Review Article
External Beam Radiation Therapy for Orthopaedic Pathology Abstract Christopher E. Gross, MD Rachel M. Frank, MD Andrew R. Hsu, MD Aidnag Diaz, MD Steven Gitelis, MD
External beam radiation therapy is essential in the management of a wide spectrum of musculoskeletal conditions, both benign and malignant, including bony and soft-tissue sarcomas, metastatic tumors, pigmented villonodular synovitis, and heterotopic ossification. Radiation therapy, in combination with surgery, helps reduce the functional loss from cancer resections. Although the field of radiation therapy is firmly rooted in physics and radiation biology, its indications and delivery methods are rapidly evolving. External beam radiation therapy mainly comes in the form of four sources of radiotherapy: protons, photons, electrons, and neutrons. Each type of energy has a unique role in treating various pathologies; however, these energy types also have their own distinctive limitations and morbidities.
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From Rush University Medical Center, Chicago, IL. Dr. Gitelis or an immediate family member has received royalties from Wright Medical Technology, serves as a paid consultant to Stryker, and has stock or stock options held in Wright Medical Technology. None of the following authors or any immediate family member has received anything of value from or owns stock in a commercial company or institution related directly or indirectly to the subject of this article: Dr. Gross, Dr. Frank, Dr. Hsu, and Dr. Diaz. J Am Acad Orthop Surg 2015;23: 243-252 http://dx.doi.org/10.5435/ JAAOS-D-14-00022 Copyright 2015 by the American Academy of Orthopaedic Surgeons.
xternal beam radiation therapy (RT) is essential to the management of orthopaedic neoplasia. Its use has evolved as our understanding of cancer biology has developed. The physics of RT, radiobiology, and delivery methods is paramount to understanding the therapeutic uses and limitations of radiation in orthopaedics. The ultimate goal of RT is to provide an adequate dose of radiation to achieve local tumor control while minimizing local normal tissue complications.
Physics of Radiation Therapy The physics behind RT rests in the creation of ionizing radiation, or energy strong enough to displace an orbiting electron from its nucleus. Energy can be particulate, as with protons, electrons, neutrons, and heavy ions, or electromagnetic, as with photons in x-rays or gamma rays.1,2 These particles can then directly or indirectly cause damage to the DNA structure of a cell (Figure 1).
Indirectly, an electron dislodged by a photon will ionize a water molecule to produce a hydroxyl radical, a free radical that will then damage the DNA. In the direct mechanism, a dislodged electron directly causes damage to the DNA structure. The deposition of energy and injury is a random event, with the same proportion of cells damaged per dose. The damage to the DNA molecule may cause either a single- or a double-strand helical break, which can lead to chromosomal aberration and subsequently apoptosis, carcinogenesis, or mutagenesis. Double-stranded breaks are the most lethal to cells. Radiosensitivity of tissue is highest in those tissues with a high mitotic index and lowest in differentiated tissues. Cells tend to be more radiosensitive when they have a high metabolic rate and when they are of a nonspecialized type, such as epithelium, hematopoietic tissues, and germinal cells (ie, ovary, testes). The cell is most susceptible while in the G2 phase of the cell cycle.2
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beyond the distal edge of the tumor and region at risk for microscopic disease, which increases the chances for local tissue complications. Thus, it is technically more difficult to precisely target a tumor that is surrounding important structures because the tolerance of these adjacent critical structures may be less than the dose we would like to prescribe to the target; compromises in dose need to be made to minimize the risk of damage to these adjacent critical structures. As noted in the QUANTEC (Quantitative Analyses of Normal Tissue Effects in the Clinic) study,3 native tissues have a varying sensitivity to radiation, with many critical structures having a documented, well-established dose and volume limitation for radiation exposure.
Figure 1
Particulate Radiation
Illustration demonstrating the direct and indirect action of photons on the DNA structure. In the indirect mechanism, an electron dislodged by a photon ionizes a water molecule to produce a free radical, which will damage the DNA. In the direct mechanism, a dislodged electron directly causes damage to the DNA structure.
Electromagnetic Radiation Electromagnetic radiation follows the inverse square law, in which the intensity of the beam is inversely related to the square of the distance away from the radiation source. When these high-energy photons move through matter, the photons pass their energy to an orbiting electron. When the photon is absorbed, one of three interactions occurs: the photoelectric effect, the Compton effect, or pair production. In the photoelectric effect, a photon strikes the electron and transfers all of its energy to the
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electron, which ionizes other surrounding atoms. The Compton effect occurs, for example, in the manner that a cue ball hits a billiard ball. A photon strikes an electron, and both are deflected. Both the photon and electron can then go on to interact with other atoms. This type of reaction dominates in cancer therapeutics. In pair production, the photon interacts with the nucleus of an atom to produce a positron-electron pair, which will then go on to be biologically active. A limitation of photon therapy is that energy is deposited at a distance
Electrons are small, electronically negative particles that can be accelerated nearly to the speed of light with high-energy linear accelerators. They are especially useful in treating superficial tumors up to a depth of 5 cm as well as areas once treated with photon beam therapy1 (Table 1). The absorption of electrons increases as they pass through air, and it decreases as they pass through bone. Protons are positively charged particles that are approximately 2,000 times heavier than electrons. Currently there is much interest in the utilization of photons, mostly for the reduction (approximately 60%) in total radiation dose to regions of the patient that are outside the targeted treatment region.4 As protons penetrate tissue, they slowly begin to degrade by depositing energy. At a critical threshold, there is a very large deposition of energy called the Bragg peak, followed by an abrupt fall-off of dose. The Bragg peak can be targeted precisely to the tumor depth and contour; it is responsible for the biologic effectiveness of the proton and favorable dose
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Table 1 Advantages and Disadvantages of Radiation Depending on Type of Radiation Types of Radiation Electromagnetic (photon) Electrons
Neutrons
Advantage Cost effective and available in most institutions Long track record, well characterized Available at most institutions Effective Long track record, well characterized Highly lethal Does not need oxygen to be lethal Effective despite cell cycle
Protons
Heavy ions
Bragg peak; no exit dose Sharp dose fall-off leads to decreased integral dose to patient Dose distribution similar to protons As lethal as neutrons
distribution. The main advantage is that there is no exit dose, thus significantly decreasing the integral dose to the patient for a comparable conformal photon plan. Currently, the application of protons is restricted to the relatively few domestic treatment centers available offering proton-based therapy. Protons are valuable in the management of pediatric tumors (where limiting dose to uninvolved tissues is critical to avoid the risk of second malignancy); for radioresistant tumors, such as chondrosarcoma, in locations where photons cannot achieve as high a dose without increased risk of damaging normal organs (Figure 2); and in the retreatment of previously irradiated tissues. The depth-dose curve for each particle is important in understanding each particle’s biologic effect, clinical utility, and limitations (Figure 3). With photons, the energy that trails distally from the tumor bed can cause damage to surrounding healthy tissue. By contrast, protons have a sharp peak by which their energy dissipates.
Disadvantage Poor dose fall-off leading to increased integral dose to patient Not as precise as protons Poor tissue penetrance Limited application in bony tumors Dose fall-off is not as precise as protons Not skin sparing Significant collateral damage Poor dose distribution and very poor dose fall-off No therapeutic index between tumor and normal tissue Expensive, increased difficulty of sophisticated dose manipulation Technology not available in most locations and not well characterized Extremely expensive Technology not available in most locations and not well characterized
This is useful because it spares tissue that is farther away from the radiation source than the tumor.
Fractionation and the Four R’s Fractionation is the division of the total dose of radiation over multiple sessions. This treatment method, important to photon therapy, is based on the radiobiological principles of the so-called four R’s: repair of cellular damage, reoxygenation of the tumor, redistribution within the cell cycle, and repopulation of cells. With smaller doses of radiation, both the normal and tumor cells are exposed to sublethal damage, which damages but does not kill cells. Whereas most healthy tissue can repair itself within 3 to 24 hours, some tumor cells lack the ability to repair as quickly and thus are more susceptible to further doses of radiation. Tumor areas have low oxygen tension due to temporary vessel constriction from mass effect, and tumors may have outgrown their native blood
supply. Hypoxic cells are more resilient to radiation because an environment without oxygen has less potential for the creation of free radicals. Radiation doses may shrink the tumor, allowing hypoxic cells to receive more oxygen; therefore, radiation may produce more free radicals during treatment.5 Cells hit with one dose of radiation are usually in a radioresistant phase of the cell cycle. Allowing time in between doses allows for redistribution to other, more sensitive phases of the cell cycle. Rapidly and slowly growing tumors initially have exponential growth until they plateau. When a tumor mass is shrunk by radiation, its cells undergo rapid repopulation at a more accelerated growth rate. Because some rapidly dividing cells are potentially more radiosensitive, they may be more likely to be killed with the next radiation dose.
Soft-tissue Sarcoma External beam radiation plays a role in the treatment of a variety of primary orthopaedic tumors. Historically, RT
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Figure 2
Illustration demonstrating the dose precision of proton versus electromagnetic radiation (photons). The depth-dose curve for each particle is important in understanding the clinical utility and limitations of each particle. (Reproduced with permission from Hall E, Cox J: Physical and biologic basis of radiation therapy in radiation oncology, in Cox J, Ang K: Radiation Oncology: Rationale, Techniques, Results, ed 9. Philadelphia, PA, Elsevier, 2010, p 41.)
has played a role in the local control of selected primary malignant bone tumors, such as Ewing sarcoma and primary lymphoma of bone, and as an adjuvant therapy for soft-tissue sarcomas. Recent dramatic advances in chemotherapeutic and immunologic agents have improved survival rates, thereby expanding the role of RT in various orthopaedic neoplasms. RT is useful for many pathologies, including soft-tissue sarcoma, Ewing sarcoma,
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giant cell tumor, metastatic disease, desmoid tumor, primary bone lymphoma, pigmented villonodular synovitis, and heterotopic ossification. For purposes of brevity, the more common orthopaedic applications of external beam RT, including soft-tissue sarcomas, bony metastases, primary bone lymphoma, and heterotopic ossification, will be discussed here. Soft-tissue sarcomas of the extremities are often locally and systemically aggressive. Treatment requires local tumor control, usually with limb salvage. Most cases require complete surgical resection along with radiation, sometimes combined with chemotherapy. Soft-tissue sarcomas are surgically challenging because they often invade normal tissue next to the gross tumor. Thus, excision must be performed with wide, negative margins to decrease the risk of local recurrence.6 The creation of wide margins often results in significant morbidity to the local tissue, compromising limb function and cosmesis. Wide margins often require resection of the neurovascular bundle or bone. An alternative is conservative surgical excision, combining wide and marginal margins by the neurovascular bundle, with adjuvant, local RT. However, RT is not without complications, most notably the risk of late secondary malignancy and the risk of local wound, osseous, and soft-tissue compromise. Rosenberg et al7 have shown that RT at doses of 50 to 65 Gy with wide surgical margins is as effective as radical resection at eliminating microscopic tumor extension beyond the gross lesion. Specifically, the combination of limb-sparing surgery and RT for soft-tissue sarcomas has been shown to have a similar rate of disease-free and overall survival compared with that of patients undergoing amputation (disease-free survival, 71% and 78% at 5 years, and overall survival, 83% and 88% at 5 years, respectively),7 with the benefit of
a functional limb. Local control rates up to 90% have been reported following combination treatment with margin-negative limb-sparing surgery and RT for high-grade sarcomas, and up to 100% following treatment of low-grade soft-tissue sarcomas.6-11 Finally, multimodal therapy has also been shown to have a beneficial effect on overall survival of patients with metastatic soft-tissue sarcoma compared with patients treated with single-modality treatments.12
Radiation and Surgery for Sarcoma Radiation combined with surgery is used for most soft-tissue sarcomas,13-15 especially large tumors deep to the fascia close to critical structures, such as nerves, arteries, veins, and bone. Enneking et al16,17 described the growth of the sarcoma as “centrifugal.” As the cancer progresses, an interface, known as a pseudocapsule, develops between the tumor and the surrounding normal structures. It differs from a true capsule because it is contaminated with cancer cells. Islands or pseudopods of tumor extend into this fibrovascular reactive zone, and thus the tumor is not truly encapsulated by a dense fibrotic rim. Any surgical procedure that removes the tumor and passes through this reactive zone (marginal margin) will leave microscopic tumor behind. Enneking et al16,17 also defined four surgical margins. An intralesional margin occurs when the surgical procedure enters into the cancer, thus leaving gross tumor in the surgical bed. A marginal margin passes through the reactive zone around the tumor and will likely leave microscopic tumor behind. A wide margin removes the cancer with a cuff of normal tissue completely encircling the tumor. Conceptually, a wide margin will remove the pseudocapsule and microscopic cancer cells; it represents the benchmark of most soft-tissue sarcoma
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Figure 3
Dose distribution of electromagnetic radiation (A), electrons (B), and protons (C). Notice that when the proton is modulated, the Bragg peak (BP) spreads out over several centimeters. SOBP = spread-out Bragg peak. (Reproduced with permission from Ang KK, Milas L, Shiv A, Myers EN: General Principles of Radiation Therapy for Cancer of the Head and Neck. Philadelphia, PA, Elsevier, 2003, pp 1-850.)
operations. Finally, a radical margin, rarely used, is the removal of the cancer along with the muscular compartment from origin to insertion. An intra-articular sarcoma requires removal of the joint en bloc. Similarly, sarcomas with extensive disease
involvement encasing nearby neurovascular structures may also need to be removed via radical resection. Adequacy of tumor margin resection is significantly associated with local relapse, whereas the size of the tumor is associated with the risk of
systemic disease.18 Other prognostic factors include age .60 years, extracompartmental location, high histologic grade, and location in the lower extremity.19 When a soft-tissue sarcoma is irradiated, predictably the tumor
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will become truly marginated. Rather than a pseudocapsule surrounding the tumor, a fibrotic margin is created after the irradiation.20 Radiation will make a wide/ marginal margin adequate under some circumstances. Most surgeons who use preoperative RT will try to achieve a wide margin around most of the cancer and will accept a marginal margin by nerves, arteries, and veins for that part of the surgical dissection. Combining preoperative RT and surgery, even with a mixed wide/marginal margin, achieves local control comparable to that of an amputation. The incidence of local recurrence is 5% to 10% when radiation is combined with surgery in a limb-salvage technique.21 This number is comparable to what would be achieved with amputation. Not all soft-tissue sarcomas require RT, including some low-grade tumors with negative margins; however, treatment is dependent on many factors and must be individualized.22 Yang et al23 performed a prospective, randomized clinical trial in patients with high-grade lesions who underwent surgery plus postoperative chemotherapy, with or without postoperative adjuvant RT, and in patients with low-grade lesions who underwent surgery, with or without postoperative adjuvant RT. At 10 years postoperative, the authors found no local recurrences in the high-grade RT group compared with a 22% local recurrence rate in patients who had not undergone RT; similar results were found in the low-grade group (4% with RT versus 33% without RT). Of note, RT did not have an effect on overall survival in any of the groups.23
Preoperative and Postoperative Radiation Therapy The timing of RT in soft-tissue sarcoma is also under debate.13-15 One advantage of preoperative RT is that
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there exists a “defined target” that is more distinct than a postoperative bed; therefore, less normal tissue is irradiated. In addition, preoperative RT can cause tumor shrinkage, depending on the cancer type. Preoperative RT will cause variable amounts of tumor necrosis and will predictably marginate the tumor. Although a paucity of data exists on this specific topic, one prospective randomized trial by Davis et al13 did report on the functional and health status outcomes of 190 patients with extremity soft-tissue sarcomas who underwent preoperative versus postoperative RT. Despite the fact that patients in the postoperative group had better functional outcomes at 6 weeks, there was no difference with regard to local recurrence, overall survival, or functional outcome at later time points. Furthermore, patients whose tumors exhibited certain characteristics (eg, larger lower extremity, motor nerve damage) and who had wound complications had significantly worse functional outcomes.13 In patients with soft-tissue sarcomas with positive margins following preoperative RT followed by surgical excisions, a postoperative radiation boost (typically, 16 Gy postoperatively) did not provide any increased local recurrence survival compared with similar patients not given a boost.24 Interestingly, while wound complications are noted more often in the preoperative group, these are typically reversible. In contrast, in postoperative RT patients, irreversible local soft-tissue complications are more frequently encountered. Of note, tumor proximity to the skin surface (,3 cm) is an independent risk factor for major wound complications following preoperative RT and surgery.25 These complications can be minimized with the use of durable muscle flaps covering the tumor bed and radiation field (Table 2). In a randomized trial conducted by O’Sullivan et al14 that compared
preoperative to postoperative RT in patients with soft-tissue sarcomas, preoperative RT was associated with a greater risk of wound complications. Overall survival was significantly improved in preoperative RT patients compared with postoperative RT patients. Preoperative RT requires lower overall doses and smaller overall field sizes compared with postoperative RT, which may be related to the late toxicity and thus worse functional outcomes associated with higher doses of RT required when therapy is given postoperatively.
Optimal Radiation Therapy Treatment Volume Ideally, radiation treatments aim to avoid inclusion of the entire joint space, a full dose to adjacent bone, and irradiation of adjacent normal tissue outside what is deemed an appropriate margin. The unique biology of sarcomas must be taken into account because sarcomas typically infiltrate along tissue planes as opposed to through tissue planes.26 Recently, the Radiation Therapy Oncology Group reported that the clinical target volume (CTV) for high-grade soft-tissue sarcomas includes the gross tumor volume (GTV) plus 3-cm margins in longitudinal directions. If these margins force the field of treatment beyond the compartment, the field can be shortened to include the end of the compartment.26 This group has also noted that most cases using a CTV of 2 cm (defined as 2 cm longitudinal and 1-cm radial margins) or a CTV of 3 cm (defined as 3 cm longitudinal and 1.5-cm radial margins) contain peritumoral edema, in 97% and 99.8% of cases, respectively.27 This finding is important when considering the proposed RT target volume because peritumoral edema may contain sarcoma cells that may be missed with a smaller CTV. The use of advanced imaging, including T1- and
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Table 2 Advantages and Disadvantages in Giving Preoperative Versus Postoperative Radiation Therapy XRT Preoperative
Advantages An inoperable tumor may become resectable Smaller radiation portals Decreases positive margins intraoperatively
Lower radiation dose than postoperatively
Postoperative
Decreases possibility of tumor seeding during surgery Better surgical staging Total radiation dose is based on residual tumor burden Better wound healing; decreased surgical complications Surgically easier to remove tumor if tissue is not irradiated
Disadvantages Delayed wound healing Increased surgical complications25 Tumor downstaging may make selection of resection margins more difficult in some cases and also confuse whether postoperative chemotherapy would be appropriate May make histologic diagnosis and margin evaluation more difficult due to radiation changes
Must be given in higher doses relative to preoperative doses25 Possibility to seed other tissue If there are healing problems, there is a delay in XRT The volume of tissue to be irradiated is larger because it must now encompass the field, scars, and drain site
If positive margins are left, it is easier to define them with surgical clips XRT = external beam radiation
T2-weighted MRI sequences with gadolinium, has advanced the ability of radiation oncologists to specify the CTV of radiation needed to achieve good local control rates.
Radiation Protocol Preoperative radiation doses are typically 50 Gy delivered over 5 weeks, followed 3 to 5 weeks later by surgical resection. When surgery produces a margin-free resection, postoperative radiation boosts are usually unnecessary. If surgical margins are positive, postoperative boost doses of 16 to 18 Gy to the tumor bed, following adequate healing of the surgical wound, are commonly used, although the data supporting the use of postoperative boost treatment are inconsistent.24 In patients undergoing postoperative RT, treatment usually begins 3 to 4 weeks following resection to allow seroma resorption and wound heal-
ing. The CTV includes the entire surgical bed and large margins, often 4 cm longitudinally and 1.5 to 2 cm radially.26,27 The recommended postoperative dose is controversial, with most studies reporting doses between 50 and 68 Gy.18,28-31 Accepted postoperative RT doses include 60 Gy for patients with negative margins and 66 to 68 Gy in patients with positive margins.8
Metastatic Disease External beam radiation for metastatic disease is typically used for the purpose of pain control rather than for primary treatment of the disease. In cases of long bone metastatic disease, surgical intervention to stabilize the extremity before the application of external beam RT may be indicated. This is especially true in the setting of known pathologic fractures, as well
as with pending pathologic fractures in weight-bearing bones. Typically, external beam RT with a single-fraction dose of 8 Gy is used to provide palliative relief from bone metastases, with rates as high as 60% reported in the literature.32 Multiple trials have demonstrated improved pain relief and better cost effectiveness with this regimen compared with a longer regimen of fractionated doses or with lower single-time doses. 33,34 Of note, pain relief and treatmentrelated toxicity ramifications were similar in each of these trials comparing single fractions of 8 Gy to multiple fractions of lower doses with a high cumulative dose (up to 20 to 30 Gy); however, a minority of patients receiving single fractions did require repeat treatment at an increased rate compared with the multiple-fraction patients.33,34 Some patients may experience a transient increase in bone pain
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immediately after treatment, which lasts for 1 or 2 days.35 Although in most patients, these symptoms are temporary and of no significance, these patients should be monitored closely, and clinicians must evaluate for the possibility of low-energy trauma leading to pathologic fractures.
Primary Lymphoma of Bone Primary bone lymphoma accounts for approximately 3% to 5% of all malignant bone tumors, and overall, it accounts for ,1% of all non-Hodgkin lymphomas.36 Histologically, the most common subtype of primary bone lymphoma is diffuse large B cell lymphoma, responsible for up to 70% of cases. Treatment of primary bone lymphoma most often includes a combination of multi-agent chemotherapy and radiotherapy.37 Surgery is reserved only for the treatment of pending or existing pathologic fractures. Currently, there is no agreed-upon benchmark for the treatment of primary lymphoma of bone. Furthermore, with recent advances in the development of immunologic agents, some studies have shown high rates of complete response following chemotherapy without adjuvant RT.36 Nevertheless, there are currently no randomized, controlled, clinical trials comparing treatment options, though the literature does show a trend toward combined modality therapy. As noted by Ng and Mauch,38 the addition of RT to systemic chemotherapy helps reduce the percentage of isolated relapse at initial sites. These authors do note, however, that the true contribution of RT to disease-free and overall survival, compared with the current standard systemic therapy (for B cell lymphoma) without RT, is still unknown.38 Currently, there are no conclusive data on the appropriate volume and dose of adjuvant external beam radiation; however, most studies with this information available describe treatments in
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the range of 35 to 45 Gy in 1.8- to 2Gy fractions.36 Whereas higher doses may be used in cases of suboptimal response, it is important to note that doses .50 Gy have been associated with an increased risk of pathologic fracture in weight-bearing bones.36
Heterotopic Ossification Prophylaxis Heterotopic ossification (HO) is the process of bone formation in soft tissue outside the skeleton. Although uncommon, the development of HO after total hip arthroplasty, and less commonly after total knee arthroplasty or intra-articular elbow surgery, can be devastating. The triggering factor initiating the development of HO remains unknown, but once the process is started, primitive mesenchymal stem cells differentiate into osteoprogenitor cells, which ultimately form osteoblasts. Osteoid matrix begins to form in these tissues, which ultimately calcifies into lamellar bone. This process typically occurs within 16 hours of the index operation, with maximal stimulus for bone formation at 32 hours postoperatively. Thus, prophylactic strategies to counteract the development of HO are most beneficial preoperatively or within the first 24 to 48 hours postoperatively. Interestingly, HO typically remodels and increases in mass size over the first year to 2 years postoperatively as osteoblastic activity continues to occur while the host soft tissue matures. Because there is a high recurrence rate after resection, the key to treatment is prevention, especially in high-risk patients such as those with a prior history of HO. HO prophylaxis is typically done either with the use of NSAIDs or with external beam radiation. Commonly used protocols include postoperative, single-dose regimens of 600 to 800 Gy performed by postoperative day 3 as well as preoperative, singledose regimens of 800 Gy performed
within 6 hours before surgery. It is thought that the external beam radiation disrupts the ability of the mesenchymal cells to differentiate, thereby decreasing the production of osteoblasts and HO formation. Recent literature has shown promising results with external beam RT; however, equally acceptable results have also been found with NSAID treatment for HO prophylaxis in the hip.39 Complications associated with immediate postoperative radiation for HO prophylaxis are not inconsequential, as noted by a recent randomized trial analyzing RT used for HO prophylaxis after elbow trauma that was cut short following an unacceptably high rate of nonunion in the treatment group (single-dose radiation) compared with that of the control group (no radiation).40
Complications Associated With Radiation Therapy As overall long-term survival rates improve, presumably as a result of better chemotherapy regimens and advances in surgical techniques, late sequelae of RT,41 including wound complications, secondary malignancies, limb-length discrepancy, joint contractures, and pathologic fractures, are becoming increasingly prevalent. Overall, RT for local control of softtissue sarcoma must be considered carefully, and treatment decisions must be individualized. Secondary malignant neoplasms following RT are typically aggressive sarcomas, whereas chemotherapy is more often associated with the late development of hematologic malignancies. The reported incidence of secondary malignancies following the treatment of soft-tissue sarcoma is inconsistent; however, some authors have suggested an overall incidence of 20%, with higher rates in patients who had undergone RT (relative risk, 2.7) as part of their treatment program.42 Expendable bones, such as the rib, fibula, scapula,
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anterior arch of the pelvis, and wing of the ileum, are generally resected without radiation when margins are negative. The risk of long bone fracture is increased if the periosteum is removed, and intramedullary rod fixation should be considered. Long bone diaphyses and joints can be resected, but reconstruction is necessary. The development of a second, radiation-induced sarcoma following RT typically occurs within the prior radiation field43 and is not limited to RT at high doses because even lowdose exposure has been shown to be associated with the development of secondary malignancies.44 Importantly, the risk of developing a future bone sarcoma as well as soft-tissue sarcoma is increased after childhood exposure to high-dose fractionated radiation, including doses $10 Gy.44 This risk has been shown to increase linearly, up through doses of 40 Gy.44 As demonstrated in multiple publications describing the development of soft-tissue sarcomas in survivors of atomic bomb explosions, even lower doses of RT, including exposures of 1 Gy, when sustained at any age, place patients at risk for the development of a future sarcoma.45 Even more worrisome is the recent evidence that suggests that radiationassociated soft-tissue sarcomas have an inferior prognosis compared with sarcomas not related to prior radiation exposure.46 Specifically, Gladdy et al46 conducted a multivariate analysis of 7,649 patients with softtissue sarcomas, 130 of which were associated with prior RT, and found that regardless of sarcoma histology, disease-specific survival was significantly worse in the radiationassociated group. Certainly, given the worsening prognosis of radiationinduced secondary sarcomas, caution is warranted when recommending and administering RT, and a multidisciplinary approach, explaining the risks, benefits, and alternatives to treatment, is warranted in each case.
Future Directions Much research has gone into developing the means to both plan and deliver large, precise doses of radiation to a specific area. Intensitymodulated RT is a highly advanced, precise way to deliver radiation to a desired location. Each radiation beam is shaped with computercontrolled beams to fit the profile of the individual tumor. The shaping, or collimation, of the beam is performed by a multileaf collimator, which modulates the flux of the beam per length. This allows greater sparing of normal tissue and critical structures from the high-dose region. A tradeoff does exist in that large volumes of tissue do receive a low level of radiation. This inherently increases the risk for secondary malignancies. Another frontier technology is imageguided radiation therapy, in which a tumor is imaged with a CT scanner immediately before radiation, such that the patient’s position or computer radiation parameters can be adjusted to reduce interfractional set-up variability. Normally, skin markers are used for positioning. However, this does not take into account positions of the internal target or other healthy tissue structures.47 This RT hopes to improve accuracy while reducing exposure to normal tissue.48 Combining preoperative radiation with chemotherapy for soft-tissue sarcoma is increasingly popular. To minimize complications, the timing of these treatments is critical. Finally, recent advances in our understanding of tumor biology may affect the treatment of soft-tissue sarcomas in the future, especially as our understanding of specific radiosensitizers and radioprotectors improves.49
Conclusion Combined with new ways to image and minimize collateral damage, RT
is evolving rapidly. With advancements in our ability to manipulate radiation to treat musculoskeletal pathology, the hope is to increase the quality of life and disease-free survival for thousands of patients. Although sarcoma was used as our cancer paradigm, other types of cancers will undoubtedly benefit from the advancements in radiation oncology.
References References printed in bold type are those published within the past 5 years. 1. Gazda MC, Coia LR: Principles of radiation therapy, in Pazdur R, Coia LR, Hoskins WJ, Wagman LD, eds: Cancer Management: A Multidisciplinary Approach: Medical, Surgical, and Radiation Oncology, ed 10. Lawrence, Kansas, CMPMedica, 2007. 2. Hall EC: Physical and biologic basis of radiation therapy, in Cox JA, ed: Radiation Oncology, ed 9. Philadelphia, PA, Mosby Elsevier, 2010, pp 3-49. 3. Bentzen SM, Constine LS, Deasy JO, et al: Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC): An introduction to the scientific issues. Int J Radiat Oncol Biol Phys 2010;76(suppl 3):S3-S9. 4. DeLaney TF: Proton therapy in the clinic. Front Radiat Ther Oncol 2011;43:465-485. 5. Brown JM, Lemmon MJ: Tumor hypoxia can be exploited to preferentially sensitize tumors to fractionated irradiation. Int J Radiat Oncol Biol Phys 1991;20(3):457-461. 6. DeLaney TF, Spiro IJ, Suit HD, et al: Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas. Int J Radiat Oncol Biol Phys 2003;56(4):1117-1127. 7. Rosenberg SA, Tepper J, Glatstein E, et al: The treatment of soft-tissue sarcomas of the extremities: Prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 1982;196(3):305-315. 8. Delaney TF: Radiation therapy: Neoadjuvant, adjuvant, or not at all. Surg Oncol Clin N Am 2012;21(2):215-241. 9. Eilber FR, Eckardt J: Surgical management of soft tissue sarcomas. Semin Oncol 1997; 24(5):526-533. 10. Karakousis CP, Emrich LJ, Rao U, Krishnamsetty RM: Feasibility of limb salvage and survival in soft tissue sarcomas. Cancer 1986;57(3):484-491.
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External Beam Radiation Therapy for Orthopaedic Pathology 11. Brant TA, Parsons JT, Marcus RB Jr, et al: Preoperative irradiation for soft tissue sarcomas of the trunk and extremities in adults. Int J Radiat Oncol Biol Phys 1990;19(4):899-906. 12. Bedi M, King DM, Charlson J, et al: Multimodality management of metastatic patients with soft tissue sarcomas may prolong survival. Am J Clin Oncol 2014;37 (3):272-277. 13. Davis AM, O’Sullivan B, Bell RS, et al: Function and health status outcomes in a randomized trial comparing preoperative and postoperative radiotherapy in extremity soft tissue sarcoma. J Clin Oncol 2002;20(22):4472-4477. 14. O’Sullivan B, Davis AM, Turcotte R, et al: Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: A randomised trial. Lancet 2002;359 (9325):2235-2241. 15. Davis AM, O’Sullivan B, Turcotte R, et al; Canadian Sarcoma Group; NCI Canada Clinical Trial Group Randomized Trial: Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol 2005;75(1):48-53. 16. Enneking WF, Spanier SS, Goodman MA: A system for the surgical staging of musculoskeletal sarcoma. 1980. Clin Orthop Relat Res 2003;415:4-18. 17. Enneking WF, Spanier SS, Goodman MA: A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop Relat Res 1980;153:106-120. 18. Bell RS, O’Sullivan B, Liu FF, et al: The surgical margin in soft-tissue sarcoma. J Bone Joint Surg Am 1989;71(3):370-375. 19. Vraa S, Keller J, Nielsen OS, Sneppen O, Jurik AG, Jensen OM: Prognostic factors in soft tissue sarcomas: The Aarhus experience. Eur J Cancer 1998;34(12):1876-1882. 20. Gitelis S, Thomas R, Templeton A, Schajowicz F: Characterization of the pseudocapsule of soft-tissue sarcomas: An experimental study in rats. Clin Orthop Relat Res 1989;246:285-292. 21. Kong CB, Song WS, Cho WH, Oh JM, Jeon DG: Local recurrence has only a small effect on survival in high-risk extremity osteosarcoma. Clin Orthop Relat Res 2012;470(5):1482-1490. 22. Cahlon O, Spierer M, Brennan MF, Singer S, Alektiar KM: Long-term outcomes in extremity soft tissue sarcoma after a pathologically negative re-resection and without radiotherapy. Cancer 2008;112(12):2774-2779. 23. Yang JC, Chang AE, Baker AR, et al: Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1998;16(1):197-203. 24. Al Yami A, Griffin AM, Ferguson PC, et al: Positive surgical margins in soft tissue sarcoma
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treated with preoperative radiation: Is a postoperative boost necessary? Int J Radiat Oncol Biol Phys 2010;77(4):1191-1197.
three canadian cancer centers. Int J Radiat Oncol Biol Phys 2009;75(1):193-197. 36.
Mikhaeel NG: Primary bone lymphoma. Clin Oncol (R Coll Radiol) 2012;24(5):366-370.
25. Baldini EH, Lapidus MR, Wang Q, et al: Predictors for major wound complications following preoperative radiotherapy and surgery for soft-tissue sarcoma of the extremities and trunk: Importance of tumor proximity to skin surface. Ann Surg Oncol 2013;20(5):1494-1499.
37. Beal K, Allen L, Yahalom J: Primary bone lymphoma: Treatment results and prognostic factors with long-term follow-up of 82 patients. Cancer 2006;106(12):2652-2656.
26. Wang D, Bosch W, Roberge D, et al: RTOG sarcoma radiation oncologists reach consensus on gross tumor volume and clinical target volume on computed tomographic images for preoperative radiotherapy of primary soft tissue sarcoma of extremity in Radiation Therapy Oncology Group studies. Int J Radiat Oncol Biol Phys 2011;81(4):e525-e528.
39. Vavken P, Castellani L, Sculco TP: Prophylaxis of heterotopic ossification of the hip: Systematic review and meta-analysis. Clin Orthop Relat Res 2009;467(12):3283-3289.
27. Bahig H, Roberge D, Bosch W, et al: Agreement among RTOG sarcoma radiation oncologists in contouring suspicious peritumoral edema for preoperative radiation therapy of soft tissue sarcoma of the extremity. Int J Radiat Oncol Biol Phys 2013;86(2):298-303. 28. Fein DA, Lee WR, Lanciano RM, et al: Management of extremity soft tissue sarcomas with limb-sparing surgery and postoperative irradiation: Do total dose, overall treatment time, and the surgery-radiotherapy interval impact on local control? Int J Radiat Oncol Biol Phys 1995;32(4):969-976. 29. Mundt AJ, Awan A, Sibley GS, et al: Conservative surgery and adjuvant radiation therapy in the management of adult soft tissue sarcoma of the extremities: Clinical and radiobiological results. Int J Radiat Oncol Biol Phys 1995;32(4):977-985. 30. Pao WJ, Pilepich MV: Postoperative radiotherapy in the treatment of extremity soft tissue sarcomas. Int J Radiat Oncol Biol Phys 1990;19(4):907-911. 31. Robinson M, Barr L, Fisher C, et al: Treatment of extremity soft tissue sarcomas with surgery and radiotherapy. Radiother Oncol 1990;18(3):221-233. 32. Chow E, Zeng L, Salvo N, Dennis K, Tsao M, Lutz S: Update on the systematic review of palliative radiotherapy trials for bone metastases. Clin Oncol (R Coll Radiol) 2012;24(2):112-124. 33. Dennis K, Makhani L, Zeng L, Lam H, Chow E: Single fraction conventional external beam radiation therapy for bone metastases: A systematic review of randomised controlled trials. Radiother Oncol 2013;106(1):5-14. 34. Lutz S, Berk L, Chang E, et al; American Society for Radiation Oncology (ASTRO): Palliative radiotherapy for bone metastases: An ASTRO evidence-based guideline. Int J Radiat Oncol Biol Phys 2011;79(4):965-976. 35. Hird A, Chow E, Zhang L, et al: Determining the incidence of pain flare following palliative radiotherapy for symptomatic bone metastases: Results from
38. Ng AK, Mauch PM: Role of radiation therapy in localized aggressive lymphoma. J Clin Oncol 2007;25(7):757-759.
40. Hamid N, Ashraf N, Bosse MJ, et al: Radiation therapy for heterotopic ossification prophylaxis acutely after elbow trauma: A prospective randomized study. J Bone Joint Surg Am 2010;92(11):2032-2038. 41. Paulino AC: Late effects of radiotherapy for pediatric extremity sarcomas. Int J Radiat Oncol Biol Phys 2004;60(1):265-274. 42. Friedman DL, Whitton J, Leisenring W, et al: Subsequent neoplasms in 5-year survivors of childhood cancer: The Childhood Cancer Survivor Study. J Natl Cancer Inst 2010;102(14):1083-1095. 43.
Wu LC, Kleinerman RA, Curtis RE, Savage SA, de González AB: Patterns of bone sarcomas as a second malignancy in relation to radiotherapy in adulthood and histologic type. Cancer Epidemiol Biomarkers Prev 2012;21(11):1993-1999.
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Berrington de Gonzalez A, Kutsenko A, Rajaraman P: Sarcoma risk after radiation exposure. Clin Sarcoma Res 2012;2(1):18.
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Samartzis D, Nishi N, Cologne J, et al: Ionizing radiation exposure and the development of soft-tissue sarcomas in atomic-bomb survivors. J Bone Joint Surg Am 2013;95(3):222-229.
46. Gladdy RA, Qin LX, Moraco N, et al: Do radiation-associated soft tissue sarcomas have the same prognosis as sporadic soft tissue sarcomas? J Clin Oncol 2010;28(12): 2064-2069. 47. MacKay RI, Graham PA, Logue JP, Moore CJ: Patient positioning using detailed three-dimensional surface data for patients undergoing conformal radiation therapy for carcinoma of the prostate: A feasibility study. Int J Radiat Oncol Biol Phys 2001;49(1):225-230. 48. Hansen EK, Larson DA, Aubin M, et al: Image-guided radiotherapy using megavoltage cone-beam computed tomography for treatment of paraspinous tumors in the presence of orthopedic hardware. Int J Radiat Oncol Biol Phys 2006;66(2):323-326. 49. Spalding AC, Lawrence TS: New and emerging radiosensitizers and radioprotectors. Cancer Invest 2006;24(4):444-456.
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External Beam Radiation Therapy for Orthopaedic Pathology Abstract Christopher E. Gross, MD Rachel M. Frank, MD Andrew R. Hsu, MD Aidnag Diaz, MD Steven Gitelis, MD
External beam radiation therapy is essential in the management of a wide spectrum of musculoskeletal conditions, both benign and malignant, including bony and soft-tissue sarcomas, metastatic tumors, pigmented villonodular synovitis, and heterotopic ossification. Radiation therapy, in combination with surgery, helps reduce the functional loss from cancer resections. Although the field of radiation therapy is firmly rooted in physics and radiation biology, its indications and delivery methods are rapidly evolving. External beam radiation therapy mainly comes in the form of four sources of radiotherapy: protons, photons, electrons, and neutrons. Each type of energy has a unique role in treating various pathologies; however, these energy types also have their own distinctive limitations and morbidities.
E
From Rush University Medical Center, Chicago, IL. Dr. Gitelis or an immediate family member has received royalties from Wright Medical Technology, serves as a paid consultant to Stryker, and has stock or stock options held in Wright Medical Technology. None of the following authors or any immediate family member has received anything of value from or owns stock in a commercial company or institution related directly or indirectly to the subject of this article: Dr. Gross, Dr. Frank, Dr. Hsu, and Dr. Diaz. J Am Acad Orthop Surg 2015;23: 243-252 http://dx.doi.org/10.5435/ JAAOS-D-14-00022 Copyright 2015 by the American Academy of Orthopaedic Surgeons.
xternal beam radiation therapy (RT) is essential to the management of orthopaedic neoplasia. Its use has evolved as our understanding of cancer biology has developed. The physics of RT, radiobiology, and delivery methods is paramount to understanding the therapeutic uses and limitations of radiation in orthopaedics. The ultimate goal of RT is to provide an adequate dose of radiation to achieve local tumor control while minimizing local normal tissue complications.
Physics of Radiation Therapy The physics behind RT rests in the creation of ionizing radiation, or energy strong enough to displace an orbiting electron from its nucleus. Energy can be particulate, as with protons, electrons, neutrons, and heavy ions, or electromagnetic, as with photons in x-rays or gamma rays.1,2 These particles can then directly or indirectly cause damage to the DNA structure of a cell (Figure 1).
Indirectly, an electron dislodged by a photon will ionize a water molecule to produce a hydroxyl radical, a free radical that will then damage the DNA. In the direct mechanism, a dislodged electron directly causes damage to the DNA structure. The deposition of energy and injury is a random event, with the same proportion of cells damaged per dose. The damage to the DNA molecule may cause either a single- or a double-strand helical break, which can lead to chromosomal aberration and subsequently apoptosis, carcinogenesis, or mutagenesis. Double-stranded breaks are the most lethal to cells. Radiosensitivity of tissue is highest in those tissues with a high mitotic index and lowest in differentiated tissues. Cells tend to be more radiosensitive when they have a high metabolic rate and when they are of a nonspecialized type, such as epithelium, hematopoietic tissues, and germinal cells (ie, ovary, testes). The cell is most susceptible while in the G2 phase of the cell cycle.2
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beyond the distal edge of the tumor and region at risk for microscopic disease, which increases the chances for local tissue complications. Thus, it is technically more difficult to precisely target a tumor that is surrounding important structures because the tolerance of these adjacent critical structures may be less than the dose we would like to prescribe to the target; compromises in dose need to be made to minimize the risk of damage to these adjacent critical structures. As noted in the QUANTEC (Quantitative Analyses of Normal Tissue Effects in the Clinic) study,3 native tissues have a varying sensitivity to radiation, with many critical structures having a documented, well-established dose and volume limitation for radiation exposure.
Figure 1
Particulate Radiation
Illustration demonstrating the direct and indirect action of photons on the DNA structure. In the indirect mechanism, an electron dislodged by a photon ionizes a water molecule to produce a free radical, which will damage the DNA. In the direct mechanism, a dislodged electron directly causes damage to the DNA structure.
Electromagnetic Radiation Electromagnetic radiation follows the inverse square law, in which the intensity of the beam is inversely related to the square of the distance away from the radiation source. When these high-energy photons move through matter, the photons pass their energy to an orbiting electron. When the photon is absorbed, one of three interactions occurs: the photoelectric effect, the Compton effect, or pair production. In the photoelectric effect, a photon strikes the electron and transfers all of its energy to the
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electron, which ionizes other surrounding atoms. The Compton effect occurs, for example, in the manner that a cue ball hits a billiard ball. A photon strikes an electron, and both are deflected. Both the photon and electron can then go on to interact with other atoms. This type of reaction dominates in cancer therapeutics. In pair production, the photon interacts with the nucleus of an atom to produce a positron-electron pair, which will then go on to be biologically active. A limitation of photon therapy is that energy is deposited at a distance
Electrons are small, electronically negative particles that can be accelerated nearly to the speed of light with high-energy linear accelerators. They are especially useful in treating superficial tumors up to a depth of 5 cm as well as areas once treated with photon beam therapy1 (Table 1). The absorption of electrons increases as they pass through air, and it decreases as they pass through bone. Protons are positively charged particles that are approximately 2,000 times heavier than electrons. Currently there is much interest in the utilization of photons, mostly for the reduction (approximately 60%) in total radiation dose to regions of the patient that are outside the targeted treatment region.4 As protons penetrate tissue, they slowly begin to degrade by depositing energy. At a critical threshold, there is a very large deposition of energy called the Bragg peak, followed by an abrupt fall-off of dose. The Bragg peak can be targeted precisely to the tumor depth and contour; it is responsible for the biologic effectiveness of the proton and favorable dose
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Table 1 Advantages and Disadvantages of Radiation Depending on Type of Radiation Types of Radiation Electromagnetic (photon) Electrons
Neutrons
Advantage Cost effective and available in most institutions Long track record, well characterized Available at most institutions Effective Long track record, well characterized Highly lethal Does not need oxygen to be lethal Effective despite cell cycle
Protons
Heavy ions
Bragg peak; no exit dose Sharp dose fall-off leads to decreased integral dose to patient Dose distribution similar to protons As lethal as neutrons
distribution. The main advantage is that there is no exit dose, thus significantly decreasing the integral dose to the patient for a comparable conformal photon plan. Currently, the application of protons is restricted to the relatively few domestic treatment centers available offering proton-based therapy. Protons are valuable in the management of pediatric tumors (where limiting dose to uninvolved tissues is critical to avoid the risk of second malignancy); for radioresistant tumors, such as chondrosarcoma, in locations where photons cannot achieve as high a dose without increased risk of damaging normal organs (Figure 2); and in the retreatment of previously irradiated tissues. The depth-dose curve for each particle is important in understanding each particle’s biologic effect, clinical utility, and limitations (Figure 3). With photons, the energy that trails distally from the tumor bed can cause damage to surrounding healthy tissue. By contrast, protons have a sharp peak by which their energy dissipates.
Disadvantage Poor dose fall-off leading to increased integral dose to patient Not as precise as protons Poor tissue penetrance Limited application in bony tumors Dose fall-off is not as precise as protons Not skin sparing Significant collateral damage Poor dose distribution and very poor dose fall-off No therapeutic index between tumor and normal tissue Expensive, increased difficulty of sophisticated dose manipulation Technology not available in most locations and not well characterized Extremely expensive Technology not available in most locations and not well characterized
This is useful because it spares tissue that is farther away from the radiation source than the tumor.
Fractionation and the Four R’s Fractionation is the division of the total dose of radiation over multiple sessions. This treatment method, important to photon therapy, is based on the radiobiological principles of the so-called four R’s: repair of cellular damage, reoxygenation of the tumor, redistribution within the cell cycle, and repopulation of cells. With smaller doses of radiation, both the normal and tumor cells are exposed to sublethal damage, which damages but does not kill cells. Whereas most healthy tissue can repair itself within 3 to 24 hours, some tumor cells lack the ability to repair as quickly and thus are more susceptible to further doses of radiation. Tumor areas have low oxygen tension due to temporary vessel constriction from mass effect, and tumors may have outgrown their native blood
supply. Hypoxic cells are more resilient to radiation because an environment without oxygen has less potential for the creation of free radicals. Radiation doses may shrink the tumor, allowing hypoxic cells to receive more oxygen; therefore, radiation may produce more free radicals during treatment.5 Cells hit with one dose of radiation are usually in a radioresistant phase of the cell cycle. Allowing time in between doses allows for redistribution to other, more sensitive phases of the cell cycle. Rapidly and slowly growing tumors initially have exponential growth until they plateau. When a tumor mass is shrunk by radiation, its cells undergo rapid repopulation at a more accelerated growth rate. Because some rapidly dividing cells are potentially more radiosensitive, they may be more likely to be killed with the next radiation dose.
Soft-tissue Sarcoma External beam radiation plays a role in the treatment of a variety of primary orthopaedic tumors. Historically, RT
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Figure 2
Illustration demonstrating the dose precision of proton versus electromagnetic radiation (photons). The depth-dose curve for each particle is important in understanding the clinical utility and limitations of each particle. (Reproduced with permission from Hall E, Cox J: Physical and biologic basis of radiation therapy in radiation oncology, in Cox J, Ang K: Radiation Oncology: Rationale, Techniques, Results, ed 9. Philadelphia, PA, Elsevier, 2010, p 41.)
has played a role in the local control of selected primary malignant bone tumors, such as Ewing sarcoma and primary lymphoma of bone, and as an adjuvant therapy for soft-tissue sarcomas. Recent dramatic advances in chemotherapeutic and immunologic agents have improved survival rates, thereby expanding the role of RT in various orthopaedic neoplasms. RT is useful for many pathologies, including soft-tissue sarcoma, Ewing sarcoma,
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giant cell tumor, metastatic disease, desmoid tumor, primary bone lymphoma, pigmented villonodular synovitis, and heterotopic ossification. For purposes of brevity, the more common orthopaedic applications of external beam RT, including soft-tissue sarcomas, bony metastases, primary bone lymphoma, and heterotopic ossification, will be discussed here. Soft-tissue sarcomas of the extremities are often locally and systemically aggressive. Treatment requires local tumor control, usually with limb salvage. Most cases require complete surgical resection along with radiation, sometimes combined with chemotherapy. Soft-tissue sarcomas are surgically challenging because they often invade normal tissue next to the gross tumor. Thus, excision must be performed with wide, negative margins to decrease the risk of local recurrence.6 The creation of wide margins often results in significant morbidity to the local tissue, compromising limb function and cosmesis. Wide margins often require resection of the neurovascular bundle or bone. An alternative is conservative surgical excision, combining wide and marginal margins by the neurovascular bundle, with adjuvant, local RT. However, RT is not without complications, most notably the risk of late secondary malignancy and the risk of local wound, osseous, and soft-tissue compromise. Rosenberg et al7 have shown that RT at doses of 50 to 65 Gy with wide surgical margins is as effective as radical resection at eliminating microscopic tumor extension beyond the gross lesion. Specifically, the combination of limb-sparing surgery and RT for soft-tissue sarcomas has been shown to have a similar rate of disease-free and overall survival compared with that of patients undergoing amputation (disease-free survival, 71% and 78% at 5 years, and overall survival, 83% and 88% at 5 years, respectively),7 with the benefit of
a functional limb. Local control rates up to 90% have been reported following combination treatment with margin-negative limb-sparing surgery and RT for high-grade sarcomas, and up to 100% following treatment of low-grade soft-tissue sarcomas.6-11 Finally, multimodal therapy has also been shown to have a beneficial effect on overall survival of patients with metastatic soft-tissue sarcoma compared with patients treated with single-modality treatments.12
Radiation and Surgery for Sarcoma Radiation combined with surgery is used for most soft-tissue sarcomas,13-15 especially large tumors deep to the fascia close to critical structures, such as nerves, arteries, veins, and bone. Enneking et al16,17 described the growth of the sarcoma as “centrifugal.” As the cancer progresses, an interface, known as a pseudocapsule, develops between the tumor and the surrounding normal structures. It differs from a true capsule because it is contaminated with cancer cells. Islands or pseudopods of tumor extend into this fibrovascular reactive zone, and thus the tumor is not truly encapsulated by a dense fibrotic rim. Any surgical procedure that removes the tumor and passes through this reactive zone (marginal margin) will leave microscopic tumor behind. Enneking et al16,17 also defined four surgical margins. An intralesional margin occurs when the surgical procedure enters into the cancer, thus leaving gross tumor in the surgical bed. A marginal margin passes through the reactive zone around the tumor and will likely leave microscopic tumor behind. A wide margin removes the cancer with a cuff of normal tissue completely encircling the tumor. Conceptually, a wide margin will remove the pseudocapsule and microscopic cancer cells; it represents the benchmark of most soft-tissue sarcoma
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Figure 3
Dose distribution of electromagnetic radiation (A), electrons (B), and protons (C). Notice that when the proton is modulated, the Bragg peak (BP) spreads out over several centimeters. SOBP = spread-out Bragg peak. (Reproduced with permission from Ang KK, Milas L, Shiv A, Myers EN: General Principles of Radiation Therapy for Cancer of the Head and Neck. Philadelphia, PA, Elsevier, 2003, pp 1-850.)
operations. Finally, a radical margin, rarely used, is the removal of the cancer along with the muscular compartment from origin to insertion. An intra-articular sarcoma requires removal of the joint en bloc. Similarly, sarcomas with extensive disease
involvement encasing nearby neurovascular structures may also need to be removed via radical resection. Adequacy of tumor margin resection is significantly associated with local relapse, whereas the size of the tumor is associated with the risk of
systemic disease.18 Other prognostic factors include age .60 years, extracompartmental location, high histologic grade, and location in the lower extremity.19 When a soft-tissue sarcoma is irradiated, predictably the tumor
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will become truly marginated. Rather than a pseudocapsule surrounding the tumor, a fibrotic margin is created after the irradiation.20 Radiation will make a wide/ marginal margin adequate under some circumstances. Most surgeons who use preoperative RT will try to achieve a wide margin around most of the cancer and will accept a marginal margin by nerves, arteries, and veins for that part of the surgical dissection. Combining preoperative RT and surgery, even with a mixed wide/marginal margin, achieves local control comparable to that of an amputation. The incidence of local recurrence is 5% to 10% when radiation is combined with surgery in a limb-salvage technique.21 This number is comparable to what would be achieved with amputation. Not all soft-tissue sarcomas require RT, including some low-grade tumors with negative margins; however, treatment is dependent on many factors and must be individualized.22 Yang et al23 performed a prospective, randomized clinical trial in patients with high-grade lesions who underwent surgery plus postoperative chemotherapy, with or without postoperative adjuvant RT, and in patients with low-grade lesions who underwent surgery, with or without postoperative adjuvant RT. At 10 years postoperative, the authors found no local recurrences in the high-grade RT group compared with a 22% local recurrence rate in patients who had not undergone RT; similar results were found in the low-grade group (4% with RT versus 33% without RT). Of note, RT did not have an effect on overall survival in any of the groups.23
Preoperative and Postoperative Radiation Therapy The timing of RT in soft-tissue sarcoma is also under debate.13-15 One advantage of preoperative RT is that
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there exists a “defined target” that is more distinct than a postoperative bed; therefore, less normal tissue is irradiated. In addition, preoperative RT can cause tumor shrinkage, depending on the cancer type. Preoperative RT will cause variable amounts of tumor necrosis and will predictably marginate the tumor. Although a paucity of data exists on this specific topic, one prospective randomized trial by Davis et al13 did report on the functional and health status outcomes of 190 patients with extremity soft-tissue sarcomas who underwent preoperative versus postoperative RT. Despite the fact that patients in the postoperative group had better functional outcomes at 6 weeks, there was no difference with regard to local recurrence, overall survival, or functional outcome at later time points. Furthermore, patients whose tumors exhibited certain characteristics (eg, larger lower extremity, motor nerve damage) and who had wound complications had significantly worse functional outcomes.13 In patients with soft-tissue sarcomas with positive margins following preoperative RT followed by surgical excisions, a postoperative radiation boost (typically, 16 Gy postoperatively) did not provide any increased local recurrence survival compared with similar patients not given a boost.24 Interestingly, while wound complications are noted more often in the preoperative group, these are typically reversible. In contrast, in postoperative RT patients, irreversible local soft-tissue complications are more frequently encountered. Of note, tumor proximity to the skin surface (,3 cm) is an independent risk factor for major wound complications following preoperative RT and surgery.25 These complications can be minimized with the use of durable muscle flaps covering the tumor bed and radiation field (Table 2). In a randomized trial conducted by O’Sullivan et al14 that compared
preoperative to postoperative RT in patients with soft-tissue sarcomas, preoperative RT was associated with a greater risk of wound complications. Overall survival was significantly improved in preoperative RT patients compared with postoperative RT patients. Preoperative RT requires lower overall doses and smaller overall field sizes compared with postoperative RT, which may be related to the late toxicity and thus worse functional outcomes associated with higher doses of RT required when therapy is given postoperatively.
Optimal Radiation Therapy Treatment Volume Ideally, radiation treatments aim to avoid inclusion of the entire joint space, a full dose to adjacent bone, and irradiation of adjacent normal tissue outside what is deemed an appropriate margin. The unique biology of sarcomas must be taken into account because sarcomas typically infiltrate along tissue planes as opposed to through tissue planes.26 Recently, the Radiation Therapy Oncology Group reported that the clinical target volume (CTV) for high-grade soft-tissue sarcomas includes the gross tumor volume (GTV) plus 3-cm margins in longitudinal directions. If these margins force the field of treatment beyond the compartment, the field can be shortened to include the end of the compartment.26 This group has also noted that most cases using a CTV of 2 cm (defined as 2 cm longitudinal and 1-cm radial margins) or a CTV of 3 cm (defined as 3 cm longitudinal and 1.5-cm radial margins) contain peritumoral edema, in 97% and 99.8% of cases, respectively.27 This finding is important when considering the proposed RT target volume because peritumoral edema may contain sarcoma cells that may be missed with a smaller CTV. The use of advanced imaging, including T1- and
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Table 2 Advantages and Disadvantages in Giving Preoperative Versus Postoperative Radiation Therapy XRT Preoperative
Advantages An inoperable tumor may become resectable Smaller radiation portals Decreases positive margins intraoperatively
Lower radiation dose than postoperatively
Postoperative
Decreases possibility of tumor seeding during surgery Better surgical staging Total radiation dose is based on residual tumor burden Better wound healing; decreased surgical complications Surgically easier to remove tumor if tissue is not irradiated
Disadvantages Delayed wound healing Increased surgical complications25 Tumor downstaging may make selection of resection margins more difficult in some cases and also confuse whether postoperative chemotherapy would be appropriate May make histologic diagnosis and margin evaluation more difficult due to radiation changes
Must be given in higher doses relative to preoperative doses25 Possibility to seed other tissue If there are healing problems, there is a delay in XRT The volume of tissue to be irradiated is larger because it must now encompass the field, scars, and drain site
If positive margins are left, it is easier to define them with surgical clips XRT = external beam radiation
T2-weighted MRI sequences with gadolinium, has advanced the ability of radiation oncologists to specify the CTV of radiation needed to achieve good local control rates.
Radiation Protocol Preoperative radiation doses are typically 50 Gy delivered over 5 weeks, followed 3 to 5 weeks later by surgical resection. When surgery produces a margin-free resection, postoperative radiation boosts are usually unnecessary. If surgical margins are positive, postoperative boost doses of 16 to 18 Gy to the tumor bed, following adequate healing of the surgical wound, are commonly used, although the data supporting the use of postoperative boost treatment are inconsistent.24 In patients undergoing postoperative RT, treatment usually begins 3 to 4 weeks following resection to allow seroma resorption and wound heal-
ing. The CTV includes the entire surgical bed and large margins, often 4 cm longitudinally and 1.5 to 2 cm radially.26,27 The recommended postoperative dose is controversial, with most studies reporting doses between 50 and 68 Gy.18,28-31 Accepted postoperative RT doses include 60 Gy for patients with negative margins and 66 to 68 Gy in patients with positive margins.8
Metastatic Disease External beam radiation for metastatic disease is typically used for the purpose of pain control rather than for primary treatment of the disease. In cases of long bone metastatic disease, surgical intervention to stabilize the extremity before the application of external beam RT may be indicated. This is especially true in the setting of known pathologic fractures, as well
as with pending pathologic fractures in weight-bearing bones. Typically, external beam RT with a single-fraction dose of 8 Gy is used to provide palliative relief from bone metastases, with rates as high as 60% reported in the literature.32 Multiple trials have demonstrated improved pain relief and better cost effectiveness with this regimen compared with a longer regimen of fractionated doses or with lower single-time doses. 33,34 Of note, pain relief and treatmentrelated toxicity ramifications were similar in each of these trials comparing single fractions of 8 Gy to multiple fractions of lower doses with a high cumulative dose (up to 20 to 30 Gy); however, a minority of patients receiving single fractions did require repeat treatment at an increased rate compared with the multiple-fraction patients.33,34 Some patients may experience a transient increase in bone pain
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immediately after treatment, which lasts for 1 or 2 days.35 Although in most patients, these symptoms are temporary and of no significance, these patients should be monitored closely, and clinicians must evaluate for the possibility of low-energy trauma leading to pathologic fractures.
Primary Lymphoma of Bone Primary bone lymphoma accounts for approximately 3% to 5% of all malignant bone tumors, and overall, it accounts for ,1% of all non-Hodgkin lymphomas.36 Histologically, the most common subtype of primary bone lymphoma is diffuse large B cell lymphoma, responsible for up to 70% of cases. Treatment of primary bone lymphoma most often includes a combination of multi-agent chemotherapy and radiotherapy.37 Surgery is reserved only for the treatment of pending or existing pathologic fractures. Currently, there is no agreed-upon benchmark for the treatment of primary lymphoma of bone. Furthermore, with recent advances in the development of immunologic agents, some studies have shown high rates of complete response following chemotherapy without adjuvant RT.36 Nevertheless, there are currently no randomized, controlled, clinical trials comparing treatment options, though the literature does show a trend toward combined modality therapy. As noted by Ng and Mauch,38 the addition of RT to systemic chemotherapy helps reduce the percentage of isolated relapse at initial sites. These authors do note, however, that the true contribution of RT to disease-free and overall survival, compared with the current standard systemic therapy (for B cell lymphoma) without RT, is still unknown.38 Currently, there are no conclusive data on the appropriate volume and dose of adjuvant external beam radiation; however, most studies with this information available describe treatments in
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the range of 35 to 45 Gy in 1.8- to 2Gy fractions.36 Whereas higher doses may be used in cases of suboptimal response, it is important to note that doses .50 Gy have been associated with an increased risk of pathologic fracture in weight-bearing bones.36
Heterotopic Ossification Prophylaxis Heterotopic ossification (HO) is the process of bone formation in soft tissue outside the skeleton. Although uncommon, the development of HO after total hip arthroplasty, and less commonly after total knee arthroplasty or intra-articular elbow surgery, can be devastating. The triggering factor initiating the development of HO remains unknown, but once the process is started, primitive mesenchymal stem cells differentiate into osteoprogenitor cells, which ultimately form osteoblasts. Osteoid matrix begins to form in these tissues, which ultimately calcifies into lamellar bone. This process typically occurs within 16 hours of the index operation, with maximal stimulus for bone formation at 32 hours postoperatively. Thus, prophylactic strategies to counteract the development of HO are most beneficial preoperatively or within the first 24 to 48 hours postoperatively. Interestingly, HO typically remodels and increases in mass size over the first year to 2 years postoperatively as osteoblastic activity continues to occur while the host soft tissue matures. Because there is a high recurrence rate after resection, the key to treatment is prevention, especially in high-risk patients such as those with a prior history of HO. HO prophylaxis is typically done either with the use of NSAIDs or with external beam radiation. Commonly used protocols include postoperative, single-dose regimens of 600 to 800 Gy performed by postoperative day 3 as well as preoperative, singledose regimens of 800 Gy performed
within 6 hours before surgery. It is thought that the external beam radiation disrupts the ability of the mesenchymal cells to differentiate, thereby decreasing the production of osteoblasts and HO formation. Recent literature has shown promising results with external beam RT; however, equally acceptable results have also been found with NSAID treatment for HO prophylaxis in the hip.39 Complications associated with immediate postoperative radiation for HO prophylaxis are not inconsequential, as noted by a recent randomized trial analyzing RT used for HO prophylaxis after elbow trauma that was cut short following an unacceptably high rate of nonunion in the treatment group (single-dose radiation) compared with that of the control group (no radiation).40
Complications Associated With Radiation Therapy As overall long-term survival rates improve, presumably as a result of better chemotherapy regimens and advances in surgical techniques, late sequelae of RT,41 including wound complications, secondary malignancies, limb-length discrepancy, joint contractures, and pathologic fractures, are becoming increasingly prevalent. Overall, RT for local control of softtissue sarcoma must be considered carefully, and treatment decisions must be individualized. Secondary malignant neoplasms following RT are typically aggressive sarcomas, whereas chemotherapy is more often associated with the late development of hematologic malignancies. The reported incidence of secondary malignancies following the treatment of soft-tissue sarcoma is inconsistent; however, some authors have suggested an overall incidence of 20%, with higher rates in patients who had undergone RT (relative risk, 2.7) as part of their treatment program.42 Expendable bones, such as the rib, fibula, scapula,
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Christopher E. Gross, MD, et al
anterior arch of the pelvis, and wing of the ileum, are generally resected without radiation when margins are negative. The risk of long bone fracture is increased if the periosteum is removed, and intramedullary rod fixation should be considered. Long bone diaphyses and joints can be resected, but reconstruction is necessary. The development of a second, radiation-induced sarcoma following RT typically occurs within the prior radiation field43 and is not limited to RT at high doses because even lowdose exposure has been shown to be associated with the development of secondary malignancies.44 Importantly, the risk of developing a future bone sarcoma as well as soft-tissue sarcoma is increased after childhood exposure to high-dose fractionated radiation, including doses $10 Gy.44 This risk has been shown to increase linearly, up through doses of 40 Gy.44 As demonstrated in multiple publications describing the development of soft-tissue sarcomas in survivors of atomic bomb explosions, even lower doses of RT, including exposures of 1 Gy, when sustained at any age, place patients at risk for the development of a future sarcoma.45 Even more worrisome is the recent evidence that suggests that radiationassociated soft-tissue sarcomas have an inferior prognosis compared with sarcomas not related to prior radiation exposure.46 Specifically, Gladdy et al46 conducted a multivariate analysis of 7,649 patients with softtissue sarcomas, 130 of which were associated with prior RT, and found that regardless of sarcoma histology, disease-specific survival was significantly worse in the radiationassociated group. Certainly, given the worsening prognosis of radiationinduced secondary sarcomas, caution is warranted when recommending and administering RT, and a multidisciplinary approach, explaining the risks, benefits, and alternatives to treatment, is warranted in each case.
Future Directions Much research has gone into developing the means to both plan and deliver large, precise doses of radiation to a specific area. Intensitymodulated RT is a highly advanced, precise way to deliver radiation to a desired location. Each radiation beam is shaped with computercontrolled beams to fit the profile of the individual tumor. The shaping, or collimation, of the beam is performed by a multileaf collimator, which modulates the flux of the beam per length. This allows greater sparing of normal tissue and critical structures from the high-dose region. A tradeoff does exist in that large volumes of tissue do receive a low level of radiation. This inherently increases the risk for secondary malignancies. Another frontier technology is imageguided radiation therapy, in which a tumor is imaged with a CT scanner immediately before radiation, such that the patient’s position or computer radiation parameters can be adjusted to reduce interfractional set-up variability. Normally, skin markers are used for positioning. However, this does not take into account positions of the internal target or other healthy tissue structures.47 This RT hopes to improve accuracy while reducing exposure to normal tissue.48 Combining preoperative radiation with chemotherapy for soft-tissue sarcoma is increasingly popular. To minimize complications, the timing of these treatments is critical. Finally, recent advances in our understanding of tumor biology may affect the treatment of soft-tissue sarcomas in the future, especially as our understanding of specific radiosensitizers and radioprotectors improves.49
Conclusion Combined with new ways to image and minimize collateral damage, RT
is evolving rapidly. With advancements in our ability to manipulate radiation to treat musculoskeletal pathology, the hope is to increase the quality of life and disease-free survival for thousands of patients. Although sarcoma was used as our cancer paradigm, other types of cancers will undoubtedly benefit from the advancements in radiation oncology.
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