British Journal of Radiology (2005) 78, S112-S116
© 2005 British Institute of Radiology
doi: 10.1259/bjr/71272679
Advances in radiotherapy for prostate cancer
D Ash, FRCP, FRCR
Department of Clinical Oncology, Cookridge Hospital, Hospital Lane, Leeds LS16 6QB, UK
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Introduction
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Until the advent of prostate-specific antigen (PSA) testing prostate cancer was relatively rarely diagnosed in men under the age of 70 years and only a small proportion of patients were diagnosed at a stage when curative treatment was appropriate. Radical radiotherapy was limited both by poor localization and staging and by the fact that it was only possible to deliver treatment with square or rectangular fields that irradiated large volumes of normal tissue. There was a relatively low limit to the dose achievable to the prostate without incurring serious side effects. It was also very difficult to evaluate outcome by anything other than digital rectal examination and overall survival.
Over the last 20 years there have been huge advances in imaging, radiotherapy delivery systems and methods of outcome analysis. These have transformed outlook for the increasing numbers of men now being diagnosed with localised potentially curable cancers of the prostate.
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The importance of radiation dose
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It has been known for some time that the higher the dose of radiation delivered the greater the probability of achieving local control while at the same time increasing the risk of the probability of side effects. Hanks et al [1] in 1988 showed that 5 year local recurrence rate could be reduced from 37% for patients who received less than 60 Gy to 19% in those who received more than 70 Gy (Table 1
). With the techniques available at the time however it was not possible to exceed 70 Gy without incurring a prohibitively high risk of complications. New developments have however now made it possible to increase the dose without increasing the risk of complication. These include:- three-dimensional (3D) conformal radiation
- intensity-modulated radiation (IMRT)
- particle beam therapy
- brachytherapy
3D conformal radiation makes it possible to accurately identify the prostate volume on sequential CT slices and to also identify the critical normal tissues adjacent to the prostate such as bladder and rectum. These data are linked to multileaf collimators in the linear accelerator which can appropriately shape the radiation beam to the identified target volume. Using these techniques the amount of normal tissue included in the radiation fields can be significantly reduced.
IMRT is a further sophistication which not only allows shaping of the field by multileaf collimation but also by shaping the profile of the radiation beam within each field. This enables an even better conformality between the target volume and the irradiated volume. These techniques also allow a detailed analysis of dose and volume parameters, which can be correlated to outcome, both in terms of local control probability and risk of complications.
Using 3D conformal radiation it is now possible to achieve doses of more than 80 Gy to the prostate and a number of dose escalation studies such as that of Zelefsky et al [2] (Table 2) have shown that 5 year actuarial PSA relapse free survival increases from 56% with 64.8 Gy to 90% with 81 Gy. This has been achieved without a significant increase in the risk of serious complications.
A randomized clinical trial by Dearnaley et al [3] has shown that when the same dose of radiation is given with 3D conformal radiation compared with conventional fields there is a significant reduction in the risk of side effects. Most of the data on 3D conformal radiation or IMRT has shown that increasing the dose achieves improvements in PSA relapse free survival but not in overall survival. For low risk patients however there seems to be no advantage in going above 70 Gy. A randomized trial reported by Pollack et al [4] comparing 70 Gy with 78 Gy does however show a significant improvement in failure free survival at 5 years which is 69% for 70 Gy and 79% for 78 Gy. Longer follow up is likely to confirm survival improvements for other studies.
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Impact of prognostic factors
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The most powerful prognostic factors for prostate cancer are the Gleason score and the presenting PSA. The higher the Gleason score and the higher the presenting PSA the less likely it is to achieve local control and the more likely it is that patients fail outside the prostate. Hanks et al [5] showed that for Gleason scores of 6 or less biochemical control was achieved in 75% of patients. This fell to 18% for Gleason score 7 and 0% for Gleason score 8 to 9 (Table 3). He also showed that biochemical control was achieved in 92% of patients who presented with a PSA of 0 to 10, 83% when the PSA was 10 to 20 and only 49% when the PSA was greater than 20.
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Role of adjuvant hormone therapy with radical radiotherapy
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It is known that 80–90% of patients with advanced or metastatic prostate cancer respond well to hormone therapy. There is a good chance, therefore, that hormone therapy may also improve the outcome for patients who receive radical radiotherapy. This has been investigated in a large EORTC study reported by Bolla et al [6]. Patients were randomized to receive either 70 Gy radiation alone or 70 Gy plus 3 years of hormone therapy using Zoladex. At 5 years there was an improvement in local control from 79% to 97%, an improvement in clinical disease free survival from 40% to 75% and an improvement in overall survival from 62% to 78% for those cases treated with Zoladex in addition to radiation. This has been confirmed by a number of other studies. While it is clear that adjuvant hormone therapy improves outcome when given with external beam radiation, it remains unclear what the optimum duration of hormone therapy is.
As a result of experience gained over the last few years it is reasonable to conclude that patients suitable for radical radiotherapy should be treated with 3D conformal radiation or IMRT delivering doses of greater than 70 Gy except for low risk patients and that those with locally advanced disease or adverse prognostic features should also receive neo-adjuvant hormone therapy.
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Impact of new imaging technology
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As far as radical radiotherapy is concerned the main roles for imaging are to accurately stage and localize the tumour and to assist in the localization of radiation beams. The latter is normally achieved by CT scanning.
MRI scanning is currently the most sensitive way of evaluating local tumour extent. It is also often valuable in identifying disease outside the prostate, which may make radical treatment inappropriate. Newer developments in biological imaging may also help in identifying sites of metabolically active tumour which can be targeted to receive extra dose.
Detailed pathology studies on radical prostatectomy specimens [7] have shown that up to 25% of patients thought on staging to have localized disease are later demonstrated to have extracapsular tumour spread. For patients with good prognostic features selected for surgery, however, the extent of extracapsular disease is mostly within 3–4 mm of the prostate capsule which is within the range of both external beam radiation and brachytherapy and the studies also show that the majority of extracapsular extent is in the posterolateral parts of the prostate [8].
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Brachytherapy
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The implantation of radioactive sources into a tumour provides the best form of conformal radiation because the radiation can be concentrated within the tumour while very little affects the surrounding normal tissues. There have been several attempts over the last 100 years to apply brachytherapy to prostate cancer. This was first done with radium needles and later in the 1920s there was a period when radon seeds were used. Radioactive iodine seeds were extensively used in the 1970s and were implanted manually through an open supra-pubic approach [9]. It was very difficult to achieve a consistent and accurate dose distribution and although good results were at first claimed the technique was gradually abandoned as it became clear that local control was not regularly achieved. In the early 1980s Holm described the transrectal ultrasound and template technique for needle guided biopsies in the prostate and soon afterwards described a technique for implanting radioactive iodine seeds into the prostate [10]. This was taken up by the team in Seattle who refined the technique and demonstrated that it was possible to achieve a consistent and accurate seed distribution with good local control [11] (Figure 1). Advances in ultrasound and computing now make it possible not only to introduce radioactive seeds under visual control but also link the placement with interactive on-table dosimetry so that the achievement of a satisfactory implant can be assured before the patient completes the procedure.
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Figure 1. Schematic representation of the prostate implant. Seeds and needles are inserted according the x, y, and z co-ordinate as produced by the treatment plan.
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The majority of prostate brachytherapy is delivered with permanent seed implants using either I125 or Pd103. It is however possible to use removable implants at high dose rate (HDR) using Ir192. For this technique hollow needles or catheters are implanted into the prostate to act as vectors for a high activity Ir192 source which passes into the needle by a remote afterloading machine. The advantage is that the computer controlled stepping source can optimize the dose distribution and at the end of the procedure all radioactivity is removed from the patient. The disadvantage is that it is mostly necessary to use the implant as a boost after 4 to 5 weeks of external beam radiation and the implant dose either has to be delivered in several fractions or with more than one implant procedure. Nevertheless good results have been reported using the HDR technique [12].
Not all patients are suitable for brachytherapy. Because of the very short range of the radioactive iodine seeds the treatment is best for those in whom the cancer is likely to be confined within the prostate capsule or no more than 2–3 mm outside it. The best patients are therefore those with a Gleason score of 6 or less and a PSA of less than 10. Patients with intermediate risk tumours, i.e. Gleason score 7 or PSA greater than 10 but not both, can also be considered for treatment though the results are not quite so good.
The results in 667 patients treated in Leeds between 1995 and 2001 [13] show an overall PSA relapse free survival of 74.9% (Figure 2). 110 patients had a biochemical relapse defined as three successive rises in PSA with a 3 month interval between. 20 patients have had a clinical relapse but only 10 have died from prostate cancer. Sub-group analysis confirms the prognostic significance of Gleason score and initial PSA (Figures 3–5).
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Figure 2. Actuarial prostate-specific antigen (PSA) relapse-free survival (RFS) for all 667 patients. The 8.2 years (98.2 months) PSA-RFS is 74.9%.
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Figure 3. Actuarial prostate-specific antigen (PSA) relapse-free survival according to pre-treatment PSA. PSA-RFS is 81.4%, 69.8%, and 36.3% for patients cohorts of PSA less or equal to 10, 10.1–20, and greater than 20, respectively (p<0.0001) (solid line, PSA 10; dashed PSA 10.1–20; dotted PSA>20). Initial PSA is a predictive tool of PSA control.
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Figure 4. Actuarial prostate-specific antigen (PSA) relapse-free survival according to biopsy Gleason score. PSA-RFS is 78.3%, 66.5%, and 56.4% for patients cohorts of Gleason score less than 7, equal 7, and greater than 7, respectively (p<0.001) (solid line, Gleason<7; dashed Gleason=7; dotted Gleason>7). Gleason score is a predictive factor of PSA control.
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Figure 5. Actuarial prostate-specific antigen (PSA) relapse-free survival (RFS) according to ESTRO risk groups based on initial PSA and Gleason score prior to treatment. PSA-RFS is 84.3%, 73.9%, and 52.6% for patients cohorts of risk groups low, intermediate, and high, respectively (p0.0001) (solid line, low risk; dashed intermediate risk; dotted high risk).
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Unlike external beam radiation the addition of hormone therapy to brachytherapy has no significant impact on PSA relapse free survival (Figure 6). This may either be due to the fact that the brachytherapy group have much better prognostic features than the external beam radiotherapy group or because the duration of hormone therapy was only 3 months rather than 3 years.
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Figure 6. Actuarial prostate specific antigen (PSA) relapse-free survival (RFS) according pre-treatment hormones. PSA-RFS is 76.1%, for patients cohort being on pre-treatment hormones and 72.6% for patients not on hormone therapy (p=0.107) (solid line not on hormones; dashed line on hormones).
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Prostate brachytherapy is technically demanding and there is therefore a significant learning curve. This can, however, be shortened by appropriate mentoring.
One of the advantages of brachytherapy is that it has a relatively low risk of major complications compared with surgery and external beam radiation. The Leeds study shows that the risk of incontinence is less than 1%, the risk of rectal injury is less than 0.2% and only 2.5% of patients complain of any significant urethral symptoms 2 years after treatment. There is, however, a risk of impotence as for all other treatments and this can be up to 50% though it is less in younger, fully potent patients. Viagra resolves erectile dysfunction in approximately 75% of brachytherapy patients.
A number of series have now shown that biochemical disease free survival at 5 years for low risk patients is 85–90%, 60–70% for intermediate risk patients and approximately 50% for high risk patients [14–16].
There are no randomized trials which compare brachytherapy with surgery or with external beam radiation but a number of large series in similarly selected patients achieve very similar results. Because of its convenience and relatively low risk of serious side effects [17] brachytherapy has become the treatment of choice for many men with prostate cancer and is now performed more often than radical prostatectomy in the USA.
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References
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- Hanks GE, Martz KC, Diamond JI. The effects of dose on local control of prostate cancer. Int J Radiat Oncol Biol Phys 1988;15:1299–305.[Medline]
- Zelefsky MJ, Fuks Z, Hunt M, et al. High dose intensity modulated radiation therapy for prostate cancer: early toxicity and biochemical outcome in 772 patients. Int J Radiat Oncol Biol Phys 2002;53:1111–6.[CrossRef][Medline]
- 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.[CrossRef][Medline]
- Pollack A, Zagars GK, Starkschall G, et al. Prostate cancer radiation dose response: results of the MD Anderson phase III randomised trial. Int J Radiat Oncol Biol Phys 2002;53:1097–105.[CrossRef][Medline]
- Hanks GE, Hanlon AL, Hudes G, Lee WR, Sunsin W, Schultheiss TF. Patterns of failure analysis of patients with high pre-treatment PSA levels treated by radiation therapy; the need for improved systems and loco-regional treatment. J Clin Oncol 1996;14:1093–7.[Abstract/Free Full Text]
- Bolla M, Collette L, Blank L, et al. Long term results with immediate androgen suppression and external radiation in patients with locally advanced prostate cancer. (An EORTC Study): a Phase III randomised trial. Lancet 2002;360:103–6.[CrossRef][Medline]
- Partin AW, Kattan MW, Subon EN, et al. Combination of prostate specific antigen, clinical stage and gleason score to predict pathological stage of localised prostate cancer. JAMA 1997;277:1445–51.[Abstract/Free Full Text]
- Sohayda C, Kupelian PA, Levin HS, Klein EA. Extent of extracapsular extension in localised prostate cancer. Urology 2000;55:382–6.[CrossRef][Medline]
- Hilaris BS, Whitmore WF, Batata M, Barzell W. Behavioural patterns of prostate adenocarcinoma following an I125 implant and pelvic node dissection. Int J Radiat Oncol Biol Phys 1977;7–8:631–7.
- Holm HH, Juul N, Pedersen JF, Hansen H, Stroyer I. Transperineal iodine 125 seed implantation in prostatic cancer guided by transrectal ultrasonography. J Urol 1983;130:183–6.[Medline]
- Blasko JC, Ragde H, Schumacher D. Transperineal percutaneous iodine-125 implantation for prostatic carcinoma using transrectal ultrasound and template guidance. Endocurither/Hyperthem Oncol 1987;3:131–9.
- Martinez A, Gustafson G, Gonzalez J, et al. Dose escalation using conformal high-dose rate brachytherapy improves outcome in favourable prostate cancer. Int J Radiat Oncol Biol Phys 2002;53:316–27.[CrossRef][Medline]
- Joseph J, Al-Qaisieh B, Ash D, Bottomley D, Carey B. Prostate specific antigen relapse free survival in patients with localised prostate cancer treated by brachytherapy. Br J Urol Int 2004;94:1235–8.
- Zelefsky MJ, Hollister T, Raben A, Matthews S, Wallner K. Five year biochemical outcome and toxicity with transperineal CT planned permanent Iodine 125 prostate implantation for patients with localised prostate cancer. Int J Radiat Oncol Biol Phys 2000;47:1261–6.[Medline]
- Stock RG, Stone NN, Tabert A, Iannuzzi C, DeWyngaert JK. A dose response study for Iodine 125 prostate implants. Int J Radiat Oncol Biol Phys 1998;41:101–8.[CrossRef][Medline]
- Ragde H, Elgamal AA, Snow PB. Ten year disease free survival after transperineal sonography guided Iodine 125 brachytherapy with or without 45 Gy external beam irradiation in the treatment of patients with clinically localised low to high grade Gleason prostate carcinoma. Cancer 1998;83:898–1001.
- Gelblum DY, Potters L, Ashley R, et al. Urinary morbidity following ultrasound guided transperineal prostate seed implantation. Int J Radiat Oncol Biol Phys 1999;45:59–67.[Medline]
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Introduction
The importance of radiation...
