Cancer and Prostatic Diseases (1999) 2 Suppl 2, S8±S11 ß 1999 Stockton Press All rights reserved 1365±7852/99 $15.00 http://www.stockton-press.co.uk/pcan Is there a place for neoadjuvant hormonal before radical prostatectomy or in the management of prostate cancer?

P Teillac* St Louis Hospital, Department of Urology, Paris, France

Introduction Neoadjuvant hormonal therapy in Why should one ask about the possible aim and role for conjunction with radical prostatectomy: neoadjuvant hormonal therapy prior to radical prosta- the French experience tectomy or radiation therapy in prostate? First, there are a number of bene®ts that neoadjuvant hormone depriva- In conjunction with surgery, we have participated in a tion might be expected to offer. For example, reducing the multicenter French study comparing maximal androgen size of the prostate with hormonal deprivation would be blockade (MAB) prior to radical prostatectomy with very bene®cial, as would downstaging of the cancer, to radical prostatectomy alone (direct surgery, DS). In this obtain a better prognosis. In addition, if it could also help study, ultrasound was used to determine prostate size reduce the incidence of extraprostatic disease and positive and check if there was indeed a downsizing following margins, this would be a signi®cant advantage. Other preoperative androgen deprivation. Furthermore, sur- potential effects include reducing the morbidity asso- geons were asked if downsizing, if any, made the surgical ciated with local treatments and improving overall survi- procedure any easier.1,2 val. Numerous studies have been carried out to investigate all these potential bene®ts. Which subsets of patients are likely candidates for neoadjuvant hormonal therapy? Clearly, since neoadju- Pathological and clinical criteria vant therapy is intended only for local therapy, it is unsuitable for patients with metastatic disease. In addi- Pathological criteria included factors such as the effect of tion, it is not suitable for treating very small tumours that androgen deprivation on downstaging as well as on are known to be con®ned within the prostate and can be margin-positivity status. Clinical criteria included the successfully managed with surgery or radiotherapy. effect of neoadjuvant androgen deprivation on contin- Therefore, neoadjuvant hormonal therapy appears to be ence, urinary symptoms and impotence. Our results best suited to T2 ± 4 tumors, particularly pT3 which is no showed that there is about a 35% reduction in the size longer clinically localized. This is supported by the well- of the prostate. recognized fact that there is a high incidence of clinical understaging in prostate cancer, with clinical T2 tumors found in many cases to be pT3 or greater on pathologic examination. In this regard, neoadjuvant hormonal ther- Dif®culty in surgery apy may be useful for reducing the percentage of pT3 disease, as well as increasing the percentage of The second issue addressed was whether reduction of organ-con®ned T2 disease when a cT3 cancer is suspected prostate size would contribute to making surgery any (Table 1). easier. In this regard, surgeons were asked to assess the dif®culty in dissection of the prostate on a scale of 1 ± 3. Preoperative androgen deprivation was shown to make the surgical procedure not signi®cantly more dif®cult in the MAB group compared to the DS group, with the only difference reported being that dissection of seminal vesicles were more dif®cult to perform in the MAB group. One possible explanation for this may be that *Correspondence: P Teillac, St Louis Hospital, Department of Urology, 1 Avenue Claude Vellefaux, Paris F-75475, France. there were more T3 patients in the MAB group than in E-mail: [email protected]. the DS group. Neoadjuvant hormonal therapy P Teillac

Table 1 Indications for neoadjuvant hormonal therapy in reducing after 1 year, only about 10% in both groups were capable S9 local and systemic recurrences of erections, showing that neoadjuvant therapy had no Indication Stage Goal of therapy: bene®cial or harmful effect on this parameter. downstaging Patients were also assessed for continence status in terms of their need to wear incontinence pads after radical Locally advanced T3 T4 N0 M0 Increase probability of pT2 prostatectomy. Although there was signi®cantly less need tumor for pads in the MAB group at 1.5 months, this difference Clinically localized T2 N0 M0 Decrease probability of pT3 tumor had disappeared at 12-month follow-up. In terms of overall results, there were no clinical ®ndings of any major difference between the two groups, with only a small difference seen at 1.5 months and 3 months with Pathological investigations regard to continence status, which is unlikely to suggest a clear bene®t for preoperative androgen deprivation. Pathological investigations were carried out using a scor- ing system from 7 2to ‡ 1 in which downstaging was scored as follows: from cT3 to cT1 ( 7 2), from cT2 to cT1 ( 7 1), and no downstaging (0). Conversely, upstaging from any cT by one stage (e.g. cT2 to cT3) received a score Review of the literature: radical of ‡ 1. As a result, it was clearly shown that in the MAB prostatectomy with or without group the staging remained unchanged in 59% of patients, while 40% showed downstaging by one stage, neoadjuvant hormonal therapy and 1% by two stages. The highest percentage of In regard to the effect of pathological downstaging on improvement comprised those with an initial staging of prognosis, a survey of the literature shows that there were cT3, although this subset accounted for only 11 patients. three published studies in 1997 which found no signi®- With regard to the Gleason score, there was no differ- cant difference between radical prostatectomy alone and ence between the two groups, and no downgrading was radical prostatectomy plus hormonal therapy (Table 2), seen in these groups. However, the histopathological although in these studies patients were followed up for characteristics of the prostate were found to change relatively long periods of 2 y or more.3±5 after maximal androgen blockade, thus making it more There has been a considerable number of studies dif®cult to evaluate the Gleason score. Thus, in patholo- comparing the effect of radical prostatectomy with or gical terms, the Gleason score may not have the same without androgen blockade on positive margins (Table meaning following androgen blockade. 3).1,5 ± 11 All of these studies have shown an improved In contrast, margin positivity status was shown to be positive margin rate ranging between 20% and 30% in signi®cantly improved in the MAB group at 31% vs 54% patients receiving hormone deprivation before radical in the DS group. Urinary symptom scores at inclusion prostatectomy. It is clear that prostate volume is reduced and before and after surgery were assessed to see if by neoadjuvant hormonal therapy before radical prosta- neoadjuvant androgen deprivation would give better tectomy, although this has had no bene®cial effect on local results than surgery alone. This showed that the differ- control. In addition, androgen deprivation has failed to ence seen between the two groups was due to the down- make surgery any easier or reduce blood loss during sizing of the prostate associated with hormonal surgery. deprivation, although this difference disappeared after In this regard, the key endpoint is overall survival and, surgery. at present, preoperative androgen deprivation does not appear to improve it, although this needs to be con®rmed in a large-scale study with a longer follow-up.

Potency and continence: QOL issues Potency and continence were shown to be obviously very Review of the literature: radiation with important factors affecting the patient's quality of life. At inclusion, about 80% of patients were able to achieve an or without neoadjuvant hormonal erection; however, 77% had become impotent before therapy surgery due to the effects of maximum androgen block- ade. After surgery, only 2% in each group were able to A second area where neoadjuvant hormonal therapy achieve an erection, and although this ®gure improved might be of use is radiation therapy (Table 4). A study

Table 2 Biological disease-free survival results of preoperative androgen deprivation: does pathological downstaging improve prognosis?

Author Evaluable points Progression, Follow-up (y) (total points) Treatment RP/H ‡ RP (months)

Goldenberg (1997) 161 (213) Cyproterone acetate alone 20%/28% (NS) 24 Soloway (1997) 256 (256) MAB 21.6%/21% (NS) 24 Aus (1997) 112 LHRH-a alone 25%/27% (NS) 30

MAB, maximal androgen blockade; LHRH, luteinizing hormone-releasing hormone; NS, not signi®cant; RP, radical prostatectomy; H, hormonal therapy. Neoadjuvant hormonal therapy P Teillac S10 Table 3 Results of preoperative androgen deprivation: margin positivity

Author (y) Clinical stage No. of patients Treatment Mg ‡ (%), RP/H ‡ RP pT2 (%), RP/H ‡ RP

Labrie (1993) T2, T3 161 MAB 34/8 34/77 Fair (1993) T2, T3 141 MAB 33/10 48/74 Debruyne (1994) T2, T3 290 MAB 47/28 26/48 Soloway (1995) T2b 287 MAB 48/18 22/53 Pedersen (1995) T2 111 LHRH-a 46/24 Ð Goldenberg (1996) A2, B 213 Cyproterone acetate 64/34 20/42 Teillac (1997) T2, T3 151 MAB 54/31 Ð Totals 19 ± 30% 22 ± 31%

Mg ‡ , margin positivity; MAB, maximal androgen blockade; LHRH-a, luteinizing hormone-releasing hormone-analog; RP, radical prostatectomy; H, hormonal therapy.

published by Pilepich et al in 1995 had a long-term follow- while the response was found to be better if 75.6 Gy or up averaging 4.5 y.12 In this study, in which patients in the above was used. combined treatment arm received 2 months of hormone deprivation prior to radiation therapy, then a further 2 months during radiation, statistically signi®cant differ- ences were shown in favor of combined therapy in terms Conclusion of improved local control and disease-free survival, although the impact on overall survival is still unknown It is clear from the published data that neoadjuvant and longer follow-up may be required. hormonal therapy administered before local treatment, Two other studies published in 1995 showed better whether radical prostatectomy or radiation therapy, local control and survival without evidence of biological reduces the prostate volume. Although this can lead to progression in patients receiving androgen deprivation better local control in some cases, the impact on overall prior to radiation, as well as a reduction in positive survival still remains unknown. biopsies after irradiation. However, again, there were no data available on overall survival. More recently, Zelefsky et al looked at the clinical target volume consisting of the prostate and seminal vesicles in References a study using conformal radiation therapy, which showed that the planned target volume was greater than the 1 Teillac P, Lucas C, Leblanc V. Neoadjuvant treatment with LHRH clinical target volume.13 While this study was not analogue 1 month depot and antiandrogen before radical pros- tatectomy in patients with clinical T2 or T3 N0 M0 prostate cancer: designed to evaluate the effect of neoadjuvant hormonal a multicentric randomized trial. In: EAU and EUF Symposium, therapy, 29% of patients had received this treatment to Symposium III: Therapeutic Options for Localized and Locally produce downsizing, with up to 81 Gy of radiation deliv- Advanced Prostate Cancer, 16 ± 17 May 1997, Brussels, p 8 ered to the bladder, rectum, seminal vesicles and prostate. (abstract). This study demonstrated that 4 y survival depended on 2 Teillac P, Lucas C. Maximal androgen blockade before radical the number of favourable classical prognostic factors, prostatectomy versus prostatectomy: a 1 year follow-up in a randomised multicenter prospective study. Eur Urol 1999; including PSA, staging and Gleason score (Table 5), 35(Suppl 2): 87 (abstract no. 348). 3 Goldenberg SL, Klotz LH, Jewett MA, Barkin J, Chetner M, Fradet Y, Chin J and the Canadian Uro- Group. A randomized trial of neoadjuvant androgen withdrawal therapy Table 4 Results of neoadjuvant hormonal therapy before radiotheraphy in PCa prior to radical prostatectomy: 24 months post-treatment PSA results. J Urol 1997; 157(part 2): 92 (abstract no. 357). Local control Metastases-free Disease-free 4 Soloway M, Shari® R, Wajsman Z, Puras-Baez A. Radical pros- Treatment (%) survival (%) survival (%) tectomy alone vs radical prostectomy preceded by androgen blockade in cT2b prostate cancer: 24 month results. J Urol 1997; Radiotherapy alone 29 59 15 157(4): 160. Hormonal therapy ‡ 54 66 36 5 Aus G, Abrahamsson PA, Ahlgren G, Hugosson J, Lundberg S, radiotherapy Schain M, Schelin S, Pedersen K. Hormonal treatment before P < 0.001a P ˆ 0.09a P < 0.001a radical prostatectomy: a 3-year followup. JUrol1998; 159(6): 2013 ± 2016 (discussion of 2016 ± 2017). Stages, T2b ± T4; n ˆ 471; median follow-up, 4.5 y. 6 Labrie F, Dupont A, Cusan L, Gomez J, Diamond P, Koutsilieris a Versus radiotheraphy alone. M, Suburu R, Fradet Y, Lemay M, Tetu B et al. Downstating of localized prostate cancer by neoadjuvant therapy with ¯utamide and lupron: the ®rst controlled and randomized trial. Clin Invest Table 5 Results of conformal radiotheraphy in PCa: survival Med 1993; 16(6): 499 ± 509. without progression at 4 y 7 Fair WR, Aprikian A, Sogani P, Reuter V, Whitmore WF Jr. The role of neoadjuvant hormonal manipulation in localized prostatic Prognostic statusa No. of patients 4 y survival cancer. Cancer 1993; 71(Suppl 3): 1031 ± 1038. Favorable (three factors) 167 85% 8 Debruyne FM, Witjes WP, Schulman CC, van Cangh PJ, Ooster- Intermediate (one factor) 269 65% hof GO. A multicentre trial of combined neoadjuvant androgen Unfavorable (no factors) 307 35% blockade with Zoladex and ¯utamide prior to radical prostatec- tomy in prostate cancer. The European Study Group on Neoad- a Favorable factors: PSA  10, stages T1 ±T2, Gleason score  6. juvant Treatment. Eur Urol 1994; 26(Suppl 1): 4. Neoadjuvant hormonal therapy P Teillac

9 Soloway MS, Shari® R, Wajsman Z, McLeod D, Wood DP Jr, 12 Pilepich MV, Krall JM, al-Sarraf M, John MJ, Doggett RL, Sause S11 Puras-Baez A. Randomized prospective study comparing radical WT, Lawton CA, Abrams RA, Rotman M, Rubin P et al. Andro- prostatectomy alone versus radical prostatectomy preceded by gen deprivation with radiation therapy compared with radiation androgen blockade in clinical stage B2 (T2bNxM0) prostate therapy alone for locally advanced prostatic carcinoma: a random- cancer. The Lupron Depot Neoadjuvant Prostate Cancer Study ized comparative trial of the Radiation Therapy Oncology Group. Group. JUrol1995; 154(2, part 1): 424 ± 428. Urology 1995; 45(4): 616 ± 623 (see comments). 10 Hugosson J, Abrahamsson PA, Ahlgren G, Aus G, Lundberg S, 13 Zelefsky MJ, Lyass O, Fuks Z, Wolfe T, Burman C, Ling CC, Schelin S, Schain M, Pedersen K. The risk of malignancy in the Leibel SA. Predictors of improved outcome for patients with surgical margin at radical prostatectomy reduced almost three- localized prostate cancer treated with neoadjuvant androgen fold in patients given neo-adjuvant hormone treatment. Eur Urol ablation therapy and three-dimensional conformal radiotherapy. 1996; 29(4): 413 ± 419. J Clin Oncol 1998; 16(10): 3380 ± 3385. 11 Goldenberg SL, Klotz LH, Srigley J, Jewett MA, Mador D, Fradet Y, Barkin J, Chin J, Paquin JM, Bullock MJ, Laplante S and the Canadian Urologic Oncology Group. Randomized, prospective, controlled study comparing radical prostatectomy alone and neoadjuvant androgen withdrawal in the treatment of localized prostate cancer. JUrol1996; 156(3): 873 ± 877.