Prostate Cancer and Prostatic Diseases (2004) 7, 45–49 & 2004 Nature Publishing Group All rights reserved 1365-7852/04 $25.00 www.nature.com/pcan Mitoxantrone, vinorelbine and prednisone (MVD) in the treatment of metastatic hormonoresistant prostate cancer — a phase II trial

D Bernardi1*, R Talamini2, M Zanetti1, C Simonelli1, E Vaccher1, M Spina1 & U Tirelli1 1Division of Medical Oncology A, Centro di Riferimento Oncologico, Aviano (PN), Italy; and 2Epidemiology Unit, Centro di Riferimento Oncologico, Aviano (PN), Italy

A total of 28 patients were treated with mitoxantrone, vinorelbine and prednisone every 3 weeks. In all, 11 patients (46%) had a significant prostate-specific antigen decline for a median duration of 11.4 months. Eight patients (33%) achieved a partial response on pain, while seven (29%) obtained a stabilisation of the symptom. Median duration of the response was 9.5 months. A confirmed partial response was obtained in three out of seven patients who had bidimensionally measurable disease. Toxicity was manageable. Our study provides further support to the concept of combined antimicrotubule therapy for metastatic harmonoresis- tant prostate cancer, promoting the exploration of new regimens containing antimicrotubule agents in addition to mitoxantrone–prednisone. Prostate Cancer and Prostatic Diseases (2004) 7, 45–49. doi:10.1038/sj.pcan.4500685

Keywords: chemotherapy; hormone resistance; mitoxantrone; prostate cancer; vinorelbine

Introduction Chemotherapy has been tested in patients with hormone-unresponsive disease. The difficulties in deter- Prostate cancer is a significant health problem through- mining the activity of new agents in hormonoresistant out the world, being the most common male malignancy prostate cancer (HRPC) are mainly related to the fact that and the second leading cause of death in men after lung only about 20% of patients have bidimensionally cancer.1 Androgen deprivation is the standard therapy measurable disease.4 Metastases typically occur in the for newly diagnosed metastatic cancer and produces bone, which is difficult to evaluate by bone scan because symptomatic improvements in 60–70% of patients, but bone repair process and disease flares resemble progres- results in only a small prolongation in both progression- sive disease. So, the standardised response criteria free survival and overall survival.2 In fact, despite commonly used in other solid tumours are inadequate. initially effective hormonal ablation therapy for patients With these limits, chemotherapeutic agents have shown a with metastatic prostate carcinoma, the majority of these response rate ranging from 15 to 30%. Clearly, survival patients progress to a hormone refractory state, with a remains the most important goal, but none of the median survival of less than 2 years.3 Therefore, cytotoxic agents used so far has been shown to have a subsequent treatment is needed for these patients. significant impact on survival.5,6 Therefore, surrogate end points have been developed in the 1990s, such as changes in the prostate-specific antigen (PSA) serum levels and palliation.7,8 In fact, some patients benefit *Correspondence: D Bernardi, Division of Medical Oncology A, from chemotherapy, as manifested by decreased pain or Centro di Riferimento Oncologico, IRCCS, Via Pedemontana improved functional status. In view of the goal of Occidentale 12, 33081 Aviano (PN), Italy. E-mails: [email protected], [email protected] treating HRPC (palliation), it is appropriate to consider Received 17 April 2003; revised 10 September 2003; accepted 24 alternative end points that might substantiate the clinical September 2003 benefit of chemotherapy. MVD in metastatic prostate cancer D Bernardi et al 46 The regimen of mitoxantrone and low-dose corticos- To control the effects of androgen ablation, luteinising teroids has been shown in phase III studies to be more hormone-releasing hormone therapy was maintained. effective in decreasing pain and/or narcotic require- Baseline testosterone levels were not obtained. Adequate ments without, unfortunately, prolonging survival when haematological function (granulocyte count41500/ compared with steroids alone.9,10 Recently, advances mmc, platelets410 0000/mmc, haemoglobin49 g/dl), have been made in understanding the biology of renal function (creatinine level o2x the institutional hormone-refractory prostate carcinoma, which is eluci- upper limit of normal) and hepatic function (serum dating potential targets for new drugs.11 aspartate aminotransferase o3 Â the institutional upper Vinorelbine is a new semisynthetic vinca-alkaloid limit of normal, bilirubin level o1.5 Â the institutional derivative with antimicrotubular activity that has shown upper limit of normal) were required at entry. Patients to be highly effective in small-cell lung cancer compared who had active angina, symptomatic heart failure, a with vinblastine and vindesine12,13 and in hormone- history of myocardial infarction within 6 months, dependent tumours such as breast cancer.14 Moreover, it uncontrolled hypertension, or uncontrolled active infec- has less neurotoxicity because it has limited effects on the tions were excluded. Patients had to have recovered for axonal microtubules. Also significant is the fact that at least 4 weeks after radiation therapy with no radio- vinorelbine, as a single agent, has a documented activity isotope therapy within 8 weeks of entry into the study. in HRPC.15,16 In a phase II study of 37 evaluable patients, six patients received 30 mg/m2 weekly and 31 patients 2 received 22 mg/m weekly because of dose delays due to Therapy granulocytopenia in the higher levels cohort.15 Of 37 evaluable patients (39%), 14 had a clinical benefit Treatment was administered on an outpatient basis. The response (improvement in Karnofsky Performance Sta- chemotherapy regimen was as follows: mitoxantrone tus, 25% or greater improvement in Pain Visual Analog 12 mg/m2 i.v. day 1, vinorelbine 20 mg/m2 i.v. day 1, scale or at least a 50% decrease in analgesics, all lasting prednisone 10 mg orally days 1–21. Cycles were repeated for a minimum of 12 weeks). Of these 14 patients, 11 every 3 weeks. Administration of bone marrow growth were able to discontinue all analgesics. Four of these 14 factors was discouraged. Treatment was administered if patients had a concomitant reduction in serum PSA of at granulocyte count was 41500/mmc and platelets were least 50%. Therapy was well tolerated with no unanti- 4100 000/mmc. Treatment was withdrawn if one of cipated toxicity. these conditions occurred: any G4 nonhaematological Therefore, taking into account the well-documented toxicity, G4 haematological toxicity on day 1 of the activity and the low-toxicity profile of vinorelbine, and following cycle of chemotherapy after a delay of 1 week. the proven efficacy of the mitoxantrone + low-dose Oral antiemetics were prescribed for nausea as needed. corticosteroids regimen, at the Aviano National Cancer Institute, we conducted a phase II trial, testing a regimen including mitoxantrone, vinorelbine and prednisone in Evaluation HRPC. Each patient was screened by taking their medical history, a physical examination, an assessment of ECOG PS, complete blood cell count, serum chemistry profile, Patients and methods ECG, PSA determination, chest X-rays, bone scan, images of measurable disease (if appropriate), and Pain Study design Visual Analog Score evaluation. Complete blood cell counts were monitored weekly Patients with metastatic HRPC were enrolled in this and serum chemistry profile and PSA determination study. Written informed consent was obtained, in were repeated every 3 weeks on day 1 of each accordance with institutional guidelines. Patients were chemotherapy cycle. CT scans, chest X-rays or bone required to have a histological diagnosis of metastatic scans were repeated every three cycles of chemotherapy HRPC with evidence of documented disease progression if measurable disease was present. Pain intensity was with increased serum PSA (twice as nadir), with two assessed every 3 weeks, on day 1 of each chemotherapy consecutive measurements taken 2 weeks apart and/or cycle, on a 10 cm Visual Analog Scale on which 0 cm ¼ no an increase in bidimensionally measurable soft tissue pain and 10 cm ¼ intolerable pain. The primary objectives metastases or in the area of bone involvement and/or the of this phase II study were to investigate response rate, appearance of new foci on a bone scan and/or sympto- time to progression, PSA response (450% decline) and matic disease which required analgesia. Patients were symptom improvement. At the time the study was required to have an Eastern Cooperative Oncology conducted, a response of 20% was considered low and Group (ECOG) Performance Status (PS) of 0–1 and a life 50% worthy of further study. This study with 24 expectancy of at least 3 months. No prior chemotherapy evaluable patients had 90% power to detect an improve- was allowed. There was no limitation on the number of ment from 20 to 50% in overall response rate with an prior hormonal manipulations, but patients did have to one-sided alpha error of 0.05. Time to progression was demonstrate progressive disease after at least one measured from the time of initiation of therapy to the hormonal treatment. All patients previously treated with time progression was documented. Survival times were an antiandrogen were required to undergo antiandrogen established from the date the patient was registered into withdrawal. Patients were required to be off all anti- the study until time of death or the last follow-up. androgens for at least 4 weeks, with further evidence of Survival curves were calculated by the Kaplan–Meier disease progression after cessation of the antiandrogen. method.

Prostate Cancer and Prostatic Diseases MVD in metastatic prostate cancer D Bernardi et al 47 Definition of response Table 1 Patients characteristics Therapeutic effect was assessed using criteria for measur- Number of patients 28 able disease, if present, change in serum PSA and pain Number of evaluable patients 24 Performance status: evaluation. Owing to the difficulty of analysing efficacy 0 6/24 of criteria, taking into account serum PSA changes, 1 18/24 tumour response and clinical benefit, we decided to Median age 66 y (range 55–77) separate these parameters for response criteria. Median PSA value 135.5 (range 5.2–3940) Sites of metastasis Bone 24/24 Measurable disease. Objective response was evaluated Abdominal lymph nodes 6/24 17 Supraclavicular lymph nodes 2/24 according to World Health Organisation criteria. A Liver 3/24 complete response was defined as the total disappear- Lung 2/24 ance of all clinically detectable disease measured by Pretreatment (14/24 patients) physical examination and/or radiographic studies for a Radiotherapy 11/14 period of at least 4 weeks. A partial1 remission was Intravenous radioisotope 1/14 defined as X50% decrease in the sum of the products of Estramustine 1/14 Cisplatin+doxorubicin 1/14 the two longest perpendicular diameters of all measur- Median number of cycles 6 (range 3–13) able lesions for a period of at least 4 weeks without an increase 425% in the size of any area known to contain malignant disease and without the appearance of any new areas of malignancy. Progressive disease was estramustine and one patient cisplatin + doxorubicin, but defined as an increase of at least 25% in the size of they were not excluded from analysis because of these measurable lesions. protocol violations. ECOG PS was 0 or 1 in six and 18 patients, respectively.

Serological disease. A complete serological response was defined as normalisation of PSA for two consecutive Response and survival measurements taken more than 2 weeks apart and a significant PSA decline was at least a 50% decrease in In all, 11 patients (46%) had a significant PSA decline PSA for two consecutive measurements taken more than lasting at least 2 months. Two patients obtained a 2 weeks apart. Serological progressive disease was stabilisation of PSA values (8%). The median duration defined as a 50% increase in PSA from the lowest level of the response on PSA was 11.4 months (95% CI 7.1– recorded and was confirmed more than 2 weeks later on 12.2). Eight patients (33%) achieved a partial response on the study. Stable disease was defined by a decrease in pain, while seven (29%) obtained a stabilisation of the PSA o50%.8,18 symptom, for a total response rate of palliation on symptoms of 62%. Median duration of the response was 9.5 months (95% CI 6.9–11.5). Out of the seven patients Pain evaluation. A partial response in pain intensity who had bidimensionally measurable disease, three had was defined by a 425% improvement (ie decrease) from a confirmed partial response lasting 7 months, 10.5 the baseline Visual Analog Scale measurement. A months and 11 months, respectively. One patient progression in pain intensity was defined by 425% achieved a stable disease that lasted for 4.5 months. worsening (ie increase).15,19 At the time of the present analysis, 20 patients died of disease progression and four patients are still alive. In two of the patients who died, a concomitant neoplasia Results was present (superficial bladder cancer in one patient and chronic lymphocytic leukaemia in one patient). Patients Median overall survival was 11.9 months (95% CI 9.4– 18.2), 1-year overall survival was 50% (95% CI 30–70), From June 1998 to June 2001, 28 men with a median age while 2-year overall survival was 17% (95% CI 1–33) of 66 years (range 55–77 years) were enrolled (Table 1). (Figure 1). Seven patients had measurable disease. Median PSA value was 135.5 ng/ml (range 5.2–3940 ng/ml). In all, 24 patients were fully evaluable. Two patients were admi- nistered only one cycle of chemotherapy and decided not to proceed with treatment and two patients were entered onto the study but never treated due to withdrawal of informed consent. All evaluable patients had bone metastases, while abdominal lymph nodes and supra- clavicular lymph nodes were sites of metastases in six and two patients, respectively. Liver metastases were present in three patients, lung metastases in two patients. In all, 11 patients had received radiation therapy prior to entering the study and one patient had been adminis- Figure 1 Overall survival of 24 patients affected by metastatic tered intravenous radioisotope. One patient had received hormonoresistant prostate cancer treated with MVD.

Prostate Cancer and Prostatic Diseases MVD in metastatic prostate cancer D Bernardi et al 48 Table 2 Toxicity

Patients (tot. 24) Cycles (tot. 160)

G 1–2 % G 3–4 % G 1–2 % G 3–4 %

Leukopenia 6 25 11 46 23 14 13 8 Anaemia 7 29 3 12 23 14 5 3 Thrombocytopenia 4 17 0 — 7 4 0 — Infection 0 — 2 8 0 — 2 1 Gastrointestinal 2 8 0 5 3 0 — Neurologic 1 4 0 2 1 0 —

Toxicity while seven patients obtained a stabilisation of pain, for a total response rate of palliation on symptoms of 62%. The National Cancer Institute expanded Common Median duration of the response was 9.5 months. Seven Toxicity Criteria (NCI-CTC) was used to evaluate patients had bidimensionally measurable disease; three patients for toxicity during each cycle. A total of 24 of them had a confirmed partial response lasting 7, 8 and patients completed two or more cycles of treatment and 10.5 months, respectively. One patient achieved a stable were evaluable for toxicity (Table 2). A total of 160 cycles disease that lasted for 4.5 months. The median survival of chemotherapy (median 6 cycles; range 3–13) were of 11.9 months observed in this trial is similar to that seen administered. Grade 3–4 granulocytopenia was observed in other phase II trials in HRPC. in 11 patients (46%), grade 3–4 anaemia was observed in Therapy for HPRC remains palliative and the efficacy three patients (13%). In two patients, grade 2 thrombo- of a regimen has to be balanced against toxicity. Our cytopenia was registered. No patients required a reduc- MVD schedule was given on an outpatient basis and was tion of the dose of chemotherapy and only in 3% of the well tolerated. Granulocytopenia was the main toxicity, cycles there was a delay due to hematologic toxicity. being observed in 11 patients (46%). Although two Severe infection was registered in two patients; in one episodes of febrile neutropenia occurred in two patients, patient hospitalisation was necessary, and this patient one requiring hospitalisation, there were no treatment- discontinued treatment after three cycles of chemo- related deaths. therapy. Nevertheless, no lethal toxicity was seen and A phase II study that has been recently published by other nonhaematological toxicities were negligible. Sweeney et al21 reports on a regimen consisting of vinorelbine and estramustine given in a community setting in HRPC patients. The results of this study are impressive, with a PSA response rate of 71%, a median Discussion overall survival of 15.1 months and a 1-y overall survival of 71%. However, the toxicity of oral estramustine, even After several reports had established the activity of if given as a short course (as in this study), is still mitoxantrone in HRPC, Tannock et al 9 and Kantoff et al 10 problematic. In the Sweeney et al study, almost half of the demonstrated in 1996 that the combination of mitoxan- patients required diuretic therapy and 17% had a trone and prednisone or hydrocortisone more reliably thrombotic complication. There is an outstanding interest achieved a palliative response and for a longer duration in regimens employing drugs that block the microtubule than glucocorticoids alone. The activity of vinorelbine in apparatus, especially when used in combination with HRPC has been shown in phase II trials, in terms of estramustine. In fact, besides vinorelbine,22,23 several tumour response, PSA decline and clinical benefit studies have combined a taxane with estramustine criteria. In the study by Oudard et al 18 on 47 patients, with encouraging results in terms of response rate and six patients (17%) had a 450% decline in measured PSA survival.24–27 However, significant toxicity was again values and in 23 (49%) no tumour change was observed. observed in all of these studies. The thrombotic Clinical benefit from vinorelbine was observed in 15 of complications have been a source of concern for many the 21 evaluable patients (32%). This clinical benefit of investigators and have resulted in prophylactic regimens vinorelbine was roughly similar to the two Canadian being introduced into the trials, with the aim of studies on mitoxantrone, giving a palliative response mitigating this toxicity.28 in 36 and 29%, respectively. Another recent report by The mitoxantrone–prednisone regimen has still to be Fields-Jones et al15 showed in 37 evaluable patients a 39% considered the standard treatment for metastatic HRPC, clinical benefit assessed by analgesic consumption and even if a survival advantage with this regimen has not performance status. been demonstrated. With our MVD regimen, we ob- A PSA decrease of 50% or more from the baseline has served a slightly better palliative effect. However, we are been reported to be a surrogate biologic endpoint for aware that a comparison with a multicentre phase III response.8,20 In our study, 11 patients (46%) had a study was not the purpose of this phase II study. The significant PSA decline lasting at least 2 months and incidence of side effects in the present study is somehow two patients obtained a stabilisation of PSA values (8%). higher than that reported in previous studies, especially The median duration of the response on PSA was 11.4 in terms of grade 3–4 leukopenia. This could be partially months. Eight patients achieved a palliative response, due to the fact that bone marrow growth factors could be

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