Abstract
We present the impact of systematic radiation dose escalation from 64 Gy to 66 Gy to 70 Gy on the outcome after radiation therapy (RT) alone or combined with hormonal treatment (HT) in a series of 494 consecutive localised prostate cancer patients treated during 1990–1999. Prognostic factors for prostate-specific antigen (PSA) failure, overall survival (OS) and prostate cancer specific survival (CSS) were investigated using multivariate analysis. T stage, pre-treatment PSA, grade, radiation dose and HT were found to be independent predictors of PSA failure. T stage, grade and HT were also independent predictors of both OS and CSS, while radiation dose was a significant predictor for OS and indicated a trend (p = 0.07) for CSS. A dose of 70 Gy combined with hormonal treatment improves PSA failure free survival and survival in localised prostate cancer compared with doses of 64–66 Gy.
Prostate cancer is the most common malignancy in Norway, with more than 3 000 new cases a year Citation[1]. Most cases are now diagnosed at a localised stage as a result of the widespread use of prostate-specific antigen (PSA) testing used in Norway since 1987.
External beam radiation therapy (EBRT) has been used as primary therapy for localised prostate cancer for many years in Norway, but was initially regarded as inferior to surgery. Major technological improvements in conformal radiation treatment planning and delivery for prostate cancer allow substantially higher doses to be delivered to the prostate gland with minimal or no additional normal tissue toxicity Citation[2–4]. The use of endocrine therapy further enhances the effect of radiation, and if administered prior to radiotherapy (RT), it may shrink the gland and thereby allow for additional normal tissue shielding Citation[5–7]. Along with the introduction of conformal RT techniques we have stepwise increased the institutional standard tumour dose from 64 Gy to 66 Gy to 70 Gy. Hormonal therapy (HT) was administered according to a regional consensus among urologists referring patients for radiation, mostly initiating HT at the time of referral for RT. We here report the outcome of these three consecutive patient cohorts treated by a systematic dose escalation schedule.
Material and methods
Patients
Between 1990 and 1999, 502 patients with T1-3NxM0 prostate cancer were treated with radical RT with or without adjuvant/neoadjuvant HT at Haukeland University Hospital. In this period the tumour dose was stepwise increased from 64 Gy via 66 Gy to 70 Gy. Eight patients were excluded from the analysis as they for different reasons were given a tumour dose less than 60 Gy, leaving 494 patients available for analysis. The patients were staged by physical examination, PSA testing and isotope bone scan. For most patients a diagnostic transrectal ultrasound and computer tomography (CT) scan was also performed. Surgical lymph node staging and magnetic resonance imaging (MRI) were not routinely performed, but 123 men (25%) underwent pelvic lymphadenectomy for staging prior to RT. In 108 (88%) of these men, the lymphadenectomy did not disclose lymph node metastases. The primary tumour was assigned a T-category based on digital rectal examination Citation[8]. Histology was in the first part of the study based on World Health Organisation (WHO) histological grading (302 patients) Citation[9], later according to the Gleason scoring system (192 patients) Citation[10]. As the treatment decisions were based on the original WHO grading, we have used the original grading in the current analysis. In the uni-and multivariate analysis we converted Gleason score into WHO grading: Gleason score 4–6 to well differentiated, Gleason score 7 to moderately differentiated and Gleason score 8–10 to poorly differentiated Citation[11]. All patients displayed a performance status of 0 or 1 and had a life expectancy of at least five years.
Radiotherapy and hormonal therapy
All patients underwent EBRT with individualised treatment planning, using high-energy photons to a total tumour dose of 64–70 Gy, in 2 Gy fractions five days a week, over 6–7 weeks. Before 1995 the treatment plan was based on a diagnostic CT with adaptation to the patients contour at simulation, later all treatment plans were based on images from our dedicated CT scanner. Until 1995 we applied a four-field box technique (opposing anterior-posterior fields and two opposing lateral fields) with 2 cm uniform margins to 50 Gy before a boost with smaller margins (5 mm for the CTV and 5 mm for ITV) were delivered using four fields or two lateral fields to a total dose of 64 Gy. Field shaping with individually customised blocks was used occasionally in the first part of the study period, and routinely from 1994. In 1996, the use of customised blocks was substituted by multileaf collimation. In addition, the dose was increased, first to a total dose of 66 Gy, and then further increased to 70 Gy in 1997. Details of the 3-D conformal radiotherapy technique have been published elsewhere Citation[12].
Neoadjuvant and adjuvant HT was used in 402 of 494 (81%) patients. Androgen ablations consisted of luteinizing hormone releasing hormone (LhRh) agonist in 53 of these 402 patients (13%), antiandrogen in 2 (1%) and total androgen blockade (TAB) in 347 (86%). In the first part of the study period LhRh agonist was used to downstage tumours before RT for an average of 4–6 months. TAB was used as short-course (≤6 months) treatment in 89% of the cases and as a long-term treatment (between 6 months and 3 years) in 11%. TAB was initiated when the patient was referred for RT, i.e. 8–12 week's prior to start of RT.
Follow-up
Follow-up was individualised according to the standard health care service, which in general implied routine follow-up at local hospitals. The patients were scheduled to be followed at the department of urology at the local hospital, or as a secondary alternative, with the patient's general practitioner (GP). The frequency of follow-up examinations was left to the responsible urologist, but annual reports were sent to the Department of Oncology, reporting on clinical progression, adverse effects and death. The follow-up included physical examination and serum PSA determinations. For all patients seen at a hospital, the clinical charts and hospital records were reviewed; for patients seen by their GP we had communication with the GP when appropriate. All patients were followed to death or to May 5, 2004.
Progression
PSA level was used as a surrogate endpoint for disease activity, using the definition of relapse as a PSA increase of 2 ng/ml greater than the nadir PSA (“Houston criteria”) Citation[13], Citation[14]. All patients with a rising PSA above this level were considered as having biochemical failures (BF). Local recurrence was defined as symptomatic and clinically detectable prostate tumour growth. Bone scan or other radiological procedures were performed in case of a steadily rising PSA or clinical symptoms to define the location of possible tumour metastases.
Adverse effects
Because of the previously described follow-up routines, there were reasons to suspect underreporting of adverse effects by controlling clinicians as no formal scoring system was used. In the present study we focus on the effect on the tumour, while the risk of late effects currently are being investigated prospectively in a later cohort of patients.
Statistical methods
All statistical analyses were performed with the SPSS statistics package (v 12.0, SPSS Inc., Chicago, USA). The primary endpoint was cancer-specific survival (CSS), with overall survival (OS) and BF being secondary endpoints. The time to the relevant events was measured from the start of radiation therapy, analysed by Kaplan-Meier plots and assessed by the log-rank test Citation[15]. Differences between groups were analysed by Kaplan-Meier plots and tested for statistical significance initially using the log-rank test, while Cox regression was used for univariate analyses of continuous covariates. Multivariate analysis was conducted using the Cox proportional hazard regression model. The variables entered into univariate and multivariate analyses were T stage, PSA (log scale), histological grade, radiation dose and year of treatment. PSA was markedly skewed, but approximately normal distributed after log transformation. The statistical significance of the variables entered into the multivariate analysis was assessed using likelihood ratio tests. The project complies with the national research ethics committee's requirements.
Results
Pretreatment characteristics
summarises the clinical characteristics and treatment of the 494 patients included in the three groups given 64 Gy (Group 1), 66 Gy (Group 2) and 70 Gy (Group 3). Nearly half of the cases had T3 disease (42%). The mean initial PSA level (iPSA) was 15.4 ng/ml (range: 0.5–298 ng/ml). The median age was 67 years (range: 47–85 years). Only 91 patients (18%) had EBRT alone, the rest had a combination of HT and EBRT (82%). The median age was different in the three consecutive cohorts, 68 years in Group 1, 66 years in Group 2 and 67 years in Group 3, respectively (p < 0.001). The median pre-treatment PSA was lower in the last cohort: 13.1 ng/ml in Group 3, compared with 20.5 and 20.8 ng/ml in Group 1 and Group 2, respectively (p < 0.001). T-stage was also generally lower in the last cohort (p = 0.006). There were no statistically significant differences in the distribution of grade among the groups.
Table I. Clinical characteristics and treatment of the 494 patients.
Clinical endpoints
The numbers of patients with biochemical, local and distant failures are shown in . The numbers of deaths are also included. Due to the sequential design of the study, differences in follow-up time clearly exist between the cohorts, with the longest follow-up at the lowest dose level. The median follow-up was 107 (2–171) months for those treated with 64 Gy, 81 (13–131) months for those receiving 66 Gy and 61 (8–135) months for those given 70 Gy.
Table II. Outcome.
Biochemical failure
Of the 494 patients, 175 (35%) had PSA failure at a median interval of 29 months (range: 4–150 months) after start of RT. PSA failure was observed for 97 patients (69%) in Group 1, compared to 39 (37%) in Group 2 and 39 (15%) in Group 3. Of the 175 cases with PSA failure, 88 (47%) died, vs. only, 52 (16%) of the 320 cases without PSA failure. The 5 years PSA relapse free survival for Group 1 was 43%, 70% for Group 2 and 85% for Group 3 (p < 0.001) ().
Figure 1. PSA free survival.
shows the results of the Cox proportional hazards univariate and multivariate analysis of factors affecting PSA relapse. In univariate analysis T stage, pre-treatment PSA, grade, radiation dose, HT and year of therapy were independent predictors of PSA failure. All of these factors except year of therapy remained independent predictors of PSA failure in the multivariate analysis. When analysed as risk groups Citation[16], there were significant effects of radiation dose on PSA failure both in moderate and high risk groups (p < 0.001).
Table III. Results from univariate and multivariate Cox regression, assessing influence of different parameters on PSA recurrence.
Overall survival
The 5-year OS rate for the entire group was 85% (95 % CI: 81–88 %). The 5-year OS was 76% in Group 1, 85% in Group 2 and 90 % in Group 3 ().
Figure 2. Overall survival stratified by groups.
shows the results of the Cox proportional hazards univariate and multivariate analysis of factors affecting overall survival. T stage, grade, radiation dose, HT and year of therapy were significant predictors of survival in the univariate analysis, but only T stage, grade, radiation dose and HT remained independent predictors of survival in the multivariate analysis.
Table IV. Results from univariate and multivariate Cox regression, assessing influence of different parameters on overall survival.
Cancer specific survival
The 5-year CSS rate for all cases was 92%. The 5-year CSS for Group 1 was 83%, 93% for Group 2 and 96% for Group 3 (p < 0.001) when assessed with or without HT (). When assessed in patients having both endocrine therapy and radiation the differences in CSS between the groups was still significant: 87% in Group 1, 91% in Group 2 and 96% in Group 3 (p = 0.01) (). Only a slightly higher CSS was found for patients receiving both EBRT and HT compared to those receiving EBRT alone in Group 1, but this was not statistically significant (p = 0.12).
Figure 3a. Cancer specific survival stratified by groups.
Figure 3b. Cancer specific survival in patients receiving both EBRT and HT, stratified by radiation.
shows the results of the Cox proportional hazards univariate and multivariate analysis of factors affecting cancer specific survival. On univariate analysis T stage, PSA, radiation dose, grade, year of therapy and HT were significant predictors of survival. T stage, grade and HT remained independent predictors of survival in multivariate analysis, while there was a trend (p = 0.07) for radiation dose. When analysed as risk groups, there were significant effect of radiation dose in high risk patients (p<0.001), but only a trend for moderate risk patients (p = 0.09), on CSS.
Table V. Results from univariate and multivariate Cox regression, assessing influence of different parameters on cancer specific survival.
Time periods
To disclose a possible time effect, we repeated the multivariate analysis stratified by period after deleting the dose variable as it is almost completely determined by era. The stratified analysis did not show a significant relationship between cancer-specific survival and year of therapy (p = 0.09). Also, separate analyses within each era failed to show significant relationships with year of therapy. However, similar analyses for total survival showed a significant relationship (p = 0.004, HR = 0.81) and a significant relationship only in separate analysis for year 1990–1995 (p = 0.041, HR = 0.85). Finally, for PSA-free survival there was a significant relationship in overall stratified analysis (p = 0.047, HR = 1.15) but no significant relationship in separate analyses.
Discussion
Optimal therapy for localised prostate cancer remains a challenge despite the fact that this is the most frequent malignancy in males in many countries. In the early 1990s radiation therapy was considered inferior to radical prostatectomy which remained the recommended first choice for young and healthy patients with a life expectancy of 10–15 years Citation[17]. In the present analysis of the impact of escalating the radiation dose, we observed an improved freedom from PSA rise, as previously reported by others Citation[18] and also better cancer specific and overall survival. There were only slight modifications of our radiation technique during the study, and essentially, the RT remained a local treatment throughout the observation period. The changes in treatment volumes are unlikely to explain our findings.
The natural history of the disease may have changed the last decade Citation[19] with earlier diagnosis due to more or less systematic PSA screening Citation[20], which by itself may cause increased lead times and overdetection Citation[21]. But only a minority of incidentally detected prostate cancers with a PSA value below 3 ng/ml remains insignificant cancers Citation[22]. Better criteria to select those in need of therapy from those with innocent tumours are necessary. In a previous study the effect of radiation dose on overall mortality disappeared when year of treatment was included in the model Citation[23]. In our cohorts, on the other hand, year of treatment was not a significant factor for overall survival, while radiation dose remained a significant factor in the Cox model. The improved outcome after higher radiation dose can therefore hardly reflect a better case mix alone. We have also analysed the data by consecutive time periods, excluding dose as this also reflects the time period. Unfortunately we cannot present a randomized study where period of treatment can be separately analysed in a model containing also the dose. We can therefore not exclude that stage migration contribute to our findings as there is several significant differences between the groups as presented in . However, as multivariate Cox regression represents a scientific approach to weight for the unbalanced factors, the results indicate that dose is an important factor for outcome for patients treated by radiation therapy combined with hormone suppression.
The role of initial active therapy has been challenged Citation[24]. Therefore currently active surveillance and treatment on demand has emerged as a popular therapy option. Previously a similar policy was followed in Denmark where a conservative palliative approach prevailed Citation[25]. However, 62% of their prostate cancer patients died primarily from their malignancy, while only one third neither suffered nor died from their disease. In Scandinavia the majority (80%) of newly diagnosed patients in the period 1995–1998 still did not receive primary therapy with curative intent Citation[26]. However, a Swedish pivotal randomised study indicates a clear reduction in cancer specific mortality after radical prostatectomy compared with watchful waiting, whereas there was no difference in overall survival Citation[27]. After eight years of follow-up, the cancer-specific mortality and development of distant metastases were reduced by about 50% in the surgery group. This finding largely supports earlier studies which indicate that even presumed local cancers, i.e. stage T1 (which are impalpable), might prove to be significant due to progression outside the capsule at time of surgery, clinical progress or pathologic characteristics Citation[28]. In this context it is relevant that T1c tumours with PSA < 10 ng/ml also have a biochemical failure free survival of 97 % after 5 years follow-up after radiation Citation[29] similar to radical prostatectomy Citation[30].
We have decided not to specifically report side effects in this paper as we did not strictly apply fixed forms for recording of side effects and thus there is probably an underreporting of adverse effects in the current series. We have carefully recorded acute and late side effects in a later consecutive series of 250 patients treated at our institution, in which the acute side effects have already been reported Citation[12].
Biochemical PSA failure is widely used as an endpoint for therapy in prostate cancer, with various definitions being applied. Some authors have, however, not found an association Citation[31] or questioned its relationship with increased mortality Citation[32]. Interestingly, using the “Houston criteria” (PSA relapse is scored when PSA is 2 ng/ml greater than nadir), we found a relation between PSA failure and overall survival similar to previous studies with other definitions Citation[33], Citation[34].
The effect of radiation therapy depends on adequate cover of the primary tumour and risk areas for occult spread. We have applied a relatively homogenous tumour coverage during the study period using CT-based planning, but CT scans consistently overestimate the prostate volume Citation[35] and therefore more precise coverage of the tumour volume may reduce side effects. A recent paper reported that radiation dose was the most significant factor for freedom from PSA rise after radiation therapy, rather than radiation technique or use of hormones Citation[36]. We systematically increased the dose in accordance with other centres from 64 Gy Citation[37] via 66 Gy Citation[38] to 70 Gy. Our results confirm that the two lowest doses yielded suboptimal tumour control Citation[39]. Higher radiation doses can be used, and particularly for localised tumours in the high-risk group have doses in the range of 74–81 Gy improved the tumour control rate Citation[3], Citation[40]. Since 2002, we have further escalated the tumour dose for T1c –T3 tumours up to 78 Gy, using the BeamCath® system Citation[41].
The addition of hormone therapy improved the effect of the lowest dose, 64 Gy, but we cannot assess its role at the highest dose level as most patients had started with hormones at the time of referral. There is now general acceptance for addition of long-term hormonal suppression for locally advanced and high risk prostate cancer Citation[42–46], but short- term hormonal therapy can not substitute for radiation dose in high-risk patients Citation[47]. Short-term hormone therapy was given to most patients in the current series in order to maximise the effect of radiation. The finding that short term hormonal ablation was most beneficial in patients with Gleason score 2–6 Citation[48] has not been verified Citation[49]. It is of interest that the dose used in D'Amico's recent study in T1b-2b patients with PSA > 10 ng/ml or Gleason score at least 7 (range 7–10) had a similar radiation dose, 70 Gy, and 6 months of hormonal therapy as used in our study. Our data seems to confirm the excellent results in the combined arm. A similar dose escalation effect was reported in a randomised phase III trial comparing 70 Gy with 78 Gy radiation alone as freedom from failure increased from 64% to 70% Citation[50]. Recently a randomised pilot study suggested a radiation dose escalation effect on biochemical PSA control of disease from 59% to 71% when the dose was increased from 64 Gy to 74 Gy combined with hormone therapy Citation[51].
There is still no results from a randomised study comparing primary surgery versus radiation Citation[52]. Until randomised data are available, patients with prostate cancer stage T1c–T3 should be offered a minimum dose of 70 Gy with short term hormonal therapy, at least for intermediate and high risk patients as recently recommended in USA Citation[53] as an alternative to surgery.
This study was supported by a generous grant from the Norwegian Cancer Society. We acknowledge the contribution by the late consultant Sigmund Vaage, our initial collaborator in Stavanger.
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