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Intensity modulated radiotherapy (IMRT) in benign giant cell tumors – a single institution case series and a short review of the literature

Intensity modulated radiotherapy (IMRT) in benign giant cell tumors – a single institution case... Background: Giant cell tumors are rare neoplasms, representing less than 5% of all bone tumors. The vast majority of giant cell tumors occurs in extremity sites and is treated by surgery alone. However, a small percentage occurs in pelvis, spine or skull bones, where complete resection is challenging. Radiation therapy seems to be an option in these patients, despite the lack of a generally accepted dose or fractionation concept. Here we present a series of five cases treated with high dose IMRT. Patients and Methods: From 2000 and 2006 a total of five patients with histologically proven benign giant cell tumors have been treated with IMRT in our institution. Two patients were male, three female, and median age was 30 years (range 20 – 60). The tumor was located in the sacral region in four and in the sphenoid sinus in one patient. All patients had measurable gross disease prior to radiotherapy with a median size of 9 cm. All patients were treated with IMRT to a median total dose of 64 Gy (range 57.6 Gy to 66 Gy) in conventional fractionation. Results: Median follow up was 46 months ranging from 30 to 107 months. Overall survival was 100%. One patient developed local disease progression three months after radiotherapy and needed extensive surgical salvage. The remaining four patients have been locally controlled, resulting in a local control rate of 80%. We found no substantial tumor shrinkage after radiotherapy but in two patients morphological signs of extensive tumor necrosis were present on MRI scans. Decline of pain and/or neurological symptoms were seen in all four locally controlled patients. The patient who needed surgical salvage showed markedly reduced pain but developed functional deficits of bladder, rectum and lower extremity due to surgery. No severe acute or late toxicities attributable to radiation therapy were observed so far. Conclusion: IMRT is a feasible option in giant cells tumors not amendable to complete surgical removal. In our case series local control was achieved in four out of five patients with marked symptom relief in the majority of cases. No severe toxicity was observed. Background [1,2]. Usually patients present with small lesions after a Giant cell tumors of bone are usually benign tumors, brief history of swelling or pain but especially in the however they can be locally aggressive and in some sacral region, giant cell tumors can reach an enormous cases malignant transformation or metastatic disease size and result in massive pain in combination with occurs [1,2]. They account for approximately 5% of all severe neurological deficits. The standard of care for primary bone tumors and about 20% of benign bone giant cell tumors is function-preserving surgery [3]. tumors [1]. The majority of these tumors is located in After complete resection, local control is achieved in 85- the long bones of the extremities, however a small pro- 90% of all cases [3], but incomplete resection is fre- portion (< 10%) occurs in the pelvis, spine or skull base quently associated with tumor recurrence in up to 50% of the cases [4]. Despite the improvements in surgical techniques, complete tumor removal without major * Correspondence: Falk.Roeder@med.uni-heidelberg.de functional deficits remains challenging in some regions, Clinical Cooperation Unit Radiation Oncology, German Cancer Research especially sacral or pelvic bones, spine or skull base [4]. Center (DKFZ), Heidelberg, Germany © 2010 Roeder et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Roeder et al. Radiation Oncology 2010, 5:18 Page 2 of 7 http://www.ro-journal.com/content/5/1/18 Therefore primary radiotherapy has been advocated as stereotactic image fusion based on the localizer-derived an alternative treatment in patients suffering from giant coordinate system [8,9], all critical structures as well as cell tumors in these regions, although concerns about the target volumes were defined on each slice of the local side effects of radiotherapy with appropriate doses three-dimensional data cube. The gross tumor volume have been raised in the past [5,6]. As radiotherapy tech- (GTV) was defined as the macroscopic tumor visible on niques have extensively evolved in the last decades, CT- and MRI-scans. For the clinical target volume including the development of three-dimensional confor- (CTV) a margin of 1-2 cm was added. In cases of subto- mal radiotherapy with megavoltage energies and even tal resections the whole resection cavity was included intensity-modulated and image-guided radiotherapy, the into the CTV. Inverse treatment-planning was per- possibility to apply high doses with less toxicity and formed using the KonRad software developed at the optimal sparing of critical structures is now widely avail- German Cancer Research Center (DKFZ), which is con- able. Here we report our experience with intensity- nected to the 3D planning program VIRTUOS to calcu- modulated radiotherapy in the treatment of giant cell late and visualize the 3D dose distribution. The IMRT tumors occurring outside the extremities in combination treatment planning process has been described in detail with a short review of the literature. previously [10-13]. Radiation treatment was delivered by a Siemens accelerator (Primus, Siemens, Erlangen, Ger- Patients and Methods many) with 6 or 15 MV photons using an integrated Between 2000 and 2006 a total of five patients with motorized multileaf collimator (MLC) for the step-and- giant cell tumors have been treated with intensity shoot technique automatically delivering the sequences. modulated radiotherapy in our institution. All tumors Thetotal doseswereprescribedtothe median of the were histologically proven before start of the treatment. target volume and usually the 95% isodose surrounded All patients except one with a giant cell tumor in the the CTV. The prescribed dose ranged from 57.6 Gy to sphenoid sinus suffered from large tumors in the sacral 66 Gy with a median dose of 64 Gy, applied in conven- region. Three tumors were judged primarily irresectable, tional fractionation (single dose 1.8-2 Gy, five fractions and one patient had undergone a subtotal resection per week). Examples for dose distributions and DVH prior to radiotherapy. One patient suffered from a local data are shown in Figure 1 and 2. Time to event data recurrence after initial surgery and embolisation and was calculated from the first day of radiation treatment. received another embolisation and a subtotal resection Local progression was defined as tumor growth on of the recurrence before irradiation. All patients with repeated CT or MRI scans or increase of clinical symp- tumors in the sacral region suffered from massive pain toms which needed surgical salvage. and sensory neurological deficits prior to radiotherapy. For detailed patient characteristics see table 1. Results All patients were treated with IMRT using the step- All patients were followed with clinical examination and and-shoot approach [7]. For treatment planning, patients MRI scans in our institution or the referring hospital on were fixed in an individually manufactured precision a regular basis. Median follow up was 46 months, ran- head and body mask made of Scotch cast® (3 M, St.Paul, ging from 30 to 107 months. Minneapolis, MN) or an individually fixed vacuum pil- low in order to immobilize the body. With this immobi- Local control and salvage surgery lization system attached to the stereotactic base frame, Four out of five patients have been locally controlled we performed contrast-enhanced CT- and MRI-images without clinical or radiographic signs of progression, under stereotactic conditions, with a slice thickness of 3 resulting in an overall local control rate of 80%. One mm. We scanned the whole treatment region with a patient with a biopsy proven primary giant cell tumor of superior and inferior margin of at least 3 cm. After the sacral region developed a progression of clinical Table 1 Patients, treatment and outcome Pat. Age Gender Local. Size Treatm. Dose f/u Local Recurrence Clinical Outcome Radiographic Outcome 1 60 F Sacral 3,5 E+S*+RT 64 107 No Minor improvement No change 2 52 F Sacral 9 RT 64 46 3 months Progressive symptoms No change (salvage) 3 23 M Sphenoid 2,5 S*+RT 57,6 63 No No residual symptoms No change 4 20 M Sacral 10 RT 66 44 No Major improvement Tumor necrosis 5 30 M Sacral 11 RT 60 35 No Major improvement Tumor necrosis age [years], M: male, F: female, size [cm], S*: surgery (subtotal resection), E: embolisation, RT: radiotherapy, dose [Gy], f/u: follow up [months] Roeder et al. Radiation Oncology 2010, 5:18 Page 3 of 7 http://www.ro-journal.com/content/5/1/18 Figure 1 Sagittal dose distribution and DVH information in patient 5. graphs: PTV (3), rectum (4), bladder (5) symptoms in the meaning of pain, paralysis of the leg Radiographic outcome and bladder/rectal dysfunction without tumor progres- All patients were monitored closely with repeated MRI sion on MRI scan three months after radiotherapy. She imaging during the follow up period. None of the received salvage surgery which included complete patients showed a substantial reduction of tumor size removal of the tumor and is currently alive without evi- after radiotherapy, but in two patients typical radio- dence of disease and marked pain relief, but suffers graphic signs of massive central tumor necrosis were from impaired extremity function, complete loss of blad- found as reaction on radiotherapy during the further fol- der function and a permanent descendostoma. low up (see figure 3). Treatment toxicity Discussion The mainstay of treatment of giant cell tumors of the Acute toxicity related to the radiation treatment was of bone is complete surgical excision. Especially in patients minor grade in all cases. No acute toxicity of grade > 1 with extremity tumors, this treatment results in high according to RTOG was observed. In detail, three local control rates of more than 85% [3] without major patients suffered from mild skin erythema, one from mild complications or functional deficits. However, a small alopecia, one from diarrhea, one from urgency and one proportion of patients suffers from large giant cell from mild conjunctivitis. All acute toxicities resolved spontaneously. Beside from mild skin hyperpigmentation tumors of sacral bone, spine or skull base. In these in the irradiated areas in two patients, no late toxicities regions of the body, complete surgical removal without attributable to radiation therapy were observed so far. major functional deficits is challenging or sometimes impossible and recurrence rates of about 50% have been Clinical outcome reported after surgical treatment with intralesional mar- Reduction of pain was observed in four out of five gins [4]. Systemic treatment options are limited, patients already during radiotherapy. Considering the although there seems to be some progress through long term follow up excluding the patient with salvage improved understanding of the molecular mechanisms surgery three months after radiotherapy, one patient in the development of giant cell tumors. As they are showed a minor, two patients a major improvement of rich in stromal cells that express RANKL, a key media- their symptoms and one patient is free of symptoms. tor of osteoclast activation [14], increasing interest has Improvement included not only reduced pain but also a been paid to monoclonal antibodies against RANKL, for decrease of the sensory neurological deficits in two example denosumab. A pilot study in 37 patients patients. showed a response rate of 86% and functional Roeder et al. Radiation Oncology 2010, 5:18 Page 4 of 7 http://www.ro-journal.com/content/5/1/18 Figure 2 Transversal, coronar and sagittal dose distribution and DVH information in patient 3. graphs: PTV (1), left eye (2), right eye (3), right optic nerve (4), left optic nerve (5), chiasma (6), brainstem (7), spinal cord (8) improvements including reduced pain in 84% of the collected over long time periods, with wide variations in patients suffering from giant cell tumors treated with fractionation, total dose and radiation techniques denosumab [14]. However, no long term data about the [1-4,15-20]. recurrence rate, functional outcome and long term toxi- Beside the limited data for this treatment approach, city with this promising approach exists so far and radiotherapy has been criticized in the past also because therefore further investigation is needed to establish the of low rates of local control in some series and concerns value of this treatment option. Therefore primary radio- about side effects and induction of malignant transfor- therapy has to be considered as an alternative treatment mation [2,5,6]. Careful examination reveals that many of in patients with giant cell tumors not suitable for com- these series have been conducted in the 2-D era of plete resection, although based on small patient series, radiotherapy and radiodiagnostics more than 15 years Roeder et al. Radiation Oncology 2010, 5:18 Page 5 of 7 http://www.ro-journal.com/content/5/1/18 Figure 3 Development of central tumor necrosis in patient 4. left side: MRI before radiotherapy, right side: MRI 1 year after radiotherapy with development of massive central necrosis ago. This implicates not only a high possibility for geo- 42-68 Gy. Seider at al. [3] presented a series from the graphical misses due to the use of plain radiographs for MD Anderson and found a local control rate of 70% tumor localisation, which could have resulted in using doses of 36-66 Gy. Even after exclusion of all non- decreased coverage of the tumors by radiation therapy extremity tumors and all patients with gross total resec- and therefore decreased local control, but also the use tion prior to radiotherapy from these series, the results of orthovoltage techniques with low energies, resulting do not differ distinctly (see table 2). Thus modern ima- in high toxicity due to the unfavourable dose distribu- ging and radiation techniques offer the possibility of high tion and probably increased rates of secondary malig- tumor control rates without major side effects. nancies [21]. Considering the issue of malignant transformation, As radiation therapy techniques have strongly these concerns regarding radiation therapy, have mainly improved in the last decades including the wide-spread been based on initial reports of transformation rates up implementation of three-dimensional conformal radio- to 24% [6]. Other series using more modern radiother- therapy and even intensity-modulated and image-guided apy techniques found lower rates of 0-11% [1,4] and a radiotherapy, these lesions can now be treated with high recent metaanalysis reported an incidence of less than doses in the absence of major acute and late side effects 1% in patients treated with megavoltage radiation and to the adjacent normal tissues. In our case series, five modern radiation therapy techniques [1]. Beside that, patients were treated with intensity modulated radiother- malignant transformation and sarcoma induction have apy to a median dose of 64 Gy, which resulted in a local also been reported in patients treated without radiation control rate of 80%. Although all primary tumors have at all. For example Dahlin et al. [22] reported the devel- been localized in regions with directly adjacent organs at opment of sarcoma in 2 of 47 (4%) patients and risk, like rectum, small bowel or the optic nervous sys- Mnaymneh et al. [23] even in 2 of 25 (8%) patients after tem, no severe acute or late toxicity attributable to radia- surgery. The appearance of malignant giant cell tumors tion treatment has been observed so far. Other series of bone or malignant foci inside benign giant cell using modern radiation therapy techniques have reported tumors has been described also in a small number of similar results. For example Feigenberg et al. [1] found a patients [24,25], and pulmonary metastases can be local control rate of 77% in a series of 26 lesions with found in 2-9% of patients with benign giant cell tumors three severe and four minor complications associated [5,26-28]. Thus malignant transformation or the appear- with radiotherapy using doses of 35-55 Gy. Schwartz et ance of metastases could be part of the disease itself in al. [15] reviewed the MGH experience and observed a a small proportion of cases and should not be attributed local control rate of 85% after radiotherapy with doses of unreflected to radiation treatment. Roeder et al. Radiation Oncology 2010, 5:18 Page 6 of 7 http://www.ro-journal.com/content/5/1/18 Table 2 Literature overview series of Schwartz et al. [15], only three of thirteen 8 9 10 patients had neurological symptoms before treatment. Author Year n f/u Size RT dose LR All three patients showed improved neurological function Seider et al. [3] 1986 10 8 n.s. 45,5 30% after radiation therapy. Malone et al. [2] reported 7 1,2 patients with symptomatic disease before radiotherapy, Schwartz et al. [15] 1989 7 4 7 54 14% all have been ambulatory and independent after treat- 1,2 7 ment. In our series, all patients suffered from pain and/or Malone et al. [2] 1995 5 19 7,5 35 20% neurological deficits prior to radiotherapy. After treat- 1,2 ment, all patients showed some kind of improvement Feigenberg et al. [1] 2003 15 10 n.s. 45 20% except the patient who needed salvage surgery three 1,3 months after radiotherapy. One of the four patients is Leggon et al. [4] 2004 11 6 10 47,8 18% free of symptoms, two had major improvements and one 1,3,4 6 5 a minor improvement. Thus radiotherapy cannot only Leggon et al. [4] 2004 148 9 n.s. 47,8 47% stop the locally destructive growth of giant cell tumors but also decreases pain and other neurological symptoms Own data 2009 5 4 9 64 20% of the patients resulting in improved quality of life. Considering the radiographic outcome of giant cell Selected reports dealing with non-extremity giant cell tumors treated with RT tumors after radiotherapy, the available information in alone or after subtotal resection, : only patients with macroscopic residual disease after surgery or primary treatment included, : only patients suffering the literature is even more scanty than for clinical out- from non-extremity lesions included, : only patients treated with RT 4 5 6 come. This may be linked to the use of two-dimensional included, : pooled literature analysis, : mean dose, : mean f/u calculated 7 8 of the entire cohort including patients without RT, : single dose 2,4 Gy, : radiographs for diagnosis and follow up in most of the 9 10 [years], : [cm], : median dose [Gy], LR: crude local failure rates, f/u: median older series. The appearance of bone sclerosis after follow up radiotherapy in most cases has been described by Seider et al. [3], and tumor response in terms of involution or To date there is no generally accepted fractionation or ossification was observed in 4 of 9 patients in the series dose concept for the treatment of giant cell tumors. A reported by Leggon et al. [4]. In our series, MRI was clear dose-effect relationship has not been established used for diagnostics and regular follow up in all patients. yet, but in some series higher doses resulted in In contrast to the mentioned results, we did not find increased local control rates. For example, Feigenberg et significant tumor volume shrinkage after treatment. al. [1] found a significant increased local control rate of However, the absence of significant volume reduction is 86% with doses above 40 Gy compared to 67% with a common feature of benign lesions treated by radio- lower doses. In contrast, Leggon et al. [4] did not find a therapy, as shown in many other entities like menin- benefit in terms of local control comparing doses of < gioma, desmoids or chordoma [29-31] and should not 45 Gy, 45-55 Gy and > 55 Gy in pelvic and sacral be interpreted as a failure of treatment. lesions, but the overall local control rate in their series was only about 50%. Malone et al. [2] found a local con- Conclusion trol rate of 83% in non-extremity lesions even using Radiotherapy carried out by modern techniques based doses as low as 35 Gy in 15 fractions. In our patients, on modern imaging could be an alternative treatment we attempted doses of 60-66 Gy, a dose range which approach in patients with giant cell tumors not amend- could be safely administered without major toxicities able to function-preserving surgery. High local control based on our experiences in treating other sacral lesions rates without severe acute or late side effects and like chordoma or low grade chondrosarcoma using improvement in clinical symptoms are achievable in the IMRT in order to achieve maximal local control. majority of patients. Although a wide dose range was reported in most of the series, careful examination leads to the impression that usually patients with radiation as sole treatment and Author details non-extremity lesions were treated with higher doses. Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Radiation Oncology, However, if dose escalation beyond doses of 45 Gy University of Heidelberg, Heidelberg, Germany. increases local control, remains an open question based on the available data. Authors’ contributions FR participated in data acquisition, literature review and drafted the Considering the clinical outcome of patients with giant manuscript. CTI, FZ and CTH participated in data acquisition and literature cell tumors treated by radiotherapy,onlylittleinforma- review. MB, JD and PEH participated in drafting the manuscript and revised tion is available in the literature. For example in the it critically. All authors read and approved the final manuscript. Roeder et al. Radiation Oncology 2010, 5:18 Page 7 of 7 http://www.ro-journal.com/content/5/1/18 21. Harwood AR, Fornasier VL, Rider WD: Supervoltage irradiation in the Competing interests management of giant cell tumors of bone. Radiology 1977, 125:223-226. The authors declare that they have no competing interests. 22. Dahlin DC, Cupps RE, Johnson EW: Giant-cell tumors: A study of 195 cases. Cancer 1970, 25:1061-1070. Received: 10 December 2009 Accepted: 26 February 2010 23. Mnaymneh WA, Dudley HR, Mnaymneh LG: Giant-cell tumor of bone: An Published: 26 February 2010 analysis and follow-up study of the forty-one cases observed at the Massachusetts general Hospital between 1925 and 1960. J Bone Joint References Surg 1964, 46:63-75. 1. Feigenberg SJ, Marcus RB, Zlotecki RA, Scarborough MT, Berrey BH, 24. Witrak GA, Unii KK, Sim FH, Beabout JW, Dahlin DC: Malignant giant cell Enneking WF: Radiation Therapy for Giant cell tumors of bone. Clin tumor of bone [abstract]. Lab Invest 1979, 40:292. Orthop Rel Res 2003, 411:207-16. 25. Nacimento AG, Huvos AG, Marcone RC: Primary malignant giant cell 2. Malone S, O’Sullivan B, Catton C, Bell R, Fornasier V, Davis A: Long-term tumor of bone. Cancer 1979, 48:1393-1402. follow up of efficiacy and safety of megavoltage radiotherapy in hihg- 26. Kay RM, Eckardt JJ, Seeger LL, Mirra JM, Hak DJ: Pulmonary metastasis of risk giant cell tumors of bone. Int J Radiat Biol Oncol Phys 1995, benign giant cell tumor of bone: six histologically confirmed cases, 33:689-694. including one of spontaneous regression. Clin Orthop 1994, 302:219-230. 3. Seider MJ, Rich TA, Ayala AG, Murray J: Giant cell Tumor of bone: 27. Rock MG, Pritchard DJ, Unni KK: Metastases from histologically benign treatment with radiation therapy. Radiology 1986, 161:537-540. giant-cell tumors of bone. J Bone Joint Surg 1984, 66:269-274. 4. Leggon RE, Zlotecki R, Reith J, Scarborough MT: Giant cell tumor of the 28. Sung HW, Kuo DP, Shu WP, Chai YB, Liu CC, Li SM: Giant-cell tumor of pelvis and sacrum. Clin Orthop Rel Res 2004, 423:196-207. bone: Analysis of two hundred and eight cases in Chinese patients. 5. Goldenberg RR, Campbell CJ, Bonfiglio M: Giant cell tumor of bone: An J Bone Joint Surg 1982, 64:755-761. analysis of two hundred and eighteen cases. J Bone Joint Surg 1970, 29. Milker-Zabel S, Zabel A, Schulz-Ertner D, Schlegel W, Wannenmacher M, 52:619-664. Debus J: Fractionated stereotactic radiotherapy in patients with benign 6. McGrath PJ: Giant-cell tumor ofbone: An analysis of fifty-two cases. or atypical intracranial meningioma: long-term experience and J Bone Joint Surg 1972, 54:216-224. prognostic factors. Int J Radiat Oncol Biol Phys 2005, 61:809-816. 7. Schlegel W, Kneschaurek P: Inverse radiotherapy planning. Strahlenther 30. Rüdiger HA, Ngan SY, Ng M, Powell GJ, Choong PF: Radiation therapy in Onkol 1999, 175:197-207. the treatment of desmoid tumors reduces surgical indications. Eur J Surg 8. Schad LR, Gademann G, Knopp M, Zabel HJ, Schlegel W, Lorenz WJ: Oncol 2009. Radiotherapy treatment planning of basal meningiomas: improved 31. Henderson FC, McCool K, Seigle J, Jean W, Harter W, Gagnon GJ: tumor localization by correlation of CT and MR imaging data. Radiother Treatment of chordomas with CyberKnife: Georgetown university Oncol 1992, 25:56-62. experience and treatment recommendations. Neurosurgery 2009, 9. Debus J, Engenhart-Cabillic R, Knopp MV, Schad LR, Schlegel W, 64(2 suppl):A44-53. Wannenmacher M: Image-oriented planning of minimally invasive conformal irradiation of the head-neck area. Radiologe 1996, 36:732-6. doi:10.1186/1748-717X-5-18 10. Münter MW, Thilmann C, Hof H, Didinger B, Rhein B, Nill S, Schlegel W, Cite this article as: Roeder et al.: Intensity modulated radiotherapy Wannenmacher M, Debus J: Stereotactic intensity modulated radiation (IMRT) in benign giant cell tumors – a single institution case series and therapy and inverse treatment planning for tumors of the head and a short review of the literature. Radiation Oncology 2010 5:18. neck region: clinical implementation of the step and shoot approach and first clinical results. Radiother Oncol 2003, 66:313-21. 11. Pirzkall A, Debus J, Haering P, Rhein B, Grosser KH, Höss A, Wannenmacher M: Intensity modulated radiotherapy (IMRT) for recurrent, residual, or untreated skull-base meningiomas: preliminary clinical experience. Int J Radiat Oncol Biol Phys 2003, 55:362-72. 12. Pirzkall A, Carol M, Lohr F, Höss A, Wannenmacher M, Debus J: Comparison of intensity-modulated radiotherapy with conventional conformal radiotherapy for complex-shaped tumors. Int J Radiat Oncol Biol Phys 2000, 48:1371-80. 13. Münter MW, Nill S, Thilmann C, Hof H, Höss A, Häring P, Partridge M, Manegold C, Wannenmacher M, Debus J: Stereotactic intensity-modulated radiation therapy (IMRT) and inverse treatment planning for advanced pleural mesothelioma. Feasibility and initial results. Strahlenther Onkol 2003, 179:535-41. 14. Thomas DM, Chawla S, Skubitz K, Staddon A, Henshaw R, Blay J, Smith J, Ye Z, Roudier M, Jun S: Denosumab for the treatment of giant cell tumor (GCT) of bone: Final results from a proof-of-concept, phase II study [abstract]. J Clin Oncol 2009, 27:s15. 15. Schwartz LH, Okunieff PG, Rosenberg A, Suit HD: Radiation therapy in the treatment of difficult giant cell tumors. Int J Radiat Biol Oncol Phys 1989, 17:1089-1095. 16. Chen ZX, Gu DZ, Yu ZH, Qian TN, Huang YR, Hu YH, Gu XZ: Radiation Submit your next manuscript to BioMed Central therapy of giant cell tumor of bone: Analysis of 35 patients. Int J Radiat and take full advantage of: Oncol Biol Phys 1986, 12:329-334. 17. Daugaard S, Johansen HF, Barfod G, Laustein G, Schiødt T, Lund B: Radiation treatment of giant-cell tumor of bone (osteoclastoma). Acta • Convenient online submission Oncol 1987, 26:41-43. • Thorough peer review 18. Nair MK, Jyothirmayi R: Radiation therapy in the treatment of giant cell tumor of bone. Int J Radiat Oncol Biol Phys 1999, 43:1065-1069. • No space constraints or color figure charges 19. Chakravarti A, Spiro IJ, Hug EB, Mankin HJ, Efird JT, Suit HD: Megavoltage • Immediate publication on acceptance radiation therapy for axial and inoperable giant-cell tumor of bone. J • Inclusion in PubMed, CAS, Scopus and Google Scholar Bone Joint Surg 1999 81:1566-1573. 20. Miszczyk L, Wydmanski J, Spindel J: Efficacy of radiotherapy for giant cell • Research which is freely available for redistribution tumor of bone: given either postoperatively or as sole treatment. Int J Radiat Oncol Biol Phys 2001, 49:1239-1242. Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Intensity modulated radiotherapy (IMRT) in benign giant cell tumors – a single institution case series and a short review of the literature

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Copyright © 2010 by Roeder et al; licensee BioMed Central Ltd.
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Medicine & Public Health; Oncology; Radiotherapy
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Abstract

Background: Giant cell tumors are rare neoplasms, representing less than 5% of all bone tumors. The vast majority of giant cell tumors occurs in extremity sites and is treated by surgery alone. However, a small percentage occurs in pelvis, spine or skull bones, where complete resection is challenging. Radiation therapy seems to be an option in these patients, despite the lack of a generally accepted dose or fractionation concept. Here we present a series of five cases treated with high dose IMRT. Patients and Methods: From 2000 and 2006 a total of five patients with histologically proven benign giant cell tumors have been treated with IMRT in our institution. Two patients were male, three female, and median age was 30 years (range 20 – 60). The tumor was located in the sacral region in four and in the sphenoid sinus in one patient. All patients had measurable gross disease prior to radiotherapy with a median size of 9 cm. All patients were treated with IMRT to a median total dose of 64 Gy (range 57.6 Gy to 66 Gy) in conventional fractionation. Results: Median follow up was 46 months ranging from 30 to 107 months. Overall survival was 100%. One patient developed local disease progression three months after radiotherapy and needed extensive surgical salvage. The remaining four patients have been locally controlled, resulting in a local control rate of 80%. We found no substantial tumor shrinkage after radiotherapy but in two patients morphological signs of extensive tumor necrosis were present on MRI scans. Decline of pain and/or neurological symptoms were seen in all four locally controlled patients. The patient who needed surgical salvage showed markedly reduced pain but developed functional deficits of bladder, rectum and lower extremity due to surgery. No severe acute or late toxicities attributable to radiation therapy were observed so far. Conclusion: IMRT is a feasible option in giant cells tumors not amendable to complete surgical removal. In our case series local control was achieved in four out of five patients with marked symptom relief in the majority of cases. No severe toxicity was observed. Background [1,2]. Usually patients present with small lesions after a Giant cell tumors of bone are usually benign tumors, brief history of swelling or pain but especially in the however they can be locally aggressive and in some sacral region, giant cell tumors can reach an enormous cases malignant transformation or metastatic disease size and result in massive pain in combination with occurs [1,2]. They account for approximately 5% of all severe neurological deficits. The standard of care for primary bone tumors and about 20% of benign bone giant cell tumors is function-preserving surgery [3]. tumors [1]. The majority of these tumors is located in After complete resection, local control is achieved in 85- the long bones of the extremities, however a small pro- 90% of all cases [3], but incomplete resection is fre- portion (< 10%) occurs in the pelvis, spine or skull base quently associated with tumor recurrence in up to 50% of the cases [4]. Despite the improvements in surgical techniques, complete tumor removal without major * Correspondence: Falk.Roeder@med.uni-heidelberg.de functional deficits remains challenging in some regions, Clinical Cooperation Unit Radiation Oncology, German Cancer Research especially sacral or pelvic bones, spine or skull base [4]. Center (DKFZ), Heidelberg, Germany © 2010 Roeder et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Roeder et al. Radiation Oncology 2010, 5:18 Page 2 of 7 http://www.ro-journal.com/content/5/1/18 Therefore primary radiotherapy has been advocated as stereotactic image fusion based on the localizer-derived an alternative treatment in patients suffering from giant coordinate system [8,9], all critical structures as well as cell tumors in these regions, although concerns about the target volumes were defined on each slice of the local side effects of radiotherapy with appropriate doses three-dimensional data cube. The gross tumor volume have been raised in the past [5,6]. As radiotherapy tech- (GTV) was defined as the macroscopic tumor visible on niques have extensively evolved in the last decades, CT- and MRI-scans. For the clinical target volume including the development of three-dimensional confor- (CTV) a margin of 1-2 cm was added. In cases of subto- mal radiotherapy with megavoltage energies and even tal resections the whole resection cavity was included intensity-modulated and image-guided radiotherapy, the into the CTV. Inverse treatment-planning was per- possibility to apply high doses with less toxicity and formed using the KonRad software developed at the optimal sparing of critical structures is now widely avail- German Cancer Research Center (DKFZ), which is con- able. Here we report our experience with intensity- nected to the 3D planning program VIRTUOS to calcu- modulated radiotherapy in the treatment of giant cell late and visualize the 3D dose distribution. The IMRT tumors occurring outside the extremities in combination treatment planning process has been described in detail with a short review of the literature. previously [10-13]. Radiation treatment was delivered by a Siemens accelerator (Primus, Siemens, Erlangen, Ger- Patients and Methods many) with 6 or 15 MV photons using an integrated Between 2000 and 2006 a total of five patients with motorized multileaf collimator (MLC) for the step-and- giant cell tumors have been treated with intensity shoot technique automatically delivering the sequences. modulated radiotherapy in our institution. All tumors Thetotal doseswereprescribedtothe median of the were histologically proven before start of the treatment. target volume and usually the 95% isodose surrounded All patients except one with a giant cell tumor in the the CTV. The prescribed dose ranged from 57.6 Gy to sphenoid sinus suffered from large tumors in the sacral 66 Gy with a median dose of 64 Gy, applied in conven- region. Three tumors were judged primarily irresectable, tional fractionation (single dose 1.8-2 Gy, five fractions and one patient had undergone a subtotal resection per week). Examples for dose distributions and DVH prior to radiotherapy. One patient suffered from a local data are shown in Figure 1 and 2. Time to event data recurrence after initial surgery and embolisation and was calculated from the first day of radiation treatment. received another embolisation and a subtotal resection Local progression was defined as tumor growth on of the recurrence before irradiation. All patients with repeated CT or MRI scans or increase of clinical symp- tumors in the sacral region suffered from massive pain toms which needed surgical salvage. and sensory neurological deficits prior to radiotherapy. For detailed patient characteristics see table 1. Results All patients were treated with IMRT using the step- All patients were followed with clinical examination and and-shoot approach [7]. For treatment planning, patients MRI scans in our institution or the referring hospital on were fixed in an individually manufactured precision a regular basis. Median follow up was 46 months, ran- head and body mask made of Scotch cast® (3 M, St.Paul, ging from 30 to 107 months. Minneapolis, MN) or an individually fixed vacuum pil- low in order to immobilize the body. With this immobi- Local control and salvage surgery lization system attached to the stereotactic base frame, Four out of five patients have been locally controlled we performed contrast-enhanced CT- and MRI-images without clinical or radiographic signs of progression, under stereotactic conditions, with a slice thickness of 3 resulting in an overall local control rate of 80%. One mm. We scanned the whole treatment region with a patient with a biopsy proven primary giant cell tumor of superior and inferior margin of at least 3 cm. After the sacral region developed a progression of clinical Table 1 Patients, treatment and outcome Pat. Age Gender Local. Size Treatm. Dose f/u Local Recurrence Clinical Outcome Radiographic Outcome 1 60 F Sacral 3,5 E+S*+RT 64 107 No Minor improvement No change 2 52 F Sacral 9 RT 64 46 3 months Progressive symptoms No change (salvage) 3 23 M Sphenoid 2,5 S*+RT 57,6 63 No No residual symptoms No change 4 20 M Sacral 10 RT 66 44 No Major improvement Tumor necrosis 5 30 M Sacral 11 RT 60 35 No Major improvement Tumor necrosis age [years], M: male, F: female, size [cm], S*: surgery (subtotal resection), E: embolisation, RT: radiotherapy, dose [Gy], f/u: follow up [months] Roeder et al. Radiation Oncology 2010, 5:18 Page 3 of 7 http://www.ro-journal.com/content/5/1/18 Figure 1 Sagittal dose distribution and DVH information in patient 5. graphs: PTV (3), rectum (4), bladder (5) symptoms in the meaning of pain, paralysis of the leg Radiographic outcome and bladder/rectal dysfunction without tumor progres- All patients were monitored closely with repeated MRI sion on MRI scan three months after radiotherapy. She imaging during the follow up period. None of the received salvage surgery which included complete patients showed a substantial reduction of tumor size removal of the tumor and is currently alive without evi- after radiotherapy, but in two patients typical radio- dence of disease and marked pain relief, but suffers graphic signs of massive central tumor necrosis were from impaired extremity function, complete loss of blad- found as reaction on radiotherapy during the further fol- der function and a permanent descendostoma. low up (see figure 3). Treatment toxicity Discussion The mainstay of treatment of giant cell tumors of the Acute toxicity related to the radiation treatment was of bone is complete surgical excision. Especially in patients minor grade in all cases. No acute toxicity of grade > 1 with extremity tumors, this treatment results in high according to RTOG was observed. In detail, three local control rates of more than 85% [3] without major patients suffered from mild skin erythema, one from mild complications or functional deficits. However, a small alopecia, one from diarrhea, one from urgency and one proportion of patients suffers from large giant cell from mild conjunctivitis. All acute toxicities resolved spontaneously. Beside from mild skin hyperpigmentation tumors of sacral bone, spine or skull base. In these in the irradiated areas in two patients, no late toxicities regions of the body, complete surgical removal without attributable to radiation therapy were observed so far. major functional deficits is challenging or sometimes impossible and recurrence rates of about 50% have been Clinical outcome reported after surgical treatment with intralesional mar- Reduction of pain was observed in four out of five gins [4]. Systemic treatment options are limited, patients already during radiotherapy. Considering the although there seems to be some progress through long term follow up excluding the patient with salvage improved understanding of the molecular mechanisms surgery three months after radiotherapy, one patient in the development of giant cell tumors. As they are showed a minor, two patients a major improvement of rich in stromal cells that express RANKL, a key media- their symptoms and one patient is free of symptoms. tor of osteoclast activation [14], increasing interest has Improvement included not only reduced pain but also a been paid to monoclonal antibodies against RANKL, for decrease of the sensory neurological deficits in two example denosumab. A pilot study in 37 patients patients. showed a response rate of 86% and functional Roeder et al. Radiation Oncology 2010, 5:18 Page 4 of 7 http://www.ro-journal.com/content/5/1/18 Figure 2 Transversal, coronar and sagittal dose distribution and DVH information in patient 3. graphs: PTV (1), left eye (2), right eye (3), right optic nerve (4), left optic nerve (5), chiasma (6), brainstem (7), spinal cord (8) improvements including reduced pain in 84% of the collected over long time periods, with wide variations in patients suffering from giant cell tumors treated with fractionation, total dose and radiation techniques denosumab [14]. However, no long term data about the [1-4,15-20]. recurrence rate, functional outcome and long term toxi- Beside the limited data for this treatment approach, city with this promising approach exists so far and radiotherapy has been criticized in the past also because therefore further investigation is needed to establish the of low rates of local control in some series and concerns value of this treatment option. Therefore primary radio- about side effects and induction of malignant transfor- therapy has to be considered as an alternative treatment mation [2,5,6]. Careful examination reveals that many of in patients with giant cell tumors not suitable for com- these series have been conducted in the 2-D era of plete resection, although based on small patient series, radiotherapy and radiodiagnostics more than 15 years Roeder et al. Radiation Oncology 2010, 5:18 Page 5 of 7 http://www.ro-journal.com/content/5/1/18 Figure 3 Development of central tumor necrosis in patient 4. left side: MRI before radiotherapy, right side: MRI 1 year after radiotherapy with development of massive central necrosis ago. This implicates not only a high possibility for geo- 42-68 Gy. Seider at al. [3] presented a series from the graphical misses due to the use of plain radiographs for MD Anderson and found a local control rate of 70% tumor localisation, which could have resulted in using doses of 36-66 Gy. Even after exclusion of all non- decreased coverage of the tumors by radiation therapy extremity tumors and all patients with gross total resec- and therefore decreased local control, but also the use tion prior to radiotherapy from these series, the results of orthovoltage techniques with low energies, resulting do not differ distinctly (see table 2). Thus modern ima- in high toxicity due to the unfavourable dose distribu- ging and radiation techniques offer the possibility of high tion and probably increased rates of secondary malig- tumor control rates without major side effects. nancies [21]. Considering the issue of malignant transformation, As radiation therapy techniques have strongly these concerns regarding radiation therapy, have mainly improved in the last decades including the wide-spread been based on initial reports of transformation rates up implementation of three-dimensional conformal radio- to 24% [6]. Other series using more modern radiother- therapy and even intensity-modulated and image-guided apy techniques found lower rates of 0-11% [1,4] and a radiotherapy, these lesions can now be treated with high recent metaanalysis reported an incidence of less than doses in the absence of major acute and late side effects 1% in patients treated with megavoltage radiation and to the adjacent normal tissues. In our case series, five modern radiation therapy techniques [1]. Beside that, patients were treated with intensity modulated radiother- malignant transformation and sarcoma induction have apy to a median dose of 64 Gy, which resulted in a local also been reported in patients treated without radiation control rate of 80%. Although all primary tumors have at all. For example Dahlin et al. [22] reported the devel- been localized in regions with directly adjacent organs at opment of sarcoma in 2 of 47 (4%) patients and risk, like rectum, small bowel or the optic nervous sys- Mnaymneh et al. [23] even in 2 of 25 (8%) patients after tem, no severe acute or late toxicity attributable to radia- surgery. The appearance of malignant giant cell tumors tion treatment has been observed so far. Other series of bone or malignant foci inside benign giant cell using modern radiation therapy techniques have reported tumors has been described also in a small number of similar results. For example Feigenberg et al. [1] found a patients [24,25], and pulmonary metastases can be local control rate of 77% in a series of 26 lesions with found in 2-9% of patients with benign giant cell tumors three severe and four minor complications associated [5,26-28]. Thus malignant transformation or the appear- with radiotherapy using doses of 35-55 Gy. Schwartz et ance of metastases could be part of the disease itself in al. [15] reviewed the MGH experience and observed a a small proportion of cases and should not be attributed local control rate of 85% after radiotherapy with doses of unreflected to radiation treatment. Roeder et al. Radiation Oncology 2010, 5:18 Page 6 of 7 http://www.ro-journal.com/content/5/1/18 Table 2 Literature overview series of Schwartz et al. [15], only three of thirteen 8 9 10 patients had neurological symptoms before treatment. Author Year n f/u Size RT dose LR All three patients showed improved neurological function Seider et al. [3] 1986 10 8 n.s. 45,5 30% after radiation therapy. Malone et al. [2] reported 7 1,2 patients with symptomatic disease before radiotherapy, Schwartz et al. [15] 1989 7 4 7 54 14% all have been ambulatory and independent after treat- 1,2 7 ment. In our series, all patients suffered from pain and/or Malone et al. [2] 1995 5 19 7,5 35 20% neurological deficits prior to radiotherapy. After treat- 1,2 ment, all patients showed some kind of improvement Feigenberg et al. [1] 2003 15 10 n.s. 45 20% except the patient who needed salvage surgery three 1,3 months after radiotherapy. One of the four patients is Leggon et al. [4] 2004 11 6 10 47,8 18% free of symptoms, two had major improvements and one 1,3,4 6 5 a minor improvement. Thus radiotherapy cannot only Leggon et al. [4] 2004 148 9 n.s. 47,8 47% stop the locally destructive growth of giant cell tumors but also decreases pain and other neurological symptoms Own data 2009 5 4 9 64 20% of the patients resulting in improved quality of life. Considering the radiographic outcome of giant cell Selected reports dealing with non-extremity giant cell tumors treated with RT tumors after radiotherapy, the available information in alone or after subtotal resection, : only patients with macroscopic residual disease after surgery or primary treatment included, : only patients suffering the literature is even more scanty than for clinical out- from non-extremity lesions included, : only patients treated with RT 4 5 6 come. This may be linked to the use of two-dimensional included, : pooled literature analysis, : mean dose, : mean f/u calculated 7 8 of the entire cohort including patients without RT, : single dose 2,4 Gy, : radiographs for diagnosis and follow up in most of the 9 10 [years], : [cm], : median dose [Gy], LR: crude local failure rates, f/u: median older series. The appearance of bone sclerosis after follow up radiotherapy in most cases has been described by Seider et al. [3], and tumor response in terms of involution or To date there is no generally accepted fractionation or ossification was observed in 4 of 9 patients in the series dose concept for the treatment of giant cell tumors. A reported by Leggon et al. [4]. In our series, MRI was clear dose-effect relationship has not been established used for diagnostics and regular follow up in all patients. yet, but in some series higher doses resulted in In contrast to the mentioned results, we did not find increased local control rates. For example, Feigenberg et significant tumor volume shrinkage after treatment. al. [1] found a significant increased local control rate of However, the absence of significant volume reduction is 86% with doses above 40 Gy compared to 67% with a common feature of benign lesions treated by radio- lower doses. In contrast, Leggon et al. [4] did not find a therapy, as shown in many other entities like menin- benefit in terms of local control comparing doses of < gioma, desmoids or chordoma [29-31] and should not 45 Gy, 45-55 Gy and > 55 Gy in pelvic and sacral be interpreted as a failure of treatment. lesions, but the overall local control rate in their series was only about 50%. Malone et al. [2] found a local con- Conclusion trol rate of 83% in non-extremity lesions even using Radiotherapy carried out by modern techniques based doses as low as 35 Gy in 15 fractions. In our patients, on modern imaging could be an alternative treatment we attempted doses of 60-66 Gy, a dose range which approach in patients with giant cell tumors not amend- could be safely administered without major toxicities able to function-preserving surgery. High local control based on our experiences in treating other sacral lesions rates without severe acute or late side effects and like chordoma or low grade chondrosarcoma using improvement in clinical symptoms are achievable in the IMRT in order to achieve maximal local control. majority of patients. Although a wide dose range was reported in most of the series, careful examination leads to the impression that usually patients with radiation as sole treatment and Author details non-extremity lesions were treated with higher doses. Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Radiation Oncology, However, if dose escalation beyond doses of 45 Gy University of Heidelberg, Heidelberg, Germany. increases local control, remains an open question based on the available data. 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Published: Feb 26, 2010

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