Prostate Cancer Treatment: the Times They Are A' Changin'

COMMENTS

be alert to the early warning signs of REFERENCES interventional bronchoscopy to avoid bronchial obstruction, noting that in practice uncontrollable bleeding: a case report this is difficult because symptoms related to 1 Braman SS, Whitcomb ME. of endobronchial metastasis of renal treatment toxicity, such as everolimus- Endobronchial metastasis. Arch Intern cell carcinoma. Intern Med 2011; 50: induced pneumonitis, may overlap with Med 1975; 135: 543–7 135–9 those of EBM. 2 Greenberg BE, Young JM. Pulmonary 8 Larkin J, Gore M. Is advanced renal cell metastasis from occult primary sites carcinoma becoming a chronic disease? Although systemic therapy appeared to resembling bronchogenic carcinoma. Dis Lancet 2010; 376: 574–5 impact little upon the clinical outcomes Chest 1958; 33: 496–505 9 Motzer RJ, Escudier B, Oudard S et al. seen in this series, delaying the onset of 3 Heitmiller RF, Marasco WJ, Hruban Efficacy of everolimus in advanced renal EBM is preferable to attempting to palliate a RH, Marsh BR. Endobronchial cell carcinoma: a double-blind, mechanical obstruction once established. metastasis. J Thorac Cardiovasc Surg randomised, placebo-controlled phase III Achieving this aim requires further 1993; 106: 537–42 trial. Lancet 2008; 372: 449–56 improvements in the systemic management 4 Kiryu T, Hoshi H, Matsui E et al. 10 Seijo LM, Sterman DH. Interventional of metastatic RCC, to delay the development Endotracheal/endobronchial metastases: pulmonology. N Engl J Med 2001; 344: of resistant disease. Most importantly, clinicopathologic study with special 740–9 clinical trials which include routine reference to developmental modes. 11 Dumon JF. A dedicated tracheobronchial assessment of tumour tissue, including Chest 2001; 119: 768–75 stent. Chest 1990; 97: 328–32 metastatic sites, at important time points 5 Dursun AB, Demirag F, Bayiz H, may identify molecular markers predictive of Sertkaya D. Endobronchial metastases: Correspondence: James M. Larkin, Medical resistance to therapy, and may also a clinicopathological analysis. Oncologist, Royal Marsden NHS Trust, distinguish those cohorts of patients at risk Respirology 2005; 10: 510–4 Fulham Road, London SW3 6JJ, UK. of developing particular complications such 6 Sakumoto N, Inafuku S, Shimoji H e-mail: [email protected] as EBM. In the meantime, oncologists faced et al. Endobronchial metastasis from with this very difficult clinical problem renal cell carcinoma: report of a case. Abbreviations: EBM, Endobronchial require careful guidance from a Surg Today 2000; 30: 744–6 metastases; mTOR, mammalian target of multidisciplinary team, which includes a 7 Suyama H, Igishi T, Makino H et al. rapamycin; VEGF, vascular endothelial respiratory physician, in the management of Bronchial artery embolization before growth factor. the individual patient. Our experience in RCC in the targeted era of treatment shows that EBM is not rare, with an incidence of ≈10%. This is in contrast to the incidence reported PROSTATE CANCER TREATMENT: THE TIMES THEY ARE A’ in older literature, and may reflect the fact that patients treated with anti-VEGF and CHANGIN’ Roger Kirby , Ben Challacombe * , Prokar Dasgupta * † mTOR treatments have a significantly and John M. Fitzpatrick – The Prostate Centre, London , * Guy ’ s Hospital, King ’ s improved life expectancy compared with College London, London, UK , and † the Mater Misericordiae Hospital and Irish Cancer Society, historical cohorts. Dublin, Ireland Accepted for publication 20 June 2012

CONFLICT OF INTEREST INTRODUCTION towards allaying the fears surrounding the Consultant or advisory role: James M. ‘ over-treatment ’ of clinically insignifi cant Larkin, Pfizer, Bayer, GlaxoSmithKline, Over the past few decades the treatment of tumours. Novartis; Lisa M. Pickering, Pfizer, Novartis; prostate cancer has evolved from a primarily Martin E. Gore, Pfizer, Bayer, hormonal approach, to include open and The 1966 Nobel Prize winning observation of GlaxoSmithKline, Novartis, Roche. subsequently minimally invasive radical Charles Huggins and Clarence Hodges [ 2 ] surgery and radiotherapy (RT) to newer, still that remission of prostate cancer could be Stock ownership: None. unproven, focal methods. In addition, the achieved by testosterone deprivation recent development of effective second-line constituted a landmark in the management Honoraria: James M. Larkin, Pfizer, Bayer, medical therapies, including docetaxel, of this increasingly prevalent disease. The GlaxoSmithKline, Novartis; Lisa M. Pickering, cabazitaxel and abiraterone, has resulted in next major breakthrough came when the Pfizer, Novartis, GlaxoSmithKline; Martin E. improved survival rates in men with glycoprotein PSA, secreted by columnar cells Gore, Pfizer, Bayer, GlaxoSmithKline, castration-resistant prostate cancer (CRPC) within the prostate, which liquefi es semen Novartis, Roche. [ 1 ] . The debate surrounding screening and after ejaculation, was discovered. The early detection using PSA testing continues, measurement of PSA levels in the Research funding: James M. Larkin, but the rising popularity of active bloodstream, which rise when prostate Pfizer, Bayer, Novartis; Lisa M. Pickering, surveillance (AS) as a means of managing cancer develops, resulted in a stage shift Pfizer. low-risk disease has gone some way downward in the detection of prostate

FIG. 1. Cabazitaxel. men who do have disease progression hormones, the PSA starts to rise. during AS by defi ning more clearly the Chemotherapy with a taxane has been Cabazitaxel triggers for intervention. shown to be effi cacious in this situation. For O OCH3 H3CO men with CRPC, the median survival in O Which treatment then should now be recent phase III studies has ranged from O O NH O offered to those men with clinically localised 12.2 to 21.7 months, with improvements in H O O OHO intermediate- or high-risk cancer deemed to survival seen mostly with docetaxel-based OH O O be at signifi cant risk of progression? regimens (8 – 11). Two studies have fi rmly Technological advances have transformed established the benefi ts of this therapy. In Systematic (IUPAC) name both surgery and RT. The development of the landmark TAX-327 trial, docetaxel (1S, 2S, 3R, 4S, 7R, 9S, 10S, 12R, 15S)-4- laparoscopic prostatectomy and more 75 mg/m2 every 3 weeks showed a survival (Acetyloxy)-15-{[(2R,3S)-3-{[(tert- butoxy)carbonyl]amino}-2-hydroxy-3- recently robot-assisted radical advantage compared with weekly docetaxel phenylpropanoyl]oxy}-1-hydroxy-9,12- prostatectomy have reduced hospital stay, and mitoxantrone (18.9 vs 16.5 months; P < dimethoxy-10,14,17,17-tetramethyl-11-oxo-6- complication and transfusion rates, and 0.009). PSA response, pain control and oxatetracyclo[11.3.1.03,10 .04,7]heptadec-13- ene-2-yl benzoate improved the patients ’ experience of surgery health-related quality of life were also [ 6 ] and seems both oncologically sound with signifi cantly better with docetaxel given excellent functional outcomes in higher every 3 weeks compared with mitoxantrone volume centres [ 7 ] . The deployment of [ 10 ] . An update of the results of the cancer, with resultant calls for PSA intensity modulated RT (IMRT) has enhanced TAX-327 trial from 2007 confi rmed an screening. Unfortunately, PSA proved to be a targeting of RT treatment. Low-dose on-going survival benefi t with 18.6% of less than perfect marker for prostate cancer, brachytherapy is available for those patients alive at 3 years, for the docetaxel because of the very large number of men unwilling to consider either surgery or the group compared with 13.5% with with BPH, with similarly raised PSA values. 7-week daily treatment regime required mitoxantrone (P = 0.005) [ 11 ] . Nonetheless, the European Randomised for IMRT and can be given as a boost to Study of Prostate Cancer Screening (ERSPC), IMRT for those with intermediate/high-risk A study by the Southwest Oncology Group initiated in the 1990s, has recently reported disease wishing to avoid hormonal ablation. (SWOG) 99-16 also showed survival benefi t a 21% reduction in prostate cancer For locally advanced tumours most agree with docetaxel of 17.5 vs 15.6 months for mortality in the screened arm at 11 years that external-beam RT preceded by 3 mitoxantrone (P = 0.02), with a median time [ 3 ] , but at the price of a considerable months of androgen deprivation is the best to progression (6.3 vs 3.2 months; P < ‘ over-diagnosis ’ of low-risk, clinically alternative. 0.001) and PSA declines of 50% (50% vs insignifi cant cancers. 27%; P < 0.001) [ 12 ] . These two trials Very recently there has been a fl urry of showed a 20 – 24% reduction in mortality in ‘ Over-diagnosis ’ of prostate cancer is only publicity about focal treatment of localised patients with CRPC treated with docetaxel- worrisome if it results in ‘ over-treatment ’. prostate cancer using high-intensity focused based chemotherapy. Most reported series of radical ultrasound (HIFU). A recent publication [ 8 ] prostatectomy and RT treatments for reported data at 1 year in 42 patients There is now new hope for patients who localised prostate cancer undoubtedly treated with minimal impact on either progress after docetaxel-based contained a proportion of patients with sexual function or continence. However, four chemotherapy. A new generation taxane, low-risk cancers that may never have patients required re-treatment and others cabazitaxel, is now available to overcome progressed within their natural lifespan. might be anticipated to relapse with further docetaxel resistance ( Fig. 1 ). Cabazitaxel, like Hence the current trend towards AS for men follow-up [ 9 ] . A randomised controlled trial docetaxel, is a semi-synthetic microtubule with Gleason pattern 6 cancers present in comparing HIFU to more conventional stabiliser extracted from needles of the only a small proportion of biopsy cores, and therapy is urgently needed to provide better European Yew tree. Results of a large phase with no evidence of a large tumour on evidence of effi cacy. III trial (TROPIC) involving 755 patients with multi-parametric MRI [ 4 ] . Indeed, the metastatic CRPC progressing during or after recently publicised Prostate Cancer Androgen ablation therapy remains the docetaxel treatment have been reported Intervention versus Observation Trial (PIVOT) mainstay for patients who either present [ 13,14 ] . Cabazitaxel signifi cantly reduced the trial shows no difference in overall survival with metastases or develop them in spite of overall risk of death by 30% (P < 0.001) (OS) for older men with low/intermediate surgery and/or RT. A LHRH analogue, with a median OS of 15.1 vs 12.7 months risk disease treated with radical preceded by an antiandrogen to avoid with mitoxantrone. Progression-free survival, prostatectomy at 10 years compared with problems with a tumour fl are, is the usual tumour response and PSA response were those only observed. In contrast the treatment of choice. The new LHRH also signifi cantly improved with cabazitaxel. Scandinavian randomised trial of radical antagonists, such as degarelix, constitute a In this population with very advanced prostatectomy vs watchful waiting (SPCG-4) useful hormonal alternative, and obviate the disease and heavily pre-treated with can now provide individualised patient need for pre-treatment with an chemotherapy, there were higher rates of benefi t calculations as well as its overall antiandrogen. neutropenia (81.7% vs 58%), febrile message that surgery can reduce prostate neutropenia (7.5% vs 1.3%) and diarrhoea cancer mortality [ 5 ] . However, more work Eventually, however, in most patients with (6.2% vs 0.3%) with cabazitaxel compared needs to be done to reliably detect those advanced prostate cancer treated with with mitoxantrone. Patients should clearly

be carefully monitored for these adverse recombinant antigen is designed to target FIG. 2. Abiraterone. events. antigen-presenting cells, and may help direct the immune response to PAP. Minimal Abiraterone Recently the CYP inhibitor, abiraterone residual levels of the intact human N acetate, has been shown to extend life PAP-GM-CSF fusion protein are detectable expectancy in patients with CRPC, but is in the fi nal sipuleucel-T product. The cellular currently approved only for use after composition of sipuleucel-T is dependent on chemotherapy ( Fig. 2 ). Abiraterone inhibits the composition of cells obtained from the 17 α -hydroxylase/C17,20 lyase (CYP17A1), patient ’ s leukapheresis. The activated, H an enzyme which is expressed in testicular, antigen-loaded antigen-presenting cells are adrenal, and prostatic tumour tissues. CYP17 then infused into the patient, where they H H catalyses two sequential reactions: (i) the can potentially stimulate a T cell response conversion of pregnenolone and against prostate cancer cells. The process is HO progesterone to their 17α -hydroxy performed three times over the course of a derivatives by its 17α -hydroxylase activity, 4-week period. The vaccine has been studied and (ii) the subsequent formation of in three phase III clinical trials. In the fi rst dehydroepiandrosterone (DHEA) and phase III study, D9901, consisting of 127 androstenedione, respectively, by its C17,20 men with asymptomatic, metastatic CRPC, lyase activity. DHEA and androstenedione compared sipuleucel-T every 2 weeks for are androgens and precursors of three cycles with placebo in a 2:1 ratio. The testosterone. Inhibition of CYP17 activity fi nal 3-year follow-up of the D9901 phase by abiraterone thus decreases circulating III study showed a median survival benefi t Systematic (IUPAC) name levels of testosterone. A phase III trial in of 4.5 months and a three-fold (3â)-17-(pyridin-3-yl)androsta-5,16-dien-3-ol patients previously treated with docetaxel improvement in survival at 36 months for started in 2008. A placebo-controlled patients who were randomised to receive randomised phase III clinical trial in patients Provenge [ 18 ] . In another trial, 98 men with In conclusion, there can be few tumours with CRPC who are chemotherapy-naive asymptomatic, metastatic CRPC had a 21.4% that have been associated with more opened to accrual in April 2009. OS was improvement in OS for patients randomised controversy than prostate cancer, or in increased by 3.9 months [ 15 ] . However, to sipuleucel-T. In both studies, the vaccine which treatment options have changed so recently presented data suggest that it may was well tolerated, and the most common radically over recent years. Much work also have a role before chemotherapy is adverse events were chills and fatigue. The remains to be done to evaluate in deployed [ 16 ] . Another emerging agent, third phase III trial, D9902B, also known as randomised controlled trials the comparative MDV3100, is an androgen receptor the IMPACT trial (Immunotherapy for risks and benefi ts of the various emerging antagonist, which has recently been shown Prostate Adenocarcinoma Treatment) was a therapies. However, in these changing times, to improve survival in men with metastatic randomised, double-blind, placebo- it is heartening that the prospects for the CRPC previously treated with docetaxel controlled study comparing Provenge with very many men presenting with either chemotherapy [ 17 ] . placebo in 512 men with CRPC randomised localised or advanced, and even castration- in 2:1 ratio. The median OS favoured the resistant, prostate cancer have never been Recent evidence has also indicated a role for vaccine arm with a 4.1-month increase in better than they are now. vaccine-based immunotherapy in CRPC. OS for patients treated with sipuleucel-T = Sipuleucel-T (Provenge) consists of (25.8 vs 21.7 months; P 0.032). Also, ACKNOWLEDGEMENTS autologous peripheral blood mononuclear the 36-month survival probability was cells, including antigen-presenting cells, 31.7% in the sipuleucel-T group vs 23.0% Professor Prokar Dasgupta acknowledges which have been activated during a defi ned in the placebo group. Therapy with support from the MRC Centre for culture period with a recombinant fusion sipuleucel-T was also associated with a Transplantation and the Comprehensive protein consisting of prostatic acid positive OS effect in an analysis that Biomedical Research Centre, King ’ s Health phosphatase (PAP), an antigen expressed in included 18 additional deaths observed Partners. prostate cancer tissue, linked to between the data-cutoff and study- granulocyte-macrophage colony-stimulating completion dates, with a median of 36.5 factor (GM-CSF), an immune cell activator. months of follow-up (hazard ratio, 0.76; CONFLICT OF INTEREST The patient ’ s peripheral blood mononuclear 95% CI 0.61 – 0.95; P = 0.02) [ 19 ] . cells are obtained via a standard Sipuleucel-T is the fi rst active None declared. leukapheresis procedure ≈ 3 days before the immunotherapy to show an improvement in infusion date. The active components are OS for advanced prostate cancer. Given the REFERENCES autologous antigen-presenting cells and short duration of the therapy (1 month) human PAP-GM-CSF fusion protein. During and its favourable benefi t-to-risk ratio, 1 Kirby R , Fitzpatrick JM . Improved culture, the recombinant antigen can bind sipuleucel-T provides an interesting, albeit survival prospects for patients with to and be processed by antigen-presenting expensive, new option for the management castration-resistant prostate cancer . BJU cells into smaller protein fragments. The of advanced prostate cancer. Int 2 0 1 1 ; 107 : 697 – 700

2 Glina S , Rivero MA , Morales A , 9 Challacombe B , Zakri R , Murphy D , in metastatic prostate cancer . N Engl J Morgentaler A . Studies on prostatic Cahill D . High intensity focused Med 2 0 1 1 ; 364 : 1995 – 2005 cancer I. The effect of castration, of ultrasound – early experience and 16 Payne H , Bahl A , Mason M , Troup J , estrogen and of androgen injection on 2 year results . BJU Int 2009 ; 104 : De Bono J . Optimizing the care of serum phosphatases in metastatic 200 – 4 patients with advanced prostate carcinoma of the prostate by Charles 10 Tannock IF , de Wit R , Berry WR et al . cancer in the UK: current challenges Huggins and Clarence V. Hodges . J Sex Docetaxel plus prednisone or and future opportunities . BJU Int Med 2 0 1 0 ; 7 : 640 – 4 mitoxantrone plus prednisone for 2012 ; [ Epub ahead of print ] . DOI: 3 Schroder FH , Hugosson J , Roobol MJ advanced prostate cancer . N Engl J Med 10.1111/j.1464-410X.2011.10886.x et al . Prostate-cancer mortality at 11 2004 ; 351 : 1502 – 12 17 Scher HI , Beer TM , Higano CS et al . years of follow-up . N Engl J Med 2012 ; 11 Berthold DR , Pond GR , Soban F , de Antitumour activity of MDV3100 in 366 : 981 – 90 Wit R , Eisenberger M , Tannock IF . castration-resistant prostate cancer: a 4 Klotz L . Active surveillance for Docetaxel plus prednisone or phase 1 – 2 study . Lancet 2 0 1 0 ; 375 : favorable-risk prostate cancer: mitoxantrone plus prednisone for 1437 – 46 background, patient selection, triggers advanced prostate cancer: updated 18 Small EJ , Schellhammer PF , Higano CS for intervention, and outcomes . Curr survival in the TAX 327 study . J Clin et al . Placebo-controlled phase III trial Opin Urol 2012 ; 22 : 222 – 30 Oncol 2008 ; 26 : 242 – 5 of immunologic therapy with 5 Vickers A , Bennette C , Steineck G 12 Petrylak DP , Ankerst DP , Jiang CS sipuleucel-T (APC8015) in patients with et al . Individualized estimation of the et al . Evaluation of prostate-specifi c metastatic, asymptomatic hormone benefi t of radical prostatectomy from antigen declines for surrogacy in refractory prostate cancer . J Clin Oncol the Scandinavian Prostate Cancer Group patients treated on SWOG 99-16 . J Natl 2006 ; 24 : 3089 – 94 Randomized Trial . Eur Urol 2012 ; 62 : Cancer Inst 2006 ; 98 : 5 1 6 – 2 1 19 Kantoff P , Higano C , Shore D et al . 204 – 9 13 De Bono JS , Oudard S , Ozguroglu M Sipuleucel-T immunotherapy for 6 Goldstraw MA , Challacombe BJ , Patil et al . Cabazitaxel or mitoxantrone with castration-resistant prostate cancer . N K . Overcoming the challenges of prednisone in patients with metastatic Engl J Med 2 0 1 0 ; 363 : 4 1 1 – 2 1 robot-assisted radical prostatectomy . castration-resistant prostate cancer Prostate Cancer Prostatic Dis 2012 ; 15 : (mCRPC) previously treated with Correspondence: Roger Kirby, The Prostate 1 – 7 docetaxel: fi nal results of a multinational Centre, 32 Wimpole Street, London 7 Coelho RF , Rocco B , Patel MB et al . phase III trial (TROPIC) . J Clin Oncol W1G 8GT, UK. Retropubic, laparoscopic, and robot- 2 0 1 0 ; 28 ( Suppl .): 4508 e-mail: [email protected] assisted radical prostatectomy: a critical 14 de Bono JS , Oudard S , Ozguroglu M review of outcomes reported by et al . Prednisone plus cabazitaxel or Abbreviations : AS , active surveillance ; CRPC , high-volume centers . J Endourol 2 0 1 0 ; mitoxantrone for metastatic castration- castration-resistant prostate cancer ; DHEA , 24 : 2003 – 15 resistant prostate cancer progressing dehydroepiandrosterone ; GM-CSF , 8 Ahmed H , Hindley R , Dickinson L et al . after docetaxel treatment: a randomised granulocyte-macrophage colony-stimulating Focal therapy for localised unifocal and open-label trial . Lancet 2 0 1 0 ; 376 : factor ; HIFU , high-intensity focused multifocal prostate cancer: a prospective 1147 – 54 ultrasound ; OS , overall survival ; PAP , development study . Lancet Oncol 2012 ; 15 de Bono JS , Logothetis CJ , Molina A prostatic acid phosphatase ; (IM)RT , 13 : 622 – 32 et al . Abiraterone and increased survival (intensity-modulated) radiotherapy .