Radiation Therapy

Safia K. Ahmed, MD

Neither Dr. Ahmed nor any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this chapter.

This chapter is adapted from Ahmed SK, Owen D: Radiation therapy, in Biermann JS, Siegel GW, eds: Orthopaedic Knowledge Update^®: Musculoskeletal Tumors 4. American Academy of Orthopaedic Surgeons, 2021, pp 83-96.

ABSTRACT

Radiation therapy plays a crucial role in the multimodal management of soft-tissue sarcoma. It is important to discuss the role, rationale, and logistics associated with delivering radiation therapy for soft-tissue sarcomas, along with its role in limb-sparing approaches and the radiation planning and delivery process. Orthopaedic surgeons should be aware of the different radiation treatment modalities, toxicities associated with treatment, and future directions with radiation therapy for the treatment of soft-tissue sarcomas.

INTRODUCTION

Radiation therapy plays a critical role in the multimodal management of soft-tissue sarcoma. Its role in reducing local recurrence has permitted more limb-sparing surgeries for a disease that historically was managed with amputation. It is important to discuss the indications for radiation therapy, the radiation techniques used in sarcoma treatment, and emerging approaches that are potentially paradigm changing.

SOFT-TISSUE SARCOMA

Establishing Radiation Therapy and Limb Salvage Surgery as a Standard of Care

It is well established that radiation therapy is a crucial component of curative treatment in the setting of limb salvage surgery (LSS). Radiation therapy kills cancer cells by causing cellular DNA damage. Cancer cells in which DNA is damaged beyond repair will not divide and consequently die. Before the 1990s, the standard of care for the management of extremity sarcoma was amputation. During the 1980s and 1990s, several randomized trials established radiation therapy and wide local excision (limb-sparing surgery) as an equivalent standard of care.

The first prospective randomized study was the National Cancer Institute trial from 1982 that randomized patients to amputation versus limb-sparing surgery and postoperative external beam radiation therapy (EBRT) to the tumor bed.¹ All patients received adjuvant chemotherapy. There was no difference in disease-free survival and overall survival. Four of 27 patients had local recurrence in the limb-sparing arm and none of 16 had recurrence in the amputation arm.

In 1998, the National Cancer Institute published a phase III trial randomizing 141 patients to limb-sparing surgery plus postoperative EBRT versus limb-sparing surgery alone, with stratification by low-grade and high-grade histology. There was no difference in overall survival between the groups, but postoperative EBRT markedly reduced the risk of recurrence post resection, with zero recurrence in the EBRT and surgery arm (regardless of low-grade or high-grade histology) and 22% local recurrence in the surgery-only arm at 10 years. This difference was despite more patients in the radiation arm having a close margin resection.²

In 1996, the Memorial Sloan Kettering Cancer Center randomized patients to postoperative brachytherapy (internal catheter-based radiation) and no additional treatment after surgery following limb-sparing surgery. This trial again showed no overall survival benefit from brachytherapy but a substantial reduction in local recurrence from 30% to 9% in the surgery-alone arm versus the surgery-plus-brachytherapy arm. The improvement in local control was mostly limited to those with high-grade disease.³

These trials demonstrated the quintessential role of adjuvant radiation therapy with LSS; however, they did not detail the optimal indications, timing, dose, and treatment volumes for radiation therapy, or treatment-associated morbidity.

Radiation Therapy Timing: Preoperative Versus Postoperative

As the aforementioned studies demonstrate, adjuvant radiation therapy can be safely and effectively delivered after LSS to reduce local recurrence. To address whether preoperative radiation therapy was equally effective, the seminal National Cancer Institute of Canada (NCIC) SR2 trial randomized patients to preoperative EBRT versus postoperative EBRT. Patients who underwent preoperative radiation therapy were allowed to receive additional radiation postoperatively (a boost) if they had a positive margin resection. The preoperative radiation therapy dose was 50 Gy in 25 fractions, whereas the postoperative radiation therapy dose was 60 to 66 Gy in 30 to 33 fractions (60 Gy for negative margin resection, 66 Gy for positive margin resection). A higher dose is required in the postoperative setting because of tissue hypoxia in the tumor bed as shown in the previous studies.⁴

The NCIC trial was originally designed to enroll 266 patients but closed early because of a planned preliminary analysis showing a significant difference. In total, 190 patients were randomized with the primary end point defined as the presence or absence of a major wound complication, such as a secondary surgery under general or regional anesthesia for wound repair (débridement, surgical drainage, and secondary wound closure).⁵

With a median follow-up of 3.3 years, there was a much higher risk of wound complications in the preoperative radiation therapy arm than in the postoperative radiation therapy arm (35% versus 17%). These results are not surprising because radiation therapy can impair healing, resulting in a greater risk of wound complications in the acute phase.⁵ In contrast, the higher dose of radiation therapy in the postoperative setting causes more scarring and fibrosis, which results in more long-term morbidity such as joint stiffness and fracture.⁶ Additional advantages of preoperative radiation therapy include a targetable tumor with a smaller radiation field and better tissue oxygenation and efficacy of radiation. In addition, response to radiation therapy may aid with surgical management. Table 1 summarizes the pros and cons of preoperative and postoperative radiation therapy.

Table 1 Relative Advantages and Disadvantages of Preoperative Versus Postoperative Radiation Therapy

	Preoperative RT	Postoperative RT
Advantages	Smaller RT treatment volume	Lower risk of wound complications
	Lower RT dose (50 Gy, conventionally fractionated)	Entire untreated specimen available for pathologic review, which allows for individualized treatment
	Lower risk of (irreversible) late toxicities
	Potential to render unresectable or marginally resectable tumors resectable
	Potential to prevent tumor seeding of surgical bed and/or systemic circulation
	Potential for better oxygenation of tissues as a result of uninterrupted vasculature
	Relative simplicity of RT target definition for a tumor in situ
Disadvantages	Higher risk of wound complications	Larger RT treatment volume
	Potential for less informative pathologic analysis as a result of treatment	Higher RT dose (60 to 66 Gy, conventionally fractionated)
		Higher risk of (irreversible) late toxicities^a
		Potential inability to deliver RT at all if major wound complication occurs
		Potential increased hypoxic environment as a result of surgical disruption of vasculature
		Relative complexity of RT target definition to include prior site of tumor and the surgical bed
RT = radiation therapy
^aLate toxicities include subcutaneous fibrosis, joint stiffness, edema, pain, and bone fractures.

Despite these differences, there was no difference in local control or overall survival between those who received preoperative and postoperative radiation therapy.⁵ Although there are many advantages to preoperative radiation therapy, the timing of radiation therapy should be discussed between the orthopaedic surgical oncologist and radiation oncologist to individualize care.

Role of a Postoperative Boost

In patients who have received preoperative radiation therapy, there is a clinical conundrum of whether additional radiation therapy, either at the time of surgery or in the postoperative setting, should be offered to patients who have a positive margin resection.

The NCIC SR2 trial did offer an additional 16 Gy in eight fractions of EBRT at 6 to 8 weeks after resection in this scenario.⁵ Retrospective data have questioned whether an EBRT boost is beneficial. These studies showed no improvement in local recurrence, with additional EBRT after preoperative radiation and a positive margin resection.⁷^,⁸^,⁹ It is possible that the EBRT boost of 16 Gy is an inadequate dose for addressing a positive margin.

In contrast, intraoperative radiation therapy (IORT), which delivers radiation directly to the tumor bed in the operating room immediately after surgery, has been shown to improve local control. The dose that is delivered is higher than that achieved with EBRT and is focused on the positive margin site with direct input from the surgeon.¹⁰^,¹¹

In patients who have received preoperative radiation therapy and who have a known positive margin at the time of surgery, there should be a multidisciplinary discussion about the role of additional radiation therapy for local control.

Considerations of Radiation Therapy for High-Grade Versus Low-Grade Sarcomas

The National Cancer Institute, Memorial Sloan Kettering Cancer Center, and NCIC-SR2 trials all showed significant improvement in local control after LSS in patients with high-grade sarcoma. High-grade histology has been shown to be a strong predictor of local recurrence.¹²^,¹³ The omission of radiation therapy in high-grade extremity soft-tissue sarcomas is not standard of care and if pursued, needs to be discussed in detail in a multidisciplinary setting.

In contrast, extremity low-grade soft-tissue sarcomas do not usually warrant radiation therapy in addition to LSS. Small and/or superficial low-grade tumors (stage T1) have a local recurrence risk of approximately 10% at 10 years.¹⁴^,¹⁵ However, deeply located tumors larger than 5 cm and positive margin resection are predictive of local recurrence. As such, these patients should be offered radiation therapy. Patients who have locally recurrent low-grade tumors should also be considered for radiation therapy, either in the preoperative or postoperative period in conjunction with wide local reexcision if limb sparing is possible. Patient age, comorbidities, and adherence to surveillance are factors that must also be considered when omitting radiation therapy in low-grade soft-tissue sarcomas. Given the multiple aspects of care associated with these situations, the decision to omit radiation therapy in low-grade soft-tissue sarcomas must be made by an experienced multidisciplinary team on a case-by-case basis.

Preoperative Radiation Therapy Dose Reduction for Myxoid Liposarcoma

Myxoid liposarcoma represents approximately 2% of all soft-tissue sarcomas (STSs). Data suggest that myxoid liposarcoma is the STS subtype most sensitive to radiation therapy. The tumor volume shrinks during and/or after radiation therapy, and these tumors are associated with exceptionally high local control rates of 96% to 98% following standard 50 Gy preoperative radiation therapy.¹⁶^,¹⁷^,¹⁸^,¹⁹^,²⁰ In addition, pathology studies demonstrate at least 50% pathologic response in 78% to 100% of resected myxoid liposarcoma specimens following standard preoperative radiation therapy.¹⁹^,²⁰ These data suggest that reduction of preoperative radiation therapy dose may be an effective treatment strategy for myxoid liposarcomas. The benefit of reducing radiation therapy dose is a lower risk of wound complications and long-term, irreversible adverse effects.

The Dose Reduction of Preoperative Radiotherapy in Myxoid Liposarcomas study in 2021 prospectively evaluated the efficacy of reducing the preoperative radiation therapy dose from 50 to 36 Gy in 2-Gy fractions for myxoid liposarcomas.²¹ Seventy-nine patients were enrolled on the multicenter, phase II, nonrandomized controlled trial. The primary end point was extensive treatment response in the definitive resection specimen, defined as 50% or better histologic treatment effect. The dose reduction was considered successful if at least 70% of patients achieved an extensive treatment response. Seventy-one percent of tumors had no more than 5% round cell component. An extensive pathologic treatment response was observed in 91% of patients, and after a median follow-up of 25 months, no local relapses occurred. Furthermore, the wound complication rate was 17% and the rate of grade 2 or higher toxicity was 14%.²¹

The Dose Reduction of Preoperative Radiotherapy in Myxoid Liposarcomas study results suggest that a reduced preoperative radiation therapy dose of 36 Gy is effective in the treatment of myxoid liposarcomas and is likely associated with less morbidity than that in historical control patients.⁵^,²¹^,²² Therefore, 36 Gy in 2-Gy fractions can be considered the standard preoperative radiation therapy approach for most myxoid liposarcomas. What remains unclear is the optimal preoperative radiation therapy dose in tumors with a high round cell component and the precise definition of this, given that percent round cell differentiation is associated with a poorer prognosis.²³

Hypofractionated Preoperative Radiation Therapy

Radiation therapy has traditionally been delivered using conventional fractionation (1.8 to 2 Gy per fraction) over several weeks. With the advent of newer radiation techniques and improved image guidance, there is increasing interest in the delivery of more abbreviated radiation courses using hypofractionation. This means delivery of an equivalent dose of radiation that would normally be administered in 5 weeks over a course of 1 to 3 weeks, using higher doses each day (>2 Gy per fraction).

Table 2 summarizes studies evaluating the use of hypofractionated preoperative radiation therapy in extremity STS.²⁴^,²⁵^,²⁶^,²⁷^,²⁸^,²⁹ One of the first studies enrolled 272 patients and used a preoperative EBRT dose of 25 Gy in five fractions followed by immediate surgery.²⁴ These patients had a lower-than-expected local control rate of 80% at 3 years. The wound complication rate was 7% (defined as an event requiring repeat surgery).²⁴ Equivalent total dose in 2-Gy fractions (EQD2) is a formula that is used to convert a hypofractionated dose to the equivalent conventionally fractionated dose of 2 Gy per fraction. The EQD2 for 25 Gy in five fractions is 40 Gy. This is lower than the conventionally fractionated 50 Gy used for preoperative radiation therapy and likely the reason this trial showed substandard local control outcomes. A phase II trial of 52 patients from the University of California Los Angeles underwent treatment with a preoperative dose of 30 Gy in five fractions.²⁵ The EQD2 with this approach is 50 Gy, on par with conventional fractionation. Follow-up is
short; however, local control was more acceptable with a 94.3% rate at 2 years. The wound complication rate was 32% (their primary end point).²⁵

Table 2 Summary of Hypofractionated Preoperative Radiation Therapy Studies for Extremity Soft-Tissue Sarcoma

Study	Dose/Fractionation	N	Median Follow-Up (mo)	Wound Complications	Local Control	Overall Survival
Koseła-Paterczyk et al (2014)	25 Gy/5 fx (EQD2 = 40 Gy)	272	35	32.4%	81% at 3 yr	72% at 5 yr
Kalbasi et al (2020)	30 Gy/5 fx (EQD2 = 50 Gy)	52	29	32%	94.3% at 2 yr	NR
Pennington et al (2018)	28 Gy/8 fx (EQD2 = 35 Gy)	116	71	10%	89% at 3 yr	82% at 3 yr
Parsai et al (2020)	30 Gy/5 fx (EQD2 = 50 Gy)	16	10.7	31.2%	100% at 1 yr	NR
Bedi et al (2022)	30 Gy/5 fx (EQD2 = 50 Gy)	32	36.4	25%	100% at 3 yr	82.2%
Guadagnolo et al (2022)	42.75 Gy/15 fx (EQD2 = 50 Gy)	120	24	31%	93% at 2.5 yr	91% at 2 yr
EQD2 = equivalent total dose in 2-Gy fractions, Fx = fraction

Hypofractionated 3-week preoperative radiotherapy for patients with soft-tissue sarcomas was a prospective, single-arm, phase II study that evaluated 42.75 Gy in 15 fractions (EQD2 = 50 Gy) in 120 patients, making this study the largest study of its kind to date.²⁹ The wound complication rate was 31% (primary end point). Median follow-up thus far is 24 months. Six patients experienced a local recurrence at a median time of 16 months. There were no instances of grade 3+ acute radiation therapy toxicity. Four patients experienced late grade 3 radiation therapy toxicity, including femur fracture, lymphedema, and skin ulceration.²⁹ Long-term follow-up with oncologic and functional outcomes are still pending. These results suggest that modest hypofractionation of 3 weeks is associated with an acceptable wound complication rate and preliminary results of oncologic outcomes and toxicity rates are promising. Two additional trials are currently evaluating modest hypofractionation in large cohorts of patients (https://classic.clinicaltrials.gov/ct2/home; NCT04562480 and NCT04425967).

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