JBJS | Indomethacin Compared with Localized Irradiation for the Prevention of Heterotopic Ossification Following Surgical Treatment of Acetabular Fractures

The Journal of Bone & Joint Surgery, Volume 83, Issue 12

Scientific Article | December 01, 2001

Indomethacin Compared with Localized Irradiation for the Prevention of Heterotopic Ossification Following Surgical Treatment of Acetabular Fractures

Timothy A. Burd, MD; Kent J. Lowry, MD; Jeffrey O. Anglen, MD

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Investigation performed at the Department of Orthopaedic Surgery, University of Missouri-Columbia Hospital and Clinics, Columbia, Missouri

Timothy A. Burd, MD
Kent J. Lowry, MD
Jeffrey O. Anglen, MD
Department of Orthopaedic Surgery, University of Missouri-Columbia Hospital and Clinics, MC213, One Hospital Drive, Columbia, MO 65212. E-mail address for J.O. Anglen: anglenj@health.missouri.edu

The authors did not receive grants or outside funding in support of their research or preparation of this manuscript. They did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

A commentary is available with the electronic versions of this article, on our web site (www.jbjs.org) and on our quarterly CD-ROM (call our subscription department, at 781-449-9780, to order the CD-ROM).

The Journal of Bone & Joint Surgery. 2001; 83:1783-1788

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Abstract

Background: There is controversy surrounding the relative effectiveness of local irradiation and oral indomethacin for prophylaxis against heterotopic ossification following surgical treatment of acetabular fractures. The purpose of this study was to compare the efficacy of these two commonly used methods in a prospective, randomized trial.

Methods: From July 1992 to June 1999, 166 patients in whom a fracture of the acetabulum was treated surgically through a posterior, extensile, or combination approach were randomized to receive either indomethacin or radiation therapy postoperatively. Seventy-eight patients received 800 cGy of local radiation therapy within seventy-two hours after surgery, and seventy-two patients received a six-week course of indomethacin (25 mg three times a day) beginning within twenty-four hours after surgery. Sixteen additional patients were randomized but did not receive treatment with either prophylactic regimen. At an average of fourteen months, the extent of heterotopic ossification was assessed on plain radiographs with use of the classification of Brooker et al. The grade of ossification was correlated with hip motion.

Results: There was no significant difference between treatment groups with regard to patient age, gender, Glasgow Coma Scale, operative time, estimated operative blood loss, duration of follow-up, or presence of closed head injury. The Injury Severity Score appeared to be the only covariate that was significantly different between the groups (p = 0.019). Grade-III or IV ossification developed in eight (11%) of the patients in the indomethacin group and three (4%) in the radiation therapy group. The difference was not significant (p = 0.22; 95% confidence interval, -1.1%, +15.7%). No complications related to the prophylaxis were noted in either group. Heterotopic ossification developed in all sixteen patients who did not receive prophylaxis, with six demonstrating grade-III or IV changes. The overall prevalence of grade-III or IV heterotopic ossification was 7% (eleven of 150) in the treated groups and 38% (six of sixteen) in the untreated group.

We did not find any association between the prevalence of heterotopic ossification and fracture type (p = 0.296) or posterior hip dislocation (p = 0.306). Grade-I, II, and III heterotopic ossification did not decrease the range of motion of the hip except in flexion.

Conclusions: Both local radiation therapy and indomethacin were found to provide effective prophylaxis against heterotopic ossification following surgical treatment of acetabular fractures through a posterior or extensile approach. We detected no significant difference in efficacy between the two prophylactic regimens.

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Introduction

Introduction | Materials and Methods | Results | Discussion | References

Heterotopic ossification is a well-known complication of surgical approaches to the hip that involve dissection of the gluteal muscles^1-6. The exact mechanism for heterotopic bone formation has not been thoroughly elucidated; however, it appears to involve pluripotent mesenchymal cell differentiation into osteoprogenitor cells after tissue injury or dissection^7-13. This process begins as soon as sixteen hours after injury and is maximal at thirty-six to forty-eight hours^8,13-15. The surgical approach to the acetabulum appears to be a major risk factor for heterotopic ossification. Posterior and extensile approaches to the acetabulum may result in a prevalence of Brooker grade-III or IV ossification of up to 50%^3,9,15-22. Additional reported risk factors for heterotopic ossification include thoracic and abdominal trauma, male gender, T-type fracture, high Injury Severity Score¹⁷, delay in fracture fixation¹⁶, and closed head injury^4,23,24. The reported prevalence of heterotopic ossification after open reduction and internal fixation of acetabular fractures ranges from 18% to 90%^20,21,25,26. Radiographic evidence of heterotopic ossification is usually apparent by three to six weeks, and maximum heterotopic bone formation is seen by six to twelve weeks^14,20,21,27.

Both radiation therapy and indomethacin provide effective prophylaxis against heterotopic bone formation^{14,16,20,21,27}. Radiation prevents heterotopic ossification when administered twenty-four hours before surgery or within seventy-two hours after it^10,14,28-31. Indomethacin reduces the rate of heterotopic ossification after surgical treatment of acetabular fractures by 30% to 45%^{7-9,12,13,20,21,27,32,33}.

Controversy remains regarding the preferred method of prophylaxis after operative treatment of acetabular fractures³⁴. The purpose of this study was to determine whether local radiation therapy or indomethacin is more effective in preventing heterotopic bone formation in a prospective, randomized trial.

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TABLE I: Demographics of One Hundred and Fifty Patients Receiving Indomethacin or Radiation Therapy

*The values are given as the mean, with the range in parentheses. †One-way analysis of variance. ‡Chi-square test. §Kruskal-Wallis test.

	Treatment		P Value
Radiation (N = 78)	Indomethacin (N = 72)
Age* (yr)	??44 (16-87)	?41 (16-89)	0.29†
Gender
Male	??57	?48	0.40‡
Female	??21	?24
Glasgow Coma Scale* (points)	??14 (3-15)	?14 (3-15)	0.10§
Injury Severity Score* (points)	??14 (9-41)	?15 (9-41)	0.019§
Closed head injury (% of patients)	??14	?17	0.66‡
Operative time* (min)	?253 (75-700)	219 (66-463)	0.21§
Estimated blood loss* (mL)	1045 (150-4260)	913 (100-3200)	0.65§
Duration of follow-up* (mo)	??16 (2.5-78)	?13 (2.5-43)	0.73§

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TABLE I: Demographics of One Hundred and Fifty Patients Receiving Indomethacin or Radiation Therapy

*The values are given as the mean, with the range in parentheses. †One-way analysis of variance. ‡Chi-square test. §Kruskal-Wallis test.

	Treatment		P Value
Radiation (N = 78)	Indomethacin (N = 72)
Age* (yr)	??44 (16-87)	?41 (16-89)	0.29†
Gender
Male	??57	?48	0.40‡
Female	??21	?24
Glasgow Coma Scale* (points)	??14 (3-15)	?14 (3-15)	0.10§
Injury Severity Score* (points)	??14 (9-41)	?15 (9-41)	0.019§
Closed head injury (% of patients)	??14	?17	0.66‡
Operative time* (min)	?253 (75-700)	219 (66-463)	0.21§
Estimated blood loss* (mL)	1045 (150-4260)	913 (100-3200)	0.65§
Duration of follow-up* (mo)	??16 (2.5-78)	?13 (2.5-43)	0.73§

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Table II: Outcome According to Brooker Grade* (N = 150)

*The values are given as the number of patients.

	Grade 0	Grade I	Grade II	Grade III	Grade IV
Radiation	59	10	6	2	1
Indomethacin	49	8	7	7	1
Total	108 (72%)	18 (12%)	13 (9%)	9 (6%)	2 (1%)

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Table II: Outcome According to Brooker Grade* (N = 150)

*The values are given as the number of patients.

	Grade 0	Grade I	Grade II	Grade III	Grade IV
Radiation	59	10	6	2	1
Indomethacin	49	8	7	7	1
Total	108 (72%)	18 (12%)	13 (9%)	9 (6%)	2 (1%)

Materials and Methods

Introduction | Materials and Methods | Results | Discussion | References

From July 1992 to June 1999, 224 acetabular fractures were treated surgically with open reduction and internal fixation at the University of Missouri-Columbia Hospital and Clinics by the senior author (J.O.A.). One hundred and eighty-two patients were considered to be at risk for heterotopic ossification because they had been treated through a surgical approach that involved dissection through the gluteal muscles. The remaining forty-two patients underwent an anterior ilioinguinal approach and were excluded from the study. Sixteen of the 182 patients were not followed for at least ten weeks and were also excluded from the study. None of those patients had any evidence of heterotopic ossification on radiographs made before they were lost to follow-up. One hundred and thirty-four patients (81%) of the remaining 166 patients underwent a Kocher-Langenbeck approach, and thirty-two had either an extended iliofemoral approach (nine patients; 5%) or a combined Kocher-Langenbeck and ilioinguinal approach (twenty-three patients; 14%). The protocol was approved by the University of Missouri Institutional Review Board, and all patients provided informed consent prior to inclusion in the study.

Patients were randomized according to the sum of the digits in the medical record number. If the sum was odd, the patient received indomethacin; if it was even, the patient received radiation therapy. Of the 166 patients, sixteen (eight who had been randomized to receive indomethacin and eight who had been randomized to receive radiation) did not receive prophylactic treatment because they were too unstable medically to be transported for radiation or because indomethacin treatment had not been given or had been terminated prematurely. These patients were included in the study as an "intent-to-treat" group. Therefore, 150 patients received prophylaxis and were followed: seventy-eight received 800 cGy of local radiation therapy to the hip within seventy-two hours after the operation, and seventy-two received a complete six-week course of indomethacin (25 mg three times a day) beginning within twenty-four hours after surgery. Radiation therapy was performed at an affiliated cancer treatment hospital because of the lack of facilities in our institution. Radiation portals were set up to shield the fracture site and to irradiate only the capsular and gluteal muscles.

The age, gender, Glasgow Coma Scale³⁵, Injury Severity Score³⁶, operative time, estimated intraoperative blood loss (as recorded by anesthesia staff), presence of closed head injury, and follow-up period were recorded. The range of flexion, external rotation, internal rotation, and abduction of the hip was assessed clinically by the senior author, with use of the contralateral, uninjured hip for comparison. Data recorded in the medical record at each postoperative visit were recovered for this study. Patients were followed at two, six, twelve, twenty-four, thirty-six, and fifty-two weeks and yearly thereafter. All fractures were classified by the senior author with use of the system described by Letournel and Judet⁴. Radiographs, including anteroposterior, iliac oblique, and obturator oblique views of the pelvis, were made at 1.5, three, six, twelve, twenty-four, thirty-six, and forty-eight months after the operation. The extent of heterotopic ossification was assessed with the classification system of Brooker et al.¹, in which grade 0 signifies no heterotopic ossification, grade I indicates islands of bone within soft tissues about the hip, grade II indicates bone spurs from the pelvis or proximal end of the femur with 1 cm left between opposing spurs, grade III is the same as grade II except that <1 cm is left between acetabular and femoral spurs, and grade IV indicates complete osseous ankylosis of the hip. The most recent radiographs of the first seventy-five patients in the study were assessed by three orthopaedic surgery chief residents who were blinded to the method of prophylaxis. If there was discrepancy between the interpretations of the viewers, the highest grade of heterotopic ossification was recorded. Comparison of those grades with the grades recorded in the chart by the attending physician who had trained the residents revealed no differences. The radiographs of the remaining ninety-one patients were assessed by this attending surgeon, who was also unaware of the method of prophylaxis at the time of his evaluations.

At the time of final follow-up, forward flexion, external rotation with the hip flexed, internal rotation with the hip flexed, and abduction with the hip extended were measured with the patients in the supine position, and these ranges of motion were compared with those on the contralateral side. The average durations of follow-up in the indomethacin and radiation therapy groups were thirteen and sixteen months, respectively. Compliance with indomethacin treatment was assessed by questioning the patients or caregivers and reviewing nursing home or rehabilitation hospital records.

Statistical analysis was performed with use of one-way analysis of variance for age, the Kruskal-Wallis test for quantitative variables (Glasgow Coma Scale, Injury Severity Score, operative time, estimated blood loss, and duration of follow-up), and the chi-square test for qualitative measurements. The outcomes were compared between the two test groups with use of the Cochran-Armitage test to account for the ordinal nature of the Brooker classification. To determine confidence intervals, the Brooker classifications were divided into two groups: mild (grades 0, I, and II) and severe (grades III and IV) because functional limitations or other symptoms are rarely associated with grade 0, I, or II. The sixteen patients who did not receive the full six-week course of indomethacin, or who did not have radiation therapy because of severe illness, were included in the analysis.

The Wilcoxon rank-sum test was utilized to determine whether dislocation of the femoral head was associated with the degree of heterotopic ossification, and the Kruskal-Wallis test was used to assess whether fracture pattern was associated with the degree of heterotopic ossification. The relationship between the range of motion of the hip and the grade of heterotopic ossification was determined with use of the Spearman rank correlation coefficient and the Jonckheere-Terpstra test for ordered alternatives. Significance was set at p £ 0.05.

Results

Introduction | Materials and Methods | Results | Discussion | References

Patient Demographics

There was no significant difference between groups with regard to patient age, gender, Glasgow Coma Scale, operative time, operative blood loss, duration of follow-up, fracture type, or presence of an associated closed head injury (Table I). The only covariate that appeared to be significantly different between the groups was the Injury Severity Score (p = 0.019). This difference is unexplained; however, the magnitude of the difference (1.25 points) was not clinically relevant. Because the most common reason for not receiving radiation was that the patient was too severely injured to be transported, the patients who were treated with radiation and those who were randomized to receive radiation but were not treated had significantly different Injury Severity Scores (mean, 13.1 and 23.9 points, respectively). On the basis of the Spearman rank correlation between Injury Severity Score and heterotopic ossification grade, a significant correlation was found (p = 0.0035) when the radiation therapy group and the group randomized to radiation who did not receive treatment were compared.

Heterotopic Ossification

Brooker grade-III or IV heterotopic ossification developed in eleven patients (14%) randomized to treatment with indomethacin and six patients (7%) randomized to treatment with radiation therapy. The Cochran-Armitage test did not reveal a significant association between treatment group and heterotopic ossification (p = 0.13). Chi-square testing for treatment effect, with use of the dichotomized outcomes "mild" or "severe," yielded a p value of 0.15, with a 95% confidence interval of —2.5%, +16.7%. Of the 150 randomized patients who actually received treatment, eight (11%) had Brooker grade-III or IV heterotopic ossification after treatment with indomethacin and three (4%) had it after treatment with radiation (Table II); the p value was 0.22 on Cochran-Armitage testing, with a 95% confidence interval of —1.1%, +15.7% for the dichotomized outcome analysis. All sixteen patients who did not receive treatment had heterotopic ossification, which was grade III or IV in six of them.

Relationship of Fracture Type or Posterior Hip Dislocation with Prevalence of Heterotopic Ossification

The two groups did not differ significantly with regard to the fracture type distribution. Also, there w[as no significant association (p = 0.296) between any of the seven fracture patterns and the prevalence of heterotopic ossification.

Of the 182 acetabular fractures, eighty (44%) were associated with a posterior hip dislocation. However, there was no significant association between the grade of heterotopic bone formation and the presence or absence of dislocation (p = 0.306).

Relationship of Other Covariate Factors with Prevalence of Heterotopic Ossification

With heterotopic ossification dichotomized to "mild" or "severe," logistic regression was used to detect correlations of covariate factors and outcome. With use of Spearman rank correlation coefficients, correlations were found with five factors: Glasgow Coma Scale (p = 0.0019), Injury Severity Score (p = 0.0035), operative time (p = 0.0196), operative blood loss (p = 0.0030), and duration of follow-up (p = 0.0003).

Relationship of Range of Motion with Grade of Heterotopic Ossification

In the series as a whole, the difference in the ranges of motion between the injured and uninjured sides averaged 7Â° in forward flexion, 9Â° in external rotation, 8Â° in internal rotation, and 7Â° in abduction. Use of Spearman rank correlation coefficients showed that, of the four range-of-motion measurements, only forward flexion had a significant relationship (p = 0.011) with the grade of heterotopic ossification. As the grade of heterotopic ossification increased, so did the loss of forward flexion. Use of linear regression analysis showed no significant relationship between the change in forward flexion and the treatment group (indomethacin or radiation therapy) (p = 0.40).

Complications

No complications related to prophylactic treatment were identified in either group. No patient taking indomethacin required termination of treatment because of gastrointestinal symptoms, although several patients had treatment stopped by other physicians who did not understand the purpose of the medication. No problems with surgical wound-healing were encountered in the patients treated with radiation.

Discussion

Introduction | Materials and Methods | Results | Discussion | References

Reported risk factors for heterotopic ossification following acetabular surgery include thoracic and abdominal trauma, male gender, closed head injury^4,23,24, high Injury Severity Score¹⁷, delay in fracture fixation¹⁶, T-type fracture, and extensile approaches²¹. The extended iliofemoral, combined anterior and posterior, and Kocher-Langenbeck approaches are associated with the highest prevalences of heterotopic ossification (57%, 45.4%, and 26.3%, respectively)⁴, whereas nonoperative treatment and anterior approaches that do not violate the gluteal muscles are believed to be associated with a lower rate of heterotopic ossification. We did not find a relationship between gender, age, fracture type, presence of head injury, or hip dislocation and the ultimate grade of heterotopic ossification in our series of patients, most of whom received prophylaxis. There was a relationship between heterotopic ossification and the Glasgow Coma Scale, Injury Severity Score, operative blood loss, operative time, and duration of follow-up. The correlation with the Glasgow Coma Scale and with the Injury Severity Score may be confounded by the fact that more severely injured patients sometimes did not receive prophylactic treatment because they could not be transported for radiation or because their managing physicians failed to order the indomethacin. Failure to receive treatment strongly predicted the development of heterotopic ossification. Operative blood loss and operative duration may be markers of more severe injury to the gluteal muscles, which may predispose a patient to heterotopic ossification.

The relationship between the duration of follow-up and the grade of heterotopic ossification was strong, which is puzzling. It is possible that it represents a learning curve phenomenon, with the more recently treated patients being treated by a more experienced surgeon (presumably with superior technical skills). It is also notable that many of the patients who did not receive prophylactic treatment were seen early in the series, when the trauma service and others in the institution were less familiar with the necessity for prophylaxis. There was an unexplained three-month difference in the duration of follow-up between the two treatment groups, but this difference was not significant and did not appear to have had any effect on the results.

Much has been written regarding the most effective method of preventing heterotopic ossification; however, the best treatment remains controversial. Stannard and Alonso³⁴ conducted a survey in which fourteen senior trauma surgeons were asked to select the "best method" of prevention; the results were mixed, reflecting a lack of consensus. Most (50%) believed that indomethacin was the best treatment after posterior and extensile approaches to the acetabulum. Several authors have expressed the opinion that indomethacin is effective in preventing heterotopic ossification^{16,20,21,24,37}. However, in a recent prospective, randomized study in which three-dimensional computed tomography reconstruction was used to assess heterotopic ossification, Matta and Siebenrock³³ determined that indomethacin was not effective as prophylaxis following surgery for acetabular fractures and that there was a significant association between male gender and the volume of heterotopic ossification (p = 0.002). The authors also demonstrated that 9.4% of the patients receiving indomethacin had at least Brooker grade-II ossification compared with 4.8% of the patients who did not receive prophylactic treatment. In our study, 11% of the patients treated with indomethacin had severe heterotopic ossification compared with 38% of the untreated patients. Indomethacin may cause gastric ulcerations, decreased platelet function, renal toxicity, and impaired fracture-healing^38-40. We found it to be well tolerated, and our patients had no bleeding or gastrointestinal complications.

Radiation appears to prevent pluripotent mesenchymal cell differentiation into osteoprogenitor cells and should be administered twenty-four hours before surgery or within seventy-two hours after it⁸. It has previously been shown to be effective in patients treated with fixation of an acetabular fracture¹⁴. Disadvantages of radiation therapy include cost ($2400 at our institution compared with $12 for a six-week course of indomethacin) and the necessity of transferring multiply injured patients to the treatment facility. Although Moed and Letournel⁴¹ assessed both indomethacin and radiation as a combined therapeutic strategy, we are not aware of any study in which the efficacy of the two was compared. We think that the 95% confidence interval of our data (—1.1%, +15.7%) indicates a very low likelihood of any clinically relevant difference in efficacy, and we concluded that the treatments are equally effective when compared with no prophylaxis. Decisions regarding the treatment of individual patients should be based on both medical and economic considerations.

Our study was limited by the lack of a randomized untreated concurrent control group with which to prove that either therapy was better than a placebo. The risk of heterotopic ossification has been well established in the literature, and we thought that inclusion of a placebo group would be unethical. Another limitation is the lack of clear proof of compliance with the indomethacin regimen. However, the risk of noncompliance with the medication regimen is an inherent aspect of this treatment, and the fact that we did not rigidly evaluate or enforce compliance makes the comparison in our study more realistic and applicable to what is achievable in practice. The continuation of the study to include more patients would have allowed us to narrow the 95% confidence intervals. However, we discontinued the study when we became convinced that there was no significant difference in efficacy.

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Introduction | Materials and Methods | Results | Discussion | References

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TABLE I: Demographics of One Hundred and Fifty Patients Receiving Indomethacin or Radiation Therapy

*The values are given as the mean, with the range in parentheses. †One-way analysis of variance. ‡Chi-square test. §Kruskal-Wallis test.

	Treatment		P Value
Radiation (N = 78)	Indomethacin (N = 72)
Age* (yr)	??44 (16-87)	?41 (16-89)	0.29†
Gender
Male	??57	?48	0.40‡
Female	??21	?24
Glasgow Coma Scale* (points)	??14 (3-15)	?14 (3-15)	0.10§
Injury Severity Score* (points)	??14 (9-41)	?15 (9-41)	0.019§
Closed head injury (% of patients)	??14	?17	0.66‡
Operative time* (min)	?253 (75-700)	219 (66-463)	0.21§
Estimated blood loss* (mL)	1045 (150-4260)	913 (100-3200)	0.65§
Duration of follow-up* (mo)	??16 (2.5-78)	?13 (2.5-43)	0.73§

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TABLE I: Demographics of One Hundred and Fifty Patients Receiving Indomethacin or Radiation Therapy

*The values are given as the mean, with the range in parentheses. †One-way analysis of variance. ‡Chi-square test. §Kruskal-Wallis test.

	Treatment		P Value
Radiation (N = 78)	Indomethacin (N = 72)
Age* (yr)	??44 (16-87)	?41 (16-89)	0.29†
Gender
Male	??57	?48	0.40‡
Female	??21	?24
Glasgow Coma Scale* (points)	??14 (3-15)	?14 (3-15)	0.10§
Injury Severity Score* (points)	??14 (9-41)	?15 (9-41)	0.019§
Closed head injury (% of patients)	??14	?17	0.66‡
Operative time* (min)	?253 (75-700)	219 (66-463)	0.21§
Estimated blood loss* (mL)	1045 (150-4260)	913 (100-3200)	0.65§
Duration of follow-up* (mo)	??16 (2.5-78)	?13 (2.5-43)	0.73§

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Table II: Outcome According to Brooker Grade* (N = 150)

*The values are given as the number of patients.

	Grade 0	Grade I	Grade II	Grade III	Grade IV
Radiation	59	10	6	2	1
Indomethacin	49	8	7	7	1
Total	108 (72%)	18 (12%)	13 (9%)	9 (6%)	2 (1%)

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Table II: Outcome According to Brooker Grade* (N = 150)

*The values are given as the number of patients.

	Grade 0	Grade I	Grade II	Grade III	Grade IV
Radiation	59	10	6	2	1
Indomethacin	49	8	7	7	1
Total	108 (72%)	18 (12%)	13 (9%)	9 (6%)	2 (1%)