MD, Consultant and Honorary Senior Lecturer in Clinical Oncology,. Royal Marsden ... hensive Cancer Network are representative of the type of classification ...
18 Prostate cancer
PART-WORK
The seventh in a series of articles on prostate cancer
Treatment of early prostate cancer: radiotherapy, including brachytherapy ALISON TREE AND VINCENT KHOO The authors discuss the radical treatment of early localised prostate cancer by external beam radiotherapy and interstitial therapy, also called prostate brachytherapy. They outline the different techniques available and emphasise the importance of discussing the relative advantages and disadvantages of each with the patient. Dr A. Tree, MRCP, FRCR, Specialist Registrar in Clinical Oncology, Royal Marsden NHS Foundation Trust; Dr V. Khoo, FRACR, FRCR, MD, Consultant and Honorary Senior Lecturer in Clinical Oncology, Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London. Series Editor: Professor David Dearnaley, MA, MD, FRCP, FRCR, Consultant Oncologist, Royal Marsden Hospital, Sutton, Surrey.
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rostate cancer is now the most common cause of cancer in men in the UK, with approximately 34 000 men diagnosed annually.1 The incidence of prostate cancer is rising and this may be due to public awareness, with increased numbers of men having their PSA tested. Most cases of prostate cancer are potentially curable at presentation and 70 per cent of men diagnosed with prostate cancer now survive to five years. For those who present with early organ-confined disease, this figure can rise to 99 per cent survival at five years.2 The range of management options available for men with early localised prostate cancer includes active treatment using either prostatectomy or radical radiotherapy, as well as the opportunity for active surveillance as outlined in the NICE guidelines3 (see the previous articles in this series).4,5 Radiotherapy is also the main treatment method for cases of locally advanced prostate cancer. In this article, we will address the radical treatment of early localised prostate cancer by external beam radiotherapy (Figure 1) and interstitial therapy, also called prostate brachytherapy. Assessment and management After a diagnosis of prostate cancer, usually by transrectal biopsy, it is essential that these men are staged appropriately in order to determine the extent of disease and to stratify them into risk groups. Risk stratification is helpful for selection of the most suitable treatment and to confer prognosis. There are many risk classifications available and most use a combination of clinical and laboratory Trends in Urology Gynaecology & Sexual Health September/October 2009
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Figure 1. An illustration of the beam’s eye view for the anterior beam of a conformal radiotherapy plan for prostate cancer. The field is automatically shaped by heavy metal leaves called multileaf collimators to ‘conform’ the profile of the prostate gland in that beam orientation.
parameters such as prostate-specific antigen (PSA), Gleason summed score, and disease stage such as the tumour node metastases classification shown in Box 1.6 The criteria outlined by the National Comprehensive Cancer Network are representative of the type of classification commonly used by most oncologists (Box 2).7 In general, high-dose external beam radiotherapy can be used for each of these clinical risk groups, but the intent of treatment may vary from a curative approach in the localised prostate cancer group to an attempt to achieve local control of the disease in those with T4 disease or pelvic nodal involvement. There are various options for active treatment for men with early localised prostate cancer (Box 3). The appropriate selection for the individual patient is governed not only by their clinical details but should also include other important factors such as medical comorbidities, life expectancy, fitness for anaesthesia and patient preference. Previous radical pelvic irradiation is a specific contraindication to radical radiotherapy for prostate www.tugsh.com
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Box 1. American Joint Committee on Cancer tumour node metastases classification of prostate cancer.6
Box 2. National Comprehensive Cancer Network classification of prostate cancer.7
T1 No tumour palpable or visible by imaging – T1a: 5 per cent tumour in transurethral resection chips – T1c: Diagnosed by transrectal ultrasound biopsy (eg because of elevated PSA)
Clinically localised Low risk: T1–T2a and Gleason score ≤6 and PSA 20
•
T2 Palpable tumour confined to the prostate – T2a: Tumour involves 50 per cent of one lobe or less – T2b: Tumour involves >50 per cent of one lobe – T2c: Tumour involves both lobes
•
T3 Tumour extends through prostate capsule – T3a: Extracapsular extension – T3b: Seminal vesicle extension
•
T4 Tumour is fixed or invades adjacent structure, eg bladder neck, rectum, pelvic wall
•
cancer. The presence of substantial or susceptible bowel within the radiotherapy fields, as a result of diverticular or inflammatory bowel disease for example, is a relative contraindication. Rationale for external beam radiotherapy Irradiation for prostate cancer can be curative in men with localised prostate cancer. There are no randomised trials of modern external beam radiotherapy or brachytherapy versus surgery. However, external beam radiotherapy is generally accepted for early localised prostate cancer; the local control rates are similar despite the potential confounding factor that surgical series are pathologically staged whereas radiotherapy series are clinically staged and thus may include more advanced clinical cases. Evidence from the patterns of care studies in the USA demonstrates that radiotherapy can provide longterm control of local prostate cancer and these rates may be improved by increasing the radiotherapy dose.8 However, the incidence of treatment-related side-effects increases when the dose is raised. The incidence of these side-effects was found to be 6, 11 and >15 per cent for those receiving 60Gy, 65–70Gy and >70Gy, but the side-effects may be reduced by using more sophisticated methods of treatment delivery such as conformal radiotherapy (CFRT) or intensity-modulated radiotherapy (IMRT).9 www.tugsh.com
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• • •
Locally advanced T3b–T4
•
Metastatic N1 or M1
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External beam radiotherapy methodology External beam radiotherapy utilises high-energy X-ray (photon) beams, which are focused on the prostate gland and damage the reproductive ability of the cancer cells. These cancer cells divide faster than the normal prostate cells and hence are more sensitive to the mutagenic effects of radiation. Historically, treatment was planned using bony landmarks. Consequently, shaping of the treatment fields to internal anatomy was impossible; thus excessive irradiation of normal tissues could not be avoided. The advent of conformal radiotherapy with computed tomography (CT) definition of the internal target structures has enabled radiotherapy fields to be more tightly focused to the prostate gland of the individual patient and has facilitated the minimisation of dose to surrounding Box 3. Treatment options for early prostate cancer.
Standard options Radical prostatectomy – Retropubic – Perineal – Laparoscopic – Robotic External beam radiotherapy – Beam quality: photons, protons – Planning method: conformal, intensity modulation – Treatment method: standard, image-guided Brachytherapy – Low dose rate – High dose rate Combination of external beam radiotherapy and brachytherapy
• • • •
Other options Cryotherapy
•
Emerging options High-intensity focused ultrasound
•
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Figure 2. The three-dimensional reconstruction for a radical prostate conformal radiotherapy plan using three fields (anterior and opposing lateral beams) projected against the digital reconstructed radiographs of the patient’s pelvis. The anatomical relationship between prostate plus seminal vesicles (solid purple), rectum (solid brown), bladder (blue wire frame) and the treatment beams can be assessed and optimised at the radiotherapy planning workstation.
normal tissues. The use of CT information also allows the creation of digital reconstructed radiographs for field correlation, and permits improved dose calculation and assessment of the dose distribution using dose-volume histograms.10 In brief, CFRT involves detailed cross-sectional anatomical images, stacked to create a three-dimensional model of the pelvis that includes the prostate gland and seminal vesicles in spatial relationship with the adjacent and important normal pelvic organs such as the rectum, bowel and bladder. The radiotherapy treatment portal is then configured to the projected profile of the prostate target volume within the axis of the radiation beam or beam’s eye view (see Figure 1). Using several different beams, the high-dose region can be made to ‘conform’ to the shape of the prostate in three dimensions. This CFRT technique has been proven, in a randomised trial, significantly to reduce risk of treatment-related toxicity, particularly the risk of proctitis, which is the dose-limiting side-effect for prostate radiotherapy.11 With this level 1 evidence, the National Institute for Health and Clinical Excellence (NICE) has recommended CFRT as the new technique standard for prostate external beam radiotherapy.12 At the Royal Marsden NHS Foundation Trust, standard prostate external beam radiotherapy is usually given daily (Monday to Friday) over seven weeks. It targets the prostate gland with or without inclusion of the seminal vesicles, depending on the clinical criteria. A safety Trends in Urology Gynaecology & Sexual Health September/October 2009
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margin is added around this clinical target volume to create the planning target volume (PTV). Radiotherapy is then delivered to this PTV using three different radiotherapy fields, which converge onto the area (Figure 2). The dose used is 74Gy in 37 treatment fractions, such that the dose per fraction is 2Gy. Other commonly used doses in the UK range from 50 to 55Gy in 20–25 fractions, given as five fractions per week. Side-effects of prostate radiotherapy can occur during radiotherapy or develop many months or years afterwards. Using CFRT, the incidence of clinically relevant side-effects is usually less than 10 per cent. The potential short- and long-term side-effects that can occur following prostate radiotherapy include alteration of bowel and bladder function, rectal or bladder bleeding, infertility and erectile dysfunction. Advances in radiotherapy Dose escalation trials Recent randomised trials of dose escalation in prostate cancer to doses between 74 and 79.2Gy have shown improvements in biochemical (b)PSA control rates of between 6 and 19 per cent with the escalated dose arms.13–16 The largest of these randomised studies, the Medical Research Council RT-01 trial of 843 men, demonstrated improved bPSA control rates for low-risk subgroups as well as intermediate and highrisk prostate cancer subgroups. On the basis of the RT-01 trial results, the escalated dose arm of 74Gy is now the approved standard of care in the 2008 NICE guidance.3
Intensity-modulated radiotherapy There are geometric constraints that limit the degree to which the volume of tissue receiving full dose can be conformed to avoid normal structures. New radiotherapy techniques like IMRT can permit better dose distribution such that the high-dose volume appears to ‘bend’ around critical normal structures (Figure 3). The IMRT technique can deliberately produce inhomogeneous dose distributions to maximise dose to some regions while sparing others. This is achieved by subdividing the main treatment fields into many smaller fields or ‘beamlets’, each with different doses, such that the overall dose can be varied across the main field. Using this IMRT method, the Memorial Sloan Kettering Cancer Centre reported on a series of 1571 men with localised prostate cancer with a median follow-up of 10 years, where the bowel/rectal toxicities were reduced from 13 per cent using CFRT to 5 per cent using IMRT, even with radiation doses as high as 81Gy (p72Gy) or brachytherapy showed equivalent 10-year biochemical relapse-free survival.20 A large international database of patients treated with brachytherapy alone for early prostate cancer has shown excellent biochemical relapse-free survival at three years: 93, 88 and 80 per cent for low-, intermediate- and high-risk patients.21 NICE guidance on low-dose-rate brachytherapy has confirmed that the results are considered to be equivalent to surgery or external beam radiotherapy in carefully selected patients,22 and this is therefore a treatment option at centres where sufficient expertise is available. Some centres use high-dose-rate (temporary) brachytherapy as a boost after external beam radiotherapy. This technique involves the placement of flexible interstitial catheters into the prostate using transrectal ultrasound guidance. An Iridium192 source is then loaded remotely into each catheter in turn, and dwells at different positions in the prostate in order to produce the optimal dose distribution. One randomised trial of 220 patients has shown better biochemical relapse-free survival, and a better side-effect profile for those treated with lower dose external beam radiotherapy followed by brachytherapy boost, compared to those treated with external beam radiotherapy alone.23 It should be noted that for half the patients in this trial, the external beam radiotherapy was given using non-conformal techniques and so the rectal toxicity for these patients would have been higher than might now be expected with three-dimensional conformal radiotherapy. The side-effect profile of brachytherapy is distinct from that of external beam radiotherapy. The risk of urinary toxicity may be higher, and there is a risk of acute urinary retention immediately after implantation of the seeds, particularly in those men with significant lower urinary tract symptoms. This risk can be minimised by careful patient selection. The risk of rectal toxicity is less than with external beam radiotherapy, but the risk of impotence is similar. Treatment outcome and morbidity are largely dependent on implant quality and operator expertise. In order to maintain the therapeutic ratio, Trends in Urology Gynaecology & Sexual Health September/October 2009
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it is essential that patients are appropriately selected, technical expertise is available and implant treatment planning is meticulous. Androgen suppression The growth of prostate cancer, in most cases, is hormone dependent, and therefore this effect may be used to improve the effect of radiotherapy. Traditionally, androgen ablation was achieved with surgical castration, but now can be achieved with the use of luteinising hormone-releasing hormone analogues (LHRHa) such as goserelin and leuprorelin. These agents constantly stimulate the LHRH receptors in the pituitary, resulting in downregulation of these receptors and reduction of LH production, which in turn causes castrate levels of circulating androgens. The initial stimulation of the pituitary can result in a testosterone ‘flare’, so the initiation of LHRHa is always covered by a short course of antiandrogens such as cyproterone acetate. The role of androgen deprivation therapy in advanced prostate cancer is well established.24,25 In the largest of these studies, which randomised 802 men with prostate cancer to no hormone therapy versus three- or six-month hormone therapy, the use of hormone therapy, particularly the six-month duration, was significantly associated with improved patient outcomes.25 There is also evidence supporting the use of hormone therapy before and during radiotherapy for early prostate cancer. An American trial randomised 471 patients to radiotherapy with or without adjuvant hormonal therapy for two months prior to, and during, radiotherapy.26 This trial reported significant improvement in biochemical disease-free survival (24 versus 10 per cent) and cause-specific mortality (23 versus 31 per cent) using the combined treatment arm, particularly in those with lower-risk disease. The use of androgen deprivation with external beam radiotherapy is now commonly used for intermediateand high-risk subgroups. Summary The selection of patients for external beam radiotherapy and brachytherapy is tailored by the use of prognostic factors and risk groups. The technical developments in radiotherapy such as CFRT, IMRT and real-time brachytherapy planning have improved patient outcomes by permitting higher delivered doses with increased local control and decreased complication rates. More recent advances with IMRT and IGRT may further enhance the therapeutic ratio. There are now many techniques of radiotherapy for men with localised prostate cancer. The www.tugsh.com
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relative merits and disadvantages of each method need to be discussed with patients to give them an opportunity to contribute to their management decision. Conflict of interest None declared. Acknowledgements We acknowledge NHS funding to the NIHR Biomedical Research Centre. The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the NHS Executive. References 1. Cancer Research UK. CancerStats key facts on prostate cancer (http://info.cancerresearchuk.org/cancerstats/types/prostate/; accessed 29 June 2009). 2. Cancer Research UK. Specific cancers: prostate cancer: treating prostate cancer: statistics and outlook for prostate cancer (http://www.cancerhelp.org.uk/help/default.asp?page=3505; accessed 29 June 2009). 3. National Institute for Health and Clinical Excellence. Prostate cancer: diagnosis and treatment. Clinical guideline 58. February 2008 (http://www.nice.org.uk/nicemedia/pdf/ CG58FullGuideline.pdf ; accessed 29 June 2009). 4. O'Donnell H, Parker C. Treatment of early prostate cancer: active surveillance. Trends Urol Gynaecol Sex Health 2009;14(3):15–19. 5. Coull N, Thompson A. Treatment of early prostate cancer: radical prostatectomy. Trends Urol Gynaecol Sex Health 2009;14(4):10–15. 6. American Joint Committee on Cancer. AJCC cancer staging manual, 6th edn. New York: Springer-Verlag, 2002. 7. National Comprehensive Cancer Network. Clinical practice guidelines in oncology: prostate cancer, V1.2009 (www.nccn.org; accessed 2 July 2009). 8. Pilepich MV, Krall JM, Sause WT, et al. Prognostic factors in carcinoma of the prostate: analysis of RTOG study 75–06. Int J Radiat Oncol Biol Phys 1987;13:339–49. 9. Khoo VS. Radiotherapeutic techniques for prostate cancer, dose escalation and brachytherapy. Clin Oncol (R Coll Radiol) 2005;17:560–71. 10. Khoo V. Conformal radiotherapy, intensity-modulated radiotherapy and image-guided radiotherapy. In: Price P, Sikora K, Illidge T, eds. Treatment of cancer, 5th edn, ch. 53. London: Hodder Arnold Health Sciences, 2008;1254–79. 11. Dearnaley DP, Khoo VS, Norman AR, et al. Comparison of radiation side-effects of conformal and conventional radiotherapy in prostate cancer: a randomised trial. Lancet 1999;353:267–72. 12. National Institute for Health and Clinical Excellence. Improving outcomes in urological cancers: manual. September 2002 (http://guidance.nice.org.uk/CSGUC/Guidance/pdf/English; accessed 20 July 2009). 13. Pollack A, Zagars GK, Starkschall G, et al. Prostate cancer radiation dose response: results of the M.D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 2002;53:1097–105.
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14. Zietman AL, DeSilvio ML, Slater JD, et al. Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial. JAMA 2005;294:1233–9. 15. Peeters ST, Heemsbergen WD, Koper PC, et al. Doseresponse in radiotherapy for localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy. J Clin Oncol 2006;24:1990–6. 16. Dearnaley DP, Sydes MR, Graham JD, et al. Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial. Lancet Oncol 2007;8:475–87. 17. Zelefsky MJ, Levin EJ, Hunt M, et al. Incidence of late rectal and urinary toxicities after three-dimensional conformal radiotherapy and intensity-modulated radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 2008;70:1124–9. 18. Khoo VS, Dearnaley DP. Question of dose, fractionation and technique: ingredients for testing hypofractionation in prostate cancer – the CHHiP trial. Clin Oncol (R Coll Radiol) 2008;20:12–14. 19. Heemsbergen WD, Hoogeman MS, Witte MG, et al. Increased risk of biochemical and clinical failure for prostate patients with a large rectum at radiotherapy planning: results from the Dutch trial of 68 Gy versus 78 Gy. Int J Radiat Oncol Biol Phys 2007;67:1418–24. 20. Kupelian PA, Potters L, Khuntia D, et al. Radical prostatectomy, external beam radiotherapy or =72 Gy, permanent seed implantation, or combined seeds/ external beam radiotherapy for stage T1–T2 prostate cancer. Int J Radiat Oncol Biol Phys 2004;58:25–33. 21. Guedea F, Aguilo F, Polo A, et al. Early biochemical outcomes following permanent interstitial brachytherapy as monotherapy in 1050 patients with clinical T1–T2 prostate cancer. Radiother Oncol 2006;80:57–61. 22. National Institute for Health and Clinical Excellence. Low dose rate brachytherapy for localised prostate cancer. July 2005 (http://guidance.nice.org.uk/IPG132; accessed 2 July 2009). 23. Hoskin PJ, Motohashi K, Bownes P, et al. High dose rate brachytherapy in combination with external beam radiotherapy in the radical treatment of prostate cancer: initial results of a randomised phase three trial. Radiother Oncol 2007;84: 114–20. 24. Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002;360:103–6. 25. Denham JW, Steigler A, Lamb DS, et al. Short-term androgen deprivation and radiotherapy for locally advanced prostate cancer: results from the Trans-Tasman Radiation Oncology Group 96.01 randomised controlled trial. Lancet Oncol 2005;6:841–50. 26. Pilepich MV, Winter K, John MJ, et al. Phase III radiation therapy oncology group (RTOG) trial 86–10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001;50:1243–52.
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