Abstract
Treatment options for patients with castration‐resistant prostate cancer (CRPC) are limited. The purpose of our study was to investigate the safety and efficacy in terms of prostate‐specific antigen (PSA) response of a low‐dose oral combination of etoposide and prednisone in patients with CRPC. Thirty‐nine patients with prostate cancer (median age, 77.9 years) with progressive disease after standard hormonal therapy were enrolled. Etoposide (25 mg, twice daily) and prednisone (5 mg, twice daily) were administered orally. Each cycle comprised 21 consecutive days of treatment followed by a 7‐day drug holiday. All patients previously treated with an antiandrogen were required to undergo antiandrogen withdrawal prior to entry into the study. A total of 226 cycles were administered with a median of 6.7 cycles per patient (range, 1–18 cycles). Sixteen of 39 patients (41%) with elevated PSA levels at baseline achieved at least a 50% reduction in PSA levels. Median progression‐free survival for all patients was 5.9 months (range, 1–17 months). No Grade 4 toxicities were observed. The predominant toxicities were mucositis, nausea, fatigue, and anemia in twelve, nine, eight, and seven patients, respectively. Hematologic toxicity was infrequent, with no episodes of febrile neutropenia. The combination of low‐dose etoposide and prednisone is an efficacious and reasonably well‐tolerated oral regimen in the treatment of elderly patients with CRPC. This regimen can be easily administered in an outpatient setting and does not require frequent patient visits.
Keywords: Castration‐resistant prostate cancer, Chemotherapy, Etoposide, Oral
Introduction
Treatment for castration‐resistant prostate cancer (CRPC) is still not established, and CRPC is associated with an average survival of 12–16 months [1]. In China and other developing countries, most patients with prostate cancer present with metastasis and the disease will eventually progress to CRPC after androgen deprivation for 18–24 months [2]. Docetaxel‐based chemotherapy remains the first‐line treatment of choice for CRPC. However, significant toxicity, short‐lived therapeutic benefit, and heavy economic burden have led to an understandable skepticism concerning the use of intravenous chemotherapy. In addition, many patients with CRPC are unable to reach the hospital and are unwilling or unfit to be admitted to an intravenous chemotherapy treatment program. Therefore, a significant need exists for well‐tolerated oral outpatient treatment regimens.
An oral combination of estramustine phosphate (EMP) and etoposide has been reported to be effective for CRPC [[3], [4], [5]]. However, this combination may be associated with severe side effects such as cardiac complications, leukopenia, and deep venous thrombosis [6]. Etoposide is a semisynthetic derivative of podophyllotoxin, which arrests the cell cycle at the late S phase [7]. Sensitivity to oral etoposide has been demonstrated in prostate cancer, lung cancer, and non‐Hodgkin lymphoma [[8], [9]]. In a Phase II clinical trial for metastatic breast cancer, oral etoposide monotherapy was effective and well tolerated [10].
Currently, there are few data on oral etoposide in patients with CRPC. Here, we report the results of a Phase II trial of a combination of low‐dose oral etoposide and prednisone in elderly patients with CRPC.
Materials and methods
Patient eligibility
Eligible patients were required to have a histologic diagnosis of prostate adenocarcinoma with progressive disease after standard hormonal therapy. All patients previously treated with antiandrogen therapy were required to undergo antiandrogen withdrawal prior to entry into the study. Included patients had to have an Eastern Cooperative Oncology Group performance status of 0–2; adequate renal, hepatic, and hematologic function at baseline; and a life expectancy of more than 3 months. Patients were excluded from the study in case of severe uncontrolled comorbidity, second malignancies, visceral or brain metastases, or previous chemotherapy. All patients were required to provide written informed consent prior to enrollment. The ethics review committee of Fudan university shanghai cancer center approved the project.
Treatment regimen
Etoposide (25 mg, twice daily) and prednisone (5 mg, twice daily) were orally administered. Each cycle comprised 21 consecutive days of treatment followed by a 7‐day drug holiday. Therapy was continued until disease progression to the bone or soft tissue, an increase in the prostate‐specific antigen (PSA) level, or occurrence of intolerable toxicity. Treatment‐related toxicity was assessed according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version 3.0. Patients requiring more than a 4‐week delay in treatment were withdrawn from the study. If grade 3 or 4 hematologic toxicity was observed during any cycle, the patient dose was reduced to 75% of the initial dose for treatment during subsequent weeks. Drug administration was discontinued in the event of grade 4 nonhematologic toxicities or grade 3 or worse neurotoxicity.
Evaluation and response
Pretreatment evaluations included taking a complete medical history, physical examination, chest radiography, bone scanning, computed tomography (CT) of the abdomen and pelvis, and laboratory evaluations including a comprehensive chemistry profile and PSA. Clinical monitoring and complete blood cell count assessment were performed weekly. A full clinical chemistry workup was performed during each cycle. CT of the abdomen and pelvis was performed every three cycles. Bone scanning was performed every 6 months.
PSA levels were measured prior to each cycle every 4 weeks. A decline in the PSA level by >50%, confirmed by a second evaluation at least 4 weeks later, was considered a PSA response. PSA progression was defined as a 50% increase over nadir based on two values obtained at least 2 weeks apart if a >50% decline in PSA was noted or a 25% increase over nadir if a <50% or no decline in PSA was experienced. Patients who did not meet these criteria of response and progression were considered to have stable disease. Lymph node disease was evaluated according to the Response Evaluation Criteria in Solid Tumors. Disease progression was defined as PSA progression or appearance of a new lesion on bone scanning or CT.
Statistical analysis
The PSA response rate and toxicity were the primary endpoints of the study. Progression‐free survival (PFS) was the secondary endpoint, which was calculated from the beginning of etoposide/prednisone combination therapy to the time of disease progression. All patients enrolled in the study were analyzed on an intent‐to‐treat basis. All statistical analyses were performed using SPSS version 15.0 (SPSS Inc., Chicago, IL, USA).
Results
Between July 2010 and December 2012, 39 patients were enrolled into this Phase II study. The characteristics of these patients are listed in Table 1.
Table 1.
Patient characteristics.
| No. of patients | 39 |
| Eastern Cooperative Oncology Group performance status | |
| 0 | 17 (44) |
| 1 | 19 (49) |
| 2 | 3 (8) |
| Age (y) | |
| Median | 77.9 |
| Range | 63–87 |
| Osseous disease | 27 (69) |
| Pain | 19 (49) |
| No pain | 8(21) |
| Lymph node disease | 7 (18) |
| Prostate specific antigen (ng/mL) | |
| Median | 69.3 |
| Range | 2.7–2364 |
| Prior treatment | |
| Prostatectomy | 5 (13) |
| Radiotherapy | 3 (8) |
| Surgical castration | 7 (18) |
| Medical castration | 32 (82) |
| Second‐line hormone therapy | 39 (100) |
| Gleason score | |
| <7 | 8 (21) |
| >7 | 31 (79) |
Data are presented as n (%).
Treatment administered and toxicity
A total of 226 cycles were administered, with a median of 6.7 cycles per patient (range, 1–18 cycles). One patient discontinued therapy prior to completion of the first cycle because of Grade 3 fatigue. A total of 3 cycles were delayed for 7–14 days as a result of Grade 2 buccal mucositis in 3 patients. No dose modification was required for the remaining 36 patients. The predominant toxicities are listed in Table 2. Hematologic toxicity was infrequent, with no episodes of febrile neutropenia. No treatment‐related hospitalization was recorded.
Table 2.
Hematological and nonhematological toxicities.
| Toxicity | Total | Grade 1 | Grade 2 | Grade 3 |
|---|---|---|---|---|
| Anemia | 7 (18) | 6 (15) | 1 (3) | 0 (0) |
| Leukopenia | 5 (13) | 4 (10) | 1 (3) | 0 (0) |
| Mucositis | 12 (31) | 9 (23) | 3 (8) | 0 (0) |
| Nausea/vomiting | 9 (23) | 7 (18) | 2 (5) | 0 (0) |
| Fatigue | 8 (21) | 4 (10) | 3 (8) | 1 (3) |
| Liver function | 4 (10) | 3 (8) | 1 (3) | 0 (0) |
Data are presented as n (%).
Response
Sixteen of 39 patients (41.0%) achieved at least a 50% reduction in PSA levels, and six patients (15.4%) achieved at least a 75% reduction in PSA levels. The remaining 23 patients (58.9%) patients were classified as PSA nonresponders. Nineteen of 27 patients (70.4%) with bone metastases had bone pain at baseline, and among these 19 patients, symptoms improved in 11 (57.8%), no change was noted in 5 (26.3%), and worsened bone pain was noted in 3 (15.8%).
During a median follow‐up period of 18.1 months (range, 4–35 months), only 5 patients died, and the median overall survival has not yet been reached. Median PFS in the overall series was 5.9 months (range, 1–17 months, Fig. 1). Patients achieving a PSA response to therapy had a PFS of 8.1 months, which was significantly longer than that of nonresponders (3.7 months, p = 0.034). No significant differences in PFS were observed in patients classified according to baseline PSA levels (>10 vs. <10 ng/mL), and those with bone pain (relief vs. no relief) or lymph node disease (response vs. no response; Table 3).
Figure 1.
Progression‐free survival of patients included in the study.
Table 3.
Clinical response to treatment.
| Response | No. of patients (%) | Median PFS (mo, range) | p |
|---|---|---|---|
| All patients | 39/39 (100) | 5.9 (1–17) | – |
| a PSA response | 16/39 (41) | 8.1 (3–17) | 0.034 |
| PSA stable/progression | 23/39 (59) | 3.7 (1–7) | – |
| Baseline PSA | |||
| >10 ng/mL | 28/39 (72) | 5.8 (1–17) | 0.553 |
| <10 ng/mL | 11/39 (28) | 6.2 (2–13) | – |
| Bone pain | 19/39 (49) | 6.2 (1–11) | – |
| Relief | 11/19 (58) | 6.4 (2–11) | 0.562 |
| No relief | 8/19 (42) | 6.0 (1–9) | – |
| Lymph node disease | 7/39 (18) | 5.1 (1–8) | – |
| CR | 0/7 (0) | – | – |
| PR | 2/7 (29) | 5 (4–6) | 0.103 |
| SD | 4/7 (57) | 4.5 (2–6) | – |
| PD | 1/7 (14) | 1 | – |
CR = complete response; PD = progressive disease; PFS = progression free survival; PR = partial response; PSA = prostate‐specific antigen; SD = stable disease.
PSA decline >50%, confirmed by a second evaluation at least 4 weeks later.
Discussion
Cessation of antiandrogen therapy for at least 4 weeks is associated with a PSA decrease in 30% of patients who fail first‐line hormonal therapy [11]; however, most patients without antiandrogen withdrawal syndrome will eventually receive chemotherapy. Our Phase II trial was designed to assess the activity, toxicity, and feasibility of an oral low‐dose outpatient regimen of etoposide plus prednisone in elderly patients with CRPC. In the current study, the etoposide dose was reduced to 50 mg/day instead of 50 mg/m2, considering the median age of 77.9 years of our patients. Our treatment regimen resulted in a PSA response rate of 41%, similar to that noted for EMP plus etoposide, and a median PFS of 5.9 months. In addition, 57.8% of patients with bone pain experienced symptom improvement.
Toxicity requiring temporary suspension, dose reduction, and treatment withdrawal has been reported with other oral chemotherapy regimens, with occurrence rates ranging from 20% to 40% [[4], [5], [6]]. However, our regimen of low‐dose etoposide plus prednisone resulted in much better tolerance. A median of 6.7 cycles per patient were administered, and treatment interruption due to toxicity was required in only 7.7% of patients. Hematologic toxicity was infrequent, with no episodes of febrile neutropenia.
Another benefit of our regimen was the convenience of treatment and monitoring. Thus, this treatment regimen could be useful for patients in whom geographical, social, and/or physical difficulties limit access to hospitals for intravenous chemotherapy or for those otherwise unfit for combination oral chemotherapy. This treatment can be safely administered at home for prolonged periods without significant toxicity and requires minimal monitoring. Our results showed that patient symptoms and quality of life improved and PSA response was similar to that achieved with other full‐dose chemotherapeutic regimens, whereas toxicity was minimized.
A few limitations of this study merit consideration. Because of the selection criteria in the current study, patients with visceral metastases and previous chemotherapy were excluded, which might result in a selection bias. However, we set these exclusion criteria considering safety for an elderly patient group (median age, 77.9 years). In addition, a limited follow‐up period prevented us from drawing any conclusions on overall survival. Kelly et al [12] found that posttreatment PSA decline was the most important parameter associated with survival in patients with CRPC. Therefore, a PSA decrease of more than 50% from the baseline can serve as a surrogate biologic endpoint for clinical benefit. Because there is no standard therapy for patients with CRPC unwilling or unfit to be admitted for intravenous chemotherapy, no comparison with the standard therapy could be made in the current study. For ethical reasons, a placebo control group was not appropriate for patients with CRPC.
In summary, the combination of low‐dose etoposide and prednisone was an active and reasonably well‐tolerated oral treatment regimen for elderly patients with CRPC. It can be easily administered in an outpatient setting and does not require frequent patient visits.
Acknowledgments
This project was supported by Shanghai Nature Science Foundation “12ZR1406100”.
Conflict of Statement: The authors have no conflicts of interest relevant to this article.
References
- [1]. Huang X., Chau C.H., Figg W.D. Sr.. Challenges to improved therapeutics for metastatic castrate resistant prostate cancer: from recent successes and failures. J Hematol Oncol. 2012; 2: 35. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [2]. Lin G.W., Ye D.W., Yao X.D., Zhang S.L., Dai B., Zhang H.L., et al. Efficacy of low dose ketoconazole therapy for Chinese patients with castration resistant prostate cancer. Chin Med J. 2012; 28: 520–523. [PubMed] [Google Scholar]
- [3]. Serretta V., Altieri V., Morgia G., Siragusa A., De Grande G., Napoli M., et al. Oral chemotherapy in hormone‐refractory prostate carcinoma patients unwilling to be admitted to hospital. Urol Int. 2009; 83: 452–457. [DOI] [PubMed] [Google Scholar]
- [4]. Spitaleri G., Matei D.V., Curigliano G., Detti S., Verweij F., Zambito S., et al. Phase II trial of estramustine phosphate and oral etoposide in patients with hormone‐refractory prostate cancer. Ann Oncol. 2009; 20: 498–502. [DOI] [PubMed] [Google Scholar]
- [5]. Berruti A., Fara E., Tucci M., Tarabuzzi R., Mosca A., Terrone C., et al. Oral estramustine plus oral etoposide in the treatment of hormone refractory prostate cancer patients: a phase II study with a 5‐year follow‐up. Urol Oncol. 2005; 23: 1–7. [DOI] [PubMed] [Google Scholar]
- [6]. Munshi H.G., Pienta K.J., Smith D.C.. Chemotherapy in patients with prostate specific antigen‐only disease after primary therapy for prostate carcinoma: a phase II trial of oral estramustine and oral etoposide. Cancer. 2001; 1: 2175–2180. [DOI] [PubMed] [Google Scholar]
- [7]. Fujikawa‐Yamamoto K., Ota T., Miyagoshi M., Yamagishi H.. Effects of etoposide on the proliferation of hexaploid H1 (ES) cells. Hum Cell. 2012; 25: 45–50. [DOI] [PubMed] [Google Scholar]
- [8]. Slevin M.L., Clark P.I., Joel S.P., Malik S., Osborne R.J., Gregory W.M., et al. A randomized trial to evaluate the effect of schedule on the activity of etoposide in small‐cell lung cancer. J Clin Oncol. 1989; 7: 1333–1340. [DOI] [PubMed] [Google Scholar]
- [9]. Hussain M.H., Pienta K.J., Redman B.G., Cummings G.D., Flaherty L.E.. Oral etoposide in the treatment of hormone‐refractory prostate cancer. Cancer. 1994; 1: 100–103. [DOI] [PubMed] [Google Scholar]
- [10]. Yuan P., Xu B.H., Wang J.Y., Ma F., Fan Y., Li Q., et al. Oral etoposide monotherapy is effective for metastatic breast cancer with heavy prior therapy. Chin Med J. 2012; 125: 775–779. [PubMed] [Google Scholar]
- [11]. Small E.J., Srinivas S.. The antiandrogen withdrawal syndrome. Experience in a large cohort of unselected patients with advanced prostate cancer. Cancer. 1995; 15: 1428–1434. [DOI] [PubMed] [Google Scholar]
- [12]. Kelly W.K., Scher H.I., Mazumbar M., Vlamis V., Schwartz M., Fossa S.D.. Prostate‐specific antigen as a measure of disease outcome in metastatic hormone‐refractory prostate cancer. J Clin Oncol. 1993; 11: 607–615. [DOI] [PubMed] [Google Scholar]