Less Risk of Femoral Fracture with Intensity-Modulated Radiation Therapy for Thigh and Groin Sarcoma

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Intensity-modulated radiation therapy (IMRT)

Intensity-modulated radiation therapy (IMRT) confers a lower risk of femoral fracture in patients with primary soft tissue sarcoma of the thigh or groin, despite a higher dose of radiation to the target volume compared to conventional radiation, according to the results of our study published recently in the Annals of Surgical Oncology.

Our findings provide preliminary evidence that IMRT should be considered the standard of care approach for radiation therapy (RT) for soft tissue sarcoma of the extremities.
Kaled M. Alektiar

Moreover, the observed cumulative risk of femoral fracture among patients treated with IMRT was significantly less than the expected risk predicted by the Princess Margaret Hospital (PMH) nomogram.

Our findings provide preliminary evidence that IMRT should be considered the standard of care approach for radiation therapy (RT) for soft tissue sarcoma of the extremities.

We identified 92 patients with primary nonmetastatic soft tissue sarcoma of the thigh or groin who received both limb-sparing surgery and adjuvant IMRT at Memorial Sloan Kettering Cancer Center between February 2002 and December 2010. We analyzed the five-year rate of fracture and the associated risk factors. (1)

The five-year risk of femoral fracture in patients with primary soft tissue sarcoma of the thigh or groin who were treated with IMRT was 6.7 percent, significantly lower than the expected risk of 25.6 percent predicted by the PMH nomogram, which was developed based on data from patients treated with conventional (non-IMRT) RT. (1)

Our results support the use of IMRT as well as the lower dose constraints implemented in 2010 to limit radiation to the femur and reduce the risk of fracture in this patient population. The lower fracture rate with IMRT likely traces to the reduction in radiation dose to the whole circumference of the femur. Further, because doses are lower when IMRT is delivered preoperatively, this approach is particularly appropriate for patients at a high risk for fracture, such as those with anterior thigh tumors that require significant periosteal stripping. (1)

Radiation-Associated Bone Fracture in Soft Tissue Sarcoma

Soft tissue sarcoma is a rare cancer that starts in the fat, muscles, nerves, tendons, and blood and lymph vessels. There are more than 80 subtypes of soft tissue sarcoma, and 40 percent of cases occur in the arms and legs.

For patients with soft tissue sarcoma of the thigh or groin, the rate of bone fracture associated with RT is about 4 to 6 percent. (2), (3), (4) Most fractures occur in patients with lower extremity lesions, especially in the thigh. (5) Tumor location within the thigh matters; anterior compartment tumors have a higher rate of fracture compared to posterior or medial compartment tumors. (4), (6) Radiation dose also influences the fracture rate, with reports ranging from 9 percent for lower extremity soft tissue sarcoma treated to greater than 60 gray (Gy) compared to 1 percent for treatment up to 50 Gy. (5)

One potential way of reducing the risk of femoral fracture is by using IMRT, which can spare a portion of the long bone from receiving a full radiation dose. (7) MSK researchers developed IMRT in 1996 for the treatment of prostate cancer. Since then, we have made improvements to the technology and expanded its use for many other types of cancer. Compared to conventional RT, IMRT allows the radiation dose to align more precisely to the three-dimensional shapes of tumors, enabling the delivery of higher doses of radiation to tumors while sparing healthy tissue.

In a previously published study of our experience at MSK, we reported a 4.8 percent rate of bone fracture when using adjuvant IMRT for primary soft tissue sarcoma of an extremity. (8) However, determining the true impact of IMRT on the fracture rate is challenging, since several additional factors have an influence, including age, gender, tumor size, location, and the extent of periosteal stripping. (3), (4) Further, radiation-related fractures tend to occur long after treatment, about 40 months after treatment, on average. (5), (8)

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Study Results

For our study, we examined the impact of IMRT on fracture risk by comparing the observed risk of femoral fracture in primary soft tissue sarcoma treated with limb-sparing surgery and IMRT to the expected risk as calculated by the PHM nomogram(9) The PMH nomogram is based on patients who were treated with conventional RT and accounts for known risk factors. (1)

The median follow-up time for the 92 consecutive patients was 73 months (106 months in surviving patients). The average age was 58 years (range: 19 to 88). Thigh compartment was anterior in 43 patients (47 percent), posterior in 28 (30 percent), medial in 17 (18 percent), and groin in 4 (4 percent). Median tumor maximum dimension was 11.1 centimeters (cm), with a range of 2.5 to 31 cm, and 56 tumors (61 percent) were larger than 10 cm. Periosteal stripping was performed in 20 patients (22 percent). Thirteen patients (14 percent) had preoperative IMRT to 50 Gy, and 79 patients (86 percent) received postoperative IMRT to a median dose of 63 Gy (range: 59.4 to 66.6 Gy). Thirty-three patients (36 percent) received neoadjuvant or adjuvant chemotherapy. (1)

Among the 92 patients, six patients (6.7 percent) experienced grade 3 femoral fractures at a median time of 23 months. All six patients were older than 50 years of age when treated for primary soft tissue sarcoma, and all had tumors located in the anterior thigh compartment. Of these six patients, five had tumors larger than 10 cm and received an IMRT dose greater than 60 Gy. (1) Note that our study cohort was treated before the publication of two studies on which current recommendations for RT dose are based. (10), (11)

The cumulative observed rate of fracture at five years was 6.7 percent (95 percent CI, 2.8 to 16.0 percent), significantly lower than 25.6 percent, the expected rate calculated with the PMH nomogram. Established predictors of femur fracture, including gender, tumor size, and radiation therapy dose, had less impact on fracture risk when patients were treated with IMRT. Univariate analysis revealed that the significant predictors of fracture were an age of 60 years or older (p=0.03), tumor location in the anterior thigh (p=0.008), and periosteal stripping greater than 20 cm (p < 0.0001). On multivariate analysis, an age of 60 years or older and periosteal stripping greater than 20 cm retained significance (p=0.04 and p=0.009, respectively). (1)

Another important finding from our study was that there were no instances of nonunion or complications secondary to fixation for patients treated exclusively with IMRT. This insight contrasts with reports in the literature citing rates of nonunion ranging from 27 to 45 percent in patients who developed fractures after receiving conventional RT. (3), (4), (12)

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Advancing Sarcoma Cancer Treatment

At MSK, we see more than 600 new patients with soft tissue sarcoma each year. We are often able to remove tumors considered inoperable at other cancer centers. We have published lessons learned from our study of more than 10,000 people with soft tissue sarcoma treated at MSK and followed for over three decades. (13)

Our multidisciplinary team collaborates to develop individualized treatment plans for each patient, which may include surgery, chemotherapy, RT, or a combination tailored to maximize the potential for the best outcomes. Some patients may benefit from immunotherapies or targeted therapies, often offered through our clinical trials. MSK has one of the largest soft tissue sarcoma clinical trial programs in the United States. Currently, we are conducting 21 soft tissue sarcoma clinical trials, testing investigational drugs, immunotherapies, and various drug combinations.

The study was supported by grants from the National Cancer Institute via the SPORE in Soft Tissue Sarcoma (P50 CA140146 to SS) and the Cancer Center Support Grant (P30 CA008748). Co-author Michael Folkert received travel funding from Varian and research support from Augmenix. None of the other study authors have conflicts to disclose, and none have a personal or institutional financial interest in the materials or devices described in this submission.

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  1. Folkert MR, Casey DL, Berry SL, et al. Femoral fracture in primary soft-tissue sarcoma of the thigh and groin treated with intensity-modulated radiation therapy: observed versus expected risk. Ann Surg Oncol. 2019 May;26(5):1326-1331.

  2. Alektiar KM, Zelefsky MJ, Brennan MF. Morbidity of adjuvant brachytherapy in soft tissue sarcoma of the extremity and superficial trunk. Int J Radiat Oncol Biol Phys. 2000;47(5):1273–9.

  3. Blaes AH, Lindgren B, Mulrooney DA, et al. Pathologic femur fractures after limb-sparing treatment of soft-tissue sarcomas. J Cancer Surviv. 2010;4(4):399–404.

  4. Helmstedter CS, Goebel M, Zlotecki R, Scarborough MT. Pathologic fractures after surgery and radiation for soft tissue tumors. Clin Orthop Relat Res. 2001(389):165–72.

  5. Holt GE, Griffin AM, Pintilie M, et al. Fractures following radiotherapy and limb-salvage surgery for lower extremity soft- tissue sarcomas. A comparison of high-dose and low-dose radiotherapy. J Bone Joint Surg Am. 2005;87(2):315–9.

  6. Lin PP, Boland PJ, Healey JH. Treatment of femoral fractures after irradiation. Clin Orthop Relat Res. 1998(352):168–78.

  7. Hong L, Alektiar KM, Hunt M, et al. Intensity-modulated radiotherapy for soft tissue sarcoma of the thigh. Int J Radiat Oncol Biol Phys. 2004;59(3):752–9.

  8. Folkert MR, Singer S, Brennan MF, et al. Comparison of local recurrence with conventional and intensity-modulated radiation therapy for primary soft-tissue sarcomas of the extremity. J Clin Oncol. 2014;32(29):3236–41.

  9. Gortzak Y, Lockwood GA, Mahendra A, et al. Prediction of pathologic fracture risk of the femur after combined modality treatment of soft tissue sarcoma of the thigh. Cancer. 2010;116(6):1553–9.

  10. Dickie CI, Parent AL, Griffin AM, et al. Bone fractures following external beam radiotherapy and limb-preservation surgery for lower extremity soft tissue sarcoma: relationship to irradiated bone length, volume, tumor location and dose. Int J Radiat Oncol Biol Phys. 2009;75(4):1119–24.

  11. Pak D, Vineberg KA, Griffith KA, et al. Dose–effect relationships for femoral fractures after multimodality limb-sparing therapy of soft-tissue sarcomas of the proximal lower extremity. Int J Radiat Oncol Biol Phys. 2012;83(4):1257–63.

  12. McGee L, Indelicato DJ, Dagan R, et al. Long-term results following postoperative radiotherapy for soft tissue sarcomas of the extremity. Int J Radiat Oncol Biol Phys. 2012;84(4):1003–9.

  13. Brennan MF, Antonescu CR, Moraco N, Singer S. Lessons learned from the study of 10,000 patients with soft tissue sarcoma. Ann Surg. 2014;260(3):416–422.