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Keywords:

  • prostate carcinoma;
  • androgen-independent;
  • cyclophosphamide;
  • dexamethasone;
  • vincristine (CVD)

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

BACKGROUND

In this Phase II study, the authors assessed the toxicity and anti-tumor activity of a combination of oral cyclophosphamide, oral low-dose dexamethasone, and intravenous vincristine (CVD) in patients with metastatic androgen-independent prostate carcinoma (AI-PCa).

METHODS

Patients with histologic proof of adenocarcinoma of the prostate progressing despite adequate hormonal therapy and adequate organ function were treated with oral cyclophosphamide, 250 mg/daily (Days 1–14); intravenous vincristine, 1 mg daily (Days 1, 8, 15); and oral dexamethasone, 0.75 mg twice a day (Days 1–14) in 28-day cycles. Study endpoints were toxicity, rate of prostate specific antigen (PSA) decline > 50%, and/or measurable disease response.

RESULTS

Fifty-two (95%) of 55 registered patients were evaluable. The majority (65%) of patients had received prior chemotherapy. The median number of treatment cycles given was two (range, one–seven cycles). Twenty-nine percent of the patients were found to have a > 50% decline in PSA level compared with baseline levels, and 25% of the patients with bidimensionally measurable soft-tissue or visceral disease were found to have a partial response. The median progression-free survival duration was 10 weeks, and the median overall survival duration was 10.6 months. There were no thromboembolic events, and hematologic and nonhematologic toxicity was minimal.

CONCLUSIONS

CVD was found to be an active and well-tolerated regimen for AI-PCa. The low toxicity profile makes CVD a useful treatment option for patients with significant comorbidities and high risk for treatment-related toxicity, especially thromboembolic events and myelotoxicity. Cancer 2003;97:561–7. © 2003 American Cancer Society.

DOI 10.1002/cncr.11078

In the year 2002, approximately 30,200 men in the United States died of metastatic prostate carcinoma.1 Although most patients with metastatic disease initially respond to androgen ablation, most, if not all, will develop androgen-independent progressive prostate carcinoma within a median of 18–24 months after initiation of androgen ablation. Secondary hormonal manipulation can be achieved, but it usually has short-term results.2, 3 Chemotherapy has a proven palliative role in the treatment of metastatic, androgen-independent prostate carcinoma (AI-PCa), but to our knowledge, to date no overall survival benefit has been seen in randomized trials.4, 5 In fact, the median survival duration, which is 12 months, is disappointingly short. In these earlier studies, a posttherapy prostate specific antigen (PSA) level decline of ≥ 50% from baseline was achieved in approximately one-third of the patients.5 Posttherapy decline in PSA of ≥ 50% from baseline has been evaluated in multiple studies and has been associated with prolonged survival in many6–8 but not all9, 10 of them. Contemporary Phase II chemotherapy trials incorporating estramustine phosphate and newer agents (e.g., taxanes) have consistently produced a ≥ 50% decline in PSA over baseline in > 50% of the patients and have reported a median survival duration > 18 months in most cases.11–19 Although these results are encouraging, the improvement in outcome may be related to patient selection. We have previously reported our experience with weekly administration of ketoconazole plus doxorubicin alternated with vinblastine plus estramustine (KAVE), which produced a ≥ 50% decline in PSA in 67% of patients. Among the 16 patients with measurable soft-tissue disease, objective response of measurable disease was found in 75%, and the median overall survival duration was 19 months.19 Thromboembolic events were the most serious adverse effects of many estramustine-containing regimens,12, 16–19 and the frequency of these effects did not seem to decrease with fixed low-dose warfarin administration.18 The reduction of the total dose of estramustine seemed to decrease, but not to abrogate, the risk for thromboembolic events.20

In view of the advanced age of many of the patients with metastatic AI-PCa and the high frequency of significant comorbidities (e.g., cardiovascular disease), treatment options that can ensure low morbidity warrant evaluation. In this study, we investigated the toxicity and antitumor activity of a combination of oral cyclophosphamide, intravenous vincristine, and oral low-dose dexamethasone (CVD) in patients with AI-PCa. Oral cyclophosphamide has been found to be active against AI-PCa when used alone21, 22 and in other combination regimens.23–25 Vincristine has been found to have modest single-agent activity against this disease and was preferred over vinblastine because of its lack of myelosuppressive side effects26, 27 as well as the prior use of vinblastine in many of our patients. Dexamethasone has been reported to significantly reduce PSA levels.28, 29 None of these agents are associated with significant risk of thromboembolic events. The CVD regimen was designed with the goal of easy administration in the outpatient setting and with the expectation of minimal toxicity, in particular minimal cardiovascular and thromboembolic side effects.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Eligibility

Patients with histologically confirmed adenocarcinoma of the prostate (excluding those with small cell carcinoma or sarcomatoid elements) and androgen-independent progressive disease were eligible for this trial. Patients had to have castrate levels of serum testosterone (≤ 20 ng/dL) and progressive disease at least 4 weeks after withdrawal from antiandrogen therapy (6 weeks for bicalutamide) defined as either: 1) new sites of bone metastases on bone scintigraphy, 2) a ≥ 25% increase in the sum of the products of diameters of any measurable lesion, or 3) a PSA level that had risen on three consecutive measurements done at least 2 weeks apart. For asymptomatic patients, a minimum PSA level of 40 ng/dL was required prior to study enrollment. Primary testicular androgen suppression (e.g., luteinizing hormone releasing hormone [LHRL] analog) was continued in all patients who did not undergo a prior orchiectomy.

Patients were required to have a life expectancy of at least 12 weeks, a Zubrod performance status of 0–3, and adequate hematologic, renal, and hepatic function (absolute neutrophil count [ANC] ≥ 1500/μl; platelet count ≥ 100,000/μl [≥ 50,000/μl if due to tumor invasion]; aspartate aminotransferase [AST] and alanine aminotransferase [ALT] levels ≤ 4 times the institutional upper limits of normal [ULN]; serum total bilirubin level < 1.5 mg/dL; and a calculated creatinine clearance ≥ 40 ml/minute). Concurrent treatments were not allowed (except for testicular androgen ablation). Prior chemotherapy was allowed if it did not include cyclophosphamide, vincristine, or dexamethasone. A minimum of 4 weeks (6 weeks for lomustine and mitomycin C) had to have elapsed since prior chemotherapy, surgery, radiation therapy, or immunotherapy. All patients signed a written informed consent form approved by the Institutional Review Board of The University of Texas M. D. Anderson Cancer Center before participating in the trial.

Pretreatment and Follow-Up Evaluation

The pretreatment evaluation included a complete medical history and physical examination with performance status as well as laboratory testing to assess eligibility. Laboratory studies included a compete blood count; prothrombin time;, partial thromboplastin time; serum electrolytes; comprehensive screening profile (alkaline phosphatase, lactate dehydrogenase, AST, ALT, blood urea nitrogen, creatinine, calcium, albumin, glucose, and total bilirubin levels); predicted creatinine clearance calculated by the formula of Cockcroft and Gault; and carcinoembryonic antigen (CEA), PSA, and serum testosterone levels. Appropriate staging procedures were performed to define the extent of disease, including chest X-ray, computed tomography scan of abdomen/pelvis, and radionuclide bone scan.

Interim medical history and physical examinations including performance status, weight, and laboratory studies were repeated at least every cycle. Complete blood count was repeated at a minimum on Days 8 and 28 of each cycle. Radiographic studies were repeated after achievement of maximum PSA decline, at the time of biochemical or clinical progression, or at both of these endpoints.

Treatment Plan

Patients received oral cyclophosphamide, 250 mg daily (fixed dose) on Days 1–14; intravenous vincristine, 1 mg daily on Days 1, 8, and 15; and oral dexamethasone, 0.75 mg twice daily on Days 1–14. Cycles were repeated every 28 days. Chemotherapy was given if the absolute neutrophil count was ≥ 1500/μl (≥ 1000/μl for Day 8) and if the platelet count was ≥ 100,000/μl (≥ 50,000/μl for Day 8 or for bone marrow invasion). Cyclophosphamide was withheld for 1 week in the presence of Grade 2 or higher neutropenia on Day 1 (Grade 3 or higher on Day 8) or Grade 3 or higher thrombocytopenia, and was resumed upon count recovery. The dose of cyclophosphamide was reduced to 200 mg/day with Grade 4 neutropenia or thrombocytopenia. Therapy was continued for a minimum of two cycles unless there was rapidly progressive disease and for at least three cycles if there was no progression and no Grade 3–4 toxicity. The protocol called for continuation of treatment for at least three cycles after achieving maximum response. Treatment was given at the M. D. Anderson Cancer Center or by the patient's local oncologist because our intention was to create a treatment regimen that was easy to administer in the outpatient community setting and that was convenient for the patient.

Response Definition

The criteria used for assessing and reporting responses were in accordance with the consensus guidelines regarding Phase II trials of cytotoxic agents for the treatment of hormone refractory prostate cancer (HRPC).30 In reporting the study results, we tabulated the PSA declines in accordance with the consensus guidelines to report a ≥ 50% posttherapy PSA decline. The date of disease progression was the date recorded as the first increase in serum PSA. For those with bone disease, new lesions on radionuclide bone scan (but not worsening of the intensity of existing lesions) qualified as progressive disease.

All patients treated were evaluated for toxicity. All eligible patients were assessable for response. Progression-free survival (PFS) duration was calculated from the start of therapy to the off-study date, which was either the date defined by the criteria for progression based on PSA level, measurable disease, or bone disease, or the date of removal from the study because of toxicity or death. Survival duration was measured from time of registration.

Statistical Considerations

The primary objectives of the study were to determine the response rate and toxicity profile for the CVD regimen in patients with AI-PCa. Overall and progression-free survival times were secondary endpoints in this Phase II trial. The planned sample size of 55 patients ensures a 95% confidence interval (95% CI) for the estimated probability of response having width at most 0.26 (that is within ∓ 0.13 of the deserved response rate). Confidence intervals for the probabilities were computed using the method of Ghosh.32 Unadjusted probabilities of survival and PFS were estimated using the Kaplan–Meier method.33 Unadjusted between-group comparisons of survival were made using the log rank test.34 The Cox proportional hazards regression model35, 36 was used to assess the ability of patient characteristics or treatments to predict survival and PFS, with goodness-of-fit assessed by the Grambsch–Therneau test37 and martingale residual plots36 and predictive variables transformed as appropriate based on these plots. Multivariate Cox models were obtained by performing a backward elimination with a P value cutoff of 0.05, then allowing any variable previously deleted to enter the final model if its P value was < 0.05. All computations were performed in Splus.38

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Patient Characteristics

A total of 55 patients were enrolled in this study between March 1997 and May 1999. Two patients refused to receive any treatment after enrollment and one was found to be ineligible after registration and did not receive therapy (his serum testosterone level was 180 ng/dl). Therefore, 52 patients were evaluable for toxicity and response. Patients' baseline characteristics are listed in Table 1. The median age at study entry was 70 years (range, 45–85 years). Most of the patients (47 of 52) had bone metastases: 17 with stage OI disease (osseous metastases involving the axial skeleton) and 30 with stage OII disease (extensive bone involvement of the appendicular skeleton). Liver and lymph node involvement were found in 8 (15%) and 16 (31%) of the 52 patients, respectively. Despite the extent of metastatic disease, most patients (39 of 52) had a good performance status (0–1). All 30 patients who had prior antiandrogen therapy had evidence of progression after antiandrogen withdrawal. Thirty-four of 52 (65%) patients had prior combination chemotherapy; 19 of the 34 had prior KAVE. Of the 34 patients treated with prior combination chemotherapy, 21 had responded to the previous chemotherapy. Most of the patients had histologically aggressive disease, with 69% having a Gleason score of 8–10 at first diagnosis. A total of 147 cycles of therapy were delivered with a median of two cycles per patient (range, one–seven).

Table 1. Baseline Characteristics of Patients
VariableMedian (range)No. of patients (%)
  1. KAVE: ketoconazole plus doxorubicin alternated with vinblastine plus estramustine; PSA: prostate specific antigen; DES: diethylstilbestrol.

No. of patients registered 55
No. of eligible patients receiving therapy 52
Age at start of treatment70 (45–85) 
Time from 1st diagnosis to treatment (yrs)5.9 (0.3–19.8) 
Hormone treatment duration (yrs)2.3 (0.2–17.1) 
Gleason score at 1st diagnosis  
 6, 7 16 (31)
 8–10 36 (69)
Metastases at study entry  
 Bone 47 (90)
  OI 17 (33)
  OII 30 (58)
 Liver 8 (15)
 Lymph node 16 (31)
Performance status1 (0–3) 
 0, 1 39 (75)
 2, 3 13 (25)
Laboratory values  
 Hemoglobin, g/dL12.05 (7.9–14.4) 
 Alkaline phosphatase, IU/L161 (65–1589) 
 PSA, ng/mL126.6 (6.8–2698) 
Prior therapy  
 Prostatectomy 8 (15)
 Prostate radiotherapy 22 (42)
 Palliative radiotherapy 16 (31)
 Strontium-89 10 (19)
 Androgen ablation 52 (100)
 Antiandrogen 30 (58)
 20 Hormonal therapy (DES, ketoconazole) 8 (16)
 Chemotherapy 34 (65)
  No. of prior chemotherapy regimens1 (0–5) 
  Prior KAVE chemotherapy 19 (37)
  Responded to prior chemotherapy 21 (40)

Clinical Results

Fifty-two patients were assessable for clinical outcome. All were followed until death or March 2001 when the data were collected for analysis. The median follow-up is 44.7 weeks. All 52 patients were assessable for posttherapy changes in serum PSA concentration. Fifteen of 52 patients (29%; 95% CI 18–42%) had a ≥ 50% decrease in serum PSA level (compared with the baseline level). Only 3 (6%) patients achieved ≥ 80% decrease in PSA level, and none had normalization of serum PSA levels. Serum alkaline phosphatase was elevated (> 126 IU/L; the institutional upper limit of normal) in 35 (67%) of 52 patients. Follow-up assessments were available in 30 of these patients. Only 6 (20%) of the 30 patients had a ≥ 50% reduction in serum alkaline phosphatase level during therapy (5 of whom achieved normal levels). Computed tomography scans showed bidimensional disease in 22 patients at baseline. Follow-up evaluations showed a partial response (PR) in 2 (25%) of 8 patients with liver metastasis and in 4 (25%) of 16 patients with lymph node disease. In all, 5 of these 22 (23%; 95% CI 10–43%) patients with measurable disease achieved partial response by radiographic criteria (Table 2).

Table 2. Clinical Outcomes
 OutcomeNo. of patients%
  1. PSA: prostate specific antigen; SD: stable, disease; PD: progressive disease; CR: complete response; PR: partial response.

PSA≥ 80 percent PSA decrease3/526
 ≥ 50–79 percent PSA decrease12/5223
 SD16/5231
 PD21/5240
Measurable diseaseCR00
 PR5/2223
 SD5/2223
 PD12/2254

Survival Analysis

The median overall PFS duration was 10.11 weeks (95% CI 8.91–14.87) (Fig. 1). Median overall survival (OS) duration was 10.6 months (95% CI 7.24–14.1) (Fig. 2) but was not significantly different between patients who achieved a ≥ 50% serum PSA decline and those who did not (data not shown). The following variables were assessed by the Cox multivariate analysis as potential predictive covariates of OS: duration of prior response to hormonal therapy, prior chemotherapy, performance status at study entry, pretreatment serum PSA concentration, hemoglobin level, alkaline phosphatase level, and extent of bone involvement. It appeared that higher hemoglobin level, lower alkaline phosphatase level, and lack of prior chemotherapy for AI-PCa were all associated with a higher probability of longer OS duration (Table 3). In addition, duration of PFS was longer in patients with a longer duration of response to hormonal therapy and a lower serum alkaline phosphatase level at study entry (data not shown).

thumbnail image

Figure 1. Progression-free survival (Kaplan–Meier analysis). The solid line represents the median. The dotted lines represent the confidence intervals.

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thumbnail image

Figure 2. Overall survival (Kaplan–Meier analysis). The solid line represents the median. The dotted lines represent the confidence intervals.

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Table 3. Cox Model for Overall Survival
VariableEstimated coefficientSEP value
  1. SE: standard error.

Hemoglobin−0.390.100.0002
log (alkaline phosphatase)0.600.180.001
Prior chemotherapy0.710.350.04

The probability of achieving a ≥ 50% PSA decline with CVD treatment was not different between the patients who had received prior chemotherapy (23%) and those who had not (33%) (data not shown). Although the trend favored patients who did not receive prior chemotherapy, there was no statistically significant difference between the two groups. Among the 34 patients who had received prior chemotherapy, 21 (62%) achieved a ≥ 50% PSA decline. PSA declines from baseline of ≥ 50% were seen in 7 (33%) of 21 patients who had responded to prior chemotherapy and 1 (8%) of 13 of patients who did not.

Toxicity

As expected, hematologic toxicity was the most commonly noted adverse event, although it was not severe. Seven (13%) patients had Grade 3–4 anemia. Grade 3–4 leukopenia was encountered in 15% of the patients, whereas neutropenia of the same level was seen in 11% (Table 4). Only one patient developed neutropenic fever. No patients developed Grade ≥ 3 thrombocytopenia. Neuropathy was noted to be a common adverse event, although most occurrences were mild (Grade 1–2). A total of 13% of the patients had Grade 1–2 sensory neuropathy and 18% had Grade 1–2 motor neuropathy. Only one patient developed Grade 3 motor neuropathy. This patient presented at the time of first diagnosis (5 years prior to study registration) with epidural cord compression at the lower thoracic level and had residual weakness of both lower extremities at study entry. Another patient with a history of coronary artery disease developed Grade 3 lower extremity pitting edema that was attributed to dexamethasone, although worsening of congestive heart failure could have played a role as well.

Table 4. Grade 3–4 Adverse Events (n = 52)
 No.%
Anemia713
Neutropenia611
Thrombocytopenia00
Neutropenic fever12
Fatigue00
Nausea00
Emesis00
Mucositis00
Neuropathy (Grade 3)12
Peripheral edema (Grade 3)12
Thrombosis00
Renal00

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

In the current study, we examined the efficacy of low-dose oral dexamethasone in combination with oral cyclophosphamide and intravenous vincristine in the treatment of patients with AI-PCa. All three agents used in this study have been previously reported to have antitumor activity and minimal toxicity in patients with AI-Pca.21–29 More importantly, the risk for thromboembolic events, a major concern when treating elderly patients with preexisting cardiovascular disease, has been found to be low with the use of these agents. In this study, we treated patients with progressing AI-PCa, most of whom (65%) had received prior estramustine-containing combination chemotherapy.

The CVD regimen at the doses and schedule used in this study is easy to administer in the community setting and has acceptable toxicity (of 52 patients, 1 developed neutropenic fever and 1 developed Grade 3 neuropathy). Fifteen (29%) of 52 patients achieved a ≥ 50% reduction in PSA concentration, but there was not a significant difference in OS duration between patients with favorable and unfavorable posttherapy PSA kinetics. This could be partially due to the finding that most of the nonresponders went on to receive additional salvage therapy after CVD. A recent trial of continuous low-dose dexamethasone in patients with AI-PCa (46% of whom had received prior estramustine-containing chemotherapy) found a higher (62%) rate of PSA decline > 50% from the baseline, and this change was also associated with improved survival duration.29 Conversely, our results appear to be better than those obtained with the use of cyclophosphamide alone when administered in a similar fashion (100 mg/m2/day on Days 1–14 in a 28-day cycle).21 In that small study, 20% of the patients had an objective partial response, but all patients were chemotherapy naïve.21 Whether differences in the extent of disease, extent of prior therapy, or other factors (e.g., degree of tumor differentiation, inherent chemosensitivity of the tumor, or subsequent therapies) contributed to the difference in the observed rates of PSA decline, OS duration, or both among these studies is not totally clear. It is, for example, not known whether patients treated with low-dose dexamethasone in the study of Nishimura et al.29 had responded to the prior chemotherapy regimen. It is possible that a certain subset of patients with AI-PCa have particularly chemosensitive disease and show repeated responses to subsequent therapies. Alternatively, the continuous administration of dexamethasone may have contributed to the higher observed rate of PSA decline and prolonged time to progression in that study.29

The rate of ≥ 50% PSA decline (29% of the patients, most with prior chemotherapy) and OS observed in the current study compared favorably with the results found with mitoxantrone/prednisone combination, where 38% of chemotherapy-naïve patients achieved > 50% PSA decline but with significantly higher myelotoxicity.5 The rate of PSA decline reported in this study and the OS duration was lower than that reported in other contemporary Phase II combination chemotherapy studies, most of which include estramustine and one of the taxanes.11–13, 17–20, 31 However, the majority of these studies reported results in chemotherapy-naïve patients, whereas our patients had a number of adverse prognostic features, including progressive disease after having been heavily pretreated with chemotherapy and radiation therapy. Of note, 8 (23%) of 34 patients previously treated with chemotherapy for AI-PCa had a ≥50% PSA decline with CVD. Posttherapy PSA decline of ≥ 50% was noted in 33% of patients with response and 8% of patients with progression after prior combination chemotherapy. Toxicity of CVD was much lower than that of estramustine-containing regimens, especially in regard to myelotoxicity and thromboembolic events. The median OS duration of 10.6 months in this group of heavily pretreated patients is promising.

We believe that these results provide evidence that CVD is an active and well tolerated regimen for patients with AI-PCa. CVD is a useful alternative for patients with thrombocytopenia (due to, i.e., bone marrow infiltration or disseminated intravascular coagulatopathy) and for patients who have failed or cannot tolerate estramustine-containing regimens. To further investigate the contribution of CVD in the treatment of patients with AI-PCa, we have incorporated CVD in our upfront randomized Phase II trial in chemotherapy naïve patients. In this study, patients were randomly assigned to KAVE; paclitaxel, estramustine, etoposide (TEE); paclitaxel, estramustine, carboplatin (TEC); or CVD with the objective of determining the best two-regimen combination for assessing PSA and/or measurable disease response, toxicity, and survival.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

The authors thank Linda Hicks for secretarial assistance.

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  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
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