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Dose-Response in Radiotherapy for Localized Prostate Cancer: Results of the Dutch Multicenter Randomized Phase III Trial Comparing 68 Gy of Radiotherapy With 78 Gy

Stephanie T.H. Peeters, Wilma D. Heemsbergen, Peter C.M. Koper, Wim L.J. van Putten, Annerie Slot, Michel F.H. Dielwart, Johannes M.G. Bonfrer, Luca Incrocci, Joos V. Lebesque

From the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam; Erasmus Medical Centre, Rotterdam; Haga Hospital, Den Haag; Radiotherapeutic Institute Friesland, Leeuwarden; and Zeeuws Radiotherapeutic Institute, Vlissingen, the Netherlands

Address reprint requests to Joos V. Lebesque, MD, PhD, Department of Radiation Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands; e-mail: j.lebesque{at}nki.nl

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: To determine whether a dose of 78 Gy improves outcome compared with a conventional dose of 68 Gy for prostate cancer patients treated with three-dimensional conformal radiotherapy.

PATIENTS AND METHODS: Between June 1997 and February 2003, stage T1b-4 prostate cancer patients were enrolled onto a multicenter randomized trial comparing 68 Gy with 78 Gy. Patients were stratified by institution, age, (neo)adjuvant hormonal therapy (HT), and treatment group. Four treatment groups (with specific radiation volumes) were defined based on the probability of seminal vesicle involvement. The primary end point was freedom from failure (FFF). Failure was defined as clinical failure or biochemical failure, according to the American Society of Therapeutic Radiation Oncology definition. Other end points were freedom from clinical failure (FFCF), overall survival (OS), and toxicity.

RESULTS: Median follow-up time was 51 months. Of the 669 enrolled patients, 664 were included in the analysis. HT was prescribed for 143 patients. FFF was significantly better in the 78-Gy arm compared with the 68-Gy arm (5-year FFF rate, 64% v 54%, respectively), with an adjusted hazard ratio of 0.74 (P = .02). No significant differences in FFCF or OS were seen between the treatment arms. There was no difference in late genitourinary toxicity of Radiation Therapy Oncology Group and European Organisation for Research and Treatment of Cancer grade 2 or more and a slightly higher nonsignificant incidence of late gastrointestinal toxicity of grade 2 or more.

CONCLUSION: This multicenter randomized trial shows a significantly improved FFF in prostate cancer patients treated with a higher dose of radiotherapy.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Radiotherapy is one of the treatment options for localized prostate cancer, but with standard radiation doses (64 to 70 Gy), it is not always as effective as previously believed. One of the strategies to improve the efficiency of radiotherapy is increasing the dose. Such a dose escalation has become possible with three-dimensional conformal radiotherapy (3D-CRT). This technology allows one to better conform the radiation fields to the target volume and to reduce the dose to the normal tissues.^1,2 Several phase II trials have shown that, with 3D-CRT, higher than conventional doses are feasible.^3-7 A number of phase III trials have been initiated, and three have published outcome results.^8-10 The first trial did not show an improved local control with higher doses.⁸ Two recent trials found an improved freedom from failure (FFF) at the expense of an increase in overall gastrointestinal (GI) toxicity.^9,10 The use of (neo)adjuvant hormonal therapy (HT) was not allowed in any of these trials, whereas its use significantly improves overall survival (OS).¹¹ We performed a multicenter trial to test the hypothesis that a higher radiation dose of 78 Gy would lead to a higher FFF compared with 68 Gy in patients treated for localized prostate cancer with 3D-CRT, and we allowed the use of HT. We have already reported results on toxicity.^12,13 We found no significant differences between the arms for acute and late overall genitourinary (GU) and GI toxicity. For some specific late toxicity items (rectal bleeding, rectal incontinence, and nocturia), the incidences were significantly higher in the high-dose arm. In this article, we present the first results on outcome of the trial, together with an update of overall GI and GU morbidity.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Participants
Four Dutch institutions enrolled patients onto the CKVO96-10 randomized phase III trial. Pretreatment assessment included clinical examination (including digital rectal examination), transrectal ultrasound of the prostate, laboratory studies (CBC, creatinine, alkaline phosphatase, gamma glutamyltransferases, and initial prostate-specific antigen [iPSA]), prostate biopsy with histologic evaluation, bone scan, and a lymph node evaluation by a pelvic computed tomography scan or ultrasound and/or surgical or cytologic sampling when the estimated risk of involvement of the seminal vesicles (SV) was higher than 10%.¹⁴ The Abbott IMx immunoassay (Abbott, Abbott Park, IL) was recommended to measure iPSA levels. Eligibility criteria were adenocarcinoma of the prostate; all T stages with iPSA less than 60 µg/L, except T1a and well-differentiated (or Gleason score < 5) T1b-c tumors with iPSA 4 µg/L; and Karnofsky performance score of 80. Patients with metastases, with cytologically or histologically proven positive regional lymph nodes, on anticoagulants, with previous pelvic irradiation, and with previous malignant disease (other than basal cell carcinoma) were excluded. TNM staging was scored according to the American Joint Committee on Cancer 1997 guidelines.

Patients were randomly assigned to either the conventional dose of 68 Gy or the experimental dose of 78 Gy. Random assignment was performed with a minimization technique with stratification for treatment group (groups I, II, III, or IV; see next section), institution (A, B, C, or D), age ( 70 v > 70 years), and (neo)adjuvant HT (yes v no). The protocol specified that HT was allowed but not recommended until ongoing studies had defined groups that benefit from HT. Its prescription was left at the discretion of the treating physician. The ethical committee of each institution approved the trial protocol. All patients gave written informed consent.

Treatment
The planning target volume (PTV) for radiation included the prostate with or without the SV (clinical target volumes [CTVs]), with a margin of 10 mm during the first 68 Gy and 5 mm (except towards the rectum, 0 mm) for the last 10 Gy in the high-dose arm. This 10-Gy dose could be regarded as a partial boost. Four radiation treatment groups were defined depending on the risk of tumor involvement of the SV. This risk was estimated according to Partin et al¹⁴ based on T stage, iPSA, and Gleason score or differentiation grade (Table 1). T1b-2a tumors with a risk of less than 10%, 10% to 25%, and more than 25% were included in groups I, II, and III, respectively. T2b-3a and T3b-4 tumors were included in groups III and IV, respectively. For group I, the CTV was defined as the prostate only, and for group IV, it was defined as the prostate with SV. In groups II and III, the CTV included prostate and SV, and the SVs were excluded from the CTV after 50 and 68 Gy, respectively.

Outcomes and Toxicity
The primary end point was FFF. We defined failure as biochemical or clinical failure, whichever was first. A clinical failure included local relapse (defined as palpable and/or biopsy-proven progression), regional relapse, metastases, or initiation of salvage HT. Prostate biopsies were not systematically performed. Biochemical failure was defined according to the definition of the American Society of Therapeutic Radiation Oncology (ASTRO) and was considered three consecutive increases in PSA level after a nadir.¹⁸ The date was defined as midway between the last nonincreasing value and the first increase of PSA. A second analysis without backdating was performed because of concerns that backdating may influence the failure rate.^19,20 Time to failure was calculated from the date of random assignment, with patients censored at the date of the last PSA measurement or death. Other end points were freedom from clinical failure (FFCF), OS, and toxicity. In this article, we present an update of GI and GU toxicity scored according to slightly modified Radiation Therapy Oncology Group and European Organisation for Research and Treatment of Cancer scoring criteria.¹²

Besides the radiation treatment groups, patients were retrospectively divided into three prognostic risk groups as published in the literature (low, intermediate, and high risk). They were defined according to the single-factor definition of Chism et al.²¹ The low-risk group included patients with stages T1-2, Gleason score of 6, and iPSA 10 µg/L. The high-risk group contained stages T3-4, or Gleason score of 8, or iPSA more than 20 µg/L. The intermediate-risk group included patients who did not fulfill the criteria of the low- or high-risk group. For 93 patients, the differentiation grade only was available. Forty-two of these patients had stage T3-4 or iPSA more than 20 µg/L and were, therefore, high-risk patients. For the remaining 51 patients, the differentiation grade was used to assign a risk group; well-differentiated, moderately differentiated, and poorly differentiated tumors were considered to be Gleason scores of 2 to 6, 7, and 8 to 10, respectively.

Statistical Analysis
The study was designed to have an 80% power of detecting a difference in FFF of 10% between patients treated with 68 and 78 Gy at the 5% level of significance (two sided). Analyses were performed by intention to treat. Cox proportional hazards regression was used to analyze differences (expressed in hazard ratios) in FFF, FFCF, and OS between both arms. These analyses were adjusted for the stratification factors (treatment group, institution, age, and HT). Survival curves were estimated by the Kaplan-Meier technique. To analyze the dose effect in the three risk groups and in the three HT groups (no HT, short-term HT, and long-term HT), the hazard ratios were estimated by stratified log-rank analysis.²²

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Between June 1997 and February 2003, 669 patients were recruited. Five patients were excluded from the analysis (Fig 1); three did not fulfill the eligibility criteria, and two went off study before start of radiotherapy. Therefore, we analyzed 664 patients; 331 were allocated to 68 Gy, and 333 were allocated to 78 Gy. Follow-up data were reported until May 2005. The median follow-up time was 50.7 months (range, 9.6 to 94.2 months). Patient and tumor baseline characteristics were well balanced between both arms (Table 2). The low-dose arm included slightly more patients with high-risk features, but the four treatment groups, based on risk of SV invasion, and the three risk groups were well balanced between both arms. (Neo)adjuvant HT was prescribed in two institutions for 143 patients and prescribed predominantly to high-risk patients (n = 125) and rarely to intermediate-risk (n = 13) or low-risk patients (n = 5). HT was initiated 0 to 7 months before radiotherapy for 6 months (short-term HT, institution B) or 3 years (long-term HT, institution A). Generally, a luteinizing hormone–releasing hormone agonist, preceded by a short course of an antiandrogen, was prescribed. The use of short-term and long-term HT was well balanced (Table 2). The following treatment techniques were used: four-field technique (70 patients, institution C), three-field technique using one anterior and two lateral wedged fields (553 patients), and intensity-modulated radiotherapy (simultaneous integrated boost²³ for 41 patients in the high-dose arm, institution B). In the low-dose arm, all patients received the prescribed 68 Gy, whereas in the high-dose arm, 36 patients received a dose between 68 and 76 Gy, and one patient died during treatment from a disease-unrelated cause. In 19 patients, the dose was lowered to meet the rectal (n = 7) or small bowel (n = 12) dose constraints. Other reasons were technical problems (n = 3), patient’s request (n = 5), and acute toxicity (n = 9). Only three of these 14 latter patients had severe acute GU toxicity.

View larger version (9K): [in this window] [in a new window]   Fig 1. Trial profile.

View larger version (8K): [in this window] [in a new window]   Fig 2. Kaplan-Meier estimates of freedom from failure by treatment arm, where biochemical failure was defined according to the ASTRO definition (A) with and (B) without backdating. EXP, experimental; CONV, conventional; F, failures.

View larger version (8K): [in this window] [in a new window]   Fig 3. Numbers of failures (biochemical/clinical) and hazard ratios (HRs; with 95% CIs) showing the effect of the treatment arm on freedom from failure for the low-, intermediate-, and high-risk groups, as well as for the whole patient group.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
This study shows that, for localized prostate cancer, the use of higher radiation doses significantly improved the FFF probability. The risk of failure was reduced from 64% to 54% at 5 years (Fig 2A). Failure rates were lower in the high-dose arm both in the intermediate- and high-risk groups but not in the low-risk patients (Fig 3). However, this trial was not powered to perform these subgroup analyses, and the low-risk group included only a small number of patients. Furthermore, the test for interaction showed that there was no significant difference in dose effect between the three risk groups. Therefore, we can not exclude that low-risk patients also benefit from dose escalation. Because we have shown that a high dose was a significant prognostic factor for FFF and a number of patients in the high-dose arm received a lower than prescribed dose, we also analyzed all patients by the dose actually administered (low-dose group: mean dose, 68.1 Gy; range, 68 to 72 Gy v high-dose group: mean dose, 77.9 Gy; range, 74 to 78 Gy) instead of by intention to treat as in the main analysis. Comparison of these two groups resulted in an even larger difference in FFF (P = .001; results not shown).

Two other phase III trials have found a dose response for FFF.^9,10 The M.D. Anderson Cancer Center trial compared 70 Gy with 78 Gy in 305 stage T1-3 prostate cancer patients and found a significantly improved FFF. A preliminary report showed an absolute benefit of 10% at 5 years, which is similar to our results.²⁴ In a second analysis with an additional follow-up of 20 months, the benefit at 6 years was 6%.⁹ An older phase III trial, which was carried out by the Massachusetts General Hospital, compared 67.2 Gy with 75.6 Cobalt Gy Equivalent (GyE) in 202 high-risk prostate cancer patients with stages T3-4N0-2 disease.⁸ They used a proton boost to increase the dose. No significant difference was found in local control in the entire cohort. Subsequently, they performed another phase III trial together with the Loma Linda Medical Center. That study included 393 patients and compared 70.2 GyE with 79.2 GyE, again using a proton boost and including only patients with stages T1-2b disease.¹⁰ A large advantage in freedom from biochemical failure was noted for patients treated with high doses, and this difference held true for both low-risk patients and higher risk patients. Most of the nonrandomized studies found a dose response for intermediate-risk patients,^25-27 and some also found a dose response for high-risk patients,^25,26 but only a few studies detected a benefit for low-risk patients.^28,29

Of note is that the curves for the two dose levels in our study started to separate after approximately 1.5 years when biochemical failure was defined using the ASTRO definition (Fig 2A) and after 3 years without backdating (Fig 2B). The patients with an early failure were mainly high-risk patients who developed a failure outside the prostate (results not shown). A comparable lag period before separation of the two curves was seen in the study of Zietman et al.¹⁰ We found no difference in FFCF or OS between the two dose levels. We need a longer follow-up to show a dose response in FFCF given that biochemical failure has been shown to be an early surrogate for clinical failure.^30-32 Because Kestin et al³² found that the median time between the third consecutive PSA increase and clinical failure was 1.4 years, it is not surprising that we did not find a difference in FFCF yet, given that our curves separated after 3 years (Fig 2B).

A major difference with the three other phase III trials^8-10 is that we allowed (neo)adjuvant HT. After cessation of HT, a transient increase in PSA may occur as a result of recovery of prostate tissue from testosterone suppression. This may lead to false-positive results with the ASTRO definition.³³ Therefore, discussion has arisen about whether another definition of PSA failure should be used for patients treated with HT. The results of studies that compared several definitions of biochemical failure in patients treated with HT vary with conflicting results.^33-35 Therefore, we repeated the main analysis with a proposed alternative definition of failure (nadir plus 2 µg/L)^20,35 and found that FFF was higher in the high-dose arm versus the low-dose arm (5-year FFF rate, 67% v 61%, respectively), but this difference was not significant (log-rank, P = .2). Another criticism on the ASTRO definition is that it was designed based on data for which PSA levels less than 0.5 µg/L could not be measured.³⁶ For that reason, we also analyzed FFF with data for which PSA values less than 0.5 µg/L were set to 0.5 µg/L. We found that the differences in FFF between both arms were still significant (results not shown). An advantage of this latter definition is that some of the small PSA bounces are left out. However, whatever the shortcomings of the ASTRO definition are, they probably occur in both arms because of the random assignment.

Nevertheless, increasing the dose is not without consequences with regard to toxicity. In this article, we presented an update of overall late GI and GU toxicity and found no significant differences between both randomized arms, which is in accordance with our earlier results.¹² However, for the more specific symptoms of late rectal bleeding and incontinence, a higher radiation dose resulted in significantly higher incidences.^12,13 In contrast to our first report,¹² nocturia was no longer significantly higher in the high-dose arm (data not shown). Although a higher treatment dose resulted in increased GI toxicity, the incidences were still acceptable. We also expect that, with the use of intensity-modulated radiotherapy for all patients, the complication rates will decrease.³⁷

In summary, we have shown that prostate cancer patients benefited from an increase in the dose of radiotherapy by 10 Gy in terms of FFF at the cost of slightly higher, but acceptable, incidences of late rectal bleeding and rectal incontinence. This result supports the use of a higher radiation dose in patients with localized prostate cancer.

	Authors’ Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Wilma D. Heemsbergen, Peter C.M. Koper, Wim L.J. van Putten, Luca Incrocci, Joos V. Lebesque Administrative support: Peter C.M. Koper, Joos V. Lebesque Provision of study materials or patients: Peter C.M. Koper, Annerie Slot, Michel F.H. Dielwart, Johannnes M.G. Bonfrer, Luca Incrocci, Joos V. Lebesque Collection and assembly of data: Stephanie T.H. Peeters, Wilma D. Heemsbergen, Peter C.M. Koper, Annerie Slot, Michel F.H. Dielwart, Joos V. Lebesque Data analysis and interpretation: Stephanie T.H. Peeters, Wilma D. Heemsbergen, Peter C.M. Koper, Wim L.J. van Putten, Joos V. Lebesque Manuscript writing: Stephanie T.H. Peeters, Wilma D. Heemsbergen, Peter C.M. Koper, Wim L.J. van Putten, Joos V. Lebesque Final approval of manuscript: Stephanie T.H. Peeters, Wilma D. Heemsbergen, Peter C.M. Koper, Wim L.J. van Putten, Annerie Slot, Michel F.H. Dielwart, Johannnes M.G. Bonfrer, Luca Incrocci, Joos V. Lebesque

 

	ACKNOWLEDGMENTS

 
We thank Geert van Leenders, Paula Hoynck van Papendrecht, Gerda van Wijhe, Piet van Assendelft, Ingrid Mandjes, Danny Baars, Karin vanden Elsaker, and Sippie Roukema for their contribution and Harry Bartelink for critically reading this manuscript.

	NOTES

 
Supported by the Dutch Cancer Society Grant Nos. NKI 98-1830 and CKTO 9610.

Presented at the 13th Annual Meeting of the European Conference for Clinical Oncology, Paris, France, October 30-November 3, 2005.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
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Submitted December 9, 2005; accepted January 18, 2006.

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