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Asia-Pacific Journal of Clinical Oncology 2016 doi: 10.1111/ajco.12583 ORIGINAL ARTICLE Efficacy of metronomic oral cyclophosphamide with low dose dexamethasone and celecoxib in metastatic castration-resistant prostate cancer Yumun JEONG1 and Jae Lyun LEE1,2 1 Departments of Medicine, and 2 Oncology, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, South Korea Abstract Aim: This study aimed to assess the efficacy and safety of oral metronomic chemotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: From January 2011 to February 2013, 60 patients with mCRPC received daily metronomic oral cyclophosphamide (50 mg qd), dexamethasone (1 mg qd) and celecoxib (200 mg bid). Among them 49 patients who met the preset inclusion criteria were included in this retrospective study. Adverse events and activity for reducing serum prostate-specific antigen (PSA) levels, Response Evaluation Criteria in Solid Tumor responses and symptomatic responses were reviewed. The primary endpoints were PSA response rate and time to PSA progression (TTPSA). Results: Twenty-two patients had previous exposure to docetaxel. The median age was 71 years (range, 49– 88) with a median Eastern Cooperative Oncology Group performance of 1 (range, 0–2). The Gleason score was 8 or more in 41 patients (84%) with a median baseline serum PSA of 32.1 ng/mL (range, 1.2–743.0). The PSA response rate was 39%. With a median follow-duration of 17.5 months, the median TTPSA was 5.2 months (95% CI: 3.1–7.4). The median time to composite progression was 3.9 months (95% CI: 2.2–5.6) and a median overall survival was 13.3 months (95% CI: 9.5–17.1 months). There were no significant differences in the TTPSA between the pre- and post-docetaxel groups. Grade 3–4 AEs occurred only in six patients. Conclusion: Metronomic oral cyclophosphamide chemotherapy is safe, well-tolerated and shows promising activity against mCRPC. Key words: castration-resistant prostate cancer, celecoxib, cyclophosphamide, dexamethasone, metronomic INTRODUCTION Prostate cancer is the most common type of cancer in men in the western world and is the second leading cause of cancer deaths in men.1 Currently, the incidence of prostate cancer in Asian populations, including Koreans, is increasing rapidly.2 The basis of treatment for metastatic prostate cancer is androgen deprivation. Most patients benefit from horCorrespondence: Jae Lyun Lee, MD, PhD, Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, South Korea. Email: [email protected] Conflicts of interest: none Accepted for publication 20 June 2016. C 2016 John Wiley & Sons Australia, Ltd monal manipulation, but eventually become resistant and develop metastatic castration-resistant prostate cancer (mCRPC). Docetaxel-based chemotherapy represents the standard first-line treatment in mCRPC after the confirmation of a survival benefit for this drug in two large randomized trials.3 Although the effectiveness of docetaxel is well established, it is not long lasting and nearly all patients experience disease progression with a median of 6–8 months.4–6 Cabazitaxel in combination with prednisone significantly prolonged the time to progression and overall survival compared to mitoxantrone and prednisone in the TROPIC trial.7 However, in clinical practice, hematologic toxicity and the risk of life-threatening infection were major concerns, especially in ethnic Asian patients. In a study of Korean patients, the incidence of febrile 2 Y Jeong and JL Lee neutropenia was 31%, and the treatment-related death rate was 5%, which was mainly associated with severe infection.3 Abiraterone (with prednisone) and enzalutamide improved survival in patients with mCRPC who have previously received docetaxel.8 Abiraterone (with prednisone) and enzalutamide also showed superiority over prednisone alone or a placebo, respectively, improving overall survival, PSA progression, time to clinical deterioration and time to the initiation of cytotoxic chemotherapy in patients who had not received previous chemotherapy.8 The United States Food and Drug Administration has approved abiraterone and enzalutamide as first-line therapies for mCRPC since 2012 and 2014, respectively. Nevertheless, the high-cost combined with the limited funding structure of the National Health Insurance System (NHIS) in Korea and the eventual progression that occurs because of resistance to these agents are challenges in clinical practice. Metronomic chemotherapy is rhythmic, typically involving the daily administration of oral agents at doses significantly lower than the maximum-tolerated dose, with minimal or no drug-free intervals, over an extended period of time.9 Recent studies showed that metronomic chemotherapy with oral cyclophosphamide plus a variety of agents (e.g. prednisone, celecoxib, dexamethasone, methotrexate, uracil with tegafur or capecitabine) showed significant effectiveness, as assessed by the kinetics of prostate-specific antigen (PSA) levels and pain control without significant toxicity,10–19 even in heavily pretreated patients.11,12,14,18 Thus, low-dose metronomic cyclophosphamide may have the potential to be used as an alternative therapeutic option in mCRPC, especially in situation when accessibility to newer agents is limited. Among various regimen, triple combination of cyclophosphamide, celecoxib and dexamethasone, reported in 2010, had shown best activity in terms of PSA response and time to progression,14 and we started to employ this regimen in clinical practice since 2011 for patients who could not have an access to newer agents. The current study aimed to evaluate the clinical efficacy and tolerance of metronomic oral cyclophosphamide with celecoxib and dexamethasone in Korean patients with mCRPC. METHODS Patients evaluated in this study and treatment protocol From January 2011 to February 2013, 60 patients with mCRPC received metronomic chemotherapy, which consisted of oral cyclophosphamide (50 mg daily), C 2016 John Wiley & Sons Australia, Ltd dexamethasone (1 mg daily) and celecoxib (200 mg twice daily) at the Asan Medical Center, Seoul, Korea. Predetermined eligibility criteria were as follows: (i) histological diagnosis of adenocarcinoma of the prostate with clinical or radiological evidence of metastatic disease; (ii) documented CRPC, indicated by two consecutive increases in serum PSA levels with at least 1-week intervals and ongoing castrated levels of serum testosterone ࣘ50 ng/dL during hormonal treatment; (iii) a minimum of a 4- or 8-week lapse between the withdrawal of flutamide or bicalutamide, respectively, to avoid the possibility of antiandrogen withdrawal phenomenon; (iv) Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; (v) PSA levels ࣙ2.0 ng/mL; (vi) no evidence of CNS metastases; and (vii) no serious or uncontrolled concomitant medical or psychological illnesses. Patients were excluded from analysis if they prematurely discontinued treatment without objective evidence of disease progression or intolerable toxicities or if they had another active cancer that was being treated. This study was reviewed and approved by the Asan Medical Center Institutional Review Boards, which waived the informed consent due to the retrospective nature of study design. Response criteria and toxicity assessments All medical records, and laboratory and imaging findings were retrospectively reviewed to evaluate the activity of treatment on serum PSA level reductions, soft tissue response with modified Response Evaluation Criteria in Solid Tumor (RECIST), pain responses evaluated using a numeric rating scale (NRS), and assessments of adverse events. Patient appointments were scheduled every 4 weeks for the first 3 months and every 6 weeks thereafter; laboratory monitoring, including CBC, chemistry, electrolytes and PSA, was performed upon each visit. For those patients with measurable lesions on CT or bone metastases on baseline bone scans, no fixed intervals were applied, but a follow-up CT and bone scan was usually carried out every 12 weeks or if clinical signs of disease progression developed. Lesions were evaluated based on the guidelines of the Prostate Cancer Clinical Trials Working Group 2 (PCWG2).20 Adverse events were reassessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0). Endpoints The primary endpoints were the PSA response rate and time to PSA progression (TTPSA) in all eligible patients Asia-Pac J Clin Oncol 2016 3 Metronomic therapy for CRPC Figure 1 A waterfall plot of the percentage changes in PSA from baseline. Maximum reduction (a) and the reduction at 12 weeks (b) from baseline following metronomic chemotherapy. The area marked with the dotted line shows patients who discontinued treatment before 12 weeks because of adverse events or disease progression. and separately in pre-docetaxel and post-docetaxel setting. The PSA response was defined according to the guidelines of the PCWG1,20 namely a ࣙ50% reduction from the baseline PSA level on two consecutive tests. PSA progression was defined as a ࣙ25% increase from the nadir (confirmed by a second value obtained 2–3 weeks later). When no significant reduction from baseline was documented, PSA progression was defined as a ࣙ25% confirmed increase from the baseline value. The Asia-Pac J Clin Oncol 2016 secondary endpoint was to document the pain response, adverse events, time to composite progression (TTP) and OS. The pain response was defined as a reduction in NRS score ࣙ2 on two consecutive assessments at least 2 weeks apart. Composite progression was defined as the occurrence of one or more of the following criteria according to PCWG2: PSA progression, progression of soft tissue disease per modified RECIST, disease progression on a bone scan (defined as the appearance of two or more le- C 2016 John Wiley & Sons Australia, Ltd 4 Y Jeong and JL Lee sions attributable to prostate cancer), a skeletal event (defined as a fracture or bone pain resulting in the need for radiotherapy or surgery) or symptomatic progression (defined as a worsening of ECOG performance status and/or increased pain). Statistical analysis Descriptive statistics were used to analyze patient characteristics (mean, median and 95% confidence intervals). Time-to-event variables, such as TTPSA, TTP and OS, were calculated using the Kaplan–Meier method. Quantitative variables were compared using the Student t-test, and categorical variables were analyzed using the chisquare or Fisher’s exact test, as appropriate. All statistical analyses were performed using PASW statistics (version 18; IBM Co., Armonk, NY), and two-sided p value <0.05 was considered statistically significant. RESULTS Patient characteristics and previous treatments A total of 49 patients fulfilled the eligibility criteria and were included in this analysis. There were six patients who prematurely discontinued treatment without objective evidence of disease progression or intolerable toxicities. There was one patient who was treated for another active cancer and four patients who were lost to followup after treatment with no information on activity or toxicities. Patient characteristics at baseline are listed in Table 1. The median age was 71 years (range, 49–88) with a median ECOG performance status of 1. The Gleason score was 8 or more in 41 patients (84%), and the median baseline serum PSA level was 32.1 ng/mL (range, 2.1–743.0). Most patients (78%) had concomitant diseases (median age-adjusted Charlson Comorbidity Index of 4).21 There were 16 patients who had visceral organ involvement. A total of 31 patients (63%) had previous exposure to chemotherapeutic drug(s), and 22 (45%) patients had received docetaxel-based regimens—a median of eight cycles were administered. Among patients who stopped docetaxel, 12 patients stopped because of progression and 10 patients stopped because of adverse events. Finally, 14 patients (29%) received two or more lines of chemotherapy, including docetaxel. No one had prior exposure to abiraterone or enzalutamide. Efficacy Efficacy results were detailed in Table 2. The PSA response rate was 39% (95% CI: 25–52). Waterfall plots show the maximal and initial PSA changes (during the C 2016 John Wiley & Sons Australia, Ltd Table 1 Baseline patient characteristics (n = 49) Characteristics No. (%) Median age, years (range) ECOG performance status 0 1 2 Gleason score ࣙ8 Serum PSA, median (ng/mL, range) Site of metastasis Bone Lymph node Lung Liver Presence of pain Mild, NRS 1–3 Moderate, NRS 4–6 Severe, NRS 7–10 Anemia Alkaline phosphatase, median (IU/L, range) Lactate dehydrogenage, median (IU/L, range) Prior secondary hormonal agents (excluding abiraterone and enzalutamide) Bicalutamide Flutamide Cyproterone acetate Ketoconazole Prior chemotherapy Docetexel Estramustine Cabazitaxel Mitoxantrone Median cumulative dose of docetaxel, mg/m2 (range) Prior palliative radiotherapy Type of progression PSA progression, n (%) RECIST progression, n (%) Bone scan progression, n (%) Symptomatic progression, n (%) 71 (49–88) 12 (25%) 35 (71%) 2 (4%) 41 (84%) 32.1 (2.1–743.0) 47 (96%) 18 (37%) 12 (25%) 5 (10%) 26 (53%) 14 (29%) 10 (20%) 2 (4%) 37 (76%) 104 (35–812) 214 (88–658) 49 (100%) 25(51%) 19 (39%) 12 (25%) 31 (63%) 22 (45%) 16 (33%) 7 (14%) 2 (4%) 600 (75–1350) 8 (16%) 46 (94%) 11 (22%) 14 (29%) 8 (16%) ECOG, Eastern Cooperative Oncology Group; NRS, numeric rating scale; PSA, prostate-specific antigen. first 12 weeks after starting treatment) from the baseline PSA levels (Fig. 1). The PSA response rates were not significantly different between the pre- and post-docetaxel groups (41% vs 36%, P = 0.771). The RECIST responses were evaluated in 20 patients with measurable disease. One patient achieved a complete response and another patient achieved a partial response. There were Asia-Pac J Clin Oncol 2016 5 Metronomic therapy for CRPC Table 2 Efficacy of oral metronomic chemotherapy Response criterion Result Treatment duration, median (months) 5.7 PSA response, n (%) 19 (39%) Pre-docetaxel group (n = 27) 11 (41%) Post-docetaxel group (n = 22) 8 (36%) RECIST response, n (%) 2 (10%) Complete response 1 (5%)† Partial response 1 (5%)† Stable disease 13 (65%)† Progressive disease 5 (25%)† TTPSA, median (months) 5.2 Pre-docetaxel group 5.5 Post-docetaxel group 4.9 OS, median (months) 13.3 Pre-docetaxel group 15.0 Post-docetaxel group 9.7 TTP, median (months) 3.9 Pain response, n (%) 10 (42%)‡ 95% CI 4.3–7.1 25–52 0–23 3.1–7.4 3.2–8.9 2.8–6.9 9.5–17.1 14.1–15.9 7.5–11.8 2.2–5.6 22–61 95% CI, 95% confidence interval; OS, overall survival; PSA, prostatespecific antigen; TTP, time to composite progression; TTPSA, time to PSA progression. † Out of 20 patients who had measurable lesion(s) and evaluable followup CT scan during treatment. ‡ Out of 24 patients who had pain and an assessable recording of the serial NRS score during treatment. 13 patients (65%) who achieved stable disease and five patients (25%) who demonstrated progressive disease as the best response. With a median follow-up duration of 17.5 months (95% CI: 12.2–22.9), the median treatment duration was 5.7 months (95% CI: 4.3–7.1). The median TTPSA was 5.2 months (95% CI: 3.1–7.4), and the median composite TTP was 3.9 months (95% CI: 2.2–5.6) with a median OS of 13.3 months (95% CI: 9.5–17.1; Fig. 2). There was no significant difference in the TTPSA between the pre- and post-docetaxel groups. The median TTPSA was 5.5 months (95% CI: 3.2–8.9) in the predocetaxel group versus 4.9 months (95% CI: 2.8–6.9) in the post-docetaxel group (P = 0.591; Fig. 3). However, as expected, the overall survival was significantly longer in the pre-docetaxel group (15.0 vs 7.9 months, P = 0.024). There were 26 patients who had bone pain before treatment, and among them 24 had an assessable recording of pain levels during treatment; 10 of these 24 patients (42%) achieved a pain response. After disease progression, 27 patients (55%) received other chemotherapy regimens. Toxicity profiles Clinically significant (CTCAE 4.0 grade 3 or greater), AEs only occurred in six patients (12%; including cases of Asia-Pac J Clin Oncol 2016 Figure 2 Time to PSA progression (a) and overall survival (b). anemia [2], thrombocytopenia [2], nausea/vomiting [1], asthenia [1] and abdominal pain [1], Table S1). Although grades 3 and 4 anemia and thrombocytopenia occurred, they seemed to be related to myelophthisic anemia resulting from extensive bone marrow metastases, that is, disease per se, based on peripheral blood smears and responses to transfusion, rather than metronomic agents. Therefore, none of these patients required dose reduction or modification of cyclophosphamide because of toxicities. A total of six patients required dexamethasone dose reduction (to a half dose) because of peripheral edema or minor infections (such as cellulitis or otitis media). DISCUSSION In our present study, metronomic oral cyclophosphamide plus low-dose dexamethasone and celecoxib resulted in notable activity with minimal toxicity. The PSA response rate was 39% with a median TTPSA of 5.2 months, and no patients required dose reduction or dose delay of cyclophosphamide. Although indirect comparison of C 2016 John Wiley & Sons Australia, Ltd 6 Y Jeong and JL Lee Figure 3 Time to PSA progression (a) and overall survival (b) in the pre- versus post-docetaxel groups. different studies is not recommended, our results are comparable with those studies that administered metronomic chemotherapy with oral cyclophosphamide.10–13,15–19 As shown in Table S2, previous studies included a variety of agents along with oral cyclophosphamide, and had small sample sizes, which usually used retrospective analysis on heterogeneous patients’ population. Nevertheless, the efficacies of metronomic cyclophosphamide combination regimens have been consistently reported to be favorable. When restricted to a regimen of cyclophosphamide plus corticosteroid and celecoxib, similar to our study, the PSA response rate, median TTPSA and OS were 45%, 7.7 months and 19.7 months, respectively.14 Slightly shorter survival outcomes in the current study cohort might be explained by the more advanced stage of disease, represented by the higher frequency of exposure to prior chemotherapy (63% vs 34% for any cytotoxic chemotherapy and 45% vs 31% for prior docetaxel) and visceral metastasis (35% vs 7%). Although 32% of patients in the post-docetaxel group previously received cabazitaxel and 9% had received mitoxantrone, the efficacy of metronomic therapy, in terms of the PSA response and TTPSA, was comparable to that of cabazitaxel (39%, C 2016 John Wiley & Sons Australia, Ltd 6.4 months) and was even better than those of mitoxantrone (18%, 3.1 months), which were reported in the TROPIC study. Similarly, the PSA response and TTPSA of the current regimen in the post-docetaxel group were also comparable to those of abiraterone phase II study, which didn’t exclude patients with prior exposure to ketoconazole (36%, 5.6 months).22 Generally, the outcomes of subsequent therapy are affected by a prior therapy, especially when the mechanism of action of the subsequent agents is at least partially related to that of the prior agents. For example, abiraterone showed only a modest response and a brief duration of effect after docetaxel and enzalutamide.23,24 Enzalutamide also showed limited activity in patients with mCRPC who previously received docetaxel and abiraterone.25 Similarly, second-line treatment with mitoxantrone after first-line docetaxel has shown only modest activity; the PSA response rates ranged from 9.8% to 18.0% and were associated with a TTPSA of 1.4– 3.2 months.7,26 Interestingly, the activity of metronomic oral cyclophosphamide did not differ between patients with prior exposure to docetaxel and docetaxel-naive patients. Indeed, patients in the post-docetaxel group had already been heavily treated; 14 (64%) of 22 patients had previously been exposed to two or more lines of chemotherapy, such as mitoxantrone, etoposide or cabazitaxel, after failure to respond to docetaxel. However, in the pre-docetaxel group, only 9 (33%) of 27 patients had previous exposure to estramustine. Our study showed that oral metronomic cyclophosphamide might have comparable activity, as indicated by the PSA response and TTPSA, to those of prior studies, even in patients who failed prior docetaxel or other subsequent cytotoxic chemotherapies. In terms of toxicity profiles, this combination regimen was highly tolerable and lacked serious adverse events. Dose interruptions or modifications were not required for cyclophosphamide. This favorable toxicity profile is in accord with the previously reported well-known tolerability of metronomic therapy, even in elderly, heavily treated and unfit patients.13,14,18,19 However, edema and infections were problematic, as six patients required dexamethasone dose reduction because of peripheral edema, and at least temporary dose interruption was required in three patients because of infections, such as cellulitis or upper respiratory infections. Additionally, one patient discontinued celecoxib because of epigastric soreness. Although the exact mechanism remains to be defined, the metronomic administration of cyclophosphamide has been associated with antiangiogenic effects,9 and immune-stimulation by reducing circulating regulatory T Asia-Pac J Clin Oncol 2016 7 Metronomic therapy for CRPC cells and promoting natural killer cell cytotoxicity.27 In accord with recently reported promising results of tests of antianginogenic agents (e.g. cabozantinib) and immunestimulating agents (e.g. ipilimumab), metronomic oral cyclophosphamide, which targets both angiogenesis and immunity, warrants further investigation in mCRPC.8 The concurrent use of dexamethasone or celecoxib contributed to the antitumor response and in part to managing pain control. The high pain response rate (42%) indicates the palliative role of this combination. Celecoxib showed suppressive effects in vitro on androgen receptor expression, angiogenesis and prostate cancer cell proliferation.28 However, in British STAMPEDE study,29 celecoxib failed to show meaningful benefit in terms of failure-free survival in patients with hormone-sensitive prostate cancer. But its effect on CRPC is not fully explored, and further studies are needed to establish an optimal regimen for administering metronomic chemotherapies for various cancers. In this present study, we observed the limited accessibility of newly approved agents in mCRPC patients. Over the last 5 years, the available treatments for mCRPC have expanded significantly because of the approval of several new drugs. Androgen pathway inhibitors, such as abiraterone and enzalutamide, demonstrate PFS and OS benefits in mCRPC patients, not only after docetaxel failure, but also in pre-docetaxel settings.8 Additionally, radium-223 improves quality of life, prevents clinical skeletal-related events and prolongs OS.8 Cabazitaxel also improved PFS and OS in post-docetaxel settings.7 Although these agents have been approved for use in Korea, none of the costs of these drugs has been reimbursed by the NHIS, which significantly limits their accessibility. In this present study, no patient had an opportunity to receive abiraterone or enzalutamide and patients could only receive cabazitaxel through the Compassionate Use Program.3 A nationwide discussion about how to implement affordable cancer care under the pressure of limited resources is urgently needed. Recently, NHIS decided to reimburse enzalutamide only in post-docetaxel setting. There were several notable limitations to this study, which included a small sample size, nonhomogeneous disease status, imperfect data collection by retrospective review, the absence of preset radiological reassessments and limited patient-reported outcomes such as pain responses. CONCLUSION Metronomic oral cyclophosphamide could be used as a viable option in pre- and post-docetaxel settings with the Asia-Pac J Clin Oncol 2016 advantages of convenient oral administration, a promising response rate and its duration, high tolerability and a very affordable cost, especially when newer androgen pathway inhibitors could not be employed. Prospective randomized trial with potential laboratory biomarker will be needed to draw firm conclusion on survival benefit or improvement in quality of life. ACKNOWLEDGMENTS Presented in part at 6th European Multidisciplinary Meeting on Urologic Cancers 13–16 November 2014 in Lisbon, Portugal. 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SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Table S1 Treatment emergent adverse events Table S2 A review of the literature on metronomic cyclophosphamide chemotherapy in metastatic castrationresistant prostate cancer Asia-Pac J Clin Oncol 2016