Two of the nine patients who were initially seen in our unit for treatment of a first or second local recurrence had an additional local recurrence compared with five (10 percent) of the fifty patients who were seen for a primary tumor.
Of the seven patients who had a local recurrence, one (Case 4), who had initially been seen for a primary tumor in the distal end of the radius, had a second local recurrence after repeat extensive curettage and bone-grafting. The second local recurrence was complicated by a large soft-tissue mass, which was treated with postoperative radiation therapy in addition to a repeat operation. A third local recurrence subsequently developed and was treated with curettage and cementing. At the time of follow-up, sixty months after the last procedure, the patient had remained disease-free with preservation of the distal end of the radius.
Another patient (Case 3) had a large soft-tissue mass at the time of recurrence, and he too was managed with postoperative radiation therapy in addition to a repeat operation. At the time of follow-up, at forty-eight months, he had had no additional recurrence.
Four of the patients who had a recurrence (including Case 4) were managed with repeat curettage and cementing, whereas one (Case 6) was managed with repeat curettage and repeat allografting. One of the four patients (Case 5), who had a tumor in the proximal end of the tibia, was pregnant. It was thought inadvisable to obtain an autogenous graft from the pelvis because of the risk of inducing labor, and the patient refused the use of allograft bone. Because this was the third recurrence (the patient had had two recurrences before she was seen in our unit), the patient was also managed with radiation five months after the repeat operation (two months post partum). In the other three patients, cement was used as filler because the tumor was small and distant from the surface of the joint.
Metastases occurred in one patient (Case 7), and a massive recurrence involving soft tissue and bone developed in the distal end of the femur twelve months after the initial operation. The recurrence was treated with excision and insertion of a prosthesis (Kotz Femoral Tibial Replacement System; Howmedica, Rutherford, New Jersey). At the time of the operation, the patient was noted to have two pulmonary lesions that were identified histologically as giant-cell tumors on resection. As of the time of writing, this was the only patient who needed excision of osteoarticular bone to treat a recurrence.
In general, operative treatment of the recurrences in bone was straightforward as the bone graft that had been previously inserted in the defects was removed easily with use of a high-speed burr. Soft-tissue recurrences were more difficult to treat, and radiation was used in the two patients (Cases 3 and 4) who had such a recurrence. Most patients who were managed for a recurrence remained disease-free for a prolonged period (mean, forty-five months; range, six to eighty-nine months) afterward.
Postoperative Complications and Negative Biopsies
In addition to the local recurrences, seven patients had a postoperative complication. Stiffness of the knee developed in two patients after treatment of a distal femoral grade-III lesion associated with a pathological fracture. Both patients were managed with open arthrotomy and quadricepsplasty six months postoperatively, and both recovered more than 90 degrees of flexion of the knee.
A nonunion developed at the site of a pathological fracture in a thirty-one-year-old patient who had a grade-III tumor in the distal end of the femur. The non-union was successfully treated with replacement of the plate and bone-grafting ten months after the index operation. Five years after the second operation, the patient was fully active but had some mild pain in the lateral aspect of the knee associated with mild radiographic subchondral sclerosis and osteophytic lipping as well as a limited range of motion (10 to 80 degrees). Neither the symptoms nor the radiographic changes progressed during the three years before the most recent follow-up examination. The fracture had healed in valgus angulation, which probably predisposed the patient to pain in the lateral aspect of the knee.
One patient, a fifty-six-year-old woman who had a grade-II metaphyseal lesion in the distal end of the femur, had radiographic evidence of tricompartmental degenerative arthritis three years postoperatively. The symptoms were well controlled with anti-inflammatory medication. The patient had similar symptoms in the contralateral knee; therefore, it is possible that the arthritic changes were not related to the operation for the tumor.
Two patients had prominent hardware removed, and a superficial wound infection developed in one after the removal. The infection resolved with oral administration of antibiotics. A sterile pretibial wound hematoma developed in another patient and was treated with operative drainage. There were no deep infections.
Two patients had an open biopsy performed because of a radiographically suspicious lesion, which proved to be negative for recurrence of giant-cell tumor. These lesions were filled with autogenous graft after the biopsy showed no sign of tumor. The patients were disease-free more than four years after the biopsies, and no additional changes were noted on the radiographs (Figs. 3-A, 3-B, and 3-C).
The acceptance of the phenol-and-cement method for the treatment of giant-cell tumor has likely been the result of two factors: comparison of the outcomes of this technique with those in historical series of patients managed with bone graft, and the results of a nonrandomized, multicenter study that compared the methods of treatment used by different institutions for the treatment of giant-cell tumor8,34.
The lack of a randomized, controlled trial comparing the efficacy of phenol and cement with that of bone graft for the treatment of giant-cell tumor introduces several possible sources of bias into the comparison of these two treatments. The use of cement, with or without chemical adjuvants, is a more recent method of treatment than bone-grafting, and it is possible that improved imaging methodologies, such as cross-sectional imaging with computerized tomography or magnetic resonance imaging, might contribute to better outcomes after treatment of tumor defects with cement. Shorter follow-up after treatment with cement might also bias the results in favor of this technique, especially if the use of cement delays but does not reduce the overall rate of recurrence of giant-cell tumor. Finally, the comparison of outcomes from various centers in which different techniques were used might reflect the experience and skill of the practitioners in the various centers as much as the method of treatment.
When the outcomes of intralesional treatment of giant-cell tumors are described, it is important that investigators present the total number of patients who were managed in addition to the results for patients who were managed with intralesional therapy. If this is not done, the effect of patient selection on the outcome cannot be determined. For example, if a large proportion of patients who had a grade-II or III tumor was managed with resection, one can assume that the authors are reporting the results of treatment of smaller lesions in their description of the outcomes of intralesional treatment of giant-cell tumor. In the present study, fifty-seven (85 percent) of the sixty-seven grade-II and III tumors (in the entire group of 125 tumors) that were not in the distal end of the radius were treated with intralesional curettage and bone graft. The remaining ten tumors were treated with complete excision because the defects were not amenable to repair. Six of the seven tumors of the distal end of the radius were excluded from the study because we, like Vander Griend and Funderburk40 as well as Kocher et al.22, tend to use en bloc resection for most radial tumors with extraosseous extension. The fact that only one patient in the present study had a tumor of the radius introduces a selection bias as the prevalence of local recurrence is known to be high at this anatomical site40.
When developing a treatment protocol for giant-cell tumor of bone, a surgeon must decide whether to perform an intralesional or en bloc resection, whether to use adjuvant therapy to eradicate residual microscopic disease, and what material to use to fill the resultant defect in the bone. The first of these considerations is relatively straightforward. The risk of local recurrence after an en bloc resection involving the joint followed by prosthetic or allograft reconstruction is lower than that after an intralesional procedure5,15,23. However, the long-term complications related to prosthetic or allograft reconstruction make this treatment generally inappropriate for most giant-cell tumors of bone11,12,15,23,28,34 unless a pathological fracture or progression of the disease has resulted in a clinical situation that prevents skeletal reconstruction after intralesional curettage.
Once the decision has been made to treat most tumors with intralesional therapy, the surgeon must decide whether to use adjuvant therapy to eliminate microscopic remnants of the tumor from the cavity after curettage. Surgeons began using adjuvant therapy (insertion of methylmethacrylate cement with or without liquid nitrogen or phenol) because of dissatisfaction regarding the outcome of curettage and bone-grafting. Historically, curettage, with or without bone-grafting, has been associated with a high rate of recurrence. Goldenberg et al.16 reported that fifty (52 percent) of ninety-seven tumors originating in the distal end of the femur, the proximal end of the tibia, and the distal end of the radius recurred after such treatment, Larsson et al.19 reported that fourteen (47 percent) of thirty patients had a recurrence, and Campanacci et al.5 reported that thirty-eight (29 percent) of 130 tumors recurred. Many clinicians have rejected this technique because of the reported high risk of local recurrence.
The high risk of recurrence after bone-grafting led to the technique of intralesional curettage followed by packing of the defect with methylmethacrylate cement, which was first described in 1969 by Vidal et al.41. It has been suggested that free radicals and the thermal effects of the polymerization reaction may cause as much as two to three millimeters of necrosis in cancellous bone27,34. Additional advantages of the use of cement include low cost, ease of use, lack of donor-site morbidity, elimination of the risk of transmission of disease associated with allograft bone, immediate structural stability, and potential for earlier detection of local recurrence. The results of initial studies of the use of cement after curettage of giant-cell tumors were favorable, with no recurrences reported in two studies of only two tumors each2,5 and one recurrence reported in a study of seven patients29. However, in two larger series, five of seventeen patients10 and eight of nineteen patients28 had recurrence after management with cement, rates that are equivalent to those reported after treatment without cement.
Additional adjuvant treatment of the bone bed with liquid nitrogen or phenol after removal of the tumor has been advocated to decrease the risk of local recurrence when cement is used alone. Liquid nitrogen results in effective osteonecrosis to a depth of one to two centimeters18. Marcove26 reported a 2 percent rate of recurrence in the latter stages of a seventeen-year review of 100 giant-cell bone tumors, and Malawer and Dunham24 reported a 4 percent rate of recurrence (one in twenty-five patients). However, because the depth of the osteonecrosis induced by liquid nitrogen is difficult to control, there is a high risk of fracture24,25. In one study, six fractures occurred in five of twelve patients who were treated with liquid nitrogen20.
Phenol has been advocated as a safer agent than liquid nitrogen for adjuvant therapy34. Phenol causes protein coagulation, damages DNA, and causes necrosis31,32,34. Schiller et al.35 reported local recurrence in 10 percent (three) of thirty-one patients who had been managed with curettage and phenol for a variety of benign bone tumors, including giant-cell tumor. The advantage of phenol compared with liquid nitrogen is its reduced penetration, which results in only one to one and a half millimeters of bone injury32 and hence a reduced rate of fracture. However, phenol used alone without cement after removal of giant-cell tumors has generally been less effective than phenol used with cement, with reported rates of recurrence of 21 percent (thirty-one of 147 patients)34 and 34 percent (twenty-nine of eighty-five patients, five of whom were managed with curettage without phenol)23.
The results of combined use of phenol and cement reported in several relatively small series have been promising. Gitelis et al.15 reported one recurrence in seventeen patients after three to nine years. The authors of a larger, multicenter study reported that a subset of thirty-three patients had a 3 percent rate of recurrence (one recurrence) at a mean of seventy-five months after management with phenol and cement8. However, O'Donnell et al.28 reported recurrence in three of seventeen patients at a mean of four years after they were managed with phenol and cement.
The use of 5 percent phenol was discontinued at our unit after a patient sustained a chemical burn. Most of the patients in the present study had extensive cortical disruption. Preventing leakage of phenol in this situation while at the same time allowing adequate saturation of the bone with the chemical would had been difficult and the leakage would have been potentially harmful. Phenol is toxic to the nervous system, the heart, the kidneys, and the liver and is readily absorbed through skin, mucosa, and open wounds. Death has occurred following skin exposure, and there is a theoretical concern of phenol toxicity following rapid absorption through cancellous bone32. Quint et al.32 supported the safety of 5 percent phenol only. However, the use of higher concentrations, including 75 percent phenol in one study32, has been reported34. The use of concentrations higher than 5 percent may be hazardous.
The 12 percent rate of local recurrence (seven of fifty-nine patients) in the present study is comparable with the clinical results reported after the use of chemical adjuvants and cement. Our patients did not have the high rate of recurrence reported in earlier studies of curettage with bone-grafting5,16,19, and we attribute this improvement to the extensive use of a high-speed burr as well as the availability of allograft bone from a hospital-based tissue bank, which allows the surgeon to resect involved bone extensively without concern for how to fill the defect. It is likely that a major factor in the success or failure of curettage is related to how completely the tumor is removed11.
The data presented in the present report should not be interpreted as suggesting that bone-grafting is better treatment than the insertion of cement after removal of giant-cell tumors. Indeed, other factors may militate against the use of bone graft, including the donor-site morbidity associated with removal of bone for an autogenous graft, the risk of disease transmission from allograft bone3,37, and the difficulty of visualizing recurrences within the bone graft at the time of radiographic follow-up33. However, there are long-term concerns other than local recurrence related to the use of cement, including the difficulty associated with removal of acrylic material in the case of local recurrence or fracture and the risk of long-term osteoarthritis when the cement is placed in proximity to articular cartilage43. The risk of subchondral cement causing damage to cartilage and subsequent degenerative arthritis has been alluded to in the literature but remains unproved32. Articular degeneration with associated biochemical changes after treatment with cement has been noted in the weight-bearing area in animal studies42, whereas other studies have demonstrated the superior ability of subchondral autogenous bone grafts to restore the subchondral osseous anatomy to normal14. In a combined European and American study, degeneration of the joint occurred in fourteen (7 percent) of 204 patients who had been managed with cement compared with only two (0.7 percent) of 280 patients who had been managed with bone-grafting6. Degeneration of the joint was also inversely related to the distance of the tumor from the articular cartilage6. Osteoarthritic changes developed in one patient in the present study, but these were most likely related to valgus malunion of a fracture.
We do not believe that there is good evidence in the literature that the use of cement with or without phenol or liquid nitrogen is better than the use of bone-grafting if care has been taken to remove the tumor completely. A comparison of the efficacy of cement and bone-grafting in the treatment of giant-cell tumor of bone therefore is an appropriate focus for a randomized clinical trial. However, the event rates for both forms of treatment are so low that it would be difficult to enroll the hundreds of patients needed to attain adequate power to detect differences between the two treatments. It is unlikely that such a randomized trial will be undertaken, especially since most centers obtain adequate results with either therapy.
Finally, one additional issue, related to the reporting of results of intralesional treatment of giant-cell tumors of bone, must be addressed. Recent reports have emphasized the use of adjuvant therapy, particularly phenol, as part of the treatment of giant-cell tumors. We have noticed a recent increase in the number of patients referred to our unit with recurrence of giant-cell tumor after the use of cement, with or without chemical adjuvants. Because we believe that the low risk of recurrence associated with the use of adjuvant phenol or cement, or both, in the treatment of giant-cell tumors is related not only to the adjuvant treatment but also to how thoroughly the tumor is removed, it is important that the orthopaedic community recognize that adjuvant agents cannot prevent recurrence if the tumor has not been adequately removed.
*No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. No funds were received in support of this study.
Investigation performed at the University Musculoskeletal Oncology Unit, Mount Sinai Hospital, Toronto
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