34. Uncommon indications for brachytherapy - The GEC-ESTRO Handbook of Brachytherapy

SECOND EDITION

The GEC ESTRO Handbook of Brachytherapy

PART II: CLINICAL PRACTICE 34 Uncommon indications for brachytherapy

Editors Bradley Pieters Erik Van Limbergen Richard Pötter

Peter Hoskin Dimos Baltas

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34 Uncommon indications for brachytherapy 34.1 Soft tissue sarcomas of the extremities and superficial trunk in adults Rafael Martínez-Monge, Santiago Martín Pastor, Luis I. Ramos, Benigno Barbés, Mikel San-Julián, Jorge Gómez Alvarez

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34.1 Soft tissue sarcomas of the extremities and superficial trunk in adults Rafael Martínez-Monge, Santiago Martín Pastor, Luis I. Ramos, Benigno Barbés, Mikel San-Julián, Jorge Gómez Alvarez

1. Introduction

3 3 3 4

5. Dose

4 4 5 9

2. Clinical Indications

6. Results and adverse side effects

3. Tumour and Target Volume

7. References

4. Technique

1. INTRODUCTION

2. CLINICAL INDICATIONS

Soft tissue sarcomas of the extremities and the superficial trunk are a rare (<1% of all adult tumours) and heterogeneous group of solid tumours of mesenchymal origin (more than 50 different histologic subtypes) and represent the majority of all soft tissue sarcomas [1]. Localized tumours are treated primarily with surgery and irradiation. The use of adjuvant chemotherapy in this setting is not a standard treatment. It can, however, be proposed for fit patients affected by disease at high risk of metastases [2]. Most soft tissue sarcomas share common diagnostic and treatment pathways. However, a few subtypes (e.g. rhabdomyosarcoma, desmoid tumours,) are treated according to disease-specific algorithms. Most soft tissue sarcomas are sporadic. A minority can be related to certain predisposing factors such as prior radiation therapy to the affected area, chronic lymphoedema, chemicals and genetic syndromes (e.g. Li-Fraumeni syndrome, neurofibromatosis, etc.) [3]. Amputation has long been abandoned as the standard treatment for soft tissue sarcomas since similar oncological outcomes are obtained with functional surgery and adjuvant irradiation [4]. Both adjuvant low-dose rate (LDR) brachytherapy and external beam irradiation (EBRT) have resulted in improved local control rates compared with surgery alone in two different phase III trials [5,6]. However, the timing of surgery and irradiation (i.e, preoperative vs. postoperative) does not seem to impact on local control rates or survival [7] although preoperative irradiation has been related to a higher wound dehiscence rate [7] and postoperative irradiation to greater fibrosis, joint stiffness and bone damage [8]. Current international guidelines [1] support the use of LDR (or high-dose rate (HDR) equivalent) brachytherapy alone in margin negative tumours that meet the criteria for adjuvant irradiation or LDR (or HDR equivalent) brachytherapy combined with EBRT for margin positive patients.

Brachytherapy can be used in the majority of patients with soft tissue sarcomas that require adjuvant irradiation and are technically implantable. Brachytherapy may be advantageous to external beam irradiation in specific anatomical locations or in children where the irradiated volume has to be restricted Tumour scenarios In general, surgery alone may be adequate for small (<5 cm) low grade tumours with clear surgical margins (>1 cm). There are nomograms available to assess the risk of recurrence with surgery alone in individual patients [10]. In practice, most patients with AJCC 8th edition stage Ib, II and III tumours and patients with unirradiated locally recurrent tumours are candidates for adjuvant irradiation [1] and therefore, brachytherapy can be used in these patients as the sole treatment modality or combined with EBRT. Anatomical scenarios Most tumour locations are suitable for brachytherapy as long as the implant is at least >5mm under the skin surface and target coverage is guaranteed. The presence in the surgical bed of dose limiting structures such as neurovascular bundle, bone, etc. is not a contraindication for brachytherapy [11]. In fact, tumours adjacent to these organs are at greatest risk of local failure due to the inability to obtain wide tumour-free margins and the benefit of brachytherapy for dose escalation in the presence of inadequate margins is maximal [12]. In these situations, special care must be paid to technical details to avoid organ at risk damage (see section 4 : Technique).

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3. TUMOUR AND TARGET VOLUME

External Beam Radiation Therapy (EBRT) The target definition rules of EBRT component in combination with brachytherapy follow the same rules as for patients treated with EBRT alone. When using preoperative EBRT, the CTV volumes encompassed with EBRT include the GTV (gadolinium-enhanced T1-weighted MRI) with an expansion (2-4 cm longitudinally and 1-1.5 cm radially) that is manually edited to encompass peritumoural edema (defined on T2-weighted MRI) [14,15]. With postoperative EBRT, the CTV should also account for areas of potential tumour seeding during surgery (i.e., the scar, drain port, and surgical tumour bed)[16]. The CTV needs to be defined by anatomic boundaries (i.e., fascia, bone, joint, or compartment) and potential areas of seeding from previous procedures (i.e., unresected biopsy track).

The target definition rules for the brachytherapy and the EBRT components are the same irrespective of their use as a single modality or a combined treatment.

Brachytherapy Different Clinical Target Volume (CTV) definitions have been used. Traditionally, the CTV was defined as the entire surgical bed because local recurrences were presumed to occur due to tumour cell shedding during surgical manipulation with subsequent propagation through the post-surgical seroma. Nowadays, CTV definition has evolved to more conservative proposals that may be equally useful and less toxic. The American Brachytherapy Society consensus statement for soft tissue sarcoma brachytherapy [13] advises construction of the CTV with a tumour bed expansion of 2 cm craniocaudally and 1 cm lateral to the tumour bed. Although traditional brachytherapy practice has emphasized the futility of defining a PTV that compensates for inaccuracies incurred during the treatment process due to the presumed stability of the implant with regards to the CTV, this may not be the case in all scenarios. PTVs may not need to be created in small CTVs fully covered with firmly anchored double-button catheters. However, catheter displacement may occur in large CTVs with single-button catheters. In this situation, a CTV expansion in the direction of the tubes to create a PTV may be required if the position of the catheters cannot be verified before each treatment or due to postoperative conditions (i.e, swelling, etc.) .

4. TECHNIQUE

Perioperative implants are performed at the time of surgery. After determining the CTV according to the surgical and pathological findings, as well as the preoperative imaging (MRI), the plastic tubes are implanted. The majority of CTVs can be encompassed with a single-plane implant. Larger CTVs may require two or three planes (Figure 34.1). The number of planes depends on the size of the primary tumour and the tumour bed closure technique. A large tissue defect can be converted into a smaller CTV if the different components of the tumour bed are sutured onto each other.

Figure 34.1: Multiple plane implant in a large myxoid liposarcoma of the thigh. Axial MRI at the central plane of the implant (left panel). Planning CT showing the deep and superficial catheter planes. Note outstanding tumour bed displacement after resection. The CTV (red) is encompassed by the 100% 4Gy isodose line (blue) with 150% isodose 6Gy lines (white) accounting for a small part of the irradiated volume due to the large number of catheters and dwell positions (right panel). A 5-mm tissue thickness (yellow lines) is usually enough to separate the organs at risk away from the high-dose regions.

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5. DOSE

Guide needles are implanted through the skin 1 to 2 cm away from the surgical incision. The needles may be straight or curved to fit the CTV. The guide needles are then replaced by plastic tubes. Catheters can be placed onto the tumour bed surface and fixed with sutures or tunnelized 2-3 mm under the tumour bed surface for increased stability. The plastic tubes should be implanted parallel and equidistant, along the-axis of the extremity or transverse to the the surgical incision. An intercatheter distance of 1.0 to 1.5 cm allows greater consistency during postoperative changes and allows more meticulous treatment planning due to the increased number of dwell times. To reduce the radiation dose to critical organs (nerves, vessels, bones, etc.), some intraoperative surgical procedures may be considered, e.g. a spacer or layer of muscle or fat can be inserted between the catheters and the structure to be avoided. Spacers must not be thicker than 5mm if the normal tissue to be protected is at risk of harboring microscopic disease. A 5-mm tissue thickness is usually enough to separate the organs at risk away from the high-dose regions around the catheter (Figure 34.1 and 34.2). Finally, CTV needs to be defined intraoperatively. The implant array (surrogate for the tumour bed) and fiducials (surrogates of the CTV boundaries) are needed for a reliable CTV definition in the postoperative setting.

Unirradiated Cases Patients with negative margins may be treated with LDR brachytherapy alone to a total D 90 of 45 Gy at a dose rate of 40 - 60 cGy/hour [5]. Equieffective HDR regimens include a D 90 of 36Gy in 10 fractions b.i.d. [1]. Patients with larger tumours or positive margins usually require a combination of EBRT and brachytherapy. LDR brachytherapy of D 90 of 15-20 Gy combined with 45-50Gy of EBRT is a plausible strategy [9]. If HDR brachytherapy is used instead, a bioequivalent D 90 of 14-16Gy in 4-6 fractions b.i.d. can be used. Previously Irradiated Cases The majority of the cases that require adjuvant reirradiation are usually treated with brachytherapy alone due to the constraints imposed by the prior irradiation course. Reasonable alternatives include HDR brachytherapy alone D 90 32 to 40Gy in 8 to 10 fractions b.i.d. (EQD2 10 of 37.3 to 46.7Gy) with final dose and dose per fraction dependent upon prior DVH parameters to dose-limiting structures.

Figure 34.2: Dose Volume Histogram of the case shown in Figure 34.1. Please note the skin and scar-sparing properties of brachytherapy in deep-seated locations (OAR to CTV ratio of 0.3-0.4). Tumours adjacent to the bone or the neurovascular bundle can also be implanted using special intraoperative techniques to minimize OAR irradiation (OAR to CTV ratio of 0.7-0.85).

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6. RESULTS AND ADVERSE SIDE EFFECTS

The majority of the reported adverse events can be divided for ease of description into wound healing complications, osteoradionecrosis and neural damage. Wound Healing Complications (WHC) WHC are the most common adverse events in patients treated with adjuvant brachytherapy and have been reported in 2.3% to 59.0% of patients. Severe grade 3-4 complications leading to reoperation occur in 10 to 15% of cases [25,26]. Risk factors leading to complications include time, volume, dose/volume and technical factors. Time-associated factors (time to loading) were the first variables associated with WHC. In the MSKCC trial, the significant wound complication rates were 24% in the BT monotherapy group and 14% in the control group (p =ns). However, WHC significantly increased (48%) with BT delivered prior to postoperative 5 day, whereas patients treated with BT monotherapy >5 days postoperatively had wound complication rates comparable to surgery alone (17% vs. 15%, p=ns) [27]. More recent studies however, have not described such correlation [25]. Volume-associated factors in the form of tumour volume, tumour location, extent of resection, width of skin resected, CTV size, implant volume, number of catheters, etc. are all associated with a greater risk of WHC and should be taken into consideration [20] at the time of surgical closure, brachytherapy and adjuvant EBRT. Dose-volume - associated factors have been increasingly gaining attention in the sarcoma literature. A recent report [28] described a correlation between WHC and CTV larger than 50 cm 3 (p = 0.02) and CTV 2cm 3 physical dose > 110 Gy (p = 0.02) in a multivariate analysis of a series of 139 unirradiated soft tissue sarcomas treated with adjuvant brachytherapy in combination with EBRT. When used in combination, patients with CTV volume and CTV 2cm 3 values below the constraints had a WHC rate of 13.2%. This figure increased to 44% and 77.8% with one or two values above the constraints. Hence, WHC seems to result mainly from high-dose irradiation of large tissue volumes. The goal of obtaining a suitable CTV size can only be accomplished through strict case selection. Similarly, suitable CTV 2cm 3 values can be achieved using shorter intercatheter spacing (10–12 mm) and meticulous treatment planning to minimize high- dose areas. Technical factors related to the surgical procedure, closure and postoperative play an important role in the development of WHC. In the MSKCC trial, it was noted that wound reoperation was related to the width of the excised skin (WES) [1% (WES < 4 cm) vs. 10% (WES > 4 cm), p = 0.02][26]. WHC can be also minimized with the use of free tissue closure, negative pressure wound therapy (NPWT) or temporary closure and delayed reconstruction [20]. Osteoradionecrosis (ORN) ORN is a rare complication after adjuvant brachytherapy (median 1.4%, range, 0–4.5%). ORN has been associated with periosteal stripping [29] that decreases bone viability. A recent report in 139 patients treated with adjuvant brachytherapy and EBRT described an ORN rate of 5% with a time to appearance of 59 months. ORN was associated in multivariate analysis with bone dose with a cut-off level at EQD2 3 Bone 2cm 3 of 67 Gy (p = 0.01). ORN was not observed below this constraint. Bone 2cm 3 EQD2 should be closely monitored or lowered in cases in which periosteal stripping has been performed.

6.1. Unirradiated Cases 6.1.1. Local Control

BT monotherapy has shown 5-year local control rates greater than 75% in the majority of the reports [5,17-19]. Of note, the Memorial Sloan Kettering Cancer Center (MSKCC) phase III trial showed a 5-year local control of 82% in the LDR brachytherapy group compared to 67% in the surgery-only group (p=0.049) [5]. Brachytherapy was delivered with Ir-192 LDR to a total dose of 42 45Gy over 4-6 days. Total hospital stay from the date of surgery was 10-14 days. This difference was due to the marked improvement in high grade tumours (90% vs. 65%; p=0.013) while the difference in low grade tumours was not significant. This local control advantage did not translate into improved disease-specific survival. In a later update with 202 patients, the 5-year local control remained stable at 84% [17]. The rest of the BT monotherapy literature comprises a mix of LDR, HDR and PDR series with smaller number of patients and/or shorter follow-up [20]. BT in combination with EBRT is the most common use of brachytherapy in soft tissue sarcomas, especially in those cases at higher risk of local relapse. A subgroup analysis from MSKCC [9] comparing brachytherapy alone vs. brachytherapy + EBRT in margin-positive patients showed superiority of the combined treatment with 5-year local control rates of 59% vs. 90% (p=0.08), suggesting a dose-escalation effect in high-risk patients without an increase in complications. Most series report 5-year local control results greater than 80-85% with a combination of EBRT of 45-50Gy delivered with standard fractionation and 10 to 25 Gy of LDR or pulsed-dose rate (PDR) or an HDR equivalent [21-24]. Different factors have been implicated in local control after brachytherapy alone or combined with EBRT although margin status remains the most influential prognostic factor for local control [21,22,25]. Gimeno et al. [25] showed that margin status, as defined by the MSKCC classification, was the only factor predictive of local control after multivariate analysis of a series of 106 patients treated with HDR brachytherapy of 16-24Gy and 45Gy of EBRT. The 10-year local control decreased from 95% to 74% (p=0.013) when the surgical margins were positive. 6.1.2. Adverse effects Complications are multifactorial in origin and are related to patient (age, comorbidities, ), tumour (size, location, proximity to sensitive structures, ) and treatment factors (extent of surgery, periosteal bone stripping, reconstruction, dosimetry). An exhaustive list of factors related to adverse effects can be found elsewhere [20]. A recent detailed summary published by the American Brachytherapy Society describes an all-type grade >2 complication rate of of 5 to 10% for brachytherapy monotherapy and of 25-30% for combined brachytherapy and EBRT [20]. These numbers must be taken only as an approximation due to the different systems for scoring and reporting used in the literature.

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Neural Damage (ND) ND is a rare complication after adjuvant brachytherapy. Contemporary literature describes an overall rate of chronic neuropathy below 10% with a few severe cases (median 1.7%, range 0–7.0%). The study of nerve tolerance is limited by the difficulty in delineation of peripheral nerves. Prior LDR + EBRT reports have established 90Gy as a safe dose for tumours involving the neurovascular bundle [11]. More recent HDR reports have established the safety of relatively high doses such as 50Gy in 10 fractions b.i.d. [30]. In the absence of nerve delineation, the DVH of irradiated volumes containing a neural structure may serve as a surrogate of neural damage [28]. 6.2. Previously Irradiated Cases Some patients with locally recurrent, previously irradiated soft tissue sarcomas are candidates for surgical salvage and adjuvant irradiation. Reirradiation in this setting follows the same guidelines as other disease sites with special emphasis on dose and volume reduction. Brachytherapy can spare normal tissues and potentially reduce complications in the re-irradiation setting compared with EBRT. In spite of this potential advantage, WHC represent a major issue in the reirradiation setting with some series reporting WHC rates greater than 50% as well as higher rates of amputations due to complications associated with reirradiation [31,32]. A recent analysis revealed an all-grade WHC rate of 63.3% in a prospective study of brachytherapy-alone reirradiation delivering 32-40Gy in 8-10 fractions b.i.d. [28]. In that study, WHC correlated (p = 0.01) with lifetime cumulative radiation doses to the skin (EQD2 3 Skin 2cm 3 > 84 Gy). In cases at greatest risk of developing severe WHC a reasonable alternative to immediate wound closure or immediate reconstruction is the use of delayed or staged reconstruction. Catheters are removed before final reconstruction. Delayed reconstruction allows margin re-resection if needed and minimizes WHC compared to immediate reconstruction resulting in an improved limb preservation rate [33].

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7. REFERENCES

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32. Torres MA, Ballo MT, Butler CE, Feig BW, Cormier JN, Lewis VO, Pollock RE, Pisters PW, Zagars GK. Management of locally recurrent soft-tissue sarcoma after prior surgery and radiation therapy. Int J RadiatOncol BiolPhys 2007;67:1124-1129. 33. Naghavi AO, Gonzalez RJ, Scott JG, Mullinax JE, Abuodeh YA, Kim Y, Binitie O, Ahmed KA, Bui MM, Saini AS, Zager JS, Biagioli MC, Letson D, Harrison LB, Fernandez DC. Implications of staged reconstruction and adjuvant brachytherapy in the treatment of recurrent soft tissue sarcoma. Brachytherapy 2016;15:495-503.

ACKNOWLEDGMENTS The authors of this chapter are much indebted to Eric Lartigau and Alain Gerbaulet, authors of the original version of the chapter on Soft tissue sarcomas of the extremities in adults in the first edition of the GEC-ESTRO Handbook of Brachytherapy 2002.

AUTHORS

Rafael Martínez-Monge. Department of Radiation Oncology, Cancer Center Clínica Universidad de Navarra, Spain Santiago Martín Pastor. Department of Radiation Oncology, Cancer Center Clínica Universidad de Navarra, Spain Luis I. Ramos. Medical Physics, Cancer Center Clínica Universidad de Navarra, Spain Benigno Barbés Medical Physics, Cancer Center Clínica Universidad de Navarra, Spain Mikel San-Julián. Department of Orthopedics, Cancer Center Clínica Universidad de Navarra, Spain Jorge Gómez Alvarez. Depatment of Ortopedics, Cancer Center Clínica Universidad de Navarra, Spain