Outcome analysis of 300 prostate cancer patients treated with neoadjuvant androgen deprivation and hypofractionated radiotherapy

Int. J. Radiation Oncology Biol. Phys., Vol. 65, No. 4, pp. 982–989, 2006 Copyright © 2006 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/06/$–see front matter

doi:10.1016/j.ijrobp.2006.02.029

CLINICAL INVESTIGATION

Prostate

OUTCOME ANALYSIS OF 300 PROSTATE CANCER PATIENTS TREATED WITH NEOADJUVANT ANDROGEN DEPRIVATION AND HYPOFRACTIONATED RADIOTHERAPY GEOFFREY S. HIGGINS, M.B.CH.B., DUNCAN B. MCLAREN, M.B.B.S., GILLIAN R. KERR, M.SC., TONY ELLIOTT, M.B.CH.B., AND GRAHAME C. W. HOWARD, M.D. Department of Clinical Oncology, Edinburgh Cancer Centre, Western General Hospital, Edinburgh, UK Purpose: Neoadjuvant androgen deprivation and radical radiotherapy is an established treatment for localized prostate carcinoma. This study sought to analyze the outcomes of patients treated with relatively low-dose hypofractionated radiotherapy. Methods and Materials: Three hundred patients with T1–T3 prostate cancer were treated between 1996 and 2001. Patients were prescribed 3 months of neoadjuvant androgen deprivation before receiving 5250 cGy in 20 fractions. Patients’ case notes and the oncology database were used to retrospectively assess outcomes. Median follow-up was 58 months. Results: Patients presented with prostate cancer with poorer prognostic indicators than that reported in other series. At 5 years, the actuarial cause-specific survival rate was 83.2% and the prostate-specific antigen (PSA) relapse rate was 57.3%. Metastatic disease had developed in 23.4% of patients. PSA relapse continued to occur 5 years from treatment in all prognostic groups. Independent prognostic factors for relapse included treatment near the start of the study period, neoadjuvant oral anti-androgen monotherapy rather than neoadjuvant luteinizing hormone releasing hormone therapy, and diagnosis through transurethral resection of the prostate rather than transrectal ultrasound. Conclusion: This is the largest reported series of patients treated with neoadjuvant androgen deprivation and hypofractionated radiotherapy in the United Kingdom. Neoadjuvant hormonal therapy did not appear to adequately compensate for the relatively low effective radiation dose used. © 2006 Elsevier Inc. Prostate cancer, Radiotherapy, Hypofractionation, Androgen deprivation, Dose escalation.

INTRODUCTION External beam radiotherapy is the most commonly used treatment modality for the radical treatment of prostate carcinoma within the United Kingdom. The optimal dose and fractionation regimen has not yet been identified. There is accumulating evidence that higher dose radiotherapy is associated with improved biochemical control rates (1) and overall survival in patients with high-grade cancers (2). The use of conformal radiotherapy techniques has allowed dose escalation without significantly exacerbating acute and late treatment-related toxicity. Hypofractionated radiotherapy regimes seek to exploit a potential radiobiological advantage from the low ␣/␤ ratio for prostate cancer (3). Such regimens require fewer treatment fractions and therefore also have a significant bearing on treatment resources and patient convenience. The efficacy and toxicity associated with hypofractionated radio-

therapy schedules compared with conventional schedules is not yet clear (4, 5). The use of neoadjuvant androgen deprivation can improve the therapeutic efficacy of prostate radiotherapy in two ways. It is able to reduce the volume of the prostate gland by between 20 –50% (6, 7). This reduces the amount of normal tissue irradiated, particularly the rectal dose. Neoadjuvant androgen deprivation also improves tumor control. In animal models of prostate cancer, the dose required to eradicate 50% of tumors was substantially less if given with neoadjuvant androgen deprivation than either adjuvant treatment or radiation alone (8). The use of androgen deprivation before and during radical radiotherapy at 180 –200 cGy fractions to the prostate and peripheral lymphatics has been shown to improve biochemical disease-free survival in patients with bulky T2–T4 disease compared with treatment with radiotherapy alone (9). There appeared to be a preferential benefit in those

Reprint requests to: Geoffrey Higgins, M.B.Ch.B, Edinburgh Cancer Centre, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK. Tel: (⫹44) 0131-537-1000; Fax: (⫹44) 0131-537-1029; E-mail: [email protected] Acknowledgments—The authors gratefully acknowledge the help

of the local General Practitioners, Consultant Urologists at the Edinburgh Cancer Centre and Mr. Shearer at Dumfries and Galloway Royal Infirmary in collecting the data used in this study. Received Nov 16, 2005, and in revised form Feb 3, 2006. Accepted for publication Feb 7, 2006. 982

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patients with Gleason 2– 6 disease (9). Neoadjuvant androgen deprivation and radiotherapy have also been shown to improve the biochemical disease-free survival in patients with T2–3 disease compared with radiotherapy alone (10). The Radiation Therapy Oncology Group trial 94-13 showed improved progression-free survival in patients with a greater than 15% risk of lymph node involvement who were treated with whole pelvis radiotherapy, neoadjuvant and concurrent hormone therapy compared with whole pelvis radiotherapy and adjuvant hormone therapy (11). A recent update confirms the benefit of neoadjuvant hormone therapy though longer follow-up is required to assess the magnitude of this benefit (12). A recent study by Denham et al. also showed improved outcomes for patients treated with neoadjuvant hormone deprivation before radiotherapy compared with radiotherapy alone (13). It also raised the possibility that 6 months of hormone deprivation may be superior to 3 months of treatment although greater follow-up is again required to determine this. At the Edinburgh Cancer Centre, starting in 1996, men with localized prostate cancer were routinely offered 3 months of neoadjuvant androgen deprivation and 5250 cGy in 20 fractions to the prostate ⫾ seminal vesicles in accordance with departmental protocol. We have assessed the outcomes of a continuous cohort of men treated in this center between 1996 and 2001. This cohort is one of only a few in the United Kingdom to provide data on any prostate radiotherapy schedule.

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determined the hormone treatment used for each patient. The majority of patients (88%) received a luteinizing hormone releasing hormone (LHRH) agonist, normally with initial antiandrogen cover. Twelve percent of patients received oral antiandrogen therapy alone. None of the patients analyzed remained on hormone therapy after completion of radiotherapy.

Follow-up The follow-up policy was for 3 monthly clinic reviews in the first year and 4 monthly reviews in the second year. If a patient’s prostate-specific antigen (PSA) was stable within the normal range at 2 years, then he was usually followed up thereafter by a 6 monthly symptom questionnaire and PSA measurement. One patient was lost to follow-up at 21 months, otherwise the minimum follow-up was 35 months, with a median follow-up of 58 months.

End points The principal end point was treatment failure. This was defined as either the presence of metastatic disease, local relapse, or biochemical relapse, with cause-specific survival as a secondary end point. The Houston criteria were used to define PSA relapse (14). These consider PSA relapse to be a rise of at least 2 ng/mL above the nadir (defined as the lowest recorded value). For the purpose of calculating cause-specific survival, any patient who had had a PSA relapse was considered to have local disease present at death. The Houston criteria were adopted in preference to other definitions of biochemical failure as these criteria are subject to fewer ambiguities in their interpretation, and are less sensitive to differences in duration of follow-up (14 –16). The American Society for Therapeutic Radiology and Oncology definition of biochemical failure may not be appropriate for men treated with androgen ablation and has been criticized for its dependence on backdating (14).

METHODS AND MATERIALS Using the Oncology database, we identified 334 patients who were treated with neoadjuvant androgen deprivation and radical external beam radiotherapy for prostate carcinoma at the Edinburgh Cancer Centre from 1996 to 2001. Their case notes were reviewed, and data additional to that routinely held on the database were extracted. Twenty-nine patients who continued on adjuvant hormone therapy after the completion of radiotherapy were excluded from further analysis. A further 5 patients were excluded because they presented with T4 disease and the aim of treatment had been to gain local tumor control rather than to effect a cure. This left 300 patients for analysis.

Treatment All patients received external beam radiotherapy using megavoltage linear accelerators. Patients were treated with 5250 cGy given in 20 fractions to the isocenter over 4 weeks using 15-MV photons. A three-field technique consisting of an anterior and two wedged lateral fields was employed. The gross tumor volume (GTV) included the prostate and base of seminal vesicles in all patients. In later years conformal techniques allowed all patients at risk of seminal vesicle involvement to have the entire seminal vesicles included in the GTV. The GTV to planning target volume was 1 cm in all directions, reduced to 0.6 cm posteriorly for those patients treated with conformal radiotherapy. A total of 116 patients received conformal radiotherapy. All radiotherapy was computed tomography–planned. All patients were prescribed 3 months of neoadjuvant hormone therapy before commencing radiotherapy. The treating physician

Statistical analysis Statistical analysis was undertaken using SAS software. Survival and relapse were measured from the date of starting neoadjuvant androgen deprivation. Actuarial relapse and survival rates were estimated using the Kaplan-Meier technique (17) and compared using the log–rank test (18). Survival rates are cause-specific unless otherwise stated. A multivariate analysis for factors affecting the relapse rates was performed using the proportional hazards model (19). The variables included in the multivariate analysis are shown in Table 1. Pretreatment PSA, Gleason score, and tumor stage are recognized as independent prognostic factors (20). Nu-

Table 1. Variables included in the proportional hazards analysis Year of treatment Age T stage Initial PSA Gleason score Method of diagnosis (TURP or TRUS) Radiotherapy technique (conformal or nonconformal) Use of LHRH analog Time from diagnosis to commencing hormone treatment Duration of hormone treatment Radiotherapy field size Abbreviations: LHRH ⫽ luteinizing hormone releasing hormone; PSA ⫽ prostate-specific antigen; TRUS ⫽ transrectal ultrasound; TURP ⫽ transurethral resection of the prostate.

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Table 2. Patient characteristics and prognostic groupings Number Stage (N0M0) T1 T2 T3 Gleason score 3 4 5 6 7 8 9 10 Prognostic groups Good Intermediate Poor

17.7 49.3 33.0

2 22 43 87 88 37 16 2

0.7 7.4 14.5 29.3 29.6 12.5 5.4 0.7

37 103 160

12.3 34.3 53.3

0

100 Intermediate Good Poor

25 0 2

4

6

8

‘97 ‘96

0

2

4

6

8

10

Fig. 2. Cause-specific survival grouped according to year of treatment.

Survival Eighty patients have died, giving an overall actuarial 5-year survival rate of 76.5%. Fifty-six patients have died with prostate cancer known or presumed to be present, giving an overall actuarial causespecific 5-year survival rate of 83.2%. The 5-year causespecific survival was 96.3% for patients with good prognosis disease, 92.7% for intermediate prognosis, and 74.1% for poor prognosis disease (Fig. 1).

0

‘98

Years

The distributions of T stage, Gleason score, and prognostic groupings are shown in Table 2. The patients had a mean age of 67.7 years, median 69 and mode 72 (range, 47– 80). Median pretreatment PSA was 17.8 (range, 1.4 – 487).

50

‘99

25

RESULTS

Cause specific survival (percent)

‘00

Cause 75 specific survival 50 (percent)

merous studies have proposed different criteria for defining prognostic groups (21–23). We grouped patients into good (PSA ⱕ10, Gleason score ⱕ6, and Stage T1/T2), intermediate (1 raised value), or poor (2 or more raised values) prognostic groups. This method was originally employed by Zelefsky et al. (24) and has since been used in other studies (3, 25).

75

‘01

100

%

53 148 99

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10

Years Fig. 1. Kaplan-Meier curves of cause-specific survival by prognostic group.

Proportional hazards analysis indicates only two independent prognostic variables predict for survival. These are Gleason score (p ⬍ 0.0001, hazard increasing with Gleason score) and year of treatment (p ⫽ 0.0006, hazard decreasing with year) (Fig. 2). Only one variable can be found, which is associated with year of treatment, and that is whether the patient had biopsy or transurethral resection of the prostate (TURP). Fewer patients underwent a TURP in the later years. Table 3 summarizes the factors analyzed in the univariate and multivariate analysis with corresponding p values. PSA relapse A total of 166 patients have had a PSA relapse. The actuarial rates were 7.4%, 27.7%, 42.2%, 52.1%, and 57.3% at 1, 2, 3, 4, and 5 years respectively. The 5-year relapse rate was 26.2% for the good prognosis group, 44.3% for the intermediate group, and 68.6% for the poor prognosis group (Fig. 3). Proportional hazards analysis showed that the following variables were independent prognostic factors for PSA relapse: initial PSA (p ⬍ 0.0001), Gleason score (p ⬍ 0.0001),

Table 3. Factors analyzed in the univariate and multivariate analysis of survival with corresponding p values Variable Prognostic group Year treated Age T stage Gleason score Initial PSA Diagnosis by TURP Use of LHRH analog Use of conformal radiotherapy Time from diagnosis to commencing hormone treatment Duration of hormone treatment Radiotherapy field size

Univariate analysis

Multivariate analysis

0.0002 0.004 0.047 NS ⬍0.0001 0.019 ⬍0.0001 NS NS

— 0.0005 NS NS ⬍0.0001 NS 0.053 NS NS

NS NS —

NS NS NS

Abbreviations: LHRH ⫽ luteinizing hormone releasing hormone; NS ⫽ not significant; PSA ⫽ prostate-specific antigen; TURP ⫽ transurethral resection of the prostate.

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100 Good

PSA 75 relapse 50 free survival (percent) 25

0

Intermediate Poor

0

2

4

6

8

10

Years Fig. 3. Biochemical disease-free survival in each of the prognostic groups. PSA ⫽ prostate-specific antigen.

T stage (p ⫽ 0.0015), including an LHRH analog in neoadjuvant hormone treatment (p ⫽ 0.0030, decreased hazard), year (p ⫽ 0.0149, decreased hazard), and TURP (p ⫽ 0.0377). Table 4 summarizes the factors analyzed in the univariate and multivariate analysis with corresponding p values. Metastatic relapse Sixty-seven patients have developed metastatic disease, giving a 5-year actuarial rate of 23.4% (0.0%, 10.1%, and 37.5% in the good, intermediate, and poor prognostic groups, respectively). Proportional hazards analysis showed that the following variables were independent prognostic factors for metastatic relapse: Gleason score (p ⬍ 0.0001), TURP (p ⫽ 0.0005), T stage (p ⫽ 0.0034), time from histologic confirmation to starting neoadjuvant hormones (p ⫽ 0.0140, decreased hazard), and year (p ⫽ 0.0404, decreased hazard).

DISCUSSION This retrospective study represents the largest series of patients in the United Kingdom treated with a consistent policy of 3 months neoadjuvant hormone therapy and hypofractionated radical radiotherapy. In our Centre, a very high proportion (88%) of patients presented with intermediate-risk or high-risk disease. This contrasts markedly with American published series where greater public awareness and PSA-based screening programs have been introduced (24). This difference in patient demographics is important. If screening studies demonstrate improved survival for screen-detected early-stage prostate cancer, then this would have a dramatic effect upon men in the United Kingdom. A much greater proportion of men would present with localized disease amenable to curative local therapy with a subsequent significant impact on service provision. It is well recognized that presenting PSA, Gleason score, and T stage are independent prognostic factors for prostate cancer (20), and this was again shown in our study. In this current series a multivariate analysis also found several other independent prognostic factors for disease relapse.

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The year in which patients received treatment was associated with outcome. Patients treated during the later periods had improved PSA relapse and metastatic disease. Cause-specific survival was also better in patients treated more recently (Fig. 2). The 5-year survival rate for those treated in 1996 was 58.9% compared with 93.5% for those treated in 2000. Kupelian et al. also found that in patients treated with radical radiotherapy for prostate cancer, the year of treatment was an independent predictor of outcome (26). They concluded that this was partly due to factors such as PSA screening and earlier diagnosis. In our study, the year of treatment was not associated with differences in PSA, Gleason score, or T stage. Additionally, the use of multivariate analysis takes into account the interrelationships between the pretreatment parameters. The “Will Rogers phenomenon” is a term that has been used to describe a particular trend toward “grade inflation.” Albertsen et al. (27) demonstrated that when the biopsy slides of patients treated over 13 years ago were reanalyzed by a pathologist practicing today, they were consistently given higher Gleason scores than were originally given. They went on to show that for each Gleason score stratum, the cause-specific survival of patients given that score in the contemporary Gleason score readings was significantly better than those patients originally given that Gleason score. This can falsely give the impression of therapeutic improvement. Although it is possible that the “Will Rogers phenomenon” may exist within our cohort of patients, the differences observed in outcome dependent upon the year of treatment are not based on direct comparisons between Gleason score groupings, but exist for the entire annual cohorts. It therefore seems unlikely that this phenomenon alone could account for the differences observed in outcome. Improved outcome in recent years may be attributed to advances in radiologic staging. The increased use of magnetic resonance imaging and the development of multislice computed tomography may exclude patients with early metTable 4. Factors analyzed in the univariate and multivariate analysis of PSA relapse with corresponding p values Variable Prognostic group Year treated Age T stage Gleason score Initial PSA Diagnosis by TURP Use of LHRH analog Use of conformal radiotherapy Time from diagnosis to commencing hormone treatment Duration of hormone treatment Radiotherapy field size Abbreviations as in Table 3.

Univariate analysis

Multivariate analysis

⬍0.0001 0.0001 0.005 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001 0.013 0.060

— 0.012 NS 0.002 ⬍0.0001 ⬍0.0001 0.034 0.003 NS

0.017 NS —

NS NS NS

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astatic disease from radical therapy. Increased accuracy of radiotherapy delivery with the use of portal imaging may also have contributed. The use of multileaf collimators has made it possible to treat the seminal vesicles, which may also have contributed to improved outcome in more recent years. On multivariate analysis, TURP and the use of oral antiandrogen therapy without a LHRH analog resulted in poorer outcome. It has previously been demonstrated that in a proportion of patients TURP causes prostate cells to be liberated into the bloodstream (28). Moreover, the frequency of dissemination is greater in patients undergoing TURP rather than transrectal ultrasound (TRUS) (29). We found that having a TURP was an independent prognostic factor for both biochemical and metastatic relapse. Others have suggested that patients requiring a TURP have tumors with an inherently poorer prognosis than those patients without obstructive symptoms whose disease is diagnosed by TRUS (30). Our data demonstrated that there was no significant difference in prognostic characteristics between patients who received a TURP and those who did not. The frequency of TURP declined each year, and appears to reflect a change in practice to a greater reliance on TRUSguided biopsy to establish the diagnosis. Figure 4 demonstrates the significant differences in PSA relapse for those patients who underwent a TURP at diagnosis. This would suggest that TURP itself leads to the poorer outcome and is worthy of further study. The combined use of a LHRH analog and antiandrogen before and during radiotherapy has been shown to improve outcome although the optimal duration is not yet clear (9, 13). Antiandrogen monotherapy combined with radiotherapy has been shown to reduce the risk of disease progression compared with radiotherapy alone (31, 32). Our multivariate analysis found that those patients whose hormone deprivation therapy included an LHRH analog had a reduced risk of PSA relapse (Fig. 5). Longer follow-up is required to see whether these differences translate into a survival benefit. It is possible that the delay in testosterone recovery after LHRH therapy is responsible for this difference. However, Fig. 5 would suggest that the time to the first PSA relapses was not significantly different. The difference in outcome

100 75 PSA relapse 50 free survival (percent) 25 0

TRUS

TURP

0

2

4

Years

6

8

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Fig. 4. Biochemical disease-free survival in those patients diagnosed by transurethral resection of the prostate (TURP) and by transrectal ultrasound (TRUS). PSA ⫽ prostate-specific antigen.

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100 75 PSA relapse 50 free survival 25 (percent) 0

LHRH analogue No LHRH analogue

0

2

4

6

8

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Years Fig. 5. Biochemical disease-free survival in those patients who received neoadjuvant luteinizing hormone releasing hormone (LHRH) analog and those who received neoadjuvant oral anti-androgen monotherapy. PSA ⫽ prostate-specific antigen.

may be the result of a different mechanism of interaction with radiotherapy. A LHRH analog may have a greater synergistic benefit with radiotherapy than an oral antiandrogen. It is our policy not to use oral antiandrogens alone as neoadjuvant therapy in view of these concerns. The differences in outcome dependent on the year of treatment make comparisons with other studies more difficult. Direct comparisons with other studies are also complicated by differences in patient populations although it is interesting to note that patient demographics and T stage distributions do not appear to have altered from a previous series reported by our center on patients treated between 1982 and 1992 (33). During this period, patients were usually treated with either 5000 cGy/20 fractions (37%) or 5250 Gy/20 fractions (54%). Neoadjuvant hormones were not routinely used. It is not possible to make comparisons between the different prognostic groups as PSA testing was not routinely performed before 1991. However, the 5-year cause-specific survival (63% vs. 83.2%) and frequency of metastatic spread at 5 years (37% vs. 23.4%) appears to have improved in our latest series of patients. Historical comparisons frequently overestimate the benefits of new treatments owing to stage migration and lead time bias. Despite this, it is interesting to note the potential benefit neoadjuvant hormonal therapy may have had upon the results. It is possible that neoadjuvant hormonal therapy has had an additional benefit in view of the marked differences in outcomes reported. The ␣/␤ ratio for prostate tumors is a source of considerable controversy. There is much evidence to suggest that prostate tumors act as late-responding tissues, with ␣/␤ ratios as low as 1.5 Gy (34, 35). Other studies have suggested that prostate cancer acts as a late responding tissue, but that the ␣/␤ ratio may not be as low as 1.5 Gy (36, 37). The ␣/␤ ratio appears to be the same in vitro and in vivo (38). A recent trial comparing standard and hyperfractionated conformal radiotherapy suggested that prostate cancer could not have a low ␣/␤ ratio as the hyperfractionated treatment was no less effective than the standard arm. However, this was a nonrandomized trial and the median follow-up was short (39).

Neoadjuvant androgen deprivation and hypofractionated RT for prostate carcinoma

Table 5. Comparison of outcome at 5 years by prognostic groups Study

Number of patients Dose (Gy) Median follow-up (months) Biochemical-free survival at 5 years Good Intermediate Poor Disease-specific survival at 5 years Good Intermediate Poor

Zelefsky et al.

Livsey et al.

Higgins et al.

282 64.8–70.2 36

705 50 48

300 52.5 58

84% 54% 22%

82% 56% 39%

73.8% 55.7% 31.4%

— — —

96% 91% 86%

96.3% 92.7% 74.1%

The preliminary results of a trial comparing standard radiotherapy (66 Gy in 33 fractions) with a hypofractionated arm (52.5 Gy in 20 fractions) have recently been published (5). There was no difference between the groups in overall survival or in frequency of positive prostate biopsy at 2 years. There was a greater frequency of “biochemical or clinical failure” in the hypofractionated arm although these differences were within the predefined range for noninferiority. If the ␣/␤ ratio of prostate carcinoma is indeed 1.5 Gy, the equivalent dose in 2 Gy fractions (EQD2) of the hypofractionated arm is equal to 61.9 Gy (40). It could therefore be argued that the hypofractionated arm gave a lower effective radiation dose than the standard radiotherapy arm. The radiotherapy regimen used in our center over the period of the study also has an EQD2 equal to a modest 61.9 Gy if an ␣/␤ ratio of 1.5 Gy is assumed. Table 5 (3, 24) compares the Edinburgh data with two other published series that used the same prognostic groupings. In these centers the EQD2 dose is higher than in our series and neoadjuvant hormonal therapy was not administered. In comparison the EQD2 of the hypofractionated radiotherapy technique used by Livsey et al. (50 Gy in 16 fractions) (3) can be calculated as 66.1 Gy, and that used by Zelefsky et al. (64.8 –70.2 Gy in 36 to 39 fractions) (24) as EQD2 61.1– 66.2 Gy. In our series, the outcome for the intermediate-risk and poor-risk groups is poor; 44.3% of intermediate-risk and 68.6% of poor-risk patients have PSA relapse by 5 years. Of these relapses, 22.8% and 54.7% respectively were metastatic. Local control appears poor for both these patient groups. 77.2% of the intermediate-risk and 45.3% of the poor-risk group appear to have local relapse alone. Secondary metastatic failure from poor local control is well recognized and may have contributed to the ongoing significant metastatic failure rate in our patients. The fact that all three prognostic groups continued to experience PSA relapse at 5 years of follow-up and beyond is of concern (Fig. 3). With male life expectancy likely to continue to increase, ongoing PSA failure and subsequent metastatic relapse is of great

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significance (41). With fewer competing causes of death, men with PSA relapse are at greater risk of succumbing to recurrent prostate cancer. Despite the use of neoadjuvant hormone treatment, our outcomes are not superior to other series that used higher effective radiation doses. Although it is difficult to make direct comparisons with other studies, it is noticeable that the disease-specific survival in the poor prognostic group appears to be inferior to that of Livsey et al. From our data the use of neoadjuvant hormone treatment may not fully compensate for the lower effective radiation doses used during the time of this study. Hypofractionated radiotherapy is likely to be more effective if higher radiation doses are used. Indeed there is much evidence to suggest a benefit of higher radiation doses in the treatment of prostate cancer (1, 2, 24, 42, 43). In 2001, we altered the treatment protocol for patients with prostate cancer. We now use 3 months of neoadjuvant hormone treatment followed by 55 Gy in 20 fractions (EQD2 of 66.8 Gy). We plan an analysis of these patients once the data are sufficiently mature. This increased dose is still modest in light of more recent data (1, 2, 24, 42, 43). In-house dose escalation protocols are being developed to increase the dose to 58.5 Gy in 20 fractions (EQD2 of 74 Gy). It is hoped that the growing use of additional adjuvant hormone therapy in patients with Gleason scores 8 to 10 will further improve clinical outcomes (44). In view of the high percentage of patients presenting with intermediate-risk and high-risk features, treating the prostate and seminal vesicles alone, even with a higher effective radiation dose, may under treat a significant proportion of patients at risk of occult nodal metastases. The data from the Radiation Therapy Oncology Group 94-13 trial (11) suggest that survival is improved for men with high-risk disease if the pelvis, prostate, and seminal vesicles are included within the treatment field. There are no data on safety and efficacy currently available on treating the pelvis and prostate with a hypofractionated regimen, and this is an area that requires further research. CONCLUSIONS Patients treated more recently had better outcomes than those treated at the start of the study period. This may be due to improvements in disease staging and radiotherapy delivery. Those patients who received a neoadjuvant LHRH analog rather than oral anti-androgen monotherapy had lower PSA relapse rates. This may be the result of a superior interaction with radiotherapy. Patients whose disease was diagnosed by TURP rather than TRUS had poorer outcomes. Further investigation is warranted to assess whether this could result from cancer cell dissemination during surgery. Hypofractionated radiotherapy regimens attempt to exploit a radiobiologic advantage. They have additional benefits in terms of resource expenditure and patient convenience. From our data, a low-dose hypofractionated schedule was associated with considerable failure rates. The use of

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neoadjuvant hormonal therapy failed to fully compensate for this low dose. Whether higher dose hypofractionated radiotherapy is superior has not been tested. A study using intensity-modulated radiotherapy is in development to in-

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crease the dose to 60 Gy in 20 fractions (EQD2 of 77.1 Gy) and to compare this schedule with a conventionally dose escalated regimen of 74 Gy in 37 fractions (4). The outcome of this study is eagerly awaited.

REFERENCES 1. 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: 1097–1105. 2. Valicenti R, Lu J, Pipelich M, et al. Survival advantage from higher-dose radiation therapy for clinically localized prostate cancer treated on the Radiation Therapy Oncology Group trials. J Clin Oncol 2000;18:2740 –2746. 3. Livsey JE, Cowan RA, Wylie JP, et al. Hypofractionated conformal radiotherapy in carcinoma of the prostate: Fiveyear outcome analysis. Int J Radiat Oncol Biol Phys 2003;57: 1254 –1259. 4. Khoo V, Norman I, Syndikus R, et al. Randomized pilot study of conventional or hypofractionated high dose intensity modulated prostate radiotherapy (CHHIP)—acute toxicity report. [Abstract]. In: Grunberg SM, editor. The 2005 Multidisciplinary Prosate Cancer Symposium Program/Proceedings. Alexandria; VA: America Society of Clinical Oncology; 2005. p. 78. 5. Lukka H, Hayter C, Julian JA, et al. Randomised trial comparing two fractionation schedules for patients with localized prostate cancer. J Clin Oncol 2005;23:6132– 6138. 6. Shearer RJ, Davies JH, Gelister JSK, et al. Hormonal cytoreduction and radiotherapy for carcinoma of the prostate. Br J Urol 1992;69:521–524. 7. Forman JD, Kumar R, Haas G, et al. Neoadjuvant hormonal downsizing of localised carcinoma of the prostate: Effects on the volume of normal tissue radiation. Cancer Invest 1995;13: 8 –15. 8. Zietman AL, Prince EA, Nakfoor BM, et al. Androgen deprivation and radiation therapy: Sequencing studies using the Shionogi in vivo tumor system. Int J Radiat Oncol Biol Phys 1997;38:1067–1070. 9. Pilepich M, Winter K, John M, 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;50:1243–1252. 10. Laverdiere J, Nabid A, de Bedoya LD, et al. The efficacy and sequencing of a short course of androgen suppression on freedom from biochemical failure when administered with radiation therapy for T2–T3 prostate cancer. J Urol 2004;171: 1137–1140. 11. Roach M III, DeSilvio C, Lawton C, et al. Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. J Clin Oncol 2003; 21:1904 –1911. 12. Lawton CA, DeSilvio M, Roach M, et al. An update of the Phase III trial comparing whole-pelvic (WP) to prostate-only (PO) radiotherapy and neoadjuvant to adjuvant total androgen suppression (TAS): Updated analysis of RTOG 94-13. [Abstract]. Int J Radiat Oncol Biol Phys 2005;63(Suppl. 1):S19. 13. 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– 850. 14. Pickles T, Kim-Sing C, Morris JW, et al. Evaluation of the

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