Radiotherapy in soft tissue sarcomas

Radiotherapy in soft tissue sarcomas Authors Key words L. Renard, X. Geets, P. Scalliet Soft tissue sarcoma, radiotherapy Summary Surgery and postoperative radiotherapy has become a standard of care in soft tissue sarcoma. A multidisciplinary approach by an expert team of physicians is required (surgical oncologist, radiation oncologist, medical oncologist, pathologist and imaging oncologist). Accurate pretreatment evaluation is critical for treating soft-tissue sarcomas. The indication for irradiation is based on pretreatment evaluation (size, location), type of surgery (marginal vs. wide excision margins) and tumor grade (low vs. high grade tumors). (BJMO 2008;vol 2;5:270-4) Introduction Sarcomas are rare malignant tumors that represent less than one percent of all cancers. They arise from skeletal and extra skeletal connective tissues. Roughly 78 percent of all sarcomas originate from soft tissue (soft tissue sarcoma, STS), the remainder arises from the bone. There are numerous histological subtypes of which undifferentiated pleomorph sarcoma and liposarcomas are most frequently observed. Because of the rarity of this pathology and the need for a multidisciplinary approach, these patients are best treated in centres having expertise in the management of sarcomas. 1,2 As large randomized trials are still awaited, the evidence for this has been built on small single-institution series and trials from experienced centres. 3 Surgery is the pivotal treatment for the majority of patients with localized soft tissue sarcoma. Considering the type of the surgery, amputation and compartmental resection offer the best local control. However, they have a high functional and cosmetic morbidity. If the surgical resection is marginal (R1), the recurrence rate is estimated between 60 and 90%. The recurrence rate is 100% in case of incomplete resection (R2). Wide excision offers the best compromise between local control and functional result when compartmental resection (quite large) and marginal resection (insufficient) are unfeasible. Thus, the goal of surgery is to remove the tumor with wide margins. This means removing at least one uninvolved tissue plane circumferentially. It is not as precisely defined as compartmental resection, but it specifies that margins must be clear with 2-5 cm of healthy tissue around the sarcoma (depending on grade and tumor size). Leaving a carefully considered positive margin adjacent to a critical structure to facilitate limb preservation, results in rates of local recurrence of only approximately 4% when planned irradiation is carried out. 4 The present review discusses indications of radiotherapy in localized STS. However, the topic of adjuvant or neoadjuvant medical treatment is not addressed. Figure 1 shows a decision tree for the treatment of STS. Radiotherapy alone Radiotherapy alone is considered when surgery is inappropriate or declined by the patient. It achieves local control rates of 30 to 60%. 5 However, it obviously depends on tumor characteristics. Some anecdotic series of patients, unfit for surgery (either for medical or for oncological reasons), have shown benefit from a protracted local control after high dose radiotherapy. The high dose level and the large volume of irradiation resulted in serious long-term effects in skin and soft tissues (fibrosis, necrosis). Overall the success rate was low, certainly not matching a multidisciplinary radio-surgical approach. Local control cannot be an objective when radiotherapy alone is used, except for tumors of limited size (perhaps < 5 cm). It may debulk the tumor and/or relieve compressive symptoms, or pain, but radiotherapy alone cannot be expected to control a large tumor mass. Concomitant radiochemotherapy has been discussed. Anthracyclines seem to have a supra-additive effect, but the cost in terms of skin toxicity is high. 6 270

Y Tumour <5 Y Low grade Y Surgery Clear margins N N Follow-up every 6 months Consider Adjuvant irridiation Figure 1. Decision tree for the treatment of soft tissue sarcomas. (After Standards, Options et Recommandations 2006 pour la prise en charge des patients adultes atteints de sarcome des tissus mous, de sarcome utérin ou de tumeur stromale gastro-intestinale. Revision 2005 ) The rationale for surgery plus radiotherapy As in the treatment of breast cancer, the goal of the conservative treatment in STS is to achieve a cure rate equivalent to amputation. This can be obtained by combining loco-regional radiotherapy with surgery. 4 The rationale for this combination is to avoid the functional and cosmetic deformities associated with radical surgery and the late sequel of high radiation doses to large volumes of normal tissue in patients treated with primary radiotherapy. Two small, single-institution randomized studies, reported by McNeere in 1968 and by Rosenberg in 1982 compared amputation to conservative surgery and adjuvant radiotherapy. 3,7 Both reported identical disease free survival and overall survival rates in the two arms. These trials have disqualified amputation as the primary treatment of STS. Two other randomized trials investigated the role of radiation in the setting of conservative surgery. In the trial reported by Pisters et al 164 patients with sarcoma of the extremities and the trunk were randomised preoperatively to receive adjuvant brachytherapy (45 Gy) or no further treatment after complete surgical resection. 8 The 5-year local control rates were 82% and 69% respectively for the whole population (p=0.04). For the high-grade tumors, the 5-year local control rate was significantly better in the arm with radiation (89% versus 66% p=0.0025). Nevertheless, the 5-year disease free survival was identical in both arms (84% and 81%), presumably because the improved local control in high-grade tumors was not associated with a reduction of distant metastasis. The second trial compared surgery alone to surgery plus postoperative external-beam radiotherapy, associated with chemotherapy for the high grade lesions. 9 The 10-year local control was extremely high with postoperative radiation: 100% for the highgrade tumors and 96% for the low grade. There were also no differences in the overall survival. Radio-chemotherapy has been investigated, mainly at UCLA. In a recent review it was concluded that this approach should still be considered investigational, since the late effects are clearly worse, without proven benefit. 10 Role of brachytherapy Brachytherapy is a form of radiotherapy that uses radioactive sources directly implanted in the tumor bed after local excision. It has the theoretical advantage over external radiotherapy of delivering a higher central dose, over a short period of time (one week typically). Because of the relative hypoxia in scar tissue it may be more efficient on tumor beds after surgery. 11 The practice of brachytherapy requires a specific training. The procedure is done during surgery for sarcoma, in coordination with the surgical oncologist. Non-radioactive catheters are deposited in the tumor bed and, in order to make sure that the physiological scarring process has started before irradiation, radioactive sources are inserted one week later. Accepted indications today small tumors (< 5cm) with insufficient clear margins (if re-excisions is not an option), recurring tumors of small size and recurring tumors that have already been irradiated at the time of surgery for the primary tumor. Formally, external beam radiotherapy and brachytherapy have never been compared in a randomized setting, but in the surgery plus radiotherapy arm of the Pisters trial brachytherapy was actually used. 9 Timing for the radiotherapy If radiation therapy improves local control, the sequencing between surgery and radiotherapy is still debated. A clinical trial from the Canadian Sarcoma Group sheds some light on this issue. 12 In this study, 190 patients diagnosed with soft-tissue sarcomas of the limbs were randomly assigned to preoperative radiotherapy (50 Gy in 25 fractions with a 16 Gy boost postoperative for microscopically positive surgical margins) followed by surgery vs. surgical 271

resection followed by postoperative radiotherapy (66 Gy). The primary endpoint was the presence or absence of major wound complications within 120 days after surgery. Secondary endpoints were local control, metastatic failure, progression-free survival and overall survival. The trial was closed before completion of the planned accrual. Thirty-one out of 88 eligible and evaluable patients (35%) developed wound complications in the preoperative arm versus 16 of 94 patients (17%) in the postoperative group (p=0.01). Delayed wound healing was observed specifically in sarcomas of the lower limbs. Although radiation oncologists clearly prefer preoperative irradiation (target volume easier to define, smaller irradiated volume, lower total dose), most surgeons fear the protracted wound healing process and prefer postoperative irradiation. 1 It remains a question open to debate, and long term data are needed to see if the late tolerance to treatment sufficiently improves (because of the lower dose) in order to justify the worse immediate tolerance of preoperative radiotherapy. In order to evaluate late morbidities (fibrosis, joint stiffness and oedema), O Sullivan updated the results of the Canadian Sarcoma Group at 2 years. 13 He concluded that patients treated with postoperative radiotherapy tended to have more fibrosis, which adversely affects patient s function. Tolerance to treatment Late effects are common, particularly in the skin, soft tissues and muscles. 14 Skin dystrophy (sclerosis, telangiectasia) is difficult to avoid around the surgical scar because this is one of the elective sites of recurrence that needs to receive full radiation dose. This can be corrected (at least partially) through the interpositioning of fresh, unirradiated, subcutaneous tissue. Occasionally the skin develops chronic radiolesions requiring skin grafts (especially in exposed areas as the tibial crest). Muscle sclerosis with functional loss is less common. As ankylosis may develop when joints are irradiated (if the sarcoma site requires it), protection of joints and ligaments should be taken into account during radiotherapy planning Lymphoedema is common after the treatment of large sarcomas of the lower limb. It is consecutive to sclerosis of skin and deep lymphatic vessels. It can be prevented, at least partially, by leaving a strip of healthy tissue, usually opposite to the irradiated compartment. Bone necrosis is less common (1 to 6%) and depends on the dose level and the irradiated volume. 15,16 Treatment of recurrences When recurrence is observed, amputation is required in 10 to 25% of the cases. Nevertheless, re-resection has to be considered. It will be followed by external radiotherapy if no radiation was delivered previously. When soft-tissue sarcomas recur in a previously irradiated area, further external beam radiation is generally impossible. In these cases brachytherapy allows a radiotherapeutic alternative in an attempt to reduce the risk of further local recurrence. 11 Isolated limb perfusion (mostly using melphalan) may also be an option. Addition of tumor necrosis factor α, a cytokine inducing inflammation, increases the penetration of melphalan into the tumor and may further improve the outcome. Retroperitoneal sarcomas Retroperitoneal sarcomas represent 13% of all sarcomas. Usually, the histological subtypes are liposarcoma and leiomyosarcoma. Sarcomas involving the retro-peritoneum have a worser outcome than soft tissue sarcomas located at the other side of the peritoneum. At diagnosis, retroperitoneal sarcomas are usually large and located in such a position that complete, margin-negative surgical resection, the most important prognostic factor for survival, is not feasible. In a series of 104 retroperitoneal sarcomas, treated by surgery and irradiation, a complete surgical excision rate of 43% was reported. 17 For this subgroup of patients, the survival rates at 5 and 10 years were 55% and 22% whereas the overall 5- and 10-years survival rates for the entire patient population were 36% and 14%. In contrast, those series reporting a high rate of surgical resectability, have better 5- and 10-year outcome (66% and 57% respectively), and lower local recurrence rates (25% at 5 years). 18 Histological grade is another important prognosis factor. Fifty percent of the retroperitoneal sarcomas are classified as intermediate or high grade. In a series of 183 patients treated for truncular or retroperitoneal sarcomas, high and intermediate grade patients had a five to six-fold increased risk of death. 19 The surrounding normal tissues (small bowel, spinal cord, kidney, liver) have a relatively low tolerance for radiation. Therefore, retroperitoneal sarcomas are not irradiated with the high radiation doses prescribed for soft tissue sarcoma of the extremities. Nevertheless, a non-randomized, retrospective study showed that adjuvant (postoperative) radiotherapy is associated with a reduced risk of local recurrence. However, this does not have a positive impact on survival. 272

Key messages for clinical practice 1. Postoperative radiotherapy is no substitute for inadequate surgery. 2. In case of unplanned, R1 or R2 resection, a surgical revision of the tumor bed needs to be discussed. 3. The superiority of preoperative radiotherapy to postoperative radiotherapy is still debated. 4. Preoperative radiotherapy increases the rate of delayed wound healing. 5. Postoperative radiotherapy seems to cause more late effects (fibrosis, loss of function). 6. Figure 1 on page 271 presents a decision tree for the treatment of soft tissue sarcomas. Preoperative radiotherapy offers practical advantages over postoperative radiation. First of all the gross tumor volume is easily defined allowing accurate targeting of the radiation dose. Secondly, the tumor displaces the organs at risk outside the high dose region. Pawlik et al reported the long-term results of two prospective trials of preoperative external radiotherapy for retroperitoneal sarcomas. 20 For 54 patients with primary retroperitoneal sarcoma who underwent R0 or R1 resection after preoperative radiotherapy, the 5-year local recurrence-free, diseasefree, and overall survival rates were 60%, 46% and 61% respectively. Practical considerations Accurate pretreatment evaluation is critical for treating soft-tissue sarcomas, particularly adequate imaging (MRI has preference). When an indication of radiotherapy is discussed, two elements should be taken into account: tumor grade (high grade tumors should be irradiated postoperatively, low grade tumors should not) and margin clearance. Margin clearance is a difficult aspect of STS. It depends on the surgeons skill, buttumor characteristics also have an important influence. The size determines whether limb sparing surgery is possible with clear margins. The location is also influencing margins: tumors close to bone periost or to neurovascular bundles, whatever their size, cannot be excised with broad margins unless vascular reconstruction or bone excision is used. A tumor of the lower limb in close contact to the fibula can still be excised together with the fibula itself. Hence, bone contact is not necessarily preventing clear margins. Retroperitoneal sarcomas, as discussed previously, are difficult to remove with a broad safety margin of healthy tissues. Oops surgery, i.e. the unplanned removal of a sarcoma, not previously diagnosed, is always inadequate and should be submitted to revision by an expert panel. Revision of the surgical field by an expert surgeon, postoperative irradiation, or wait-and-see policy must be debated. When the radiotherapy indication is confirmed, a careful study of the preoperative imaging and its further comparison with postoperative imaging is required, in order to adequately define the clinical target volume (CTV). A dose of 60 to 66 Gy in 30 to 33 daily fractions of 2 Gy is appropriate. 3-dimensional conformal techniques or IMRT should be used if it offers a dosimetric advantage (which is most oftenly the case). 21 Radiotherapy is not contraindicated after isolated limb perfusion with TNF, nor after skin flap for reconstruction. 22-24 Conclusion Postoperative radiotherapy is no substitute for inadequate surgery. In case of unplanned, R1 or a fortiori R2 resection, a surgical revision of the tumor bed always needs to be discussed. Whether preoperative radiotherapy is preferable above postoperative radiotherapy is still under debate. Preoperative radiotherapy doubles the rate of delayed wound healing (in lower limb tumors), but postoperative radiotherapy seems to cause more late effects (fibrosis, 273

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