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Results of a Phase II Study Using Estramustine Phosphate and Vinblastine in Combination With High-Dose Three-Dimensional Conformal Radiotherapy for Patients With Locally Advanced Prostate Cancer

From the Department of Radiation Oncology, Solid Tumor Service, Department of Medical Oncology, Department of Nursing, Department of Medical Imaging, Memorial Sloan-Kettering Cancer Center, New York, NY.

Address reprint requests to Michael J. Zelefsky, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10024; email zelefskm{at}mskcc.org

	ABSTRACT

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PURPOSE: To assess the feasibility and tolerance of neoadjuvant and concomitant estramustine phosphate and vinblastine (EV) with high-dose three-dimensional conformal radiotherapy (3D-CRT) for patients with unfavorable-risk prostate cancer.

PATIENTS AND METHODS: Twenty-seven patients with unfavorable-risk prostate cancer were enrolled onto a prospective study to determine the feasibility of combining EV with 3D-CRT. Patients were eligible if any of the following requirements were satisfied: (1) Gleason score 8 and prostate-specific antigen (PSA) > 10 ng/mL; (2) Gleason score of 7 and PSA > 20 ng/mL; (3) clinical stage T3N0M0 disease with PSA > 20 ng/mL; (4) any patient with T4N0M0 disease; or (5) patients with TXN1MO disease. Therapy consisted of three 8-week cycles of EV and 8 weeks of 3D-CRT. Estramustine phosphate was given orally beginning on week 1 and continued until the completion of 3D-CRT. Each 8-week cycle of vinblastine consisted of 6 weekly intravenous injections followed by a 2-week rest period. Radiation therapy was administered using a three-dimensional conformal approach to a prescription dose of 75.6 Gy. The median follow-up was 26 months (range, 6 to 40 months).

RESULTS: Twenty-three (85%) of 27 patients completed the entire course of therapy and were assessable for toxicities and biochemical outcome. Two patients (7%) developed grade 3 hematologic toxicity that resolved, and two patients (7%) developed grade 3 hepatoxicity, manifesting as persistent elevation of serum transaminase levels, necessitating discontinuation of the chemotherapy and withdrawal from the treatment program. The most prominent adverse effects from this regimen were mild to moderate (grade 1 to 2) nausea and fatigue related to estramustine. Mild peripheral edema was seen in 15% of patients and was treated with diuresis. 3D-CRT was tolerated well in these patients. Medications were required for relief of acute grade 2 rectal (gastrointestinal [GI]) and urinary (genitourinary [GU]) symptoms in 35% and 48% of patients, respectively. Three patients developed acute grade 3 GU toxicities. The 2-year actuarial likelihood of late grade 2 GI toxicity was 20%. No late grade 3 or 4 GI toxicities were observed. The 2-year actuarial likelihoods of late grade 2 and 3 GU toxicities were 25% and 12%, respectively. No grade 4 GU toxicity was observed.

CONCLUSION: Neoadjuvant and concomitant EV with high-dose 3D-CRT is well tolerated in patients with unfavorable-risk prostate cancer. Although the incidence of modest (grade 2) late GI and GU toxicities seem to be increased compared with 3D-CRT alone or in combination with androgen ablation therapy, no severe toxicities were encountered with this regimen.

	INTRODUCTION

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The optimal treatment strategy for patients with locally advanced prostate cancer continues to represent a challenge for the oncologist. Patients with poor prognostic features, such as prostate-specific antigen (PSA) levels greater than 20 ng/mL and Gleason scores greater than 7, have more locally aggressive primary tumors and a high likelihood of micrometastatic dissemination at the time of initial diagnosis. Thus, high rates of local and distant failure have been observed in this group after local modes of therapy. Recent studies in unfavorable-risk patients have demonstrated an improvement in local control and biochemical relapse-free survival with the use of neoadjuvant or adjuvant androgen ablation in combination with external-beam radiotherapy in contrast to treatment with radiotherapy (RT) alone.^1-3 However, despite the enhanced outcome with these approaches, the likelihood of treatment failure still remains high. In the Radiation Therapy Oncology Group trial 86-10,¹ which compared neoadjuvant androgen deprivation (NAAD) and RT versus RT alone, the 5-year biochemical relapse-free survival was improved for those who received NAAD, yet relapse rates were still high in both treatment groups (85% for RT only and 64% for NAAD + RT). Further, a conservative criterion for biochemical failure was used in that study (relapse was defined as PSA > 4 ng/mL). If the current, more strict definition of relapse were applied,⁴ the reported relapse rates would be expected to be even higher.

The role of adjuvant androgen ablation after RT also remains controversial because the randomized trials reported to date have not demonstrated a consistent survival benefit.^1,3 Because of the relatively short-term follow-up in these studies, the extent of the benefit of adjuvant androgen ablation remains unclear. Whether the tumor control advantage of prolonged hormonal therapy will outweigh the detrimental effects of long-term castration, which impacts upon the quality of life of the patient, is another important issue to be considered.

It is generally assumed that among patients with locally advanced prostate cancer, androgen-insensitive clonogens and micrometastatic foci are present at the time of diagnosis. Thus, optimal treatment requires therapeutic regimens that address both the androgen-dependent and androgen-independent local and systemic disease. Preclinical and clinical studies have shown that estramustine phosphate is a unique drug that may act as a hormonal agent and a radiosensitizer.^5-7 When estramustine is combined with microtubule inhibitor agents, such as vinblastine or paclitaxel, an additive antitumor effect has been observed in patients with androgen-independent prostate cancer. In patients with disseminated hormone-refractory prostate cancer treated with estramustine and vinblastine (EV), objective tumor regression was observed in one third of patients, and significant PSA declines occurred in 50%.^8-9 These studies have stimulated interest in EV as an adjuvant to local treatment in the setting of nonmetastatic, unfavorable-risk disease. Thus, when combined with RT, EV may not only act as a radiosensitizer, but may also have activity against local and systemic androgen-sensitive and androgen-independent tumor clones.

Encouraging preliminary results have been demonstrated with the use of EV in combination with RT for patients with localized prostate cancer with poor prognostic features. Khil et al⁷ reported the outcome of patients with disease stages T2 to T4 who were treated with concomitant EV and conventional external-beam radiotherapy to doses of 65 to 70 Gy. The overall PSA relapse-free survival rate at 5 years was 48% (relapse defined as PSA levels > 4 ng/mL), and among patients with pretreatment PSA levels less than 50 ng/mL, the PSA relapse-free survival was 60%. Longer courses of such regimens given before and during high-dose three-dimensional conformal radiotherapy (3D-CRT) have not yet been investigated and may be more effective than short-term concomitant treatment in this poor prognostic cohort. To examine the safety of combining EV with high-dose 3D-CRT, we conducted a prospective phase I study. The results demonstrate that this treatment approach is feasible and well tolerated, and the early biochemical outcome seems promising.

	PATIENTS AND METHODS

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Between September 1996 and March 1998, 27 patients with unfavorable-risk, nonmetastatic prostate cancer were enrolled onto a phase I prospective study to determine the feasibility and safety of combining EV with high-dose 3D-CRT. Patients were eligible for this trial if any of the following requirements were satisfied: (1) Gleason score 8 and PSA greater than 10 ng/mL (with any T stage); (2) Gleason score equal to 7 and PSA greater than 20 ng/mL (with any T stage); (3) clinical stage T3N0M0 disease with PSA greater than 20 ng/mL (with any Gleason score); (4) any patient with T4N0M0 disease; or (5) patients with TXN1MO disease. Node-positive disease was documented with computerized tomography (CT) or magnetic resonance imaging studies. These above mentioned eligibility criteria were selected because of previously published reports from our institution^10,11 that demonstrated that patients with these characteristics had a PSA relapse-free survival of less than 50% at 5 years from the completion of 3D-CRT. All pathology slides were reevaluated at Memorial Sloan-Kettering Cancer Center for confirmation of the Gleason score. Patients were excluded from the study if they had significant cardiac disease, angina pectoris, or myocardial infarction within 6 months of being evaluated. In addition, patients with a prior history of a thrombolic cerebrovascular accident, deep venous thrombosis, or the presence of claudication were also not eligible. Further, entry into the study required a Karnofsky performance status of 70, a WBC count greater than 3,000 cells/µL, a platelet count greater than 150,000 cells/µL, and normal renal and hepatic function profiles. All patients had a histologic diagnosis of prostate adenocarcinoma, classified according to the Gleason scoring system.¹² Serum PSA concentration was determined by radioimmunoassay (Tosoh method), with a normal range of 4.0 ng/mL and a minimal detectable level of 0.02 ng/mL. All patients signed an informed consent indicating that they were aware of the investigational nature of this institutional review board–approved study.

Before entry onto this study, all patients underwent an evaluation that included a complete blood count, liver and renal function tests, cholesterol profile, baseline PSA and testosterone levels, chest x-ray, electrocardiogram, bone scan, and baseline CT scan or magnetic resonance imaging of the abdomen and pelvis. Patients with a history of mild to moderate congestive heart failure or with a history of abnormal electrocardiogram findings were also evaluated with radionuclide angiocardiography. Patients remained eligible if the calculated cardiac ejection fraction was greater than 45% and if no evidence of ventricular aneurysm or abnormal myocardial wall motion was found.

Treatment Plan
The overall schema of the treatment program is shown in Fig 1. Therapy consisted of three 8-week cycles of EV and 8 weeks of 3D-CRT. Estramustine phosphate was administered daily beginning on week 1 and continued until the completion of 3D-CRT. Estramustine was given orally at a fixed amount of 10 mg/kg/d in three divided doses. The dose was reduced by 50% if patients developed grade 2 or greater nausea, vomiting, or hepatic dysfunction. Patients were instructed to avoid drinking milk-containing products, antacids, or calcium-rich foods because these products may impair estramustine absorption. Patients were also advised to use an oral antiemetic as needed for nausea. To counteract the thromboembolic effects of estramustine, all patients were instructed to take one aspirin tablet (325 mg) daily. The 8-week cycle of vinblastine (4 mg/m² weekly bolus) consisted of 6 weekly intravenous injections followed by a 2-week rest period. Vinblastine was withheld for a WBC of less than 2000 cells/µL or a platelet count of less than 75,000 cells/µL. The dose of vinblastine was reduced by 50% for a WBC between 2000 and 3000 cells/µL or for a platelet count between 75,000 and 125,000 cells/µL.

View larger version (35K): [in this window] [in a new window]   Fig 1. Schema for integration of chemotherapy with 3D-CRT.

Patients underwent physical examinations every 2 weeks while receiving neoadjuvant EV and weekly during 3D-CRT to monitor for adverse effects. At the beginning of each chemotherapy cycle (every 8 weeks), complete blood cell count, PSA, serum electrolytes, and liver and renal function tests were evaluated. Serum testosterone levels were obtained at baseline and repeated 3, 6, and 9 months after the completion of chemotherapy. All chemotherapy-induced toxicities were recorded using the National Cancer Institute common toxicity criteria.

RT was administered using six individually shaped coplanar fields delivered with 15 or 25 MeV x-rays in daily fractions of 1.8 Gy using a three-dimensional conformal approach, as previously described.^13,14 A dose of 75.6 Gy, which represented the minimum dose to the planning target volume, was delivered to all patients. The isocenter dose (International Commission on Radiological Units point) ranged from 4% to 7% higher than the prescription dose. Acute and late rectal (gastrointestinal [GI]) and urinary (genitourinary [GU]) toxicities were evaluated using a modification of the Radiation Therapy Oncology Group morbidity scoring scale.¹⁵

Patients were seen 1 month after completion of EV and 3D-CRT and were subsequently observed at 3-month intervals during the first year, at 4-month intervals during the second year, and at 6-month intervals thereafter. At each visit, a serum PSA, complete blood cell count, electrolytes, and liver and renal function tests were obtained. Testosterone levels were obtained at the frequency described. Radiographic imaging studies were performed as clinically indicated.

PSA relapse was defined as three successive PSA elevations observed from a posttreatment nadir PSA value according to the guidelines of the American Society of Therapeutic Radiation Oncology consensus definition for biochemical relapse.⁴ Differences between time-adjusted incidence rates were evaluated using the Mantel log-rank test for censored data.¹⁶ Distribution of times to develop radiation-induced late toxicity and disease relapse were calculated according to the product-limit (Kaplan-Meier) method.¹⁷ Disease status was determined at the time of analysis in May 1999. The median follow-up was 26 months (range, 6 to 40 months).

	RESULTS

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Twenty-seven patients were registered and eligible for this study. Four of the 27 patients did not complete the intended course of therapy. Two patients were withdrawn from the study because of persistent liver function test abnormalities related to the administration of estramustine. One of these two patients had a prior history of alcoholic liver disease, and the other patient took multiple concomitant medications that may have interfered with the estramustine metabolism. One patient was unable to receive radiation because of the presence of small bowel in close proximity to the target volume, and one patient developed a cerebral aneurysm bleed unrelated to the therapy. The remaining 23 patients completed the entire course of therapy and were assessable for toxicities and biochemical outcome. The patient characteristics grouped according to their respective clinical stages, Gleason scores, and median pretreatment PSA levels are listed in Table 1. A total of 505 of the 506 (99%) planned doses of vinblastine were administered; only three dose reductions were required.

Toxicity of Induction EV
Table 2 lists the adverse effects related to EV administration. Overall, the therapy was tolerated well, patients maintained an active lifestyle, and the majority continued to work full-time. Two patients (7%) developed grade 3 hematologic toxicity that resolved, and two patients (7%) developed grade 3 hepatoxicity manifesting as persistent elevation of serum transaminase levels to three to four times the upper limits of normal. As a result, these latter two patients were removed from the study. After discontinuation of the chemotherapy, their liver function abnormalities gradually reverted to baseline levels.

Beginning in May 1997, the study was amended to allow for the administration of epoetin alfa when hemoglobin levels decreased below 12 g/dL. With this intervention, there was a subjective improvement in fatigue based on weekly on-treatment assessments, and the hemoglobin level was maintained in the normal range. Figure 2 demonstrates the differences in the median hemoglobin levels between patients who received and did not receive epoetin alfa.

View larger version (13K): [in this window] [in a new window]   Fig 2. Median hemoglobin values shown for epoetin alfa–treated patients (initiated when hemoglobin levels were < 12 g/dL; squares, n = 11) compared with patients who did not receive epoetin alfa (diamonds, n = 15).

Effect of EV on PSA, Serum Testosterone, and Prostatic Volume Reduction
Before RT, patients underwent CT scans in the treatment position in preparation for 3D-CRT planning. To assess the extent of volume reduction with induction EV, the planning scans were compared with the baseline diagnostic CT scan obtained before EV therapy. The median reduction of the prostatic volume was 26% (range, 0% to 67%). Serum testosterone concentrations dropped to castrate levels within 1 month of administration of EV, and the median nadir testosterone level was 0 (range, 0 to 16). PSA levels decreased to a median nadir of no measurable amount, and the median time to PSA nadir was 6.1 months from the beginning of EV chemotherapy (range, 3.2 to 8.8 months).

Acute and Late Toxicity of 3D-CRT
In general, acute GI symptoms consisted of rectal discomfort, tenesmus, and diarrhea; whereas acute GU symptoms included nocturia, urgency, and dysuria. Medications were required for relief of acute GI- and GU-related symptoms in 35% and 48% of patients, respectively. Two patients developed acute bladder outlet obstruction that required temporary catheterization early in the course of radiotherapy, and one patient experienced hematuria with clot retention 2 weeks after the completion of therapy, which was relieved with catheterization (grade 3 GU toxicities).

The 2-year actuarial likelihood of late grade 2 GI toxicity was 20%. No late grade 3 or 4 GI toxicities were observed. Two patients (9%) developed grade 3 urethral strictures, which were relieved with dilatation. The 2-year actuarial likelihoods of late grade 2 and 3 GU toxicities were 25% and 12%, respectively. No late grade 4 GU toxicity was observed.

Preliminary Posttreatment Outcome
Seven (30%) of 23 patients have developed a PSA relapse. The 2-year PSA relapse-free survival rate was 60%. Among the seven patients with PSA relapse, five have relapsed only as a biochemical failure, and two have osseous metastases. Four of these seven patients underwent posttreatment sextant prostate biopsies after biochemical relapse was established and all were negative for persistent cancer. The median time to resolution of castrate serum testosterone levels (testosterone levels > 200 ng/dL) after therapy was 4 months.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
This report demonstrates the feasibility and safety of combining EV with high-dose 3D-CRT for patients with unfavorable-risk, nonmetastatic prostate cancer. Compared with our previously reported experience of patients treated with NAAD and 75.6 Gy by 3D-CRT, there was no apparent increased incidence of late grade 3 GI- and GU-related toxicities with the EV regimen and similar radiation dose levels. However, a higher incidence of late grade 2 GI- and GU-related toxicities was observed with the EV regimen when combined with 3D-CRT compared with our previously published experience with 3D-CRT alone or in combination with NAAD.¹⁸ In a recent analysis of the toxicity outcome treated with 3D-CRT alone or with NAAD, the incidence of late grade 2 GI and GU toxicities was 15% and 16%, respectively, for patients who received prescription doses of 75.6 Gy or higher. In the present report using similar doses in combination with EV, 20% of patients developed grade 2 rectal bleeding within 2 years after therapy, which was managed conservatively, and 25% developed chronic grade 2 urethritis, which necessitated the use of alpha blocker medications for symptomatic relief. Because of the relatively small number of patients treated with this regimen and the retrospective nature of this comparison, definitive conclusions can not be made regarding the increased toxicity of this regimen compared with patients treated with 3D-CRT alone or with NAAD.

Khil et al⁷ have reported the outcome with EV and RT for patients with locally advanced prostate cancer. In that study, 65 patients with disease stages T2 to T4 were treated with concomitant, but without neoadjuvant, EV in combination with conventional external-beam radiotherapy (whole pelvis treatment followed by a prostate boost) to doses of 65 to 70 Gy. One grade 3 leukopenia and one grade 3 small bowel toxicity were observed, which required hospitalization in each case. In addition, one patient required a diverting colostomy for a grade 4 radiation proctitis. The incidence of grade 2 diarrhea and proctitis were 57% and 39%, respectively, and the incidence of grade 2 GU symptoms was 72%. Despite the longer course of EV and the higher radiation doses used in our patients, the toxicity rates of combined therapy in our series were significantly lower than those observed by Khil et al.⁷ This may be attributed to our use of the 3D-CRT technique and the omission of pelvic lymph node irradiation.

Our study also suggested a potential benefit of epoetin alfa for patients who require neoadjuvant or adjuvant androgen ablation or systemic chemotherapy for locally advanced prostatic disease. Among patients treated with EV, such as in this study, and not infrequently among patients treated with longer courses of adjuvant or neoadjuvant androgen ablative therapies, decreases in hemoglobin levels of 2 g/dL or more can be observed, and this may impact significantly upon the overall quality of life of the elderly patient. Further, systemic therapy–induced anemia may not only prevent the patient from successfully completing the intended course of therapy, but can create an increased state of radioresistance because of the hypoxic cellular environment. This concern is supported by several reports that demonstrated decreased efficacy of RT for anemic women treated for carcinoma of the cervix.²⁰ In the present study, fatigue was a commonly reported side effect, which, in general, improved after epoetin administration. Formal quality-of-life assessments will be needed to verify whether this intervention would be helpful in ameliorating fatigue commonly experienced by such patients.

This phase II study is an important first step in the development of more aggressive treatment strategies for locally advanced prostate cancer. Combining paclitaxel- or docetaxel-based regimens with RT may also represent promising treatment strategies for these patients. We have recently initiated a phase I study enrolling similar patients to be treated with neoadjuvant paclitaxel, carboplatinum, and estramustine phosphate followed by 3D-CRT. Because of the radiosensitizing properties of these chemotherapy regimens, caution will be necessary when delivering these agents in combination with high-dose conformal RT. Ultimately, randomized trials will be required to determine whether these systemic chemotherapy regimens will prove to be more effective for unfavorable-risk prostate cancer than RT combined with androgen ablation therapy.

	NOTES

 
Presented at the Thirty-Third Annual Meeting of the American Society of Clinical Oncology, Denver, CO, May 17-20, 1997.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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2. Bolla M, Gonzalez D, Warde P, et al: Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 337:295-300, 1997[Abstract/Free Full Text]

3. Pilepich MV, Caplan R, Byhardt RW, et al: Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: Report of the Radiation Therapy Oncology Group protocol 85-31. J Clin Oncol 15:1013-1021, 1997[Abstract/Free Full Text]

4. American Society for Therapeutic Radiology and Oncology Consensus Panel: Consensus statement: Guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys 37:1035-1041, 1997[Medline]

5. Ryu S, Gabel M, Khil MS, et al: Estramustine: A novel radiation sensitizer in human carcinoma cells. Int J Radiat Oncol Biol Phys 30:99-104, 1994[Medline]

6. Eklov S, Essand M, Carlsson J, et al: Radiation sensitization by estramustine on cultured human prostatic cancer cells. Prostate 21:287-295, 1992[Medline]

7. Khil MS, Kim JH, Bricker LJ, et al: Tumor control of locally advanced prostate cancer following estramustine, vinblastine and radiation therapy. Cancer Sci Am 3:289-296, 1997

8. Seidman AD, Scher HI, Petrylak D, et al: Estramustine and vinblastine: Use of prostate specific antigen as a clinical trial end-point for hormone refractory prostate cancer. J Urol 147:931-934, 1992[Medline]

9. Hudes GR, Greenberg R, Krigel R: Phase II study of estramustine and vinblastine, two microtubule inhibitors in hormone refractory prostate cancer. J Clin Oncol 10:1754-1761, 1992[Abstract/Free Full Text]

10. Zelefsky MJ, Leibel SA, Kutcher GJ, et al: The feasibility of dose escalation with three-dimensional conformal radiotherapy in patients with prostatic carcinoma. Cancer J Sci Am 1:42-50, 1995

11. Zelefsky MJ, Leibel SA, Gaudin PB, et al: Dose escalation with three dimensional conformal radiation therapy affects the outcome in prostate cancer. Int J Radiat Oncol Biol Phys 41:91-500, 1998

12. Gleason DF: Histologic grading and clinical staging of prostatic carcinoma, in Tannenbaum M (ed): Urologic Pathology: The Prostate. Philadelphia, PA,Lea & Febiger, 1977, pp 171-197

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15. Lawton CA, Won M, Pilepich MV, et al: Long-term treatment sequelae following external beam irradiation for adenocarcinoma of the prostate: Analysis of RTOG studies 7506 and 7706. Int J Radiat Oncol Biol Phys 21:935-939, 1991[Medline]

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18. Zelefsky MJ, Lyass O, Fuks Z, et al: Predictors of improved outcome for patients with localized prostate cancer treated with neoadjuvant androgen ablation therapy and three dimensional conformal radiotherapy. J Clin Oncol 16:3380-3385, 1998[Abstract]

19. Zelefsky MJ, Cowen D, Fuks Z, et al: Long term tolerance of high dose three-dimensional conformal radiotherapy in patients with localized prostate cancer. Cancer 85:2460-2468, 1999[Medline]

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Submitted July 1, 1999; accepted January 10, 2000.

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