hi. J. Radialion Oncology fliol. Phys., Vol. 13, pp. 365-369 Printed in the U.S.A. All rights reserved.

0360-3016/87 $3.00 + .W Copyright 0 1987 Pergamon Journals Ltd.

??Original Contribution

PREVENTION OF HETEROTOPIC BONE FORMATION WITH EARLY POST OPERATIVE IRRADIATION IN HIGH RISK PATIENTS UNDERGOING TOTAL HIP ARTHROPLASTY: COMPARISON OF 10.00 Gy VS 20.00 Gy SCHEDULES

PAUL ANTHONY, M.D.,* HENRY KEYS, M.D.,* C. MCCOLLISTER EVARTS, M.D.,-/- PHILIP RUBIN, M.D.* AND CAROL LUSH, B.A.*

University of Rochester Medical Center Strong Memorial Hospital Rochester, New York

prior studies have demonstrated the effectiveness of postoperative radiation therapy (RT) to the hip area following total hip replacement (THR) surgery in preventing the development of heterotopic bone formation in patients considered to be at high risk for development of this complication. Previously, patients received 20.00 Gy in 10 fractions (fx) over 2 weeks, beginning as soon postop as medically feasible (usually post-op day 2). In an effort to reduce hospital stay and risk of secondary malignancy, a prospective treatment program was initiated April 1982 using a reduced dose of 10.00 Gy in 5 fx over 5-7 days. As of February 1984,46 consecutive hips determined to be at high risk were treated with this reduced dose. Prior studies have demonstrated that heterotopic bone is always radiographically evident by 8 weeks. Of the 46 hips, 41 had been evaluated with the minimum required 8 week follow-up X ray. Twenty-five of these hips, 6156, had a mean long term follow-up of 12 months. Our historical control group, consisting of 54 consecutive high risk post-THR’s, was shown to have a 68.5% incidence of hetero- topic bone. The 20.00 Gy group, when RT was started by post-op day 5, demonstrated a 3.2% incidence, compared to 4.9% in the 10.00 Gy group. Complication rates were also comparable in the two RT groups, 19.4% and 7.3% respectively; 10.00 Gy is apparently as effective as 20.00 Gy in preventing heterotopic bone formation in high risk post-THR patients.

Heterotopic bone formation, Total hip arthroplasty, Porous coated (cementless) prosthesis, Radiation therapy.

INTRODUCTION

Total hip arthroplasty is an established procedure em- ployed for treatment of painful progressive degenerative osteoarthritis.4,5,’ ’ The potential for postoperative growth of heterotopic bone in the soft tissues surround- ing the hip joint has long been recognized as a major post-THR complication.8,10*‘6,20 Complications such as nonunion of the greater trochanter, thromboembolism, infection, and dislocation of the prosthesis also occur, but heterotopic bone formation can be quite extensive, resulting in return of pain and impairment of joint mo- bility. An estimated 80,000 THR’s are performed in the U.S. each year and 30% (24,000) will develop radio- graphic evidence of heterotopic bone formation with 3- 10% demonstrating decreased range of motion and pain as a direct result of heterotopic bone.21

The mechanism by which heterotopic ossification is triggered is not fully understood. The best animal (rab- bit) study to date by Craven and Urist7 using ‘H -Thymi- dine and ‘H-&dine labelled cells showed that fibro- blasts in the soft tissues surrounding an implanted de-

mineralized bone fragment were transformed into pluripotential migrating ameboid mesenchymal cells which continued to differentiate into osteoblasts. Surgi- cal trauma is implicated as a possible inducing agent, but has not been experimentally documented.

Although the etiology of heterotopic bone formation is unclear, there are predisposing conditions by which a patient is considered at high risk for development of het- erotopic bone. The presence of (a) severe osteoarthritis with proliferative osteophytes and/or ankylosing spon- dylitis, (b) diffuse idiopathic skeletal hyperostosis (rare), and (c) heterotopic bone formation in a previously oper- ated contralateral or (d) ipsilateral hip are all predictors for the growth of heterotopic bone.3*‘4~‘6,2’~22~27 At least 90% of patients with previous THR of the ipsilateral or contralateral hip may be expected to form or reform het- erotopic bone post-THR. More importantly, the hetero- topic bone that forms will be clinically significant in the majority of these cases.21

Methods have been sought to selectively inhibit for- mation of heterotopic bone without otherwise compro- mising the functional result of the surgical procedure.

* Dept. of Radiation Oncology. diation Oncology, University of Rochester Cancer Center, Box t Dept. of Orthopaedics. 647,60 1 Elmwood Avenue, Rochester, NY 14642. Reprint requests to: Philip Rubin, M.D., Department of Ra- Accepted for publication 30 September 1986.

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366 I. J. Radiation Oncology 0 Biology 0 Physics March 1987, Volume 13, Number 3

Orthopedic surgeons have attempted to prevent the de- position of heterotopic bone by careful irrigation of the operative site and gentle handling of the tissues. Diphos- phonates, thought to prevent the growth of hydroxyapa- tite crystals within the cartilage matrix and thus ectopic bone formation, have been shown to decrease the inci- dence of heterotopic bone formation when compared to a placebo group.” However, calcification proceeded once diphosphonate administration ceased.14 Indometh- acin administered post-THR has also been used to in- hibit heterotopic bone growth but is commonly accom- panied by severe systemic side effects.25’27

Postoperative RT was proposed as a potential inhibi- tor of heterotopic bone based on the radiobiological prin- ciple that rapidly dividing cells such as the induced differentiating pluripotential mesenchymal cells should be sensitive to early post-THR RT thereby preventing pre-osteoblasts from developing into mature functioning osteoblasts. In the first studies6q’8 using postoperative RT a total dose of 20.00 Gy was delivered in 10 fx over 2 weeks. This dose was chosen based on evidence compiled by Neuhauser et a1.20 that 20.00 Gy completely arrested cartilage growth in the vertebrae of very young children and by Bonarigo and Rubin* who showed that 20.00 Gy inhibited healing of rat bone fractures by blocking chon- drogenesis (callus formation). MacLennan et al. ‘* rea- soned that heterotopic bone and callus formation might involve progenitor cells of similar radiosensitivity.

Coventry and Scanlon6 demonstrated the efficacy of post-THR RT in a series of 48 hips which received 20.00 Gy in 10 fx over 2 weeks.6 No postoperative heterotopic bone growth was shown in any hips irradiated prior to post-THR day 5. MacLennan et al. ‘* confirmed these re- sults in a review of 62 hips treated in a similar fashion, with a failure rate of only 3.2%. Both studies stressed the importance of commencement of RT before post-THR day 5.

Because the precise radiosensitivity of the mesenchy- ma1 progenitor cell (pre-osteoblast) had not been experi- mentally determined, it was felt that doses less than 20.00 Gy might be as effective in preventing heterotopic bone formation. Further credibility was given to this hy- pothesis by MacLennan et al. who reported that three patients who inadvertently received less than 20.00 Gy (all prior to post-THR day 5) did not develop heterotopic bone.” In an effort to reduce hospital stay and decrease

Table 1. 10.00 Gy Study: Distribution of patients by risk factor groups after total hip replacement (THR)

Risk factor group No. hips %

1 Osteoarthritis 21 51 (no prior THR)

2 Contralateral 3 7 (heterotopic bone growth post-THR)

3 Ipsilateral 17 42 (excision heterotopic bone with/ without replacement of prosthesis)

Fig. 1. Outline of a typical radiotherapy field. A generous mar- gin of soft tissue is required since a large volume of tissue adja- cent to the hip is at risk.

risk of second malignancy, a prospective treatment pro- gram was initiated at the University of Rochester in April 1982 using a reduced dose of 10.00 Gy delivered in 5 fx over 5 to 7 days.

METHODS AND MATERIALS

Records and X rays of 4 1 patients (46 hips) receiving 10.00 Gy RT post-THR between April 1982 and April 1984 were reviewed. Mean age was 66 years with a range of 44 to 82 years old. All patients were considered at high risk for heterotopic bone growth according to the pre- viously outlined criteria and were classified into three groups ranked by ascending probability of developing heterotopic bone post-THR (See Table 1).

Precautions were taken during surgery to minimize the risk of post-THR heterotopic bone formation by gen- tle handling of tissues and careful irrigation of the opera- tive site. As emphasized in prior studie&‘,‘* irradiation was always initiated by post-THR day 5. Fifty-one per- cent of patients commenced RT on postop day 1 and 73% by day 2 (only one patient received RT on day 5). Anterior-posterior parallel opposed fields, usually mea- suring 13 X 13 cm on the skin, were used (Fig. 1). A dose to midplane of 10.00 Gy in 5 fx over 5 to 7 days was

Prevention of heterotopic bone formation 0 P. ANTHONY et al. 367

Table 2. Modified Brooker Grading System used to assess post-THR heterotopic bone status

Grade

0 I

II

III

IV

No bone islands visible Islands of bone visible within soft tissues about hips Bone spurs from pelvis or proximal end of femur,

leaving at least 1 cm between opposing surfaces As in II but space between opposing surfaces less

than 1 cm Apparent bony ankylosis

delivered via an 18 MeV Linear accelerator at 100 cm SSD.

Effectiveness of therapy was assessed by evaluation of pre- and post-THR films graded for presence of hetero- topic bone using a modified Brooker Grading System (Table 2 and Fig. 2).3 Seventy-eight percent of the pa- tients were at least a Brooker grade III or IV pre-THR. At surgery, debilitating heteroptic bone was resected along with the hip joint. In most patients, immediate post- THR X rays showed either no residual ectopic bone or very few small bone chips. Two month post-RT X rays were then evaluated for the presence or increase in het- erotopic bone as compared to the immediate post-THR X ray. Patients demonstrating an increase in heterotopic bone were classified as treatment failures,

RESULTS

Since it has been demonstrated that heterotopic bone formation is complete at 8 weeks,6,12,26 response to treat- ment was assessed by comparison of pre-THR and 8 week or longer post-THR X rays. At the close of the re- view (January 1985) 4 1 hips were eligible for evaluation. Five patients were excluded because follow-up films were not available. Greater than 8 week follow-up was avail- able for 25 hips (6 1%) with a mean length of follow-up of 12 months (range 2 to 24 months).

Results were compared with those of a historical con- trol group treated at this institution between 1975 and 1976. This group consisted of 54 hips which did not re- ceive post THR RT but were determined to be at high risk for the development of heterotopic bone post- THR.” Radiographic evidence of heterotopic bone was found in 68.5% ofthe 54 hips reviewed. Incidence of het- erotopic bone formation was dramatically reduced in the 20.00 and 10.00 Gy studies. Two of 62 patients (3.2%) in the 20.00 Gy study exhibited minimal radiographic evidence of heterotopic bone with a comparable inci- dence of 4.9% (2 of 41 patients) in the 10.00 Gy study (Table 3). The two failures in the 10.00 Gy study were from the highest risk group (Group 3) and were Brooker grades III and IV pre-THR.

Complications in the 20.00 and 10.00 Gy studies con- sisted primarily of nonunion of the greater trochanter

Fig. 2. Modified Brooker Grading System: (1) Example of Grade III heterotopic bone prior to re-excision of bone followed by radiation therapy. (2A) Example of Grade IV of right hip prior to re-excision and radiation and (2B) osteoarthritis with osteophyte formation of left hip in the same patient.

368 I. J. Radiation Oncology 0 Biology 0 Physics March 1987, Volume 13, Number 3

Table 3. Comparison of post-total hip replacement results in nonirradiated (historical control), 20.00 Gy,

and 10.00 Gy study groups

Study group

No XRT 20.00 Gy 10.00 Gy

Total no. hips

54 62 41

With ectopic bone on X ray

%

68.5 3.2 4.9

and dislocation of the prosthesis. A 19.4% complication rate was reported in the 20.00 Gy study, the majority of which were nonunion of the greater trochanter ( 10 pa- tients). An improved fixation method has been adopted and its success is reflected in the lower incidence of non- union in the 10.00 Gy study (2 hips-4.9%). The overall complication rate for the 10.00 Gy study was 7.3%. (Ta- ble 4).

DISCUSSION

It is evident, as shown in our historical control group and the literature3.4.5,6,8,‘0’12.‘4.‘6’2”22,22226,28 that post-THR heterotopic bone formation is a formidable complica- tion. Coventry and Scanlon7 and MacLennan et ~1.‘~ demonstrated the efficacy of preventing this complica- tion with 20.00 Gy delivered post-THR. Our 10.00 Gy study comprised a relatively equivalent patient popula- tion treated with similar RT techniques and with strict adherence to initiating RT by post-THR day 5. Failure and complication rates were similar. We attribute our comparable success in preventing formation of hetero- topic bone to the assumption that the radiosensitivity of the induced osteoprogenitor cell (pre-osteoblast) is greater than previously suspected and conclude, that in high risk patients, 10.00 Gy given in 5 fractions is appar- ently as effective as 20.00 Gy in 10 fractions in inhibiting development of heterotopic bone formation after THR.

Whereas post-THR heterotopic bone formation is a significant complication, loosening of the hip implant is the major cause for revision surgery in all patients under- going THR. Although the introduction of methylmeth- acrylate cement in hip surgery by Charnley in 1970 revo- lutionized total hip arthroplasty, the problem of ensuring permanent, safe fixation of the implant to bone has not

Table 4. Complication rates in the 20.00 Gy and 10.00 Gv studies

Comnlications 20.00 Gy 10.00 Gy

# #

Nonunion of greater trochanter 10 2 Dislocation of prosthesis 0 1 Sepsis 2 0 Adhesions 1 0 Total 13 (19.4%) 3 (7.3%)

yet been resolved.” However, implantation of porous coated prostheses has recently been introduced as a pos- sible answer to this problem. The porous coated implant is physiologically anchored via boney ingrowth, negating the need for cementation.23 Orthopedic literature hails the success of this new technique in reducing implant loosening, with maximum follow-up ranging from 2 to 7 years. 9,13,17,19,24

The interest and success of porous coated hip implants has in turn generated a series of new questions regarding therapy for subsequent post-THR complications. We are obviously interested in whether post-THR irradiation of porous coated hip implants in patients at high risk for development of heterotopic bone will impair the process of implant fixation. The anchoring process of boney in- growth, as with heterotopic bone formation, involves the modulation and migration of pluripotential stem cells from the surrounding cortical bone into the fibrous exu- date within the interstices of the porous coating. The stem cells eventually differentiate into mature osteo- blasts, producing mature bone which anchors the im- plant. Because of the similarity of this process to the de- velopment of heterotopic bone, irradiation of a porous coated implant following THR could result in poor fixa- tion in a high percentage of patients. We are presently attempting to answer this question using a rabbit model.

As previously stated, heterotopic bone formation and chondrogenesis (endochondral bone growth) are sim- ilarly radiosensitive. Bonarigo and Rubin using a rat bone fracture model, showed that callus formation (chondrogenesis) is inhibited by 20.00 Gy RT and re- sulted in nonunion of the fracture. In contrast they showed that osteogenesis (intramembranous bone growth) continues on the healing in a lytic boney lesion despite 30.00 Gy RT (presuming the tumor was de- stroyed). They advised, in a weight bearing bone weak- ened by tumor, pinning the bone prior to irradiation. Doses greater than 20.00 Gy could result in blockage of callus formation and without pinning possible nonunion if the weakened bone should fracture.

We contend that the anchoring callus (formed follow- ing a fractured bone) external to the cortex is the product of an endochondral pathway whereas the sealing callus (which fixates the porous coated implant) internal to the boney shaft is an intramembranous process. This would suggest that 10.00 Gy RT following implantation of a porous coated prosthesis should not impair anchoring (via boney ingrowth) of the prosthesis.

Results of our rabbit study will be available soon for publication. This study, those of Coventry and ScanIon and MacLennan et ~1.‘~ have shown the complication rate following irradiation of cemented prostheses is sim- ilar to that in patients receiving no irradiation. Until the results of our rabbit study are tabulated, we recommend porous coated implants not be used in patients at high risk for development of heterotopic bone if they are to receive post-THR irradiation.

Prevention of heterotopic bone formation 0 P. ANTHONY et al.

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