sign in sign up
<<
Home , Capecitabine, Fluorouracil

and Prostatic Diseases (2005) 8, 364–368 & 2005 Nature Publishing Group All rights reserved 1365-7852/05 $30.00 www.nature.com/pcan Phase II study of oral in patients with hormone-refractory

J Spicer1,2, T Plunkett1, N Somaiah1, S Chan1, A Kendall1, N Bolunwu1 & H Pandha1* 1Division of Oncology, Department of Cellular & Molecular Medicine, St George’s Hospital Medical School, Cranmer Terrace, London, UK

Background: Currently available treatment for hormone refractory prostate cancer is limited in efficacy and associated with significant toxicity. This phase II study was performed to assess the efficacy of the oral fluoropyrimidine capecitabine in advanced prostate cancer. Patients and methods: Patients who had a rising prostate-specific antigen (PSA) despite androgen withdrawal, but who remained free from cancer-related symptoms. In total, 14 patients received oral capecitabine 1250 mg/m2 twice daily for two weeks of a three-week cycle. Tumour response was assessed using serum PSA measurement at 3-weekly intervals and, where present, imaging of soft tissue metastases. Results: One of 14 patients experienced a partial response as assessed by both PSA and imaging of metastases. In seven other patients (50%), treatment decreased the rate of PSA rise. The duration of PSA stabilisation was generally short, but in 5/14 patients (36%) was sustained beyond 18 weeks, and in one patient to 24 weeks. Toxicity was significant but manageable, the most common adverse events being nausea, and hand–foot syndrome, each occurring in 50% of patients. Other common side effects were diarrhoea and lymphopenia. All toxicities were grade 1 or 2, except for grade 3 hand–foot syndrome occurring in one patient, and no dose reduction was required because of toxicity. Conclusion: Capecitabine has limited activity as a single agent in prostate cancer, but appears to modulate tumour biology. Considering the added convenience of oral administration, these results support further evaluation of combinations containing capecitabine in hormone-refractory prostate cancer. Prostate Cancer and Prostatic Diseases (2005) 8, 364–368. doi:10.1038/sj.pcan.4500821; published online 2 August 2005

Keywords: capecitabine; ; PSA

Background cer,1,2 and offers some survival benefit.3,4 However, cancer patients express a strong preference for oral rather Patients treated with androgen withdrawal for advanced than intravenous therapies.5,6 Short-lived prostate-speci- prostate cancer become refractory to this therapy within fic antigen (PSA) responses are seen with prednisolone, a median 18–24 months. Combination chemotherapy can estramustine and diethylstilboestrol, but these last two improve symptoms in hormone-refractory prostate can- drugs are associated with significant thrombo-embolic toxicity.7 Most patients remain asymptomatic for some months following detection of PSA rise after androgen *Correspondence: H Pandha, Division of Oncology, Department of withdrawal, so there is a clear need for a well tolerated, Cellular & Molecular Medicine, St George’s Hospital Medical School, orally administered, disease-modifying therapy. Cranmer Terrace, London, SW170RE, UK. The fluoropyrimidine 5- (5FU), adminis- E-mail address: [email protected] 2 tered intravenously with or without , pro- Current address: Department of Medical Oncology, Academic duces few responses in hormone-refractory prostate Oncology Offices, 3rd Floor, Thomas Guy House, Guy’s Hospital, St cancer, at the expense of significant toxicity.8–12 However, Thomas Street, London SE1 9RT, UK 13,14 Received 23 March 2005; revised 19 June 2005; accepted 19 June 2005; responses were seen using low-dose infusional 5FU. published online 2 August 2005 Capecitabine (Xeloda, Roche Products) is an orally Study of oral capecitabine J Spicer et al administered fluoropyrimidine carbamate preferentially described.23 Androgen withdrawal with an LHRH 365 converted to 5-FU at sites of disease by thymidine analogue was continued in all patients. Treatment was phosphorylase expressed in tumour cells,15 including given if the neutrophil count exceeded 0.5 Â 109/l, prostate cancer cells.16 Capecitabine is active in a number lymphocyte count exceeded 0.5 Â 109/l and platelets of tumour types including colorectal, breast, stomach were greater than 100 Â 109/l. Adverse events were and . In particular, capecitabine mono- graded on a four-point scale (WHO common toxicity therapy is now well established as first-line treatment in criteria), with an additional scale for hand–foot syn- advanced ,17,18 and as a preferred option drome. Capecitabine was delayed and dosage reduced in -pretreated metastatic .19 Survival by 20% for treatment-related adverse events of grade 2 or with the combination of capecitabine and is greater. Patients were eligible to receive eight cycles, with superior to docetaxel alone in metastatic breast cancer.20 the option to continue in the event of maintained There is anecdotal evidence of capecitabine activity in response. Treatment was discontinued in the absence of prostate cancer,21 and we have conducted an open label PSA response or control (a fall in PSA velocity by 50% or phase II study to evaluate the efficacy and safety of this more) after four cycles, on PSA progression subse- drug in patients with hormone-refractory prostate quently, or on symptomatic deterioration. cancer. PSA response was chosen as the primary end point, according to published guidelines.22 Patient assessment and response criteria Patients and methods Screening assessments, including a medical history, physical examination, full blood count and chemistry Study design profile were performed within 1 week before treatment began. Serial rises in serum PSA, as above, were required This open label, phase II, non-randomised single-centre before trial entry. PSA level and full blood count were study was designed to investigate the efficacy of repeated with each 21-day cycle. A PSA response was capecitabine in prostate cancer patients with progressive defined as a X50% decrease from baseline in serum PSA, disease despite androgen withdrawal. The study re- determined by two observations not less than 4 weeks ceived ethical approval from the local ethics review apart. PSA velocity was defined as the rate of change of committee, and all patients gave written, informed the natural logarithm of PSA with time, and baseline PSA consent. velocity was calculated using at least two pre-treatment PSA values for each patient. PSA stabilisation was defined as a fall in PSA velocity by 50% or more. Patients Patient eligibility meeting neither of these criteria were considered to have progressive disease. For patients with measurable dis- Eligible patients had histologically confirmed adenocar- ease, radiological investigations were repeated after cinoma of the prostate with progression of locally three cycles, or at biochemical or clinical progression. advanced or metastatic disease despite androgen with- Response was assessed according to RECIST criteria,24 drawal with a luteinising hormone releasing hormone with partial response defined as a X30% decrease from (LHRH) agonist. Disease progression was defined as a baseline. rise in serum PSA on two consecutive occasions at least 2 weeks apart.22 Patients with measurable disease were also included. Statistical methods Patients who had received prior chemotherapy were not eligible. Previous or concurrent radiotherapy was The aims of this phase II study were to assess the efficacy allowed. Patients were required to have a WHO and toxicity of capecitabine in hormone refractory performance status of 2 or less, and to have a life prostate cancer. The primary end point was response as expectancy of at least 3 months. Those with significant assessed using serum PSA. Using a sequential analysis weight loss or severe pain were excluded. Patients with design,25 the absence of a response among the first 14 inadequate haematological, renal or liver parameters patients would indicate insufficient study drug activity (neutrophils o0.5 Â 109/l, calculated creatinine clearance to warrant further study. Thus 14 assessable subjects o50 ml/min, platelets o100 Â 109/l, bilirubin 430), were recruited. intracranial metastases or cord compression were also The analysis of efficacy was based on all patients who excluded. Other exclusion criteria included any concur- received at least one dose of capecitabine. Similarly, rent medical condition or laboratory abnormality that safety was assessed for all patients who received at least could compromise the safety of the patient or interfere one dose of the study drug. with the interpretation of the results.

Treatment regimen Results Patients were treated with oral capecitabine 1250 mg/m2 A total of 14 patients were enrolled in this study between self-administered twice daily (2500 mg/m2/day), as July 2002 and November 2003. All patients completed at intermittent therapy in 3-week cycles consisting of 14 least one cycle of capecitabine and were assessable for days of treatment followed by 7 days without treatment. response. All patients had progressed following LHRH Details of the treatment regimen have been previously therapy. The median PSA at study entry was 496 ng/ml,

Prostate Cancer and Prostatic Diseases Study of oral capecitabine J Spicer et al 366 Table 1 Baseline characteristics of patients treated 3

Age Performance Sites of Baseline PSA 2 status metastatic (ng/ml) disease 1 1 72 1 Bone 724 2 73 1 Bone 15 0 3 58 0 Bone 407 1 2 3 4 5 6 7 8 9 10 11 12 13 14 4 63 0 Bone 304 -1 5 56 1 Bone; pelvic LNa 40 PSA velocity ratio PSA velocity 6 77 1 Bone 967 -2 7 73 2 Bone 176 8 41 1 None 1308 -3 9 74 1 Bone 100 Patient number 10 70 1 Liver 1474 11 69 1 Bone & liver 796 Figure 2 PSA velocity change. PSA velocity is defined as the ratio of rate 12 79 1 Bone 107 of change in ln (post-treatment PSA) to the rate of change in ln (pre- 13 69 0 Bone 217 treatment PSA). Thus, a ratio below 1 implies a reduction in PSA velocity 14 82 1 Bone 135 (PSA stabilisation), and a negative ratio suggests a reduction in PSA.

aLN ¼ lymph nodes.

Table 2 Toxicity characteristics (WHO Common Toxicity Criteria) 2000 Toxicity Grade 1–2 Grade 3–4 n (%) n (%) 1500 Nausea 7 (50) 0 Diarrhoea 4 (29) 0 1000 Hand/foot syndrome 7 (50) 1 (7) Mucositis 7 (50) 0 Lymphopenia 5 (36) 0 PSA (ng/ml) 500

0 2 3 4 5 6 7 8 Four patients (29%) experienced progressive disease or did not tolerate treatment within the first 12 weeks of screeningbaseline/1 cycle number capecitabine therapy and discontinued study medication. Figure 1 PSA profiles for each patient treated. PSA is shown at screening and at the beginning of each cycle administered. PSA is plotted only for the duration of treatment. A marked PSA response was seen in one Toxicity patient. All patients were assessed for toxicity. The most common toxicities were nausea, mucositis and hand–foot syn- and median ECOG performance status was one. Patient drome (Table 2). The majority of toxicities were grade characteristics are summarised in Table 1. 1 or 2. Only grade 3 toxicity was hand–foot syndrome. A total of 76 cycles of capecitabine were administered, There was no grade 4 toxicity and there were no toxicity- and the median number of cycles was 5.4 (range 4–9). related deaths. Five patients experienced grade 2 One cycle was delayed because of grade 3 toxicity lymphopenia that did not require dose reduction or (Hand–foot syndrome). 3 patients (21%) were withdrawn discontinuation of treatment. Other clinical laboratory from the study because of toxicity. values were stable, and did not worsen by more than one grade in any patient. requiring dose reduction or delay was not seen. No patients discon- tinued treatment because of abnormal laboratory Response and response duration values. All 14 patients treated with capecitabine were assessed for response. The PSA profile for each patient is shown in Figure 1. One patient had a PSA response, for an Conclusion overall response rate of 7% (95% confidence interval 0– 20%, Fisher’s exact test). This partial response was In this phase II study in hormone-refractory prostate confirmed on CT-imaging of liver metastases. PSA cancer, one patient (7%) treated with capecitabine had a velocity fell in a further seven patients (50%) after response as assessed by both PSA and CT imaging of starting capecitabine treatment (Figure 2), giving a liver metastases, a response rate broadly comparable combined PSA control rate of 57%. The duration of with docetaxel-containing combination therapy.3,4 PSA PSA stabilisation was generally short (Figure 1), but in velocity fell in a further eight patients (50%). Another five patients (36%) was sustained beyond 18 weeks, and study of capecitabine in hormone-refractory prostate in one patient to 24 weeks. cancer reported a PSA response rate of 12%.26

Prostate Cancer and Prostatic Diseases Study of oral capecitabine J Spicer et al 367 Capecitabine is currently approved for the treatment 4 Tannock IF et al. Docetaxel plus prednisone or plus of patients with several tumour types including breast prednisone for advanced prostate cancer. N Engl J Med 2004; 351: and colorectal cancer, and has demonstrated good 1502–1512. tolerability in clinical trials. The most frequent treat- 5 Liu G, Franssen E, Fitch MI, Warner E. Patient preferences for ment-related adverse events in most trials were nausea, oral versus intravenous palliative chemotherapy. J Clin Oncol diarrhoea and hand–foot syndrome, with a low inci- 1997; 15: 110–115. 6 Borner MM et al. Patient preference and of dence of myelosuppression. Capecitabine was generally oral modulated UFT versus intravenous fluorouracil and well tolerated in this study. The most common treatment- leucovorin: a randomised crossover trial in advanced colorectal related adverse events were nausea, mucositis and hand– cancer. Eur J Cancer 2002; 38: 349–358. foot syndrome, each occurring in 50% of patients. The 7 Kelly WK et al. , , and only grade 3 or 4 toxicity was hand–foot syndrome, in patients with advanced prostate cancer. J Clin occurring in one patient. No treatment alteration was Oncol 2001; 19: 44–53. required for haematological toxicity. 8 Kuzel TM et al. A phase II study of continuous infusion 5- The toxicity profile of capecitabine compares favour- fluorouracil in advanced hormone refractory prostate cancer. An ably with that previously reported for palliative che- Illinois Cancer Center Study. Cancer 1993; 72: 1965–1968. motherapy in hormone-refractory prostate cancer.1–4 9 Huan SD, Aitken SE, Stewart DJ. 5-fluorouracil and high dose Grade 3 or 4 toxicity occurred in 35% of patients treated folinic acid in hormone-refractory metastatic prostate cancer: a phase II study. Ann Oncol 1994; 5: 644–645. with mitoxantrone and prednisolone, and in 43–46% 4 10 Atkins JN et al. Leucovorin and high-dose fluorouracil in following docetaxel and prednisolone. Capecitabine has metastatic prostate cancer. A phase II trial of the Piedmont the further significant advantage of oral administration. Oncology Association. Am J Clin Oncol 1996; 19: 23–25. The use of PSA as a surrogate for disease activity and 11 Breul J et al. 5-Fluorouracil versus folinic acid and 5-fluorouracil response to treatment in prostate cancer is well vali- in advanced, hormone-resistant prostate cancer: a prospective dated.27,28 The assay is inexpensive and reproducible, randomized pilot trial. Eur Urol 1997; 32: 280–283. and can provide a more objective assessment than 12 Berlin JD et al. 5-Fluorouracil and leucovorin therapy in patients imaging, because bone metastases predominate in many with hormone refractory prostate cancer: an Eastern Cooperative patients with advanced prostate cancer. PSA doubling Oncology Group phase II study (E1889). Am J Clin Oncol 1998; time provides a useful means of monitoring progression 21: 171–176. et al. of prostate cancer,29 and thus reduction in doubling time 13 Hansen R Continuous systemic 5-fluorouracil infusion in refractory prostatic cancer. Urology 1991; 37: 358–361. following capecitabine treatment may predict clinical 14 Bex A, Otto T, Lummen G, Rubben H. Phase II study of repeated benefit. single 24-hour infusion of low-dose 5-fluorouracil for palliation The results of this small study suggest that capecita- in symptomatic hormone-refractory prostate cancer. Urol Int bine has some activity in hormone-refractory prostate 2002; 69: 273–277. cancer, based on PSA response and control rates of 7 and 15 Miwa M et al. Design of a novel oral fluoropyrimidine 64%, respectively. Toxicity was significant but manage- carbamate, capecitabine, which generates 5-fluorouracil selec- able, and compares favourably with that of standard tively in tumours by enzymes concentrated in human liver and palliative chemotherapy regimens used in advanced cancer tissue. Eur J Cancer 1998; 34: 1274–1281. prostate cancer. Experience with capecitabine in prostate 16 Sivridis E et al. expression in normal, cancer in Switzerland was associated with more severe hyperplastic and neoplastic : correlation with tumour 26 associated macrophages, infiltrating lymphocytes, and angio- toxicity, including two treatment-related deaths, a genesis. Br J Cancer 2002; 86: 1465–1471. distinction possibly accounted for by pharmacogenomic 17 Hoff PM et al. Comparison of oral capecitabine versus differences in the study populations. We observed intravenous fluorouracil plus leucovorin as first-line treat- acceptable levels of toxicity, and indications of efficacy ment in 605 patients with metastatic colorectal cancer: suggest that further studies are required to evaluate the results of a randomized phase III study. J Clin Oncol 2001; 19: role of capecitabine in this disease. 2282–2292. 18 Van Cutsem E et al. Oral capecitabine compared with intrave- nous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol Acknowledgements 2001; 19: 4097–4106. We thank the patients who participated in this study and 19 Blum JL et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999; Dr Andreas Polychronis for assistance in developing the 17: 485–493. protocol. 20 O’Shaughnessy J et al. Superior survival with capecitabine plus docetaxel combination therapy in -pretreated patients with advanced breast cancer: phase III trial results. J References Clin Oncol 2002; 20: 2812–2823. 21 El-Rayes BF, Black CA, Ensley JF. Hormone-refractory prostate 1 Tannock IF et al. Chemotherapy with mitoxantrone plus cancer responding to capecitabine. Urology 2003; 61: 462. prednisone or prednisone alone for symptomatic hormone- 22 Bubley GJ et al. Eligibility and response guidelines for phase II resistant prostate cancer: a Canadian randomized trial with clinical trials in androgen-independent prostate cancer: recom- palliative end points. J Clin Oncol 1996; 14: 1756–1764. mendations from the Prostate-Specific Antigen Working Group. 2 Kantoff PW et al. Hydrocortisone with or without mitoxantrone J Clin Oncol 1999; 17: 3461–3467. in men with hormone-refractory prostate cancer: results of the 23 Mackean M et al. Phase I and pharmacologic study of cancer and leukemia group B 9182 study. J Clin Oncol 1999; 17: intermittent twice-daily oral therapy with capecitabine in 2506–2513. patients with advanced and/or metastatic cancer. J Clin Oncol 3 Petrylak DP et al. Docetaxel and estramustine compared with 1998; 16: 2977–2985. mitoxantrone and prednisone for advanced refractory prostate 24 Therasse P et al. New guidelines to evaluate the response to cancer. N Engl J Med 2004; 351: 1513–1520. treatment in solid tumors. European Organization for Research

Prostate Cancer and Prostatic Diseases Study of oral capecitabine J Spicer et al 368 and Treatment of Cancer, National Cancer Institute of the United 27 Wu JT. Assay for prostate specific antigen (PSA): problems and States, National Cancer Institute of Canada. J Natl Cancer Inst possible solutions. J Clin Lab Anal 1994; 8: 51–62. 2000; 92: 205–216. 28 Smith DC, Dunn RL, Strawderman MS, Pienta KJ. Change in 25 Gehan E. Determination of the number of patients required in a serum prostate-specific antigen as a marker of response to preliminary and a follow-up trial of a new chemotherapeutic cytotoxic therapy for hormone-refractory prostate cancer. J Clin agent. J Chronic Dis 1961; 13: 346. Oncol 1998; 16: 1835–1843. 26 Morant R et al. Capecitabine in hormone-resistant metastatic 29 Wieder JA, Belldegrun AS. The utility of PSA doubling time to prostatic carcinoma —a phase II trial. Br J Cancer 2004; 90: monitor prostate cancer recurrence. Mayo Clin Proc 2001; 76: 1312–1317. 571–572.

Prostate Cancer and Prostatic Diseases