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Randomized Trial Comparing Two Fractionation Schedules for Patients With Localized Prostate Cancer

From the McMaster University, Hamilton; University of Toronto, Toronto; University of British Columbia, Vancouver; Northeastern Ontario Regional Cancer Centre, Sudbury; and Queen's University, Kingston, Canada

Address reprint requests to Himu Lukka, MB, ChB, FRCPC, Radiation Oncology Program, Juravinski Cancer Centre, McMaster University, 699 Concession St, Hamilton, Ontario, Canada, L8V 5C2; e-mail: Himu.Lukka{at}hrcc.on.ca

	ABSTRACT

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

 
PURPOSE: The optimal radiation dose fractionation schedule for localized prostate cancer is unclear. This study was designed to compare two dose fractionation schemes (a shorter 4-week radiation schedule v a longer 6.5-week schedule).

PATIENTS AND METHODS: Patients with early-stage (T1 or T2) prostate cancer were randomly assigned to 66 Gy in 33 fractions over 45 days (long arm) or 52.5 Gy in 20 fractions over 28 days (short arm). The study was designed as a noninferiority investigation with a predefined tolerance of –7.5%. The primary outcome was a composite of biochemical or clinical failure (BCF). Secondary outcomes included presence of tumor on prostate biopsy at 2 years, survival, and toxicity.

RESULTS: From March 1995 to December 1998, 936 men were randomly assigned to treatment; 470 were assigned to the long arm, and 466 were assigned to the short arm. The median follow-up time was 5.7 years. At 5 years, the BCF probability was 52.95% in the long arm and 59.95% in the short arm (difference = –7.0%; 90% CI, –12.6% to –1.4%), favoring the long arm. No difference in 2-year postradiotherapy biopsy or in overall survival was detected between the arms. Acute toxicity was found to be slightly higher in the short arm (11.4%) compared with the long arm (7%; difference = –4.4%; 95% CI, –8.1% to –0.6%); however, late toxicity was similarly low in both arms (3.2%).

CONCLUSION: Given the results, we cannot exclude the possibility that the chosen hypofractionated radiation regimen may be inferior to the standard regimen. Further evaluation involving higher dose hypofractionated radiation regimens in contemporary radiation settings is necessary.

	INTRODUCTION

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Radiotherapy is often recommended to patients with localized, early-stage prostate cancer. In the mid-1990s, the most commonly used method to deliver radiation was external beam using a four-field technique. At that time, there was not consistent agreement on the optimal schedule to be used for patient treatment.¹ Conventional radiation schedules ranged between 60 and 70 Gy administered over 6 to 7 weeks.^2-4 Studies from the United Kingdom, Australia, and Canada reported the use of shorter radiation fractionation schedules,^5-8 which seemed to be comparable to conventional schedules. However, these studies were nonrandomized.

There are several advantages for a hypofractionated radiation treatment regimen, including convenience for patients, increased treatment capacity, and decreased cost.⁹ On the basis of the /ß model for prostate cancer radiation biology, hypofractionation would theoretically offer increased therapeutic benefit with improved tumor control, without increasing late toxicity.^10-12 This is because of the presumed low /ß ratio of prostate tumors compared with the surrounding normal tissue. This randomized trial was designed to determine whether a hypofractionated treatment regimen of 52.5 Gy in 20 fractions administered over 28 days was as effective as the conventional treatment regimen of 66 Gy in 33 fractions administered over 45 days for men with early-stage prostate cancer.

	PATIENTS AND METHODS

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Study Population
Men with early-stage adenocarcinoma of the prostate (T1-2 according to International Union Against Cancer TNM classification) were eligible for the trial. Patient exclusion criteria were as follows: a prostate-specific antigen (PSA) level of more than 40 µg/L; previous therapy for prostate carcinoma (other than biopsy or transurethral resection of the prostate); previous hormone therapy; prior or active malignancy other than nonmelanoma skin cancer, colon cancer, or thyroid cancer treated a minimum of 5 years before the trial and presumed cured; a simulated volume exceeding 1,000 mL; previous pelvic radiotherapy; presence of inflammatory bowel disease; diagnosis of serious nonmalignant disease that would preclude radiotherapy or surgical biopsy; geographically inaccessible for follow-up; a psychiatric or addictive disorder that would preclude obtaining informed consent or adherence to protocol; inability to commence radiotherapy within 26 weeks of the date of last prostatic biopsy; and failure to provide informed consent to participate in the clinical trial.

Participating centers included eight Ontario regional cancer centers (Hamilton, Princess Margaret Hospital, Toronto Sunnybrook, Sudbury, Kingston, Windsor, London, and Thunder Bay) and eight additional Canadian centers (the Vancouver and Fraser Valley Cancer Centres in British Columbia, CancerCare Manitoba in Winnipeg, the Nova Scotia Cancer Centre in Halifax, the Saint John Regional Hospital in New Brunswick, the Dr Leon Richard Oncology Centre in Moncton, the Newfoundland Cancer Treatment and Research Foundation in St John's, and the Saskatoon Cancer Centre in Saskatchewan). Recruitment for the centers outside Ontario was coordinated through the Clinical Trials Group of the National Cancer Institute of Canada. Written informed consent was obtained from eligible patients before assignment to treatment. The institutional review board at each participating center approved the study protocol.

Treatment Regimens
Patients were assigned to one of two treatment regimens according to a central computer-generated randomization schedule within strata defined by PSA ( 15 µg/L v > 15 µg/L), Gleason score (2 to 6 v 7 to 10), method of lymph node assessment (surgical v radiologic), and treatment center. Before random assignment, patients completed radiotherapy simulation and treatment planning. Serum urea, creatinine, hemoglobin, WBC, and platelet count were also required within 4 weeks before random assignment. All patients were required to have had a pelvic computed tomography (CT) scan or pelvic lymph node sampling within 12 weeks of random assignment. Patients with enlarged nodes on CT scan ( 1.5 cm) were required to proceed through histologic confirmation. Samples were obtained using fine-needle aspiration cytology or lymph node dissection. If aspiration of an enlarged node was negative, further lymph node sampling was necessary. A chest x-ray and bone scan were performed within 12 weeks of random assignment. Patients were required to have a PSA measurement within 6 weeks of commencing radiotherapy.

Patients were randomly assigned to receive prostate irradiation consisting of either 66 Gy in 33 fractions over 45 days (long arm) or 52.5 Gy in 20 fractions over 28 days (short arm). Radiation was delivered daily, from Monday through Friday. The intention was to treat the prostate gland alone with a 1.5-cm margin. CT planning was mandatory for all patients. Shielding, where appropriate, was used to keep the planning target volume under 1,000 mL. Patients were treated in the supine position with a full bladder before each treatment. The target volume was treated using a four-field box technique or using three fields in patients with prosthetic hips. The borders defining the treatment volume included a 1.5-cm margin on all sides except posteriorly, where, at the discretion of the radiation oncologist, the margin could be reduced to 1 cm. Shielding was done using either multileaf collimator or poured blocks. Differential weighting was used to achieve optimal dose distribution. The dose was prescribed at the isocenter, and the dose within the target volume was required to be within 5% of the isocenter dose. All patients were treated with a 10-MV linear accelerator. To confirm adequate coverage, port films were taken of the anterior and lateral pelvic fields of each patient in the treatment position on the first day of treatment. For further quality assurance, the first 30 patients from each center underwent real-time review. If this was satisfactory, random spot checks were performed on 20% of the remaining plans.

Follow-Up
After completion of radiation therapy, patients were observed after 4 weeks, at 6 months after random assignment, and then every 6 months thereafter. At each visit, patients underwent a medical history and physical examination with a digital rectal examination, except for the first 4-week postradiotherapy visit. Urinary and rectal symptoms were assessed at baseline and then weekly during radiotherapy (four times for the 52.5-Gy group and six times for the 66-Gy group) to document acute toxicity. Subsequently, toxicity was assessed at 2 weeks (by telephone) and at 4 weeks after radiotherapy, at 6 weeks after radiotherapy for the 52.5-Gy group, and at visits every 6 months thereafter. PSA was measured at each follow-up visit starting with the 6-month postrandomization visit. Transrectal ultrasound-guided biopsy of the prostate was scheduled 2 years after completion of radiotherapy. Patient follow-up continued until clinical evidence of metastases was found.

Outcomes
The primary outcome was biochemical or clinical failure (BCF). For this trial, BCF was defined as a cluster of any one of the following events (whichever occurred first): three consecutive increases in PSA,¹³ clinical evidence of failure (local or distant), commencement of hormonal therapy, or death as a result of prostate cancer. Blinded assessment was used to verify the occurrence of BCF and to determine the earliest date of failure. Although the trial was originally designed with biopsy positivity at 2 years after randomization as the primary outcome, the emerging literature suggested that the combination of BCF was the optimal measure of efficacy.¹³ Therefore, before the study completion and data unblinding, an amendment was issued and approved by the study Steering Committee (September 14, 2001) to change the primary outcome to BCF. The protocol modification was then distributed to all participating clinical centers. Secondary outcomes included local persistence of tumor on biopsy of the prostate at 2 years (biopsy positivity), overall survival, and acute and late radiation-induced toxicity.

The criterion for local disease recurrence was based on the clinical evaluation of the prostate at the time of digital rectal examination. Signs or symptoms of local recurrence were confirmed through prostate biopsy. Biopsies reported as suspicious were classified as positive, and biopsies reported as equivocal were classified as negative. Criteria for distant disease recurrence of metastases outside of the prostate included recurrent tumor found in regional pelvic lymph nodes, bone (abnormal bone x-rays or bone scan), liver (abnormal liver scan, ultrasound, or CT scan), and lung (abnormal chest x-ray consistent with metastases). Asymptomatic patients who presented during follow-up with an increasing PSA were investigated at the physician's discretion with a further bone scan and an abdominal and pelvic CT scan (if the bone scan was negative). If both scans were negative, a prostate biopsy was undertaken to determine clinically the cause of the increase. In patients with only PSA failure, effort was made to prolong the interval between treatment and biopsy to avoid false-positive biopsy. Treatment at the time of relapse for metastatic symptoms, clinical evidence of recurrence or residual disease, or PSA failure was at the discretion of the treating physician. Physicians were asked to refrain from intervening based solely on the results of the 2-year postradiotherapy biopsy.

The investigating physician or clinical trials nurse assessed radiation toxicity using the standardized National Cancer Institute of Canada toxicity scale and graded toxicity according to specific criteria for each symptom on a 5-point scale ranging from 0 (nontoxic) to 4 (severe toxicity). The effects of radiation therapy on the GI system (anorexia, diarrhea, GI bleeding, nausea, pain/cramping, proctitis, and vomiting), the genitourinary system (bladder changes, cystitis, fistula formation, frequency, hematuria, ureteral obstruction, and genitourinary pain), the skin, and fatigue/general malaise were evaluated using the 5-point scale.

Statistical Analysis
The study was designed as a noninferiority investigation requiring 450 patients per treatment arm. The sample size calculation was based originally on the ability to demonstrate that the percentage of patients with biopsy positivity at 2 years in the short arm was no worse than the long arm (suggested in the literature to be 25%) by more than an absolute difference of 7.5%, with a one-sided = .05 and a power of 80%. With time from random assignment to BCF as the primary outcome measure and a BCF probability over 5 years estimated at approximately 40% in either group, we estimated that a sample size of 940 men provided approximately 80% power to demonstrate noninferiority with the same 7.5% tolerance.

Overall survival was defined as the time from random assignment to death from any cause or to the date of the last visit for patients still alive. For the time to BCF outcome, patients without events were censored on the date of their last visit or prostate-unrelated death. Treatment groups were compared using a two-sided 90% CI for the difference (long arm minus short arm) of the cumulative BCF probability at 5 years. A lower confidence limit greater than –7.5% indicated noninferiority. All time to event outcomes were summarized using the Kaplan-Meier method. In addition, hazard ratios (short arm relative to long arm) and their respective 95% CIs were calculated for BCF and overall survival using the Cox proportional hazards model.

For the toxicity assessment, acute toxicity was defined as events occurring up to 5 months after randomization, and late toxicity included events occurring after 5 months. Risk differences (long arm minus short arm) and 95% CIs were calculated using the modified Wilson score method.¹⁴ All statistical analyses, which were based on the intent-to-treat principle, were undertaken by the study statistician using data provided by the Coordinating and Methods Centre of the Ontario Clinical Oncology Group located in Hamilton, Ontario, Canada.

	RESULTS

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Study Population
Nine hundred thirty-six patients were recruited for the trial between March 1995 and December 1998; 470 patients were randomly assigned to receive 66 Gy in 33 fractions over 45 days, and 466 patients were randomly assigned to receive 52.5 Gy in 20 fractions over 33 days. The median follow-up time for all patients was 5.7 years (minimum, 4.5 years; maximum, 8.3 years). The treatment groups were well balanced in terms of baseline characteristics and risk group stratification (Table 1).

BCF
At the time of analysis, 236 patients in the long arm and 263 patients in the short arm experienced BCF (Fig 1). Table 2 lists the events according to the outcome type and radiation therapy schedule. The 100 patients who died during the study of non–prostate cancer causes without experiencing BCF (54 patients in the long arm and 46 patients in the short arm) were censored on the date of death. At 5 years, the Kaplan-Meier estimates of BCF in the long arm and short arm were 52.95% and 59.95%, respectively. The difference was –7.0% (90% CI, –12.58% to –1.42%). Because the lower bound is less than the predefined tolerance of –7.5%, we could not exclude the possibility of the short arm being inferior. Overall, a hazard ratio of 1.18 (95% CI, 0.99 to 1.41) in favor of the long arm was estimated.

View larger version (18K): [in this window] [in a new window]   Fig 1. Biochemical or clinical failure (BCF) by randomized treatment arm.

Overall Survival
Overall, there were 166 deaths during the study period (89 deaths in the long arm and 77 deaths in the short arm). Of the total number of deaths in the long arm, 18 were caused by prostate cancer compared with 13 prostate cancer–related deaths in the short arm. At 5 years after random assignment, overall survival was estimated as 85.2% and 87.6% in the long and short arms, respectively (hazard ratio = 0.85; 95% CI, 0.63 to 1.15; Fig 2).

View larger version (17K): [in this window] [in a new window]   Fig 2. Overall survival by randomized treatment arm.

Radiation Toxicity
During the acute period, 7.0% of patients in the long arm and 11.4% of patients in the short arm experienced grade 3 or 4 GI or genitourinary toxicities (risk difference = –4.4%; 95% CI, –8.1% to –0.6%; Table 3). During the monitoring of late toxicity, 3.2% of patients in both treatment arms experienced severe toxicities (risk difference = 0.0%; 95% CI, –2.4% to 2.3%; Table 3). Overall, genitourinary toxicity represented two thirds of these events.

	DISCUSSION

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

We recognize that overall survival was the most important outcome for this study, but given the long natural history of prostate cancer, a surrogate outcome was chosen for treatment evaluation. The 2-year postradiotherapy biopsy was originally chosen as the surrogate outcome because evidence supported its reliability and accuracy.^17-19 Before study completion and data analysis, the primary outcome was changed to BCF based on emerging evidence supporting the value of PSA for measurement of treatment effect.¹³ The American Society for Therapeutics Radiology and Oncology (ASTRO) definition of PSA failure was used as one of four composite outcomes in this study to define biochemical failure. We anticipated that most BCF events would be a result of biochemical failure based on the ASTRO definition of the failure. However, we recognized that adherence to the strict definition of PSA failure (three consecutive PSA increases) would not capture all events; hence, the other events (clinical or distant failure, cancer death, or commencement of hormonal treatment) were included in the definition of BCF. Although the ASTRO definition is the most widely accepted definition of PSA failure, it is associated with limitations.^20,21 In our study, similar results were demonstrated by substituting the Vancouver¹⁵ and Houston¹⁶ definitions of PSA failure for the ASTRO definition. PSA doubling time of less than 3 months is a new outcome that has been proposed as a surrogate outcome for cancer-specific mortality in prostate cancer.²² However, it is not yet universally accepted as a surrogate outcome.²³ For the purposes of this analysis, we have limited the analysis to primary and secondary outcomes identified in the protocol.

Events of radiation toxicity were detected throughout the study period. Grade 3 or 4 genitourinary and GI toxicities were reported by a relatively small percentage of patients in both arms of this study. The difference in incidence of acute radiation toxicities was interesting; patients in the long arm fared approximately 5% better than patients in the short arm. However, the number of reported late toxicities was similarly low in both treatment arms (3.2%). The /ß model for prostate cancer would be predictive of this comparable late toxicity.^24,25 The small but significant increase in acute toxicity could be related to a higher net rate of stem-cell depletion in the rectal and bladder mucosa. This depletion results from an increased rate of dose accumulation in the hypofractionated arm compared with the conventional arm (13.1 v 10 Gy/wk, respectively). This same mechanism has been purported to cause the increase in acute toxicity observed in hyperfractionation protocols.²⁶

Compared with other tumors, several studies have concluded that the /ß ratio for prostate cancer is low, in the range of 1.0 to 3.0.^11,27 However, the debate on this issue continues. Some recent publications have concluded that the low /ß ratio reported in previous studies may actually be an artifact resulting from tumor hypoxia.^28-30 If the /ß value for prostate cancer is less than for normal tissue (nominally 3 Gy), it could be argued that a high dose per fraction regimen would result in a therapeutic gain by improving tumor control with acceptable late toxicity.^25,27 Models based on a low /ß ratio predict that a therapeutic gain would require a larger fraction size and a higher biologic effective dose than what was used in this study. In fact, for all /ß ratios between 0.85 and infinity, the /ß model predicts that our chosen hypofractionated regimen would result in a lower tumor control rate relative to the conventional fractionation schedule. Therefore, given our current understanding of the /ß ratio, the results of this study do not contribute meaningfully to the debate on the /ß ratio for prostate cancer. Another interpretation of this data arrived at by comparison of the study results with the dose-response curve from published retrospective studies has suggested that the results are consistent with a low /ß ratio for prostate cancer.^25,31

The dose chosen in the hypofractionated regimen was based on clinical experience from two Canadian centers and published studies at the time of study design.^5-8 Given the acute toxicity results in this study, it would have been impossible to further escalate the dose using our treatment technique. Thus, evaluation of high dose per fraction regimens using techniques that reduce toxicity, such as conformal-beam radiation or intensity-modulated therapy, is recommended.⁹

The percentage of positive biopsies reported in this trial was similar in the long and short treatment arms, which is a finding that somewhat contradicts the results of biochemical failure. Postradiotherapy biopsies are no longer a gold standard for measurement of treatment effect because they are associated with inherent problems that limit interpretation. First, there is evidence suggesting that 2 years is too early and that biopsies should not be taken before 30 to 36 months after radiation to minimize false-positive rates.³² Second, sampling error of biopsies as a result of number and length of obtained cores can affect biopsy evaluation.³³ Several studies have documented that increased biopsy sampling (standard of six biopsies v 10 or 12) has a better probability of detecting prostate cancer and may lower false-negative rates.^34,35 Last, differentiating residual tumor from postradiotherapy effects can be difficult to judge even when assessed by an experienced tumor pathologist.³² The postradiotherapy biopsy results presented here are based on the report from the original pathologist. Overall, caution should be exercised when interpreting the 2-year biopsy results, particularly when drawing comparisons to the results of biochemical failure.

In the early 1990s when this trial was designed, a four-field technique was the standard method of radiation delivery. In recent years, conformal radiation has evolved as the technique more often used, and in some centers, intensity-modulated radiation therapy is used. These radiotherapy tools allow for higher doses of radiation to be delivered to the prostate and for the margin around the prostate to be decreased.^36-38 Standard total doses of external-beam radiation used to treat early-stage prostate cancer patients now range from 70 to 78 Gy.^39,40 It could be argued that the total dose of 66 Gy delivered in 2-Gy fractions used in the long arm would be biologically comparable to 70.2 Gy delivered in 1.8-Gy fractions.^10,11 However, this dose is still low compared with current clinical doses. Both the technique and dose of radiation used in this study limit the generalizability of the results to current practice. Recent information supports the use of adjuvant hormones and potentially pelvic radiotherapy in the treatment of high-risk patients. However, when the study was designed, this was not universally accepted as standard practice and, hence, was not part of the study design.

This is the first reported randomized trial comparing a high-dose hypofractionated radiation schedule to a longer conventional dose per fraction schedule. Given the results of this study, we cannot exclude the possibility that the chosen hypofractionated radiation treatment regimen is inferior to the standard regimen for early-stage prostate cancer patients. However, this is only a preliminary analysis and discussion of the results; 5 years is not considered a long period of follow-up for prostate cancer. Further evaluation at 10 years of the outcomes between the two arms of the study is awaited. The results discussed here do have important implications for our understanding of the radiobiology of prostate cancer. Future studies evaluating high dose per fraction regimens are encouraged using modern methods of radiation delivery.

	Authors' Disclosures of Potential Conflicts of Interest

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

 
The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank S. Bouma for manuscript preparation; T. Finch, S. Chambers, and Q. Guo for data management; and Drs Daya, Jones, Scrigley, Wright, Dayes, Wu, Poon, Hodson, Fyles, Dixon, Milosevic, Rheaume, Sagar, Youssef, and Whelan for their assistance with this study

	NOTES

 
Supported by Cancer Care Ontario and the National Cancer Institute of Canada–Clinical Trials Group.

Presented at the 45th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Salt Lake City, UT, October 19-23, 2003.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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

 
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Submitted June 22, 2004; accepted April 18, 2005.

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