAPY FOR HORMONE REFRACTORY PROSTATE CANCER
236 cycles of therapy. One patient died of complete bone marrow failure within 12 weeks of initiating therapy. In the subsequent trial, 18% of patients experienced a dose reduction of etoposide secondary to cytopenia. There was only one episode of neutropenic fever in over 300 cycles of therapy. Nonhematologic toxicities consisted mainly of alopecia and nausea. Patients universally experienced some degree of alopecia. In each trial, approximately 25% of patients experienced significant nausea, and 5% of patients withdrew from the study secondary to grade 3 nausealvomiting. Ten percent of patients in the higher-dose estramustine trial and 6% of patients in the attenuated estramustine dose trial experienced deep venous thrombosis. Lower-extremity edema was experienced by 48% of patients in the higher estramustine trial and by 35% in the lower-dose trial. One patient from the initial trial died of congestive heart failure and possible myocardial infarction within 3 weeks of initiating therapy. A decrease of soft-tissue lesions has been the hallmark of response for chemotherapy trials. In prostate cancer, most patients do not present with soft-tissue lesions because the disease is limited to osseous metastasis in the large majority of patients. Early trials of chemotherapy for hormone-refractory prostate cancer limited the study population to patients with measurable disease. Obviously, this selection criterion limited the enrollees to a specific subgroup of patients with prostate cancer and greatly reduced the applicability of the results to the general population of patients. PSA is elevated in the large majority of patients with prostate cancer and serves well as a marker of disease. In both trials, both the reduction of soft-tissue lesions as well as the decline in PSA from pretreatment values were used as markers of response. The response rates for soft-tissue disease in the first and second trials were 53% and 50%, respectively. PSA declines of greater than 50% from baseline were seen in 52% of patients in the first trial and in 39% of patients in the second trial. Bone scans have been used in the past to evaluate treatment interventions in patients with prostate cancer; however, this modality is unreliable owing to the false-positive rate. Patients with improving disease can
335
demonstrate worsening of a bone scan. Only five of the nine patients with a soft-tissue response in the authors' initial trial demonstrated an improved bone scan despite shrinking disease. The median overall survival at the time of publication in the two trials was 44 and 56 weeks, respectively. A long-term analysis of 105 patients from both trials demonstrated a median survival of 46 weeks (Fig. 1).All but two of the patients have died. These two patients were alive 4 and 5 years following treatment, respectively. The PSA response was investigated as a tool to predict survival.'" Sixty-two patients were gathered from both trials to perform a landmark analysis. The landmark chosen was a PSA decline of 50% from baseline at 8 weeks. This analysis demonstrated a significantly longer survival for patients who demonstrated a PSA response when compared with those who did not. The responders had a median survival of 91 weeks and the nonresponders, a median survival of 38 weeks ( P = 0.0005) (Fig. 2). A PSA decline of 50% at any time during treatment was associated with a reduction of soft-tissue lesions. Based on this evidence, a decrease in PSA is associated with survival and response of soft-tissue lesions and should be incorporated into the response criteria of clinical trials of chemotherapy for hormone-refractory prostate cancer.
CYTOXAN, DIETHYLSTILBESTROL, AND PREDNISONE
Methods
Diethylstilbestrol is a nonsteroidal estrogen that exerts a competitive inhibitory effect on androgen-dependent carcinomas, although its mode of action in men with castrate levels of testosterone remains ~ n d e f i n e d .Diethylstil~ bestrol has a historic role in the initial treatment of advanced prostate cancer.zInitially, 5 mg/day of diethylstilbestrol was the standard dose; however, comparison studies have shown 1 mg/day to be equivalent in terms of shrinking metastatic disease with a decreased toxicity p r ~ f i l e . ~
336
KAMRADT et
ill
Survival (weeks)
Figure 1. Kaplan-Meier estimate of overall survival of patients combined from the two trials of estramustine and etoposide.
The authors combined diethylstilbestrol, 1 mg/day, with prednisone and oral cyclophosphamide.6 This regimen was then evaluated in 58 patients. The trial enrolled patients from August 1994 through November of 1996. The treatment regimen consisted of 100 mg of cyclophosphamide on days 1 to 20; diethylstilbestrol, 1 mg/day, and prednisone, 20 mg/ day, for 20 days; and then 10 mg/day, continuously. The treatment cycle for cyclophosphamide was 30 days. Therapy was continued until evidence of disease progression was noted. All patients were required to have a performance status of at least 2 as well as documented progression following antiandrogen withdrawal. Patients were allowed to have received prior chemotherapy. Disease response was assessed after the first two cycles and then every 8 weeks. A complete response required the resolution of all measurable soft-tissue lesions. A partial response required a decrease of at least 50%
for measurable lesions. A partial response by PSA required that the PSA drop by more than 50% of the baseline value for two consecutive determinations.
ResuIts The regimen was easily administered to patients, and compliance was good. Patients tolerated the combined treatment well with few side effects. There were no episodes of substantial neutropenia or thrombocytopenia. Likewise, there were no hospitalizations for infectious complications. Patients experienced minimal nausea; most patients had no nausea. One patient sustained deep venous thrombosis during treatment. Seven patients had soft-tissue lesions that were evaluable for response. Three (43%) of these patients experienced a partial response during treatment. PSA was also used as a
ORAL CHEMOTHERAPY FOR HORMONE REFRACTORY PROSTATE CANCER
337
I I
9
0
0
I
I
I
1
2
3
4
Years Figure 2. Kaplan-Meier estimate of survival from the 8-week landmark by relative decrease in PSA for patients treated with estramustine and etoposide. (From Smith DC, Dunn RL, Strawderman MS, et al: Change in serum prostate specific antigen as a marker of response to cytotoxic therapy for hormone refractory prostate cancer. J Clin Oncol 16:1835-1843, 1998)
marker of response. Twenty-one (36%) patients had a PSA decline of greater than 50% from the pretreatment value. Using a 50% decline at 8 weeks as the definition of response, the responders had a longer median survival when compared with nonresponders (Fig. 3). This finding is similar to the results of the analysis of the oral estramustine and etoposide trials. The data reaffirm the finding that a PSA decline of 50% at 8 weeks in patients receiving cytotoxic chemotherapy predicts survival. The medial overall survival for the entire group was 62 weeks (Fig. 4).
SINGLE-AGENT DIETHYLSTILBESTROL Methods
Between July 1995 and March 1997, twentyone patients with hormone-refractory prostate cancer were enrolled in a prospective trial
of diethylstilbestrol at 1 mg/day as a secondary treatment following initial androgen blockade.'2 Nine patients (43%) had prior surgical castration; the remaining 12 patients had medical castration. Patients needed to demonstrate two progressive increases in PSA to be eligible for the trial. A period of observation during antiandrogen withdrawal was also required. Results
The pretreatment characteristics for this trial demonstrated that the patients had a median age of 68 years, with all patients having a performance score of 0 or 1. Nearly all of the patients had evidence of bone metastasis. No patient exhibited soft-tissue lesions. All patients were asymptomatic at the time of enrollment. No patient had received chemotherapy; however, 38% of patients had been treated with two or more hormonal manipula tions.
338
KAMRADT et a l
I m
1
6 ?
C ._ 1 ._
1
L
$ v)
C
1
e
i 1.
a
p= 0132
7 1
2-1
7
i
I 0
50
100
150
I
200
Survival (weeks) Figure 3. Kaplan-Meier estimate of overall survival of patients treated with cyclophosphamide, diethylstilbesterol, and prednisone. = responders; o = non-responders.
250
ORAL CHEMOTHERAPY FOR HORMONE REFRACTORY PROSTATE CANCER 1 1
I
339
L
ii 0 0
50
150
100
2M)
2%
Survival (weeks)
Figure 4. Kaplan-Meier estimate of Survival from the 8-week landmark by relative decrease in PSA of patients treated with cyclophosphamide, diethylstilbesterol, and prednisone.
Toxicity was minimal. Most patients experienced nipple sensitivity; however, therapy was not stopped because of this. Three patients demonstrated gynecomastia, and one patient sustained deep venous thrombosis. Nine patients (43%) demonstrated a PSA decline of greater than 50% from baseline. Patients received an average of 5 months of therapy (range, 1 to 22 months). The median follow-up was 82 weeks, with five patients dying of prostate cancer during that time. The estimated survival rate at 2 years was 63%. Single-agent diethylstilbestrol seems to be an effective second-line agent for patients failing initial hormonal therapy. SUMMARY
The use of oral chemotherapy for the treatment of malignant disease is expanding. The
authors' experience with oral chemotherapy for hormone-refractory prostate cancer continues to grow. These therapies are well-tolerated and effective. Already, these regimens are being improved by hybridizing them with intravenous agents such as paclitaxel." Also, oral novel agents are being tested that may offer new options for the treatment of hormone-refractory prostate cancer.
References 1. Berges RR, Vukanovic J, Epstein JI, et al: Implications of cell kinetic changes during the progression of human prostatic cancer. Clin Cancer Res 1:473-480, 1995 2. Byer DP: The Veterans' Administration Cooperative Urological Research Group's studies of cancer of the prostate. Cancer 32:1126-1130, 1973 3. Byer DP, Corle DK: Hormone therapy for prostate cancer: Results of the Veterans Administration Cooperative Urological Research Group studies. NCI Monographs 7:165-170,1988
340
KAMRADT et al
4. LkMario MD, Ratain MI: Oral chemotherapy: Ratio-
5.
6.
7.
8.
nale and future directions. J Clin Oncol 16:25572567, 1998 Pienta KJ, Lehr JE: Inhibition of prostate cancer growth by estramustine and etoposide: Evidence for interaction at the nuclear matrix. J Urol 149:16221625, 1993 Pienta KJ, Esper PS, Smith DC: The oral regimen of Cytoxan, prednisone and diethylstilbestrol is an active, non-toxic treatment for patients with hormone refractory prostate cancer [abstract]. Proc Annu Meet Am Soc Clin Oncol 16:1104, 1997 Pienta KJ, Redman BG, Bandekar R, et al: A phase I1 trial of estramustine and oral etoposide in hormonerefractory prostate cancer. Urology 50:401407, 1997 Pienta KJ, Redman B, Hussain M, et al: Phase I1
evaluation of oral estramustine and oral etoposide in hormone-refractory adenocarcinoma of the prostate. J Clin Oncol 12:20052012, 1994 9. Smith DC: Secondary hormonal therapy. Semin Urol Oncol 15:3-13, 1997 10. Smith DC, Dunn RL, Strawderman MS, et al: Change in serum prostate specific antigen as a marker of response to cytotoxic therapy for hormone-refractory prostate cancer. J Clin Oncol 16:1835-1843, 1998 11. Smith DC, Esper PS, Todd RT, et al: Paclitaxel plus estramustine in metastatic hormone-refractory prostate cancer [abstract]. Proc Annu Meet Am Soc Clin Oncol 16:1105, 1997 12. Smith DC, Redman BG, Flaherty LE, et al: A phase 11 trial of oral diethylstilbestrol as a second line hormonal agent in advanced prostate cancer. Urology, in press Address rqwirif repests fo Kenneth J. Pienta, MD The University of Michigan Medical Center 1500 East Medical Center Drive Ann Arbor, MI 48109
HORMONE REFRACTORY PROSTATE CANCER
+
.OO
ORAL CHEMOTHERAPY FOR HORMONE REFRACTORY PROSTATE CANCER The University of Michigan Experience Jeffrey M. Kamradt, MD, David C. Smith, MD, and Kenneth J. Pienta, MD
Traditionally, chemotherapy for malignant disease has been administered as a bolus intravenous dose. The patient receives a large dose of a drug at the beginning of a treatment cycle, followed by a lag period until normal tissues, such as myeloid elements and mucosa, can recover prior to receiving the next dose. Oral chemotherapy offers an alternative to this approach. The agents can be delivered at lower doses over an extended period of time. This has a number of benefits. First, toxicity is generally decreased. The circulating level of the drug does not cross a threshold above which damage to normal tissues occur. Because of this, the agent can be given over an extended period of time. This is important in tumors such as prostate cancer that have a low proliferative rate.’ Patients can assume an active role in their daily treatment, and compliance is enhanced. The cost of oral chemotherapy is less than that of traditionally administered agents.4 Regimens using prolonged doses of oral chemotherapy for hormone-refractory prostate cancer have been developed at the au-
thors’ center over the past 5 years (Table 1). The combination of estramustine and etoposide has been tested in two separate trials for patients with advanced symptomatic disease. Also, the combination of cyclophosphamide, diethylstilbestrol, and prednisone has been investigated as a first-line treatment for patients with early asymptomatic hormone-refractory disease. Similarly, diethylstilbestrol has been used alone as a single agent. The authors’ experience with these agents has been positive; good responses are achieved with a minimum of toxicity. Additional trials using other novel oral agents are being conducted. It is hoped that these studies will yield new well-tolerated regimens for the treatment of hormone-refractory prostate cancer. ESTRAMUSTINE AND ETOPOSIDE Methods
The combination of oral estramustine and etoposide has been the cornerstone of recent
From the Division of Hematology and Oncology, Department of Internal Medicine (JMK, DCS), and the Department of Genitourinary Oncology (KJP), University of Michigan Cancer Center, AM Arbor, Michigan
UROLOGIC CLINICS OF NORTH AMERICA VOLUME 26 * NUMBER 2 * MAY 1999
333
334
KAMRADT et a1
Table 1. ORAL CHEMOTHERAPY REGIMENS AT THE UNIVERSITY OF MICHIGAN
Regimen
Method of Administration
Estrnmustine and etoposide Cytoxan, DES, and prednisone Single-agent DES DES
=
diethylstilbestrol; EMP
=
EMP, 280 mg, tid on days 1 to 21 ETP, 50 mg, bid on days 1 to 21 Cytoxan, 100 mg, on days 1 to 20 DES, 1 mg, qd Prednisone, 10 mg, qd DES, 1 mg, qd
estramustine phosphate; ETP
chemotherapy trials at the University of Michigan. The combination (at two different dose levels) has been tested in two separate phase I1 trials as well as combined with intravenous chemotherapy agents. Prior to its use in the clinic, the two-drug combination underwent extensive preclinical testing. In vitro, the drugs demonstrated enhanced cytotoxicity as well as an ability to impair DNA synthesis at the level of the nuclear matrix.s In vivo, the combination of the two drugs was more effective at suppressing tumor growth in an animal model of prostate cancer. This preclinical synergy provided the rationale for combining the two agents in clinical trials. Two separate trials of the combination have been performed in patients with hormonerefractory prostate cancer. The first study enrolled 42 patients from November 1991 through June 1993.xThe dose of estramustine was 15 mg/kg/day and the dose of etoposide, 50 mg/m2. The second trial enrolled 62 patients from July 1993 through March 1996.' The dose of etoposide was the same as that used in the earlier trial; however, the dose of estramustine was decreased to 10 mg/kg/ day. The treatment regimen was given for 21 days of a 28-day cycle. Patients were eligible for the study if they had a Zubrod performance status of at least 3 and demonstrated histologically proven adenocarcinoma of the prostate with distant metastasis that had become refractory to androgen deprivation. All prior therapy was completed at least 4 weeks prior to enrollment. This is particularly important in regards to therapy with the antiandrogen flutamide. The first trial enrolled patients before recognition of the "flutamide withdrawal" response; however, the enrollees all demonstrated a rise in prostate-specific
=
PSA Response
SoftTissue Response
Reference
39% to 52%,
50% to 53%
7, 8
36%
43%
6
43%"
NA
12
etoposide.
antigen (PSA) following discontinuation of the antiandrogen. For the second trial, this phenomenon was described and accounted for appropriately. In each of the trials, disease response was assessed after the first two cycles and then every 8 weeks. A complete response required the resolution of all measurable soft-tissue lesions. A partial response required a decrease of at least 50% for measurable lesions. A partial response by PSA required that the marker drop by more than 50% of the baseline value for two consecutive determinations.
Results
Pretreatment characteristics for the two trials demonstrated that the patients had a median age of 67 to 69 years, with approximately 60% having a performance score of 0 or 1. Nearly all of the patients had evidence of bone metastasis. In the first and second trial, 43% and 24% of patients exhibited a measurable soft-tissue lesion, respectively. Prior chemotherapy disqualified patients from the first study; however, 62% of patients in the second study were previously treated with chemotherapy. The estramustine-etoposide combination was tolerated reasonably well by patients. Most patients who worked before enrolling in the study continued to do so during treatment. Hematologic toxicity was manifested mainly as leukopenia and thrombocytopenia. In the initial trial, 25% of patients required a dose reduction of the etoposide because of leukopenia, thrombocytopenia, or both. There were five episodes of neutropenic fever in
ORAL CHEMOTHERAPY FOR HORMONE REFRACTORY PROSTATE CANCER
236 cycles of therapy. One patient died of complete bone marrow failure within 12 weeks of initiating therapy. In the subsequent trial, 18% of patients experienced a dose reduction of etoposide secondary to cytopenia. There was only one episode of neutropenic fever in over 300 cycles of therapy. Nonhematologic toxicities consisted mainly of alopecia and nausea. Patients universally experienced some degree of alopecia. In each trial, approximately 25% of patients experienced significant nausea, and 5% of patients withdrew from the study secondary to grade 3 nausealvomiting. Ten percent of patients in the higher-dose estramustine trial and 6% of patients in the attenuated estramustine dose trial experienced deep venous thrombosis. Lower-extremity edema was experienced by 48% of patients in the higher estramustine trial and by 35% in the lower-dose trial. One patient from the initial trial died of congestive heart failure and possible myocardial infarction within 3 weeks of initiating therapy. A decrease of soft-tissue lesions has been the hallmark of response for chemotherapy trials. In prostate cancer, most patients do not present with soft-tissue lesions because the disease is limited to osseous metastasis in the large majority of patients. Early trials of chemotherapy for hormone-refractory prostate cancer limited the study population to patients with measurable disease. Obviously, this selection criterion limited the enrollees to a specific subgroup of patients with prostate cancer and greatly reduced the applicability of the results to the general population of patients. PSA is elevated in the large majority of patients with prostate cancer and serves well as a marker of disease. In both trials, both the reduction of soft-tissue lesions as well as the decline in PSA from pretreatment values were used as markers of response. The response rates for soft-tissue disease in the first and second trials were 53% and 50%, respectively. PSA declines of greater than 50% from baseline were seen in 52% of patients in the first trial and in 39% of patients in the second trial. Bone scans have been used in the past to evaluate treatment interventions in patients with prostate cancer; however, this modality is unreliable owing to the false-positive rate. Patients with improving disease can
335
demonstrate worsening of a bone scan. Only five of the nine patients with a soft-tissue response in the authors' initial trial demonstrated an improved bone scan despite shrinking disease. The median overall survival at the time of publication in the two trials was 44 and 56 weeks, respectively. A long-term analysis of 105 patients from both trials demonstrated a median survival of 46 weeks (Fig. 1).All but two of the patients have died. These two patients were alive 4 and 5 years following treatment, respectively. The PSA response was investigated as a tool to predict survival.'" Sixty-two patients were gathered from both trials to perform a landmark analysis. The landmark chosen was a PSA decline of 50% from baseline at 8 weeks. This analysis demonstrated a significantly longer survival for patients who demonstrated a PSA response when compared with those who did not. The responders had a median survival of 91 weeks and the nonresponders, a median survival of 38 weeks ( P = 0.0005) (Fig. 2). A PSA decline of 50% at any time during treatment was associated with a reduction of soft-tissue lesions. Based on this evidence, a decrease in PSA is associated with survival and response of soft-tissue lesions and should be incorporated into the response criteria of clinical trials of chemotherapy for hormone-refractory prostate cancer.
CYTOXAN, DIETHYLSTILBESTROL, AND PREDNISONE
Methods
Diethylstilbestrol is a nonsteroidal estrogen that exerts a competitive inhibitory effect on androgen-dependent carcinomas, although its mode of action in men with castrate levels of testosterone remains ~ n d e f i n e d .Diethylstil~ bestrol has a historic role in the initial treatment of advanced prostate cancer.zInitially, 5 mg/day of diethylstilbestrol was the standard dose; however, comparison studies have shown 1 mg/day to be equivalent in terms of shrinking metastatic disease with a decreased toxicity p r ~ f i l e . ~
336
KAMRADT et
ill
Survival (weeks)
Figure 1. Kaplan-Meier estimate of overall survival of patients combined from the two trials of estramustine and etoposide.
The authors combined diethylstilbestrol, 1 mg/day, with prednisone and oral cyclophosphamide.6 This regimen was then evaluated in 58 patients. The trial enrolled patients from August 1994 through November of 1996. The treatment regimen consisted of 100 mg of cyclophosphamide on days 1 to 20; diethylstilbestrol, 1 mg/day, and prednisone, 20 mg/ day, for 20 days; and then 10 mg/day, continuously. The treatment cycle for cyclophosphamide was 30 days. Therapy was continued until evidence of disease progression was noted. All patients were required to have a performance status of at least 2 as well as documented progression following antiandrogen withdrawal. Patients were allowed to have received prior chemotherapy. Disease response was assessed after the first two cycles and then every 8 weeks. A complete response required the resolution of all measurable soft-tissue lesions. A partial response required a decrease of at least 50%
for measurable lesions. A partial response by PSA required that the PSA drop by more than 50% of the baseline value for two consecutive determinations.
ResuIts The regimen was easily administered to patients, and compliance was good. Patients tolerated the combined treatment well with few side effects. There were no episodes of substantial neutropenia or thrombocytopenia. Likewise, there were no hospitalizations for infectious complications. Patients experienced minimal nausea; most patients had no nausea. One patient sustained deep venous thrombosis during treatment. Seven patients had soft-tissue lesions that were evaluable for response. Three (43%) of these patients experienced a partial response during treatment. PSA was also used as a
ORAL CHEMOTHERAPY FOR HORMONE REFRACTORY PROSTATE CANCER
337
I I
9
0
0
I
I
I
1
2
3
4
Years Figure 2. Kaplan-Meier estimate of survival from the 8-week landmark by relative decrease in PSA for patients treated with estramustine and etoposide. (From Smith DC, Dunn RL, Strawderman MS, et al: Change in serum prostate specific antigen as a marker of response to cytotoxic therapy for hormone refractory prostate cancer. J Clin Oncol 16:1835-1843, 1998)
marker of response. Twenty-one (36%) patients had a PSA decline of greater than 50% from the pretreatment value. Using a 50% decline at 8 weeks as the definition of response, the responders had a longer median survival when compared with nonresponders (Fig. 3). This finding is similar to the results of the analysis of the oral estramustine and etoposide trials. The data reaffirm the finding that a PSA decline of 50% at 8 weeks in patients receiving cytotoxic chemotherapy predicts survival. The medial overall survival for the entire group was 62 weeks (Fig. 4).
SINGLE-AGENT DIETHYLSTILBESTROL Methods
Between July 1995 and March 1997, twentyone patients with hormone-refractory prostate cancer were enrolled in a prospective trial
of diethylstilbestrol at 1 mg/day as a secondary treatment following initial androgen blockade.'2 Nine patients (43%) had prior surgical castration; the remaining 12 patients had medical castration. Patients needed to demonstrate two progressive increases in PSA to be eligible for the trial. A period of observation during antiandrogen withdrawal was also required. Results
The pretreatment characteristics for this trial demonstrated that the patients had a median age of 68 years, with all patients having a performance score of 0 or 1. Nearly all of the patients had evidence of bone metastasis. No patient exhibited soft-tissue lesions. All patients were asymptomatic at the time of enrollment. No patient had received chemotherapy; however, 38% of patients had been treated with two or more hormonal manipula tions.
338
KAMRADT et a l
I m
1
6 ?
C ._ 1 ._
1
L
$ v)
C
1
e
i 1.
a
p= 0132
7 1
2-1
7
i
I 0
50
100
150
I
200
Survival (weeks) Figure 3. Kaplan-Meier estimate of overall survival of patients treated with cyclophosphamide, diethylstilbesterol, and prednisone. = responders; o = non-responders.
250
ORAL CHEMOTHERAPY FOR HORMONE REFRACTORY PROSTATE CANCER 1 1
I
339
L
ii 0 0
50
150
100
2M)
2%
Survival (weeks)
Figure 4. Kaplan-Meier estimate of Survival from the 8-week landmark by relative decrease in PSA of patients treated with cyclophosphamide, diethylstilbesterol, and prednisone.
Toxicity was minimal. Most patients experienced nipple sensitivity; however, therapy was not stopped because of this. Three patients demonstrated gynecomastia, and one patient sustained deep venous thrombosis. Nine patients (43%) demonstrated a PSA decline of greater than 50% from baseline. Patients received an average of 5 months of therapy (range, 1 to 22 months). The median follow-up was 82 weeks, with five patients dying of prostate cancer during that time. The estimated survival rate at 2 years was 63%. Single-agent diethylstilbestrol seems to be an effective second-line agent for patients failing initial hormonal therapy. SUMMARY
The use of oral chemotherapy for the treatment of malignant disease is expanding. The
authors' experience with oral chemotherapy for hormone-refractory prostate cancer continues to grow. These therapies are well-tolerated and effective. Already, these regimens are being improved by hybridizing them with intravenous agents such as paclitaxel." Also, oral novel agents are being tested that may offer new options for the treatment of hormone-refractory prostate cancer.
References 1. Berges RR, Vukanovic J, Epstein JI, et al: Implications of cell kinetic changes during the progression of human prostatic cancer. Clin Cancer Res 1:473-480, 1995 2. Byer DP: The Veterans' Administration Cooperative Urological Research Group's studies of cancer of the prostate. Cancer 32:1126-1130, 1973 3. Byer DP, Corle DK: Hormone therapy for prostate cancer: Results of the Veterans Administration Cooperative Urological Research Group studies. NCI Monographs 7:165-170,1988
340
KAMRADT et al
4. LkMario MD, Ratain MI: Oral chemotherapy: Ratio-
5.
6.
7.
8.
nale and future directions. J Clin Oncol 16:25572567, 1998 Pienta KJ, Lehr JE: Inhibition of prostate cancer growth by estramustine and etoposide: Evidence for interaction at the nuclear matrix. J Urol 149:16221625, 1993 Pienta KJ, Esper PS, Smith DC: The oral regimen of Cytoxan, prednisone and diethylstilbestrol is an active, non-toxic treatment for patients with hormone refractory prostate cancer [abstract]. Proc Annu Meet Am Soc Clin Oncol 16:1104, 1997 Pienta KJ, Redman BG, Bandekar R, et al: A phase I1 trial of estramustine and oral etoposide in hormonerefractory prostate cancer. Urology 50:401407, 1997 Pienta KJ, Redman B, Hussain M, et al: Phase I1
evaluation of oral estramustine and oral etoposide in hormone-refractory adenocarcinoma of the prostate. J Clin Oncol 12:20052012, 1994 9. Smith DC: Secondary hormonal therapy. Semin Urol Oncol 15:3-13, 1997 10. Smith DC, Dunn RL, Strawderman MS, et al: Change in serum prostate specific antigen as a marker of response to cytotoxic therapy for hormone-refractory prostate cancer. J Clin Oncol 16:1835-1843, 1998 11. Smith DC, Esper PS, Todd RT, et al: Paclitaxel plus estramustine in metastatic hormone-refractory prostate cancer [abstract]. Proc Annu Meet Am Soc Clin Oncol 16:1105, 1997 12. Smith DC, Redman BG, Flaherty LE, et al: A phase 11 trial of oral diethylstilbestrol as a second line hormonal agent in advanced prostate cancer. Urology, in press Address rqwirif repests fo Kenneth J. Pienta, MD The University of Michigan Medical Center 1500 East Medical Center Drive Ann Arbor, MI 48109