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Journal of Clinical Oncology, Vol 26, No 20 (July 10), 2008: pp. 3440-3444 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.16.6249 Impact of Intensity-Modulated Radiation Therapy on Local Control in Primary Soft-Tissue Sarcoma of the Extremity
From the Departments of Radiation Oncology and Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY Corresponding author: Kaled M. Alektiar, MD, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: alektiak{at}mskcc.org
Purpose One of the concerns about intensity-modulated radiation therapy (IMRT) is that its tight dose distribution, an advantage in reducing RT morbidity to surrounding normal structures, might compromise tumor coverage. The purpose of this study is to determine if such concern is warranted in soft-tissue sarcoma (STS) of the extremity. Methods Between 02/02 and 05/05, 41 adult patients with primary STS of the extremity were treated with limb-sparing surgery and adjuvant IMRT. The margins were positive/within 1 mm in 21. Tumor size was more than 10 cm in 68% of patients and grade was high in 83%. Preoperative IMRT was given to 7 patients (50 Gy) and postoperative IMRT (median dose, 63 Gy) was given to 34 patients. Complete gross resection including periosteal stripping/bone resection was required in 11, and neurolysis/nerve resection in 24. Results With a median follow-up time of 35 months, two (4.8%) of 41 patients developed local recurrence. The 5-year actuarial local control rate was 94% (95% CI, 86% to 100%). The local control rate was also 94% for patients with negative or positive/close margin. Other prognostic factors such as age, size, and grade did not impact local control either. The 5-year distant control rate was 61% (95% CI, 45% to 76%) and the overall survival rate was 64% (95% CI, 45% to 84%). Conclusion IMRT in STS of the extremity provides excellent local control in a group of patients with high risk features. This suggests that the precision with which IMRT dose is distributed has a beneficiary effect in sparing normal tissue and improving local control.
The main advantage of intensity-modulated radiation therapy (IMRT) is its ability to conform to the shape of the intended treatment target and in doing so minimize the dose of RT to the surrounding normal structures. In a previous dosimetric report comparing IMRT with conventional 3-dimentional (3-D) RT, IMRT provided an equivalent if not better coverage of the tumor volume while significantly reducing the dose to the adjacent bone.1 This was accomplished by reducing the size of the circumferential margin at the soft tissue/bone interface for IMRT but maintaining identical margin to that with 3-D RT everywhere else including longitudinal margin. The justification for tight margin at the soft tissue/bone interface is that bone represents a natural barrier to local tumor spread2 thus the conventional 2-cm circumferential margin all around may not be required. In a subsequent IMRT report, a preliminary analysis of acute and late toxicity was encouraging especially since most patients had locally advanced extremity sarcoma and some of the patients would have otherwise needed an amputation to achieve a complete gross resection.3 The concern however was that such tight margin might compromise tumor coverage. In the current report, the purpose is to update the results of our single institution experience with limb-sparing surgery and adjuvant IMRT in a group of patients with primary nonmetastatic extremity soft-tissue sarcoma (STS) to determine whether the theoretical concern about tight margin and subsequent local recurrence is valid or that the precision with which the radiation dose is distributed with IMRT has a beneficiary effect on normal tissue sparing as well as local tumor control.
Patients The patient population consisted of 41 adult patients with primary STS of the extremity treated between February 2002 and May 2005 with limb-sparing surgery and adjuvant IMRT at Memorial Sloan-Kettering Cancer Center (New York, NY). The mean age was 57 with a range from 30 to 88 years. There were 23 female and 18 male patients. Tumor size was more than 10 cm in 68% (n = 28) and tumors were deep in 90% (n = 37). The margin(s) of resections were positive in five patients and close (< 1 mm) in 16. Patient characteristics are listed in Table 1. The most common histology was malignant fibrous histiocytoma (39%, n = 16) followed by liposarcoma (32%, n = 13). Of the 41 patients, 28 (68%) were American Joint Committee on Cancer stage III, 6 stage II, and 7 stage I. Of the seven patients with stage I (low grade); five had tumors more than 10 cm, one had close microscopic margin, and one with negative microscopic margin but grossly close to the tibia). None of the patients had metastatic disease at the time of presentation. All patients had complete gross resection but in order to achieve such resection periosteal stripping or bone resection was required in nine (22%) and two (5%) patients, respectively. In addition, neurolysis or major nerve resections were needed in 24 patients. Wound closure required tissue transfer in eight patients (20%).
Adjuvant IMRT Adjuvant IMRT was used preoperatively in 17% (n = 7) of cases in an attempt to prevent treating the whole circumference of the extremity and/or improve resectability. The dose of preoperative RT was 50 Gy given in 25 fractions followed by surgery in 4 to 6 weeks. In one of seven patients, an additional postoperative boost of 16 Gy was given due to concern about a positive microscopic margin. Postoperative IMRT was given to the remaining 34 patients. The median dose was 63 Gy (range, 59.4 to 66.6 Gy) given at 1.8 Gy per fraction. The dose of postoperative IMRT varied depending on tumor grade and margins status. The IMRT techniques were previously described3 but in brief, all patients were immobilized with alpha-cradle and had computed tomography (CT) simulation. The treated limb was immobilized as close to neutral anatomic position as possible to minimize patient's movement. For patients treated with postoperative IMRT, the initial clinical target volume (CTV) consisted of the reconstructed surgical bed, which includes surgical clips placed at the time of resection and the hypodense region seen on CT simulation slices with an expansion in the superior and inferior directions of 3 cm. This 3-cm expansion was done to provide adequate coverage of potential microscopic extension in the long axis of the extremity and to ensure the inclusion of the surgical scar and drainage sites. To construct the initial planning target volume (PTV), a 2-cm margin expansion was added in all directions. If the PTV overlapped with the adjacent bone, then that portion of the PTV was modified to include only 0.5 cm of the bone cortex in order to avoid treating the whole circumference of the bone to full radiation dose. The PTV was treated to 45 Gy. For the cone down the PTV was reduced by 3 cm in the superior and inferior directions and was treated for additional 18 to 21.6 Gy to bring the total dose to 63 to 66.6 Gy. For patients treated with preoperative IMRT, the CTV consisted of the gross tumor volume (GTV) as seen on the CT simulation slices and correlated with diagnostic magnetic resonance imaging, with an additional 3-cm expansion in the superior and inferior directions. The PTV to be taken to 50 Gy was a 2-cm expansion from the CTV in all directions with the same modification if it did overlap with the bone. Thus, the planning target volume (PTV) for IMRT was constructed so that it resembles the exact volume that would be used with 3-D RT with only one exception, the interface between soft tissues and bone. Routine portal imaging was performed on weekly basis. Adriamycin-based chemotherapy was given to 12 (35%) of 34 patients with high-grade lesions at the discretion of the treating physician.
Statistical Analysis
Local Control Of the 41 patients, two (4.8%) with malignant fibrous histiocytoma developed local recurrence, both having had postoperative IMRT to 63 Gy. In one case, the patient developed in-field local recurrence 16 months from the date of surgery and was subsequently treated with wide local excision, but later the patient expired from progression of distant metastasis. In the other patient, a presumed diagnosis of recurrence was based on a magnetic resonance imaging report showing suspicious infiltration (without nodularity) in the tumor bed 19 months after surgery. It could not be confirmed histologically because the patient expired soon after from metastatic disease. The 3- and 5-year actuarial local control rate (Fig 1) was 94% (95% CI, 86% to 100%). The local control rate did not vary significantly according to prognostic factors (Table 2). The 5-year local control was 94% for those with negative margin as well as those with positive/close margin (P = .94). The rate was also 100% for those less than 50 years of age compared with 92% for those more than 50 years of age (P = .38).
Of the 41 patients, 39% (n = 16) developed distant metastasis and 29% (n = 12) died. The 5-year distant metastasis-free survival rate was 61% (95% CI, 45% to 76%) and the overall survival rate was 64% (95% CI, 45% to 84%).
Complications
Joint stiffness was seen in 19 patients (46.3%) but was grade 1 (  25% loss of range of movement) in 29.3% (n = 12) and grade 2 (> 25% –50% loss) in 17.1% (n = 7). Edema developed in 13 patients (31.7%); grade 1 (5% to 10% inter-limb discrepancy in volume) in nine patients (22%) and grade 2 (> 10% to 30% discrepancy) in five patients (12.2%). Nerve resection was part of the operation in 11 patients (26.8%). Of the remaining 30 patients, eight (26.7%) developed nerve damage, which was grade 1 in seven (23.3%) and grade 2 only in one (3.3%).
There is general consensus that adjuvant RT should encompass a wide margin in STS of the extremity, but the magnitude of that margin is disputed. It is important to recognize that while a wide margin is an accepted practice, it is by no means uniform around the tumor perimeter. Rather, the margin needs to be viewed with respect to the direction of most likely spread.2 Thus the margin in the longitudinal axis of the extremity is significantly larger than the circumferential margin (  5 cm v 2 cm, respectively). This discrepancy in the size of the margin reflects the knowledge that local spread in STS tends to be more pronounced along the long axis of the extremity.7 Furthermore, the size of the circumferential margin also varies depending on whether it is in proximity to bone, interosseous membranes, or fascial planes, which are considered as barriers to tumor spread.8 In the current study of adjuvant IMRT in STS of the extremity, the size of the margin is no different than with conventional RT except at the soft tissue/bone interface region where the margin was restricted in order to prevent the whole circumference of the bone from receiving full RT dose. This raises the question of whether the more conformal treatment volumes with IMRT would result in a higher rate of local recurrences. Such concern is in no way unique to IMRT in STS of the extremity, but was hotly debated when 3-D and later IMRT were first introduced in the treatment of localized prostate cancer9 and more recently in anal cancer.10 With a median follow-up of 35 months, the 5-year local control rate in the current study was 94% which compares favorably with our historical control,11 where the 5-year local control was 82%, especially since 51% of patients had positive/close margin (< 1 mm) and that 68% had tumors more than 10 cm in size. In addition, the high rate of local control was maintained irrespective of traditional poor prognostic factors for local control such as older age,12 positive margin,13,14 and upper extremity site.15 This apparent lack of difference in local control, however, needs to be qualified by the modest sample size in some of the subsets in the current study. One of the inherent advantages of IMRT that may explain the improved local control includes better tumor coverage in some instances. In our previous dosimetric study comparing IMRT with conventional RT, tumor coverage overall was comparable, but the dose distributions were more conformal with IMRT in patients with large tumors.1 For example with large thigh sarcomas, the contour near the groin is significantly different than toward the knee, leading to cold spots in the former and hot spots in the latter. This would force the physician treating with conventional RT to accept a cold spot with a potential local relapse in the groin in order not to magnify a hot spot in the knee, a potential for toxicity. Perhaps this explains why local control was 90% even in patients with more than 10 cm tumor size in the current study. Another advantage, though not directly related to IMRT but rather how patients receiving IMRT were immobilized, is perhaps fewer treatment setup inaccuracies. With conventional RT, positioning the body in such a way as to avoid treating the whole circumference of the extremity often requires some level of contortion of the treated limb making the patient uncomfortable and more likely to move during the treatment. On the other hand, with IMRT where multiple isocentric gantry beams are used, the extremity could be maintained in a neutral anatomic position, thus providing the patient with a greater level comfort and less risk of setup inaccuracy. The risks of complications in this study were encouragingly low. The patient population in the current study included high-risk patients16 for bone fracture (11 of 41 had periosteal stripping or bone resection at the time of surgery) yet only two patients (4.8%) developed fracture. Furthermore, the grade of bone fracture was either grade 1 or 2, meaning that no surgical intervention was required, which is unusual with RT-associated bone fractures. Lin et al17 showed that the treatment of femoral fracture after radiation is challenging due to the high rate of nonunion of the bone. Other complications such as edema and joint stiffness were also favorable when compared with conventional RT.18 Despite the excellent results of adjuvant IMRT for primary STS of the extremity in this study, more investigations are needed to confirm the data on a larger number of patients and with longer follow-up. Additional areas of research especially with regard to cone-beam CT imaging to verify the set-up error and the dose distribution obtained throughout the course of treatment are needed. In conclusion, IMRT in STS of the extremity provides excellent local control in a group of patients with high-risk features. This suggests that the precision with which the radiation dose is distributed with IMRT has a beneficial effect in sparing normal tissue with similar or improved local control over that achieved with conventional RT.
The author(s) indicated no potential conflicts of interest.
Conception and design: Kaled M. Alektiar Administrative support: Murray F. Brennan, Samuel Singer Provision of study materials or patients: Kaled M. Alektiar, Murray F. Brennan, John H. Healey, Samuel Singer Collection and assembly of data: Kaled M. Alektiar, Murray F. Brennan, Samuel Singer Data analysis and interpretation: Kaled M. Alektiar Manuscript writing: Kaled M. Alektiar, Murray F. Brennan, John H. Healey, Samuel Singer Final approval of manuscript: Kaled M. Alektiar, Murray F. Brennan, John H. Healey, Samuel Singer
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Hong L, Alektiar KM, Hunt M, et al: Intensity-modulated radiotherapy for soft tissue sarcoma of the thigh. Int J Radiat Oncol Biol Phys 59:752-759, 2004[Medline] 2. Suit HD, Spiro I: Role of radiation in the management of adult patients with sarcoma of soft tissue. Semin Surg Oncol 10:347-356, 1994[Medline] 3. Alektiar KM, Hong L, Brennan MF, et al: Intensity modulated radiation therapy for primary soft tissue sarcoma of the extremity: Preliminary results. Int J Radiat Oncol Biol Phys 68:458-464, 2007[Medline] 4. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Statist Assoc 53:457-481, 1958[CrossRef] 5. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163-170, 1966[Medline] 6. National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. http://ctep.cancer.gov/forms/CTCAEv3.pdf 7. Enneking WF, Spanier SS, Malawer MM: The effect of the anatomic setting on the results of surgical procedures for soft parts sarcoma of the thigh. Cancer 47:1005-1022, 1981[CrossRef][Medline] 8. Wylie JP, O'Sullivan B, Catton C, et al: Contemporary radiotherapy for soft tissue sarcoma. Semin Surg Oncol 17:33-46, 1999[CrossRef][Medline] 9. Leibel SA, Fuks Z, Zelefsky MJ, et al: Technological advances in external-beam radiation therapy for the treatment of localized prostate cancer. Semin Oncol 30:596-615, 2003[CrossRef][Medline] 10. Salama JK, Mell LK, Schomas DA, et al: Concurrent chemotherapy and intensity-modulated radiation therapy for anal canal cancer patients: A multicenter experience. J Clin Oncol 25:4581-4586, 2007 11. Alektiar KM, Brennan MF, Singer S: Influence of site on the therapeutic ratio of adjuvant radiotherapy in soft-tissue sarcoma of the extremity. Int J Radiat Oncol Biol Phys 63:202-208, 2005[Medline] 12. Ballo MT, Zegars GK, Cormier JN, et al: Interval between surgery and radiotherapy: Effect on local control of soft tissue sarcoma. Int J Radiat Oncol Biol Phys 58:1461-1467, 2004[CrossRef][Medline] 13. Gronchi A, Casali PG, Mariani L, et al: Status of surgical margins and prognosis in adult soft tissue sarcomas of the extremities: A series of patients treated at a single institution. J Clin Oncol 23:96-104, 2005 14. Delaney TF, Kepka L, Goldegerg SI, et al: Radiation therapy for control of soft-tissue sarcomas resected with positive margins. Int J Radiat Oncol Biol Phys 67:1460-1469, 2007[Medline] 15. Gerrand CH, Bell RS, Wunder JS, et al: The influence of anatomic location on outcome in patients with soft tissue sarcoma of the extremity. Cancer 97:485-492, 2003[Medline] 16. Lin PP, Schupak KD, Boland PJ, et al: Pathologic femoral fracture after periosteal excision and radiation for the treatment of soft tissue sarcoma. Cancer 82:2356-2365, 1998[CrossRef][Medline] 17. Lin PP, Boland PJ, Healey JH: Treatment of femoral fractures after irradiation. Clin Orthop 352:168-178, 1998[Medline] 18. Davis AM, O'Sullivan B, Turcotte R, et al: Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol 75:48-53, 2005[CrossRef][Medline] Submitted February 11, 2008; accepted March 18, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
