Honvan) Infusion in Treatment of Symptomatic Advanced Prostate Cancer
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Prostate Cancer and Prostatic Diseases (1998) 1, 204 ± 207 ß 1998 Stockton Press All rights reserved 1365±7852/98 $12.00 http://www.stockton-press.co.uk/pc Use of intravenous fosfestrol tetrasodium (Honvan) infusion in treatment of symptomatic advanced prostate cancer AR Williams and P Whelan Pyrah Department of Urology, St. James's University Hospital, Leeds, UK Fosfestrol tetrasodium (Honvan) is a synthetic oestrogen-based compound. Studies have suggested its use in the treatment of localised, advanced and hormone-refractory prostate cancer. This series of 17 patients with advanced disease documents the response, both subjective and objective, to standard dose intravenous Honvan infusion. Infusions were well tolerated, with no cardiovascular side-effects. Twelve patients received Honvan as de novo therapy, of whom 10 (83%) described subjective improvement and 11 (92%) had objective evidence of improvement, 11 (92%) had documented falls in prostate-speci®c antigen (PSA) levels. Nine patients received Honvan infusions as secondary treatment for hormone-escaped disease (1 patient received Honvan for a second time and another for a second and third time). Of these, 1 (11%) had a documented fall in PSA; 3 (33%) reported a subjective symptomatic improvement, and 2 (22%) demonstrated objective evidence of improvement. Patients with symptoms from bulk abdomino-pelvic disease seemed to fare better than those with bony metastases. This may suggest a speci®c indication for Honvan in a subgroup of patients with acute obstructive events of the ureters, urethra or circulatory vessles, in particular its value as a de novo therapy. In those patients who received Honvan as secondary therapy, some response was seen in a third, but overall these patients remained hormone-refractory. Keywords: prostate cancer; Honvan; response rates Introduction certain well-selected patients, including those with ure- teric obstruction, may bene®t from Honvan.3 Our series The synthetic oestrogen fosfestrol tetrasodium (Honvan) examined symptom relief, with or without objective dis- has been proposed to be of bene®t in both localised and ease response, in a group of patients with advanced advanced prostate cancer. Its precise mode of action disease treated with intravenous Honvan for acute symp- remains a matter for debate although it seems to possess tomatic presentations. Our indications for treatment thus direct tumoricidal activity as well as yielding oestrogen were either prompt stabilisation of symptoms before analogues as its metabolites.1 Clinical studies published starting maintenance therapy, or as secondary therapy thus far have reported variable disease response to intra- in apparently hormone-refractory disease. venous infusions of Honvan, whether given in low or high dose infusions. One such study2 incorporating its own data into a literature review reported no objective responses, although a subjective improvement in symp- Methods toms in 75% of patients. Anecdotal evidence suggests that Case notes of patients having received Honvan in the setting of advanced prostate cancer (CaP) were reviewed retrospectively. Parameters identi®ed were: age at Correspondence: Dr P. Whelan, Consultant Urologist, St. James's University Hospital, Beckett St., Leeds LS9 7TF. diagnosis of CaP; age at which Honvan was prescribed Received 26 June 1997; revised 16 December 1997; accepted for symptoms; symptom (or disease process, such as 7 January 1998 acute obstructive uropathy); disease pattern (such as Honvan and prostate cancer AR Williams and P Whelan lymphadenopathy or bony metastases); degree of differ- over the course of their disease (one received three courses 205 entiation as determined by prostate biopsy (Gleason and two received two courses). grade where available) and concurrent treatment at time In patients receiving Honvan alone de novo (9), seven of presentation with symptoms. Each patient was had symptoms from bulk abdominopelvic disease (one grouped according to whether they received Honvan de had lymphoedema of legs, two had bilateral lower limb novo or as secondary therapy. DVT, two had lower tract obstruction, two had ureteric Response to infusion of Honvan was measured simply obstruction). One patient presented with purpura and in terms of subjective response (symptomatic improve- thrombocytopaenia, and one with symptoms of cord ment as judged by the patient), objective response (such compression. All nine had objective evidence of improve- as radiological regression of lymphadenopathy), and ment, although eight reported subjective symptomatic reduction in serum concentration of PSA. Survival after improvement (the patient who did not presented an onset of Honvan infusion was noted, as were any poten- acute renal failure secondary to ureteric obstruction). tial confounding factors in symptom relief. Patients with- Eight patients had a documented fall in PSA. Three out evidence of extraprostatic disease were not patients received Honvan de novo along with a concurrent considered in this series. hormonal therapy (one with lower tract obstruction and Infusions comprised 1104 mg Honvan daily for 5 d two with bone pain). The patient with lower tract symp- prior to September 1996, 1200 mg daily for 7 d subsequent toms had both subjective and objective improvement, and to this, representing standard hospital formulary regimes one of the patients with bone pain similarly. at these times in our unit. Each infusion was given over a All nine patients receiving Honvan as secondary therapy standard 30 min, diluted to a volume of 250 ml with 0.9% had bony metastases. Three of these nine episodes were saline, and preceded by an infusion of metoclopramide as associated with subjective improvement (one patient with an antiemetic. All infusions were given on an inpatient bone pain, and one patient with two separate episodes of basis. ureteric obstruction, who had concurrent drainage on both occasions with stabilisation of renal function when mechan- ical drainage was withdrawn). In six out of nine episodes Results there were no documented response. Nine patients had died having had Honvan during the A total of 21 patients who received Honvan infusions were period of review. Three patients had repeated infusions. eligible for inclusion in this series. Notes for three of these The mean survival time after ®rst infusion was about 20 patients were unavailable for review. One patient failed to months (range 2 weeks to 93 months). There were no continue with the infusion beyond its commencement cardiovascular complications nor episodes of intractable because of intolerable vomiting. Review of 17 patients' emesis during or after infusions in the 17 patients. notes are presented in Tables 1 and 2, giving individual patterns of disease. In total, there were 21 courses of treat- ment for the 17 patients, as mentioned above. Twelve of the Discussion 21 represented de novo treatment of disease, three of these receiving Honvan concurrently with another hormonal Honvan infusions were well tolerated by all except one agent; nine of the 21 were given as secondary therapy. patient in our study, reiterating the acceptability of this Three patients received more than one course of Honvan mode of therapy and possibly indicating its use on an Table 1 Patients receiving Honvan de novo Age Symptom Disease Treatment at Days' PSA Subj. Obj. Patient at D pattern pattern Grade presentation inf. drop Y=NY=N Surv. notes HH 68 Lymphoedema Intrabdominal G4 5 None 5 92% Y Y 36 m of legs L.N. KR 62 Bilat. DVT Pelvic L.N. `Poorly diff.' None 5 N=GY Y93mD L.N. biopsy AR 73 Bilat. DVT Pelvic L.N. `Poorly diff.' None 5 99% Y Y 15 m GL 56 Obst.; Irr. Bony mets G5 None 5 42% Y Y 28 m D @ TURP JB 81 ARF Ureter obst. G5 3 None 7 99% Y Y 2 m Bony mets EF 87 ARF Ureter obst. G 3 3 None 7 99% N Y 3 m PB 80 Acute ret'n Bony mets G 5 5 None 5 54% Y Y 3 m DG 71 Leg weakness Bony mets G3 3 None 7 95% Y Y 5 m Urine incont Cord comp. AW 57 Pupura Haematuria Low plts G 3 4 None 5 99% Y Y 17 m Bone pain Bony mets NP 42 Acute ret'n Pelvic L.N. `Well diff.' Flutamide 5 95% Y Y 30 m DB 63 Purpura Low plts N=G Flutamide 5 82% N N 5 m Bone pain Bony mets MM 76 Bone pain Bony mets `Poorly diff.' CPA 5 75% Y Y 3 m * Denotes a patient having received Honvan previously; Surv. (survival) denotes post infusion recored in m (months) or w (weeks); survival at time of study; G denotes grade according to Gleason scale; Obst.; irr. denotes lower urinary tract obstructive and irritative symptoms; N=G denotes a quantity whose value was not recorded in the medical notes; ARF and CFR denotes acute and chronic renal failure respectively; Ureter obst. refers to bilateral upper tract obsctruction; L.N. denotes lymph nodes or lymphadenopathy; Cord comp. denotes presentation with acute spinal cord compression; plts denotes platelets; CPA denotes cyproterone acetone; Subscaps. orch. Denotes subcapsular orchidectomy. Honvan and prostate cancer AR Williams and P Whelan 206 Table 2 Patients receiving Honvan as secondary treatment Age Symptom Disease Treatment at Days' PSA Subj. Obj. Patient at D Rx pattern pattern grade presentation inf. drop Y=NY=N Surv. notes KR* 62 68 Obst.; irr. Bony mets G 4 5 Goserelin 7NoNN14m Stilboestrol AR* 73 75 Haematuria Bony mets `Poorly diff.' Stilboestrol 5 No Y N 1 m Bone pain GL* 56 57 ARF Ureter obst. G5 Flutamide 5 No Y Y 18 m Ureteric stents GL* 56 58 ARF Ureter obst. G5 Stilboestrol 5 61% Y Y 12 m Nephorostomies EK 74 77 Leag weakness Bony mets G 4 5 Goserelin 5 No N N 5 m Surgical Urine incont. Cord comp. decompression KH 63 64 Bone pain Bony mets. N=GCPA 5NoNN3m Prerenal ARF WW 61 61 Prerenal ARF Bony mets N=GCPA 5NoNN2w AK 75 79 CRF Bony mets N=G Subcaps.