ANTICANCER RESEARCH 26: 539-542 (2006)

Palliative Chemotherapy with Trofosfamide in Advanced Prostate Cancer

E.K. SALMINEN1, J. SUNDSTRÖM2 and V. NIKKANEN1

Departments of 1Radiotherapy and Oncology and 2Pathology, Turku University Hospital, POB 52, Fi-20521, Finland

Abstract. Background: A phase II study with trofosfamide in When resistance to hormone treatment develops, hormone-refractory prostate cancer was conducted to test the chemotherapy is used for palliation. The efficacy of palliative efficacy. Patients and Methods: Twenty patients chemotherapy in metastatic prostate cancer has been suffering from advanced prostate cancer were treated with per limited (2), although recent studies with selected patients os trofosfamide after progression on androgen ablation and/or have indicated some antitumour efficacy. Clinical and PSA estramustine. The mean age was 72 years. The patients were responses have been reported when chemotherapy is used treated with 150 mg/day as continuous treatment. The concomitantly with androgen ablation and corticosteroids in treatment was continued until progressive disease or severe patients with good performance status within clinical studies toxicity. Results: A decline in the prostate specific antigen (3). Since chemotherapy treatments have significant toxicity (PSA) level was observed in 5 patients (27%) with a 0-25% their use is often limited to patients with a relatively good decline in 2 patients and a >50% decline in 3 patients (16%, general condition. There is a need for second-line 95% confidence interval 3.4-39.6). There were no clinical or chemotherapy and less toxic treatments for patients radiological complete (CR) or partial (PR) responses in 19 progressing after first-line schedules. evaluable patients. Some toxicity was observed: 15 patients Trofosfamide is an alkylating agent, belonging to the developed anaemia and grade 2-4 adverse effects were group of oxazaphosphorines together with cyclophosphamide observed in 16 patients. One patient died of cardiac event. and ifosfamide (4). Compared to other drugs in the group, Conclusion: Trofosfamide has some activity in hormone- trofosfamide is more lipophilic (5) and, therefore, only refractory advanced prostate cancer. When used in fragile or available as an oral formulation (IxotenR). heavily pre-treated patients, careful monitoring for Trofosfamide treatment has shown response and palliative haematological and cardiac effects is recommended. effects in several solid tumours and haematological malignancies (4, 6-7). The present study was designed to Prostate cancer (PC) is the most common cancer among study the efficacy of trofosfamide in advanced HRPC. men in the Western world and also a common cause of cancer-related death; approximately 25% of men with Patients and Methods prostate cancer die of the disease. Most patients are elderly, with a mean age at diagnosis of 74 years in Patients. Twenty patients with histologically-confirmed metastatic Finland (1). There are several treatment options for early prostate cancer were treated at the Department of Radiotherapy stage PC, but once it turns to a hormone-refractory and Oncology, Turku University Hospital, Finland. Patients were cancer (HRPC) it becomes difficult to treat, especially in eligible if they had progressive metastatic prostate cancer and had failed treatment with androgen ablation and/or estramustine. old and fragile men with concomitant diseases and poor Informed consent was obtained from each patient prior to tolerance to the adverse toxic effects of potent treatment. The patient characteristics, previous treatments and sites chemotherapeutic agents. of metastases used for response evaluation are shown in Table I. The median age of the patients was 72 years (range 54-84). Seven patients had a performance status 0-1, and 13 patients had 2 on the Zubrod scale (8). Eighteen of the patients had been Correspondence to: Eeva Salminen, MD, Department of previously treated with estramustine. Bone metastases were Radiotherapy and Oncology, Turku University Hospital, POB 52, documented on X-ray examinations and skeletal scintigram prior Fin-20521 Turku, Finland. Fax: +35823336884, e-mail: [email protected] to inclusion. All patients, except 1, had elevated prostate specific antigen levels (median 220 ng/ml, range 2 – 700 ng/ml). Subjective Key Words: Prostate cancer, hormone-refractory, palliation, symptoms and the pain situation were evaluated using a formulated trofosfamide. questionnaire at every visit.

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Table I. Patients’ characteristics. Table II. Radiological and PSA response of hormone-refractory prostate cancer to trofosfamide (N=19). Characteristics Number of patients Radiological N (%) PSA response/ N (%) Total number included/evaluable 20/19 response % fall in PSA

Age, mean (range) years 72 (54-84) CR/PR 0 0-24 % 2 (11) NC 4 (21%) 25-50% 0 Performance status (Zubrod) PD 15 (79) >50% 3 (16) 0-1 7 213CR/PR=complete/partial response NC=no change Time in months from diagnosis 56 (10-168) PD=progressive disease to start of trofosfamide treatment, mean (range)

Pretreatment distribution Surgical orchiectomy 17 Radiotherapy to prostate 8 response and toxicity. The median duration of treatment Samarium 2 was 2 months (range 1-19). A1l treatment was given on an Estramustine 18 out-patient basis. Goserelin acetate 6 Polyestradiol phosphate 2 Response and clinical improvement. A PSA response with Site of metastases used for over 50% decline was seen in 3 patients (16 %, 95% CI 3.4 response evaluation –39.6) (Table II). All PSA responses were observed after 2 Skeletal 19 months of treatment. Six patients (33%) reported subjective Lung 2 Lymph nodes 4 pain situation improvement (33%). Pleura 1 Three patients had stable disease and 15 patients Soft tissue 1 progressed. The Kaplan-Meier survival curve for the 19 evaluable patients is shown in Figure 1. The median survival from the start of trofosfamide was 7.3 months.

Toxicity. The major toxic effects included anaemia; 7 patients Treatment. Oral trofosfamide administration was started with a had grade I, 5 patients grade II, 2 patients grade III and one dose of 50 mg 3 times daily. The dose was reducted to 50 mg twice patient grade IV anaemia during treatment with trofosfamide. or once daily when haematological toxicity grade 2 or 3 was Grade I leucopoenia was developed by 2 patients, grade observed. Medical castration was not maintained simultaneously II by 6 patients and grade III by 2 patients. One patient with trofosfamide treatment. developed grade I thrombocytopenia. The trofosfamide The median duration of treatment was 2 months (range 1–20 months). To be evaluable, the treatment had to continue for over 1 dose was reduced in 16 patients (84%) due to month. For evaluation of response and toxicity, the WHO criteria haematological toxicity. The treatment was stopped for 1 were used (8). Clinical evaluation, the pain situation and complete patient because of haematological toxicity and infections blood count, biochemistry and PSA were measured monthly and after 5 months. radiological imaging of metastases was done every 6 months. An Some nausea and vomiting was observed; 2 patients had objective radiological response was defined as a 50% decrease in grade I and 2 patients grade III nausea and vomiting. One metastatic changes. An objective response was also defined as a patient developed alopecia. No urotoxic adverse effects decrease of 50% or more in the PSA plasma level. A decrease less than 50% was considered as stabilization. Progression was defined were recorded. as an increase of 25% or more in the evaluated parameters. There was 1 death due to cardiac failure after 2 months’ The survival time was calculated from the date the patient treatment, but a causative connection with trofosfamide entered the study by the Kaplan-Meier method. treatment could not be verified.

Results Discussion

One of the 20 patients who entered the study was In advanced PC, androgen ablation therapy will often subsequently deemed not evaluable because of only a 1- produce dramatic responses, but the disease is not curable week treatment duration due to the general deterioration of (9) and its progression and change to hormone-refractory his condition. The remaining 19 patients were evaluable for disease through adaptation or clonal selection is inevitable.

540 Salminen et al: Trofosfamide in Prostate Cancer

median duration of treatment was short. Estramustine had been used by all but one patient previously and may have exposed patients to haematological toxicity. Of note is that with trofosfamide, urotoxic adverse effects were not problematic, unlike the haematological toxicity, which proved to be the dose-limiting factor for the PC patients. Dose reduction was required in nearly half of the patients. The toxicity of chemotherapy is related to the dose and performance status and general health of the patients. Patients with advanced hormone-refractory PC are often old and suffer from other diseases, impaired organ functions and disease-related symptoms. The careful monitoring of blood count and cardiac function is necessary to adjust the dose to toxicity. Figure 1. Survival of hormone-refractory prostate cancer patients from the Due to a lack of randomised trials, evidence-based start of palliative chemotherapy with trofosfamide (N=19). conclusions for the role of trofosfamide in palliative chemotherapy for PC cannot be drawn, since in phase II studies such as the present one, patient selection can influence the outcome and limit the use of an adequate Although recent results in phase III trials have shown more dose. Phase III studies with chemotherapy-naïve patients effective palliation and even survival benefit with relatively are needed. toxic regimens in treatment of HRPC (3, 10-11), the problem of treatment for patients not qualifying to similar eligibility Conclusion criteria as in clinical studies or progressing after first-line chemotherapy remains, and palliative schedules for those Trofosfamide has some efficacy in HRPC but its role needs patients are needed. Combination chemotherapy has not been to be further characterised since the current evidence is shown to be more effective than a single-agent treatment (2). based on small studies of selected patients with poor Therefore, we tested oral trofosfamide, which has been prognosis. relatively well tolerated and has shown efficacy in some other malignancies, even after intensive chemotherapies (7, 12). References Trofosfamide is an alkylating agent derived from the oxazaphosphorines with a half-life of about one hour, for 1 Finnish Cancer Registry. www.cancer.fi which the main metabolic pathway seems to be direct 2 Yagoda A and Petrylak D: Cytotoxic chemotherapy for 4-hydroxylation (5). It is mostly transformed to ifosfamide advanced hormone-resistant prostate cancer. Cancer 71: 1098- 1109, 1993. and, in lesser amounts, to cyclophosphamide in the liver. 3 Tannock IF, de Wit R, Berry WR et al: Docetaxel plus Trofosfamide is an attractive palliative agent for patients with prednisone or mitoxantrone plus prednisone for advanced poor prognosis and advanced disease, since it is usually prostate cancer. New Engl J Med 351: 1502-1512, 2004. relatively well tolerated and treatment on an out-patient basis 4 Boos J, Kupker F, Blaschke G and Jurgens H: Trofosfamide is possible (6). metabolism in different species – ifosfamide is the predominant Not many studies on drugs of the oxazaphosphorine group metabolite. Cancer Chemother Pharmacol 33: 71-76, 1993. have been published in relation to HRPC. The earlier 5 Brinker A, Kisro J, Letsch C, Bruggemann SK and Wagner T: New insight into the pharmacokinetics of trofosfamide. Int J combination of oral cyclophosphamide and etoposide Pharmacol Ther 40: 376-381, 2002. showed an objective response of 35% in patients with 6 Latz D, Nassar N and Frank R: Trofosfamide in the palliative advanced PC in a small phase II study (13). The present PSA treatment of cancer: a review of the literature. Onkologie 27: response rate of 16% with trofosfamide is comparable to the 572-576, 2004. 15% remission rate reported by Suhr and co-workers (14). 7 Salminen E, Nikkanen V and Lindholm L: Palliative Similar to our results, Suhr et al. did not report any chemotherapy in Non-Hodgkin's lymphoma. Oncology 54: 108- radiological responses when treating advanced prostate 111, 1997. 8 Miller A, Hogstrafen B, Staquet M and Winkler A: Reporting cancer with trofosfamide. However, the PSA response is an results of cancer treatment. Cancer 47: 207-214, 1981. accepted response criteria in PC, and in some studies · 9 Carducci MA, Carrolli PR, Dipaola RS, Nelson JB, Petrylak >50% decrease in PSA has been correlated with survival DP, Smith MR and Thompson IM: Hormone-refractory (15). In the present study, haematological toxicity limited the prostate cancer: issues, approaches, and recommendations. adequate dose level, dose reduction was common and the Urology 65: 1-2, 2005.

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10 Petrylak DP: The current role of chemotherapy in metastatic 14 Suhr J, Thomas M and Otto T: Aktuelle Aspekte in der hormone-refractory prostate cancer. Urology 65(suppl 5A): 3- Behandlung des metastasiererten Prostatakarzinoms. Urologe 8, 2005. (B) 39: 325-327, 1999. 11 Small EJ, Halabi S, Dawson NA et al: Antiandrogen withdrawal 15 Redman B and Pienta K: New treatment strategies tor hormone alone or in combination with ketoconazole in androgen- refractory prostate cancer. Sem Onc 14: 164-169, 1995. independednt prostate cancer patients: a phase III trial (GALGB 9583). J Clin Oncol 22: 1025-1033, 2004. 12 Hartmann JT and Patel S: Recent developments in salvage chemotherapy for patients with metastatic sarcoma. Drugs 65: 167-178, 2005. 13 Maulard-Durdux C, Dufour B, Hennequin C, Chretien Y, Delanian S and Housset M: Phase I study of the oral cyclophosphamide and oral etoposide combination in hormone refractory prostate carcinoma patients. Cancer 77: Received September 12, 2005 1144-1148, 1996. Accepted November 11, 2005

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