5. Treatment of localized soft tissue tumor – Soft Tissue Sarcoma
5.1 Surgical therapy
General recommendations for primary therapy
When there is clinical suspicion and/or imaging suspicion of soft tissue sarcoma, this shall be confirmed on histology.
- Consensus
- Strong consensus
The planning of the treatment of sarcomas shall take place in the interdisciplinary tumor board before treatment is instigated. At least one surgical discipline with a focus on soft tissue sarcomas, as well as hematology/oncology, pathology, radiology, and radiation oncology shall be represented in the tumor board. Site-specific surgical expertise shall be obtained on a case-by-case basis for sarcomas arising at certain anatomical locations.
- Consensus
- Strong consensus
In cases of clinical suspicion and/or imaging suspicion of soft tissue sarcoma that is smaller than 3 cm in diameter and superficially located, primary R0 resection may be performed.
- Consensus
- Strong consensus
General aspects
Surgical resection with tumor-free resection margins (R0 resection) represents the core therapeutic element for patients with adult localized soft tissue sarcoma of all sites. En bloc resection of both tumor and biopsy access should be undertaken [144]. The assessment of whether a tumor is resectable with an R0 margin can only be made by a surgeon with experience in this area. Accordingly, the tumor stage, anatomic location, comorbidities, and expected functional limitation of the patient must be considered in this context.
For resection of extremity sarcomas, the term ‚compartment resection‘ was coined by Enneking and later applied as a treatment concept. The surgical technique was developed for the treatment of osteosarcoma [145]. It meant resecting the bone tumor together with the surrounding muscles, thereby preserving the tumorcoverage. Compartmental resection according to Enneking involved the co-resection of the attachment and origin of the muscles.
A compartment (lat. ‚compartimentum‘, German ‚Loge‘) refers to functionally related skeletal muscles that are surrounded by a common aponeurosis. However, there are relatively few anatomically defined compartments in the extremities. Examples include in the thigh the adductor muscles, the quadriceps, the hamstring compartment on the dorsal thigh, and in the lower leg, the anterior lunge and the flexor and fibular lunge. In the arm, there are biceps or triceps compartments on the upper arm and extensor and flexor compartments on the forearm.
From the point of view of resection of soft tissue sarcomas, a radical compartment resection is not always required unless the tumor is located in the area of attachment and origin of muscles. If the origin and attachment of the muscle are far from the tumor, they may be preserved. This avoids unnecessary morbidity (cushioning of joints by muscle preserved components) and functionality (extension of the radiation field to the entire surgical area) [146]. For resection of soft tissue sarcomas growing centrally within a compartment, these should be resected with portions of the surrounding muscles. A complete compartmental resection is not necessary, provided that the resection of a portion of muscle can completely cover the tumor (wide resection). Preservation of muscle portions, whether longitudinal or transverse, reduces the morbidity of the surgery.
The terms for the width of the resection margins can be described analogously to Enneking [145]:
- Intralesional: Resection margin passes through tumor and leaves tumor behind.
- Marginal: Resection margin goes along the pseudocapsule (reactive zone).
- Wide resection: tumor remains covered on all sides by a layer of healthy tissue.
- Compartment resection: complete resection of the tumor-bearing muscle compartment including the origin and attachment of the muscles.
The quality of the resection margins is not to be measured only by metric safety distance [104]. Through different research groups the concept of barrier has been propagated, i.e. the anatomical boundary layer of non-tumor affected tissue (fascia, perioste-um etc.), is also of great importance [147].
5.1.1 Sarcomas of the extremities
Surgical resection / amputation
Historically, amputation of the extremity for soft tissue sarcoma was frequently advised. A comparative cohort study of patients with lower extremity sarcomas by Shiu et al. [148] suggested that local recurrence risk was lower after amputation than after monobloc resection, with a RR of 0.62 (CI 0.39-0.98). Overall survival at 10 years was not significantly more favorable after amputation (RR 4.11, CI 0.85-19.76). It should be noted that this cohort included patients with rhabdomyosarcomas and angiosarcomas and did not receive any additional drug or radiotherapy treatment. Also, nearly half of the patients underwent surgery for tumor recurrence.
A 2:1 randomized trial of extremitypreserving sarcoma resection combined with adjuvant chemotherapy and radiotherapy vs amputation and adjuvant chemotherapy failed to demonstrate a survival advantage for amputation. Patients with R0 resection had a significantly lower local recurrence rate (p<0.0001). Based on this study, the recommendation for extremity-preserving sarcoma resection [149].
However, amputation may be indicated when there is infiltration of neurovascular bundles, when trhere is life-threatening hemorrhage, for tumors with extensive ulceration or when, after conserving surgery, it is expected that the patient will not be able to return to a living situation that is manageable for him. In a cohort of patients over 15 years of 1597 patients with sarcomas, 2.3 % underwent major amputation (hemipelvectomy, thoraco-scapular) [150]. The authors report a high rate of complications, short survival, and most severe impairment of quality of life.
In a cohort study of 413 patients, 6% underwent primary amputation [151]. This group of patients had significantly larger tumors, were of older age, and had a higher risk of metastasis. However, multivariate analysis showed no effect on systemic metastasis, which was determined by tumor size and grading.
The diagnosis and therapy of soft tissue sarcoma of the extremities shall be performed by or in coordination with a certified sarcoma center or associated cooperation partner.
- Consensus
- Strong consensus
If a soft tissue sarcoma of the extremities is detected, the primary approach shall be limb preservation.
- Consensus
- Strong consensus
Resection of primary soft tissue sarcoma of the extremities shall be performed as a wide resection. The goal is an R0 resection.
Background
R0 resection is a positive predictive factor for local recurrence-free and overall survival. In a Scandinavian Sarcoma Group analysis of 559 patients with sarcoma (median tumor size 7 cm) and a median follow-up of 88 months, there was a highly significant lower risk of developing tumor recurrence after adequate tumorresection than after intralesional or marginal resection (RR 2.9 [1.8-4.6]. p<0.001). Patients did not undergo adjuvant therapy [161].
A later analysis on 426 patients who had received adjuvant radiation after sarcoma resection confirmed that patients with wide resection had more favorable local recurrence-free survival than after marginal resection (HR 1.62 [0.62-4.20], p<0.001) [156].
For the liposarcoma subgroup, the same study group reported 237 patients who had either wide resection or marginal resection [153]. Wide resection resulted in a significantly lower risk of local recurrence (RR 0.36 [0.23-0.56], p<0.001) at a median follow-up of 8 years. Similar results for liposarcomas have been reported previously. In a multivariate analysis, according to grading and tumor size, resection distance with adequate safety margin versus marginal resection was associated with a lower local recurrence rate [163].
A database analysis of the National Cancer Data Base from 2003-2012 on 27,969 patients, 79.3% of whom had been treated with R0 resection (12.4 % R1 resection, 8.5% R2 resection) demonstrated that R0 resection was associated with improved survival over R1 resection (HR 1.1438, CI 1.024-1.1869, p<0.001) [154].
Regardless of clinical outcome, the need for reoperation after R1 resection also results in a substantial additional financial burden [164].
In an analysis of 687 patients with highly malignant sarcoma of the extremities from 4 tertiary referral centers [165], it could be shown that surgical safety distance had a favorable effect against the occurrence of local recurrence with a HR of 0.61 (95% CI 0.33-1.12) for a distance of 0-2 mm, and a HR of 0.16 (95% CI 0.07-0.41) for a distance greater than 2 mm.
An exception to this is the atypical lipomatous tumor (liposarcoma G1 of the extremities). Here, due to the rather benign behavior with extremely rare dedifferentiation and metastasis, complete but marginal resection is possible in primary and recurrent cases. This also applies under the aspect of a very frequent inclusion of vital structures in the tumor [166].
5.1.1.1 Resection
The wound should be closed without tension.
- Consensus
- Strong consensus
If primary tension-free wound closure is not possible, the aim shall be to cover the wound with plastic reconstructive measures.
- Consensus
- Strong consensus
If a sarcoma grows to bony structures or is suspected, the periosteum of the affected bone section should also be resected.
- Consensus
- Strong consensus
In cases of urgent suspicion of infiltration of bone structures by a sarcoma, co-resection of the affected bone section shall be generously indicated.
- Consensus
- Strong consensus
If infiltration of blood vessels by sarcoma is suspected, preoperative vascular imaging shall be performed by appropriate imaging e.g. CT angiography, MR angiography, DSA.
- Consensus
- Strong consensus
If there is evidence of blood vessel infiltration by sarcoma, the affected vessels should be segmentally resected and reconstructed.
- Consensus
- Consent
If infiltration of functionally relevant nerves is detected, the corresponding nerves should be resected. Infiltration of such a nerve alone does not constitute an indication for amputation.
- Consensus
- Strong consensus
Background
Tumor resection should include the access route of an incisional biopsy by en bloc excision of a skin ellipse. For punch biopsies, this approach is not clearly supported by data.
It is important that wound closure is performed in a tension-free fashion so that adjuvant radiotherapy, for example, can be performed without problems. Local displacement flaps are suitable for this purpose. If a tension-free wound closure is not possible, a sterile wound closure should be performed via a VAC suction system, if necessary. The histological findings of the resection margins should be awaited before definitive wound closure. Mesh graft coverage does not constitute a wound closure suitable for irradiation.
If there is a resulting larger skin defect after surgical resection there should be a low threshold for considering plastic surgical reconstructive coverage by regional pedicled flaps aor by free flap transfer.
R0 resection is a positive predictive factor for local recurrence-free and overall survival. In contrast, infiltration of neurovascular bundle and bone by sarcoma are negative predictive factors for local recurrence-free survival [163]. These situations require special attention to avoid an R1 resection. R1 resection is also a highly significant negative predictive factor for local recurrence-free and overall survival.
In special cases, e.g. favorable tumor biology (liposarcoma) or after preoperative measures resulting in a less viable sarcoma (radiation, limb perfusion), a tissue layer such as perineurium, fascia, adventitia or periosteum may be sufficient to allow complete tumor resection.
If the soft tissue sarcoma is adjacent to the bone without infiltrating it, the extent of resection must be determined on an interdisciplinary basi [167]. In radiation-sensitive lesions, neoadjuvant RTX may allow avoidance of bony resection. However, this is an individualized case-by-case decision based on tumor size, grade, histological subtyper and patient status. The periosteum must be removed as well in these cases, as it must be considered infiltrated. Due to the deperiosis and the radiation therapy, an increasing biomechanical weakening of the bone can be assumed as a long term consequence of treatment. Therefore, in order to avoid a usually poorly healing insufficiency fracture, intramedullary prophylactic stabilization after completion of tumor therapy may be a treatment option [168].
A risk of insufficiency fractures also exists after isolated limb perfusion when during the tumor resection there is stripping of the periosteum and subsequent radiation [169].
Close association with bone by soft tissue sarcoma affects about 5-6 % of patients, of which only a few (less than 1 %) have true infiltration [170]. It is often difficult to decide preoperatively whether true bone infiltration is present. Frequently, co-resection of the bone adjacent to the sarcoma is necessary to avoid exposing the tumour surface in the tumor bearing muscle area. Often the periosteum is sufficient for this in terms of the ‚Barrier‘ concept [147], although occasionally a bone lamella has to be resected as well. Complete resection of the bone and reconstruction should be considered if the bone is encased by the sarcoma or if there is true tumor infiltration of the bone.
For sarcomas with infiltration into blood vessels, venous or arterial vascular resection and reconstruction is often required to safely ensure R0 resection. Typically, these are highly malignant stage III sarcomas that require multimodality therapy. The exception is primary vascular sarcomas, which are often grade 1 but also require vascular resection and reconstruction.
Sarcomas can affect vessels in a number of ways including simple displacement, direct infiltration, encasement but is still in itself, not an indication for amputation. or compression [171].
Vascular resection and reconstruction requires complex surgical planning involving vascular surgeons [172]. With adequate surgical expertise, treatment outcomes are no less favorable than after sarcoma resection of the extremities without vascular involvement [173], [174]. Amputation cannot be inferred from vascular infiltration alone.
When sarcomas infiltrate neurovascular bundles, nerves are often involved as well. Analogous to the classification of the anatomic relation of vessels to sarcomas, a classification regarding the relation to nerves has also been established [175]. The previous universal indication for amputation because of involvement of a major nerve in eg resection of the sciatic nerve cannot be maintained [176], [177]. In the evaluation of walking ability after sciatic nerve resection using the MSTS Rating Scale, half of the patients had a score of 25 or more points (out of a possible 30), indicating unimpaired function of the limb. No amputation indication per se can be inferred from the need to resect the sciatic nerve.
Resection of the femoral nerve is the far less favorable constellation for leg function due to the loss of innervation of the quadriceps muscle but is still in itself, not an indication for amputation.
Functionality, mobility
In the case of macroscopically close resection, if detected or suspected intraoperatively, the suspected close margins shall be marked on the resection specimen.
- Consensus
- Strong consensus
Background
If the tumor is located close to critical vessels or nerves, these do not need to be routinely removed as long as there is no direct infiltration. Resection of the adventitia or perineurium may be sufficient, taking into account the the histologic tumor subtype (most likely in liposarcomas) and the grade (most likely in grade 1).
Resection with a microscopically tumor-affected sedimentation margin (R1 resection) is an important negative predictor of local recurrence in STS [178], [179]. Microscopically positive resection margins are associated with both a higher rate of local recurrence and a shorter disease-free interval (DFS) in STS [178], [180]. In a cohort study (N=1668) of patients with STS of the extremities and trunk, which examined the main predictors of local recurrence in patients with STS, there was a significantly higher rate of local recurrence after a 10-year follow-up for patients with tumor-involved settling margins (p < 0.001) [179].
If resection with microscopically positive resection margins is anticipated, they should be marked intraoperatively for subsequent radiotherapy boost. Close collaboration between surgeons, pathologists, and radiation therapists is required for optimal treatment outcomes. After consideration of treatment alternatives, expected functional postoperative limitation, and comorbidity, a less aggressive surgical approach may also be reasonable, even if it is expected preoperatively that the microscopic deposition margins are not certainly tumor-free [181].
See also chapter Chapter 5.7.1 „Planned marginal resection“ and acceptance of minimal safety margins [105].
Stage-dependent treatment:
Following resection of a primary sarcoma and histologic findings of R1 resection (other than ALT), presentation to a sarcoma center for consideration of resection shall be made.
- Consensus
- Strong consensus
Patients with stage III soft tissue sarcoma shall be offered multimodality therapy preoperatively as part of an interdisciplinary sarcoma board.
- Consensus
- Strong consensus
Background
Stage I: T1 G1 = stage IA, tumor <5cm
Stage IB: T2a G1, Tu >5<10cm
Complete resection is the primary treatment goal in stage IA patients, tumor-free margins of deposition with a wide safety margin should be aimed for [182]. Adjuvant therapy is usually not indicated.
In stage IB (T2a G1), depending on tumor location and tumor size, a circumferential safety margin (previously required 1 cm) is sometimes not achievable. If the final histology shows a marginal resection, a further resection or adjuvant RTX may be necessary [183]. For Atypical Lipomatous Tumors (ALT), marginal resection is sufficient to achieve long-term local control [184].
Stage II: T1 G2/3
For stage II sarcomas, complete R0 resection of the tumor should be aimed for. It may be that a surgical approach alone may be an option for patients with small tumors that can be removed with a very wide safety margin. Adjuvant radiotherapy even after R0 resection should be considered in all cases.
In a phase II trial (RTOG 9514) in 66 patients with highly malignant sarcoma and a tumor size of ≥8 cm, the combination of preoperative radiotherapy of 44 Gy combined with chemotherapy of doxorubicin/DTIC/ifosfamide yielded R0 resection in 88% of patients [185]. After 7 years, the local recurrence rate and metastasis rate were both 22 %. However, this approach resulted in grade 3 and grade 4 morbidity in 97% of patients and mortality of 4.7 %.
A randomized phase II/III EORTC trial with this question failed to show a survival gain for these patients compared with surgery alone. There was no benefit in recurrence-free survival in 134 phase II patients. The phase III trial planned for survival analysis was not conducted because of slow recruitment [186]. Patients with tumors larger than 8 cm are at increased risk for local recurrence or the development of distant metastases. There is also evidence that a surgical approach alone may be adequate in selected patients with high-grade lesions. Here, a prospective study showed in the long-term results that acceptable local control and good long-term survival can be achieved if an R0 situation is achieved [187]. Here, local recurrence rates at 5 and 10 years were 7.9% and 10.6% for patients with an R0 resection. In another analysis of 242 patients, the local recurrence rate was found to be significantly increased when there was a safety margin of less than 1 cm from the resection margin [188]. In this regard, a surgical approach followed by radiotherapy should always be considered in stage II [189]. Preoperative radiotherapy may also be an option in this case.
Plastic reconstruction procedures using artificial tissue to stabilize the chest wall but also with myo-cutaneous muscle plasty may be necessary. (see Chapter 5.2)
Stage III: T2G2/3 = Stage IIIA, T3/4 (Tu > 10 or >15cm G2/3)
Even in stage III, complete R0 resection of the tumor should be aimed for, but this is often difficult due to the size of the tumor and its aggressive growth.
Table 6: Staging - extremities and superficial trunk, retroperitoneum
(UICC/AJCC 2017 [190])
|
Stage |
T |
N |
M |
Grading three-stage |
Grading two-level |
|
IA |
T1 |
N0 |
M0 |
G1 |
low grade |
|
IB |
T2, T3 |
N0 |
M0 |
G1, GX |
low grade |
|
II |
T1 |
N0 |
M0 |
G2, G3 |
high grade |
|
IIIA |
T2 |
N0 |
M0 |
G2, G3 |
high grade |
|
IIIB |
T3, T4 |
N0 |
M0 |
G2, G3 |
highly malignant |
|
IIIC |
any T |
N1 |
M0 |
any |
|
|
IV |
each T |
each N |
M1 |
each |
|
No stages are currently recommended for tumors of the head and neck and the viscera of the thorax and abdomen.
5.1.1.2 Management of the regional lymph nodes
In particular, rhabdomyosarcomas, clear cell sarcomas, epithelioid sarcomas, and synovial sarcomas may metastasize lymphogenically. Staging studies for these tumor types should include the lymphatic drainage pathways.
- Consensus
- Strong consensus
Background
The majority of sarcoma subtypes metastasize preferentially hematogenously. Therefore, systematic lymph node removal is not recommended. However, there are sarcoma entities in which this rule does not apply.
In a recent series by Keung et al, lymph node (LN) metastases (pN1 and cN1) were found in 3.5% of sarcoma patients, and in 6.1% of angiosarcomas, 13.1% of epithelioid sarcomas, 15.9% of clear cell sarcomas, and 19.1% of undifferentiated small cell sarcomas [191]. Other research groups have come to similar conclusions (e.g., Daigeler et al. 2009 [192]).
The frequency of lymph node metastases in other sarcoma subtypes is less than 10 %, such as in rhabdomyosarcomas and synovial sarcomas (4.2 % in the work of Jacobs et al. who found lymph node metastases diagnosed in 5.3 % of 15,525 patients with sarcomas in the SEER database [193]. It is important to consider which age cohorts are being studied. In the work of Jacobs et al. the high rates of LK metastases for rhabdomyosarcomas are explained by the high proportion of pediatric patients in the studied collective with a median age of 35 years.
Not infrequently, other distant metastases exist in addition to LN metastases, so the question of local resection of lymph nodes must be answered in the context of the other staging results. LN metastases are prognostically relevant only in the localized tumor stage. In general, LN metastases occur less frequently in sarcomas of the trunk and extremities than, for example, in sarcomas of the head and neck, thorax, or abdomen.
Histological confirmation of lymph node metastases shall be performed if this results in therapeutic consequences.
- Consensus
- Strong consensus
Routinely, sentinel lymph node biopsy should not be performed in patients with soft tissue sarcomas.
- Consensus
- Strong consensus
In the absence of evidence of lymphogenic metastasis, lymphadenectomy should not be performed as part of the primary tumor resection.
- Consensus
- Consent
Lymphadenectomy may be considered for locoregional lymph node involvement without systemic metastasis.
- Consensus
- Strong consensus
For cutaneous sarcomas, sentinel lymph node biopsy (SLNB) shall not be performed.
- Consensus
- Strong consensus
5.1.1.2.1 Lymphadenectomy
Lymph node dissection shall not be performed as a standard procedure during resection of soft tissue sarcoma.
- Consensus
- Strong consensus
Depending on resectability and histology, radical lymphadenectomy should be considered as resection therapy in cases of locoregional lymph node involvement of a corresponding sarcoma subtype.
- Consensus
- Strong consensus
Background
Lymph node metastases represent a route of spread in sarcomas only for certain tumor subtypes (see Chapter 5.1.1.2), predominantly clear cell sarcomas, rhabdomyosarcomas, epithelioid sarcomas, and myxoid round cell sarcomas. Thus, lymphadenectomy is not a standard of surgical primary therapy. However, for patients with locoregional lymph node involvement, radical lymphadenectomy may be a treatment option. Analysis of a database of 1772 patients between 1982 and 1991 showed that when patients with radical lymphadenectomy were compared with patients without, median survival increased from 4.3 to 16.3 months [194]. For those patients with radical lymphadenectomy and lymph node involvement, the 5-year survival was 46%.
Detection of lymph node metastases can be performed by sentinel node biopsy in individual cases. It might be helpful also to exclude non tumor-related LN enlargement caused by atypical lymphatic drainag in large primary tumors. Detection of tumor involvement by sentinel node biopsy was successful in a workup of 62 consecutive patients in 2 of 42 patients with synovial sarcoma and 6 of 12 patients with clear cell sarcoma [195]. Thus, a general indication for SN biopsy cannot be derived from this data.
5.1.2 Trunk / Thorax
Primary soft tissue sarcomas of the trunk and thorax are rare. Therefore, only few studies exist, especially hardly any prospective and randomized studies. Thereby, the clinical behavior of adult soft tissue sarcomas of the body trunk/thorax is to be evaluated similarly to that of sarcomas of the extremities [144]. Therefore, for this chapter, findings from studies involving both patients with STS of the extremities and body trunk were included, as well as those studies that evaluated results in patients with involvement of the extremities only. Radiation-induced sarcomas after multimodality therapy for breast carcinoma are a speciasl case. In sarcomas of the thoracic wall, the reconstruction is a very important part of therapeutic planning.
5.1.2.1 Resection
The treatment principles for sarcomas of the trunk/thorax are identical to those for sarcomas of the extremities (see Chapter 5.1.1).
Patients with stage III soft tissue sarcoma of the trunk or thorax shall be offered multimodality therapy preoperatively as part of an interdisciplinary sarcoma board.
- Consensus
- Strong consensus
Background
Surgical resection with tumor-free resection margins (R0 resection) also represents the core therapeutic element for patients with adult localized soft tissue sarcoma on the body trunk and thorax. The assessment of whether a tumor is R0 resectable can only be performed by a surgeon experienced in this topic. Accordingly, the tumor stage, anatomic location, comorbidities, and expected functional limitation of the patient must be considered in this context.
In patients with localized STS, resection with tumor-free resection margins (R0 resection) should be aimed for. Soft tissue sarcomas of the chest wall can be well controlled with complete surgical resection with wide margins [144]. En bloc resection of both the tumor and the incisional biopsy approach should be aimed for.
5.1.2.2 Re-resection
Following resection of a primary sarcoma and histologic findings of R1 resection, presentation to a sarcoma center for consideration of resection shall be made.
- Consensus
- Strong consensus
Background
If the margins of the resection specimen histologically show tumor cells (R1 resection), a further resection should be considered. Macroscopic as well as microscopic residual tumor imply a worse prognosis, and local control cannot be safely achieved with additive radiotherapy either [196]. In an analysis of 666 patients with localized STS and a surgical approach, resection was necessary in 295 patients with residual tumor. Among these, after 5, 10, and 15 years, 85%, 85%, and 82% of patients with resection were without local recurrence. In patients who did not receive resection, the local recurrence-free rate was 78%, 73% and 73%, respectively (p=0.03). R0 re-resection was a significant predictor of local tumor control [197].
5.1.2.3 Neoadjuvant/adjuvant therapy
If the tumor is only borderline resectable due to size or location, there is the option of neoadjuvant treatment by means of systemic therapy and/or radiotherapy (see Chapter 5.6) [198]. This decision is influenced by the expected probability of response to systemic treatment, the histology of the tumor, as well as the general condition of the patient.
Surgically, resection should again be performed in a wide, local resection if possible with a margin of healthy tissue (see also Chapter 5.4 and Chapter 5.6). When performing the resection after neoadjuvant pretreatment, wide resections with small safety margins may also be appropriate (e.g., safety margin < 2 mm), depending on the response of the tumor.
5.1.3 Head and neck
5.1.3.1 Surgical therapy of the primary tumor
Surgical „wide resection“ in healthy tissue represents the primary curative therapeutic pillar for soft tissue sarcomas of the head and neck [199], [200], [201], [202], [203], [204], [205], [206]. Wide resection in the first attempt - along with tumor size and tumor stage at initial diagnosis [200], [201], [205], [207], [208], [209], [210], [211] - is the most important prognostic factor for local tumor control, recurrence-free survival, and overall survival [200], [204], [205], [206], [212], [213], [214], [215]. Wide resection corresponds to a complete removal of the tumor surrounded on all sides by healthy tissue including a possible puncture channel or biopsy scar. Regarding safety distances and definitions (‚Marginal resection‘) or “a layer of non-tumor infiltrated tissue“ especially after preoperative multimodal therapy, please refer to chapter 5.1 “Surgical therapy - General aspects“ and chapter 5.7.1 „Planned marginal resection“.
Macroscopic non-in-sano resection (R2) has the most unfavorable prognosis compared to microscopic non-in-sano resection (R1), close margin resection or resection in healthy tissue (R0). Individual cohort studies critically discuss the benefit of resection in healthy tissue for survival and could not show a clear survival benefit of in-sano resection in retrospective analyses [199], [203], [209], [210], [216], [217], [218], [219]. Tumor invasion into adjacent structures such as bone or blood vessels was identified as an independent negative risk factor [199], [211], [218].
In the head and neck region, there is a high spatial density of critical and essential structures is present, such as the extracranial cranial nerves, the carotid artery, the orbitals, or the skull base. In addition, the integrity of function and aesthetics in the head and facial region represents an essential requirement for quality of life. The preservation or restoration of the aforementioned structures or functions cannot always be guaranteed with radical surgical therapeutic approaches. Modification of radical surgical procedures due to the aforementioned complex and vital structures in the head and neck region results in incomplete resection rates of 8-42 % [200], [205], [211], [214], [215], [218], [220] in published cohort studies. Therefore, it is critical to openly and thoroughly discuss the expected surgical morbidity or radicality with each patient in advance.
In the head and neck region, the concepts of „wide resection developed elsewhere“ do not apply in simple analogy to, for example, the criteria in the extremities because of the close anatomic relationship to important functional structures.
In case of curative therapy approach (localized primary tumor, locoregional resectable neck lymph node and resectable distant metastases), the surgical indication for the head and neck region has to be discussed in the interdisciplinary sarcoma board considering functional and aesthetic aspects. Also for the head and neck region, resection of the tumor in healthy tissue with the biopsy scar without compromising the tumor tissue and the pseudocapsule (R0) should be aimed for [221].
5.1.3.2 Cervical Lymph Node Management
In contrast to squamous cell carcinomas of the head and neck, soft tissue sarcomas rarely have lymph node metastases (3-15%); however, when these are detected, the prognosis is less favorable, corresponding to distant metastasis [199], [214], [218]. Since soft tissue sarcomas are a very heterogeneous group of malignancies, a general recommendation for neck dissection cannot be made. Thus, neck dissection in cases of clinical and radiological suspicion of neck lymph node metastases should be performed only after presentation to the interdisciplinary tumor board. B-mode sonography represents the primary diagnostic modality, but this is supplemented by cross-sectional imaging in cases of suspected sarcoma. Lymph nodes in the head and neck region should be considered suspicious if they are 10-12 mm or larger in diameter, if they are not rounded, if they form conglomerates, or if there is no hilar sign. Pathologic contrast uptake or necrosis may represent a malignancy sign [199], [206], [214], [218].
During resection of soft tissue sarcomas or recurrences, clinically and/or radiologically conspicuous lymph nodes should be removed in the sense of a modified radical neck dissection mono-bloc, if possible after histological confirmation. This is especially true for sarcoma subtypes that preferentially metastasize to lymph nodes (e.g., rhabdomyosarcoma*, clear cell sarcoma, epithelioid sarcoma, myxoid round cell sarcoma).
For subtypes such as rhabdomyosarcoma, the recommendations of the Cooperative Soft Tissue Sarcoma Study Group (CWS) are used.
* This applies to adults only, not ARMS and ERMS.
- Consensus
- Consent
5.1.3.3 Reconstructive procedures
Plastic reconstructive, especially microvascular, surgery is an essential therapeutic pillar for maintaining or restoring quality of life in soft tissue sarcomas of the head and neck.
- Consensus
- Strong consensus
Background
Because of tissue loss due to tumor resection, the use of plastic reconstructive procedures in the head and neck region is often warranted. In addition to local flaps, vessel-pedicled flaps (e.g., latissimus dorsi flap, pectoralis major flap) are important options. In addition, microvascular free tissue transfer such as the forearm flap, latissimus dorsi flap, or antero-lateral thigh flap are frequently used [222], [223], [224]. If the maxilla or mandible is involved, the microvascular scapula flap, microvascular crista-iliaca graft, or fibularis graft are most commonly used [200], [225].
In addition to surgical reconstructive procedures, epithetics and prosthetics have an important role in restoring function and aesthetics. Epithetic procedures can also be combined with surgical reconstructive procedures or used as a temporary or permanent approach [226], [227]. This may be particularly the case in multimorbid patients who are not amenable to multi-period procedures and multiple anesthesia.
5.1.4 Skin
The following chapter refers to primary cutaneous soft tissue sarcomas that do not show clinical or imaging evidence of metastasis at diagnosis. This is a very heterogeneous group of tumors of the dermis and subcutis. The most common primary cutaneous soft tissue sarcomas are dermatofibrosarcoma protuberans (DFSP), atypical fibroxanthoma (AFX), dermal undifferentiated pleomorphic sarcoma (UPS), and leiomyosarcoma.
5.1.4.1 Surgical therapy of the primary tumor
For primary cutaneous soft tissue sarcomas without the presence of metastasis, surgical resection in healthy (R0) shall be performed.
- Consensus
- Strong consensus
Depending on the entity, tumor grading, and local recurrence rate, specific safety distances should be observed for cutaneous sarcomas.
- Consensus
- Strong consensus
For cutaneous sarcomas, sentinel lymph node biopsy (SLNB) shall not be performed.
- Consensus
- Strong consensus
Background
Surgical resection in healthy tissue (R0) is the treatment of choice for primary cutaneous sarcoma without evidence of metastasis. In cases of histopathologically close (close margin) or non-in-sane resection (R1, R2), resection should be performed whenever possible to achieve R0 status.
Depending on sarcoma severity, grading, and histopathologic workup, different final safety margins are recommended for resection/post-resection (see following Table). For dermatofibrosarcoma (DFSP), according to S1 guideline of the ADO, a safety distance of 2 cm is recommended when conventional histologic section margin control is used; when three-dimensional micrographic section margin control is used, a safety distance of 1 cm is considered sufficient [228]. Three-dimensional micrographic incision margin control should be performed on paraffin embedded sections and not on the frozen sections and should be distinguished from Mohs surgery. For cutaneous angiosarcoma, a wide safety margin is considered desirable according to S1 guideline of the ADO, but without exact size specification [229]. This is different for cutaneous Kaposi's sarcoma, where tight safety margins are considered sufficient for surgery of the primary tumor due to its frequent multilfocal recurrence and good treatment alternatives, such as primary radiotherapy [229]. For rarer entities, there are no guideline-based recommendations. However, a choice of safety margin adapted to tumor grading and local recurrence propensity is generally considered reasonable. For atypical fibroxanthoma (AFX) with a high propensity for local recurrence, a three-dimensional, micrographic incision margin or a safety distance of 1-2 cm is recommended. For dermal superficial undifferentiated pleomorphic sarcoma (UPS) not associated with actinic damage, wide resection with three-dimensional, micrographic incision margin control is recommended. For pleomorphic dermal sarcomas (PDS) in actinically damaged skin with p53 mutation, evidence of a better prognosis was found, so a safety margin of 1 cm with three-dimensional, micrographic incision margin control is recommended here [230]. For cutaneous leiomyosarcoma, a wide resection with three-dimensional, micrographic incision margin control is recommended [231]. The safety margins suggested in the follwing Table are based on case series, retrospective studies, and expert opinion.
Table 7: Safety distances cutaneous soft tissue sarcomas
|
Entity |
Safety distance (SA) |
Alternative method |
Reference |
|
Dermatofibrosarcoma protuberans (DFSP) |
1 cm + DMS* DMS alone, if SA not possible |
2 cm |
[233] (n=5249, retrospective) [234] (n=70, prospective) |
|
Fibrosarcoma transformed DFSP |
wide resection** + DMS, 2 cm should be aimed for |
|
[235] (n=13, case series) |
|
Pleomorphic dermal sarcoma, superficial, assoc. with actinic damage and p53 mutations
Undifferentiated pleomorphic sarcoma, superficial, not in actinically damaged skin |
1 cm
W wide resection** + DMS, 2 cm should be aimed for
|
|
|
|
Atypical fribroxanthoma |
DMS |
|
[240] (n=91, retrospective) [237] (n=907, retrospective) |
|
Leiomyosarcoma, cutaneous location |
1 cm + DMS |
|
[241] (n=71, retrospective) |
|
Leiomyosarcoma, subcutaneous location |
wide resection** + DMS, 2 cm should be aimed for |
|
|
|
Liposarcoma |
wide resection** + DMS |
|
no studies, case series |
|
Angiosarcoma |
wide resection** + DMS |
|
|
|
Kaposi's sarcoma |
scarce SA |
|
|
|
* DMS: Three-dimensional, micrographic incision margin control; this should be performed on the kerosene section and not on the cryosection and should be distinguished from Mohs surgery. ** Wide resection: complete removal of the tumor surrounded on all sides by healthy tissue including a possible puncture channel or biopsy scar. If wide resection is not possible or prognostic, function-preserving surgery should be performed with the goal of R0 resection. |
|||
There are no reliable data on sentinel lymph node diagnostics (SLNB) for cutaneous sarcomas; therefore, it is not recommended.
Highly malignant cutaneous sarcomas, especially angiosarcomas, are treated according to the same adjuvant principles as other sarcomas, e.g. with regard to radiotherapy [243].
Radiation-associated angiosarcomas following therapy for breast carcinoma present a special problem. These tumors are always highly malignant and have a high rate of locoregional and distant metastases. Prospective study data are not currently available. A German prospective study is evaluating pazopanib and paclitaxel (GISG-06, EVA study, NCT02212015).
The risk in women with breast carcinoma and radiation of developing angiosarcoma is 26 times higher than with therapy without radiation. Even when tumors appear localized, field cancerization is almost always present. Accordingly, achieving R0 resection in these tumors is not associated with a lower rate of distant metastases or more favorable survival [244]. Mastectomy as the first therapeutic step is therefore usually not effective and followed by a recurrence rate of 55%. In contrast, preoperative or perioperative chemotherapy could achieve improved local control [244].
5.1.5 Retroperitoneum
5.1.5.1 Presentation and specific problem
Retroperitoneal sarcomas (RPS, C48.0 by ICD-10) account for approximately 12 % of all soft tissue sarcomas [245]. The tumors often present with only mild symptoms of abdominal girth gain and malaise over a prolonged period of time. Rapid tumor growth is also suggestive of a higher grade malignant tumor in RPS, e.g. Rhabdomyosarcoma. Through international cooperation (Transatlantic Retroperitoneal Sarcoma Group, TARPSWG), a large database has been generated in recent years, better allowing the development of prognostic criteria [246], [247], [248], but also providing the basis for randomized trials [249].
At diagnosis, RPS have a median diameter of about 20 cm [247]. The tumor size alone and its close relationship to surrounding organs often necessitate a complex surgical approach. According to a 2017 survey of German surgical clinics, there are large divergences between clinics with less and more experience in dealing with these tumors, especially regarding biopsy, targeted safety margins, extent of resection, or lymphadenectomy [250].
Histologic subtyping and therapeutic implications.
The distribution of histologic subtypes of sarcomas in the retroperitoneum differs significantly from sarcomas of the extremities and trunk.
Most common subtypes in the retroperitoneum are dedifferentiated liposarcomas (36 %), well-differentiated liposarcomas (26 %), and leiomyosarcomas (19%). Solitary fibrous tumors (SFT), undifferentiated pleomorphic sarcomas, and malignant peripheral nerve sheath tumors (MPNST) occur with lower frequency [247], [251]. For dedifferentiated and well-differentiated liposarcomas, cluster amplification of MDM2 and mostly also of CDK4 on chromosome 12q13-15 can be detected.
Differential diagnoses include rhabdomyosarcomas, malignant lymphomas, germ cell tumors, carcinosarcomas, desmoid fibromatoses, gastrointestinal stromal tumors, and benign tumors such as leiomyomas and schwannomas [252] . These differential diagnoses have considerable consequences for therapy (e.g., systemic therapy instead of surgery, watch and wait for desmoids). Therefore, histological clarification is mandatory before resection. Primary surgery without diagnosis of the tumor may represent a mistreatment.
5.1.5.2 Diagnostics and biopsy
If RPS is suspected, cross-sectional imaging of the abdomen and pelvis, with contrast administration if possible, shall be performed before biopsy and therapeutic measures.
- Consensus
- Strong consensus
Histologic confirmation of soft tissue tumors of the retroperitoneum shall be performed preoperatively.
- Consensus
- Strong consensus
Background
Prior to any therapeutic intervention, cross-sectional imaging with contrast administration of the thorax, abdomen, and pelvis is required to assess tumor extent (diaphragm, bladder, ureter, vessels), vasculature, and vascularization of the sarcoma, and to rule out metastasis. Sagittal and coronal reconstruction are helpful in addition to transverse imaging. The area with the highest contrast uptake should be targeted as the biopsy site, as this is where the best perfusion and highest proliferation (most representative of grading) can be assumed.
The extent of resection, i.e., the eventual acceptability of marginal resection, and the indication for preoperative radiotherapy or chemotherapy, all depend on the histologic subtype [253]. The time required for a CT-guided percutaneous core biopsy and its histologic evaluation is not significant given the history of the disease, that often goes back a long time. Even when patients displays compressive symptoms attributable to the tumour, there is usually no indication for rapid surgery or even emergency intervention. Percutaneous core biopsy has no negative consequences in terms of local recurrence risk [254], [255].
An exception with regard to biopsy are at most homogeneous lipomatous tumors without focal contrast enhancement or central necrosis areas, in which an experienced team of radiologist and surgeon can assume with high probability a low-malignant liposarcoma without dedifferentiation.
5.1.5.3 Resection treatment
Complete surgical resection (R0) shall be performed as standard therapy of retroperitoneal soft tissue sarcomas. Even without evidence of histologic infiltration of adjacent organs, (portions of) adjacent organs should be removed as part of an en bloc resection.
- Consensus
- Strong consensus
Surgical treatment of retroperitoneal sarcoma shall be performed in a sarcoma center with special expertise in surgery of RPS.
- Consensus
- Strong consensus
Background
Complete macroscopic resection of the tumor results in the best chance of long-term tumor-free survival. Therefore, optimal planning of surgical therapy is the crucial aspect for treatment. With regard to the surgical goal in terms of resection, a distinction must be made between a marginal resection and a compartment-oriented approach.
Anatomically, the retroperitoneal space is not really a compartment analogous to the muscle groups of the extremities. However, its 3-dimensional boundaries can be defined. These are ventrally the peritoneum and ipsilateral mesentery/mesocolon and colon. Cranially, it is bounded on the left by the pancreatic tail and spleen. Posteriorly and laterally, muscles (transversus abdominis muscle, iliopsoas muscle, and quadratus lumborum muscle) border the retroperitoneal space, and cranially, the diaphragm borders it on both sides.
Most RPS have minimal distance from surroundingorgans, i.e., kidney, colon, pancreas, diaphragm, aorta, v. cava, ureter, psoas muscle, femoral nerve, and adrenal gland are almost always in direct contact with the tumor. It is often mistakenly assumed that RPS represent encapsulated tumors, which is factually incorrect. Due to the growth pressure of the tumor, the surrounding tissue is stretched out and regularly shows tumor infiltration.
In the past, peeling operations were predominantly performed leaving the structures adjacent to the tumor. Resection within these limits results in recurrence rates as high as 63% [256], and 80 % of these patients die from local recurrence. Resection of the sarcoma together with its surrounding structures and organs (compartment-oriented resection) has resulted in dramatically reduced local recurrence rates, lower rates of distant metastases, and improved survival [257], [258], [259].
International recommendations consider en bloc resection with co-resection of adjacent organs and tissues covering the tumor to be the standard of care (primary multivisceral resection). The organs do not necessarily have to be tumor infiltrated, but they form the tissue layer covering the sarcoma. The strategy follows the principles of sarcoma surgery at the extremities: where adequate resection distance is possible with low morbidity (co-resection of the colon and mesocolon), organ resection is performed; where induced morbidity is significant (e.g., additional pancreatectomy), focal-marginal resection is planned rather. This has implications relating to the application of preoperative radiation (see below).
Thus, depending on tumor location, a compartment-oriented resection in the right-sided retroperitoneum typically includes the right hemicolon, the right kidney, if applicable, adrenal gland and diaphragm, and the transversus abdominis muscle as well as the fascia or portions of the psoas muscle. On the left side, the left hemicolon, transversus abdominis muscle, fascia or portions of the psoas muscle, pancreascorpus/tail and spleen, and diaphragm, if any, bordering the tumor are part of the resectate [252], [259].
Historically, the prognosis of RPS has been poor, with 5-year survival rates of 50-55 % [257]. With adoption of the surgical approach described above, 5-year survival rates of 65-70 % are achievable [246], [258], [259].
Data from the TARPSWG group [247], [260] underscore the critical role of pretherapeutic workup for RPS and histology-adapted surgeryplanning. Analysis of a patient group of 586 patients with a median follow-up of 6.5 years showed that, in addition to infiltration of adjacent organs by the sarcoma, performance of surgery by a specialized center was the most important prognostic parameter for local recurrence rate and overall survival [253]. In this regard, performing such surgery in a specialized center and avoiding incomplete resections turn out to be the two most important prognostic factors for RPS. It could be shown that these improvements in diagnostics and therapy also have a significant positive impact on the long-term prognosis of patients [261]. Comparing three 5-year periods from 2002 to 2017, analysis of 1942 patient histories showed that the 5-year OLR improved from 61.2% to 67% to 71.9% in the most recent period evidence. At the same time, the rate of incomplete (R2) resections decreased from 7.1% to 4.7%.
Under such conditions, severe perioperative morbidity (Clavien-Dindo 3) affected 16.8% of patients and 30-day mortality was 1.8% [262]. The 90-day mortality improved from 4.3% to 2.3% between 2002 and 2017 [260]. A median of one unit of blood was transfused, and half of patients managed without transfusion. Only procedures including pancreatico duodenectomy or large vessel replacement had higher morbidity, with an odds ratio of 1.5.
Data from a recently published systematic review are higher, with a morbidity of 23% and a mortality of 3% [263]. However, it should be noted that half of the patients in this database analysis (SEER, NCDB, ACS-NSQIP) had undergone surgery before 2000.
5.1.5.4 Preoperative therapy
Neoadjuvant multimodality therapy should be discussed in the interdisciplinary sarcoma board for retroperitoneal sarcomas.
- Consensus
- Strong consensus
Background
The same therapeutic principles apply to RPS as to sarcomas at other sites, i.e., in highly malignant sarcomas there is an indication to consider neoadjuvant therapy and an indication for adjuvant radiotherapy after R0 resection. However, some special problems arise:
- Given the size of the tumors, a biopsy is often not representative, so that highly malignant tumor components are not detected preoperatively.
- Adjuvant postoperative radiotherapy is usually not feasible because the small bowel loops occupy the former space of the tumor. The limited tolerance of the small bowel almost always prevents application of the necessary radiation dose.
- The size and complexity of the resection specimen significantly limit the pathologist's ability to review the resection margins with respect to R0 resection.
Under these aspects, it seems obvious to try to perform any postoperative adjuvant therapy as neoadjuvant treatment. Neither radiotherapy nor chemotherapy currently has sufficient evidence of long-term improvement in treatmentoutcome.
Data from the only randomized phase III trial of 266 patients (EORTC 62092-22092, NCT01344018, STRASS) failed to demonstrate superiority of preoperative radiotherapy [264]. The study included 266 patients with 1:1 randomization from 31 centers with expert status from Europe and the United States. Patients in the radiation arm received 50.4 Gy in 28 fractions of 1.8 Gy as 3D conformal radiotherapy or intensity-modulated radiation therapy (IMRT) according to EORTC Radiation Oncology Group (ROG) quality standards.
The primary endpoint of the study was the ‚intra-abdominal recurrence-free interval (IARFS)‘. With a median follow-up of 43.1 months, median recurrence-free survival was not significantly different in the surgery alone group at 5 years (95 % CI 3.4-nb) versus the preoperative radiotherapy group at 4.5 years (95 % CI 3.9-nb). This was true for all subtypes (well-differentiated liposarcoma, dedifferentiated liposarcoma, leiomyosarcoma). In the subgroup with well-differentiated liposarcoma, a post-hoc analysis at 3 years showed that IARFS tended to be more favorable (HR 0.62, 95% CI 0.38–1.02) in the arm ‚radiation+surgery‘ with 75.7 % (95 % CI 65.6-83.2) compared to the arm ‚surgery alone‘ with 65.2 % (95 % CI 54.5-74.0).
From these data, no general indication for radiotherapy before surgery for RPS can be derived. In this respect, a discussion of the indication for preoperative radiotherapy in RPS depends on the individual tumor situation.
Just as in previous smaller studies that used radiotherapy alone or in combination with e.g. antiangiogenic therapy, the results show good tolerability and no relevant interaction with surgery [265], [266]. In two interim safety analyses after 66 and 132 patients, respectively, the STRASS study had not shown a significantly different rate of reoperation. Only 3 % of patients in the radiation arm could not be operated on at the scheduled time due to adverse events. The perioperative complication rate was 37% in the radiation arm versus 27% in the surgery-only patient group, which was within the range of morbidity reported by the TARPS group in over 1000 patients operated on [262]. The need for blood transfusion affected 19% of the surgery-only versus 29% of the preirradiated patients. In both treatment arms, 2 patients died postoperatively.
The extent to which it is necessary to irradiate the entire tumor volume was discussed. Recurrence after adequate primary surgery typically occurs dorsally paravertebrally or along the diaphragm or the costal process. In this respect, irradiation of the ventral tumor circumference, which is well controlled surgically, may be unnecessary and can be replaced by a so-called ‚banana field‘ perivertebral or an IORT [267], [268].
RPS were also included in the neoadjuvant trial comparing systemic anthracycline-containing chemotherapy +/- regional deep-wave hyperthermia [269]. A subgroup analysis of 149 patients with abdominal or retroperitoneal sarcoma showed an analogous result to the overall study, with a long-term advantage for patients with hyperthermia. The study also proves that preoperative systemic chemotherapy, even in combination with deep hyperthermia, does not affect the surgical procedure and perioperative morbidity [269].
5.1.5.5 Preoperative measures
Patients in whom multivisceral resection of RPS is planned shall be evaluated preoperatively with side-separated renal function clearance.
- Consensus
- Strong consensus
Background
When compartment-oriented resection is the goal, side-separated renal function testing is mandatory preoperatively to ensure that a unilateral nephrectomy can be performed without compromising the patient's overall renal function.
Stentting of the ureter is optional depending on tumor location.
If it is apparent preoperatively that resection of the spleen is required, vaccination should be given according to the recommendations of the Robert Koch Institute against asplenia (pneumococci, Haemophilus influenzae type B, and meningococci) [270].
5.1.5.6 Procedure for R1 resection
If R1 resection of soft tissue sarcoma of the retroperitoneum is found, re-resection should not be performed.
- Consensus
- Strong consensus
After R1 or R2 resection of a primary RPS, presentation to a sarcoma center shall be made for consideration of further therapeutic modalities.
- Consensus
- Strong consensus
Background
After multivisceral resection of an RPS, determination of R status is particularly difficult. Workup of the entire circumference of the specimen is neither goal-directed nor efficiently performed by the pathologist. If the surgeon has marked a possible area of R1 resection or sent resection margin biopsies separately, the pathologist has a higher chance of confirming R1 resection histologically.
From a pragmatic point of view, R0 and R1 resection are combined internationally – in contrast to sarcomas of the extremities and trunk. However, it must be ensured that the tumor is macroscopically completely removed and that there is no R2 resection. Especially in well-differentiated liposarcoma (G1), the clinical course is such that even after R1 resection, tumor recurrence is often detectable only after many months.
A subsequent resection to achieve improved resection margins in relation to the surgical intervention already performed is usually not useful.
If an inadequate resection (e.g., enucleation, resection in multiple tumor parts) was performed during the initial intervention, a re-resection is generally not the first choice. If enucleation is performed, there is a small chance that the tumor is nevertheless completely removed. Depending on the age of the patient and histological subtype of the RPS, the further procedure must be discussed. In G1 liposarcoma, a wait-and-see approach is justified. In patients in whom the tumor was removed in multiple parts, it is reasonable to wait and see at which site a tumor recurrence occurs or whether a multifocal recurrence develops. Under the conditions described, preoperative irradiation of the tumor recurrence is then almost always indicated in order to achieve devitalization of the tumor parts in the surgical area.
5.1.6 Visceral
GIST are the most common soft tissue sarcomas of the digestive tract, accounting for about 90%. In addition, leiomyosarcomas occur in significant frequency, especially in the esophagus and stomach. In addition, solitary fibrous tumors (SFT), PEComas, dedifferentiated liposarcomas, and malignant lymphomas should also be considered for differential diagnosis.
5.1.6.1 Biopsy
Histologic confirmation of soft tissue tumors (non-GIST) of the digestive tract shall be performed for locally advanced tumors that can be removed only by complete resection of the affected organ or by multivisceral resection.
- Consensus
- Strong consensus
Complete surgical resection (R0) shall be undertaken as the standard treatment of localized soft tissue sarcomas (not GIST) of the digestive tract.
In case of infiltration of adjacent organs, R0 resection shall be aimed at by en bloc resection including parts of adjacent organs.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- ⊕⊕⊕⊝
Local recurrence
⊕⊕⊕⊕Overall survival
⊕⊕⊕⊝Metastasis-free survival
- Consensus
- Strong consensus
- References
- [152] [153] [154] [155] [156] [157] [158] [159] [160] [161] [162] [165]
In R1 resection of soft tissue sarcoma of the visceral organs/abdomen, resection should be pursued if it can be done specifically with knowledge of the site of incomplete resection and with reasonable morbidity.
- Consensus
- Strong consensus
If follow-up resection cannot be performed after R1 resection of soft tissue sarcoma of the visceral organs/abdomen, the option of additive radiotherapy shall be explored.
- Consensus
- Strong consensus
Background
When there is a high radiological suspicion of a GIST and a primary resection could be performed without loss of organ function, biopsy may be omitted. For all other tumors that must be considered for differential diagnosis (leiomyosarcoma, SFT, PEComa, desmoid, dedifferentiated liposarcoma), histologic confirmation is mandatory. The therapy of the tumors is very different depending on the histological subtype. Above all, the exclusion of lymphoma, carcinoid or non-malignant tumors (desmoid) is required. Analogous to the recommendations for sarcomas of the extremities, a limit for performing a biopsy of approximately 3 cm is reasonable, depending on the localization. Histologic confirmation should be sought for all locally advanced tumors that can be removed only by organ resection (gastrectomy, rectal extirpation) and those tumors whose resection results in functional changes of the GI tract (esophago-cardiac junction, duodenum, lower rectum).
For non-GIST soft tissue sarcomas, the same criteria apply with regard to the assessment of prognosis as for tumor localizations outside the abdomen (grading and tumor size). The indication for neoadjuvant and postoperative adjuvant therapies such as chemotherapy and/or radiotherapy follows the same considerations as for sarcomas of the extremities or retroperitoneum, i.e., they are predominantly indicated in TNM stage III.
Regarding the extent of resection, safety distances analogous to extra-abdominal tumors should be aimed for: metrically 1-2 cm, anatomically: at least one layer of non-tumor infiltrated tissue (e.g. diaphragm, fascia, etc).
In soft tissue sarcomas that do not originate from the hollow organs of the stomach and small intestine, R0 resection can often only be achieved by taking along adjacent structures such as the abdominal wall, diaphragm, or organs such as the liver and bladder. If this is foreseeable preoperatively, preoperative radiotherapy and/ or chemotherapy may improve the treatment outcome [271].
If R1 resection of the tumor has been performed without prior therapy (chemotherapy, radiotherapy), the extent to which the area of R1 resection can be identified must be considered. If this can be assumed with sufficient certainty by the surgeon and the findings on the resection specimen, it must be determined whether an R0 resection can be achieved by postoperative resection with acceptable morbidity and potential loss of function of abdominal structures and organs. In particular, the results of postoperative radiation are better after R0 resection than after R1 resection. It should also be taken into account that especially the abdominal structures can very often only be covered to a limited extent by external beam radiotherapy with the desired target dose.
Adjuvant chemotherapy data for high-malignant sarcomas show that prognosis in patients with R1 resection can be improved by postoperative chemotherapy [137], [272]. Due to the relatively small proportion of patients with abdominal soft tissue sarcomas in the respective studies, these data cannot be readily transferred. Furthermore, it should be noted that the studies were undertaken at a time when GIST was not yet established as a distinct tumor entity and thus GIST patients were also recruited into these studies. This further limits the transferability of the results.
5.1.7 Gynecology - Uterine Sarcomas
This chapter contains recommendations for the surgical treatment of uterine sarcomas. For further information, please refer to the S2k guideline „Uterine Sarcomas“, 2019 AWMF Registry Number: 015-074, https://www.awmf.org/leitlinien/detail/ll/015-074.html [273]. Carcinosarcomas of the uterus (malignant mixed müllerian tumors), which were previously classified as uterine sarcomas, behave biologically like endometrial carcinomas according to new findings and are therefore dealt with in the corresponding S3 guideline (AWMF 032/034-OL) [274].
Uterine sarcomas refer to a heterogeneous group of overall rare malignancies of the uterine musculature, endometrial stroma, or uterine connective tissue. They account for 3-9 % of all malignancies of the uterus. The incidence is approximately 1.5 (Caucasian) - 3 (African-American) / 100,000 population [275].
Tumor typing is according to the WHO, and staging is according to the FIGO or TNM classification [276]. The WHO classification lists the following entities as malignant mesenchymal tumors [277], [278]:
- Leiomyosarcomas (LMS).
- Low-grade endometrial stromal sarcomas (LG-ESS)
- High-grade endometrial stromal sarcomas (HG-ESS)
- Undifferentiated uterine sarcomas (UUS)
Surgical management will be presented below for these more common entities, with HG-ESS and UUS addressed together in one chapter due to their comparable tumor biology.
5.1.7.1 Leiomyosarcomas
In leiomyosarcoma confined to the uterus, complete removal of the uterus shall be performed without morcellement or uterine injury.
- Consensus
- Consent
In leiomyosarcoma, systematic pelvic and para-aortic lymphadenectomy shall not be performed if the lymph nodes are diagnostically unremarkable.
- Consensus
- Consent
Background
Removal of the uterus in total is the gold standard of surgical management. The indication for adnexal extirpation is optional depending on menopausal status. In premenopausal women with tumors confined to the uterus, the ovaries can be preserved [279], [280], [281]. Intraperitoneal morcellement leads to a worsening of prognosis; therefore, dismembering procedures such as laparoscopic supracervical hysterectomy or else laparoscopic uterus-preserving procedure with intraperitoneal morcellement for suspected sarcoma should be discouraged [282], [283].
The incidence of primary pelvic and para-aortic lymph node metastases is very low in LMS. If the lymph nodes – are affected, often already conspicuous intraoperatively, there is usually already a hematogenous metastasis. In this respect, systematic pelvic and para-aortic lymphadenectomy is not associated with an improved prognosis and is generally not recommended [284]. Lymph nodes that are suspicious for involvement should still be removed at surgery but without recourse to a formal lymphadenectomy. Very limited data are available regarding a fertility-preserving approach, so this cannot be recommended.
In case of extensive, advanced findings and symptoms, surgical tumor reduction should be attempted [279]. The recommendation to forgo systematic pelvic and para-aortic lymphadenectomy differs from the recommendation in the S2k guideline „Uterine Sarcomas“, in which it is a „should recommendation“, i.e., a weak recommendation. The guideline panel felt that a stronger recommendation was appropriate.
5.1.7.2 Low-grade endometrial stromal sarcomas.
In low-grade endometrial stromal sarcoma, complete removal of the uterus shall be performed without morcellement or uterine injury .
- Consensus
- Strong consensus
In low-grade endometrial stromal sarcoma, systematic pelvic and para-aortic lymphadenectomy should not be performed if the lymph nodes are diagnostically unremarkable.
- Consensus
- Strong consensus
Background
The treatment of choice is total hysterectomy (without morcellement) with removal of both adnexa [285].
The endocrine dependence of LG-ESS is well established. For example, a retrospective analysis of 153 LG-ESS patients showed a significantly increased recurrence rate when the ovaries were left in premenopausal patients. However, both in this analysis and in two other evaluations of the SEER database, there was no negative impact on overall survival. In this respect, the benefits of ovarian preservation in young patients should be carefully weighed against the risk of higher recurrence probability and discussed in detail with patients [286], [287], [288], [289], [290].
Lymph node involvement is rare and does not seem to have an impact on prognosis. In this respect, no prolonged survival can be expected from a systematic lymphadenectomy, as well as from adjuvant therapy options based on it, so that lymphadenectomy cannot be recommended as a standard overall [289], [291], [292].
Whether cytoreduction has an impact on patient survival in advanced tumors is unclear [293]. The indication for this results – if necessary in palliative intention – from the clinical symptoms of the patient.
5.1.7.3 High-grade endometrial stromal sarcomas and undifferentiated uterine sarcomas.
In high-grade endometrial stromal sarcoma confined to the uterus, complete removal of the uterus shall be performed without morcellation or uterine injury.
- Consensus
- Strong consensus
In high-grade endometrial stromal sarcoma, systematic pelvic and para-aortic lymphadenectomy shall not be performed if the lymph nodes are diagnostically unremarkable.
- Consensus
- Strong consensus
Background
Again, the treatment of choice is total hysterectomy (without morcellement) [294]. It is unclear whether the adnexa can be left in the premenopausal period. According to a 1998-2013 National Cancer Database (NCDB) analysis of 3797 patients, R0 resection plays a relevant role in survival for resection of HG-ESS [158]. Patients with R1 resection have a 5-year survival rate of 14.2% compared to 41.8% when R0 resection is achieved.
Although positive pelvic and/or para-aortic lymph nodes are associated with a less favorable prognosis, there is no evidence that surgical resection and subsequent adjuvant therapy options improve this limited prognosis [D'Angelo, E. et al. 2010], [296], [297], [298], [299]. The recommendation to forgo systematic pelvic and para-aortic lymphadenectomy differs from the recommendation in the S2k guideline „Uterine Sarcomas“, in which it is a „should recommendation“, i.e., a weak recommendation. The guideline panel felt that a stronger recommendation was appropriate.
Whether cytoreduction has an impact on patient survival in advanced tumors is unclear. However, a multicenter retrospective analysis was able to demonstrate a positive effect of cytoreduction on survival in this regard, in contrast to low-grade ESS [293].
5.2 Plastic reconstructive therapy
Reconstruction after surgical removal of a soft tissue sarcoma always represents an individual decision that can vary greatly from case to case.
When deciding to reconstruct, the following three types of reconstruction shall be considered:
- functional reconstruction
- bony and soft tissue reconstruction
- pure defect coverage
- Consensus
- Consent
Oncology-compatible en bloc resection of the sarcoma (primary tumor or recurrence) in healthy tissue represents the basis of any successful reconstructive therapy.
- Consensus
- Strong consensus
In the case of tension-free primary closure after tumor resection, this shall be aimed for while avoiding cavities.
- Consensus
- Strong consensus
If a drain is applied, it shall be discharged close to the wound edge.
- Consensus
- Strong consensus
Larger soft tissue defects involving multiple tissue layers such as subcutaneous fat, fascia, and muscle that cannot be closed by tension-free primary closure shall be covered by adequate soft tissue replacement.
- Consensus
- Strong consensus
Neoadjuvant/preoperative radiotherapy is not a contraindication to performing microsurgery.
- Consensus
- Strong consensus
Functional restoration can be single or double sided.
- Consensus
- Strong consensus
If blood vessel reconstruction is indicated, close coordination with radiation oncologists and surgeons shall occur.
- Consensus
- Strong consensus
The decision to amputate shall be a case-by-case decision after interdisciplinary discussion and consideration of all limb preservation options, including CTX, ILP, RHT, and HT.
- Consensus
- Consent
The planning of resection and plastic reconstruction shall be made as an interdisciplinary therapeutic decision.
- Consensus
- Strong consensus
Background
Functional reconstruction (e.g. motor function replacement surgery), bony and soft tissue reconstruction (especially flap surgery) and pure defect coverage (e.g. split skin grafting) have to be differentiated.
The following aspects should be considered when deciding on the respective reconstruction:
- resection status/probability of recurrence
- curative/palliative approach
- adequate soft tissue reconstruction (e.g. special requirements of the sole of the foot)
- safe coverage of reconstructed/exposed vessels, nerves, tendons
- optimal time to perform functional reconstructions (one-time/multi-time)
- Consideration of possible consequences of adjuvant therapy and here in particular radiation consequences, since adjuvant radiation therapy can impair healing of the reconstructed tissue (e.g. nerve and vessel interposition) (see recommendations 5.56 and 5.57)
- prophylaxis of the formation of a seroma cavity
- Primary wound healing (delay adjuvant treatment).
For this purpose, simple mobilization of the wound edges, which is performed subfascially to ensure blood supply to the extremities (so-called advancement flap), can be used. In the majority of cases, this is sufficient for secure wound closure, for example, at the most common site, the thigh. On the abdomen, mobilization of the wound edges can also be performed in the plane of Scarpa's fascia (fascia abdominalis superficialis).
Drains should be drained close to the wound edge so that, in the event of a necessary resection, the former drainage channel can be removed as well without extensive skin excision. Drains should be inserted into the former tumor bed to prevent the formation of a seroma cavity, and care should be taken to ensure consistent hemostasis during the surgical procedure. Sufficient compression therapy should also be ensured during postoperative treatment.
For reconstruction of the resected soft tissue, all techniques from split skin grafting to free, microsurgically anastomosed flapplasty are generally suitable. When choosing the appropriate technique, the postoperative procedure should be considered in addition to tumor-specific and patient-related factors. Functionally, in the plantar region, split skin may be better than flap-based reconstruction, which is too bulky. Conversely, in the gluteal region, split skin does not provide enough soft tissue cushion to allow pain-free sitting [300]. In the scalp area, most defects can be covered by split skin or rotational flaps. Deeper defects down to the skull bone can be safely covered by free flap reconstruction.
In principle, despite the more complex technique, free or pedicled flap reconstruction is preferable to split skin grafting because it results in an all-layer soft tissuereconstruction and creates a stable skin-soft tissue mantle. Split-thickness skin grafting is not sufficient to achieve permanent wound closure, especially when postoperative radiotherapy is used [301]. Postoperative wound healing disorders are particularly common after adjuvant radiatio [302], [303].
Soft tissue reconstruction must also consider the issue of possible recurrence: while classic myocutaneous flap reconstruction, such as the latissimus flap, maintain their blood supply through the pedicle for life, a modern perforator flap randomizes within 3 months. Thus, in the case of recurrence, incision can be made longitudinally or transversely through the flap without threat of loss of blood flow [146], [301], [304].
Functional restoration, for example, of the extensor function of the hand after proximal resection of the radial nerve by means of radial artery arthroplasty, can be performed one-stage (as part of the tumor operation) or two-stage. Often, the one-stage approach offers a shortening of the surgical procedure and the start of oncologic follow-up and also improves the functional outcome [146].
Conversely, after adjuvant radiotherapy, it is important to consider the effect of radiation on the tissue, which often provides poor conditions for motor replacement surgery, whereas irradiation of a replacement surgery that has already been performed tends to be well tolerated [146].
In particular, the indication for reconstruction of vessels requires close coordination with radiation therapists and vascular surgeons. Thus, irradiation of a vascular graft is associated with a significantly increased rate of thrombosis [303]. However, adjuvant irradiation 6 weeks before surgery appears to be safe and does not affect the flow of microvascular anastomoses, for example [305].
Amputation of an affected limb should always be considered in terms of reconstructive surgery. Advanced or exulcerating recurrent tumors, extensive infiltration of functionally important nerves and joints may represent indications for amputation, but the decision to do so should always be a case-by-case decision and patient-specific. The indication for amputation should be made in the interdisciplinary tumor conference of a sarcoma center, where all limb-preserving options should be explored beforehand.
With modern arthroplasty, even advanced tumors with bony infiltration can often be operated on while preserving the limb [306]. Localised infiltration of major nerves is also not a primary indication for amputation. After intensive physiotherapeutic follow-up, patients with soft tissue sarcomas and resection of the sciatic nerve showed a good functional outcome [177].
If amputation is indicated, it can be performed in the surgical department of the sarcoma center or a hospital close to home, which will then also initiate further prosthetic treatment.
5.3 Standards before histopathological evaluation of the resection specimen
5.3.1 Marking the resectate
As a minimum requirement, the surgeon shall mark the surgically removed resectate with thread markings in such a way that three-dimensional orientation is possible for the pathologist. If necessary, a schematic drawing of the removal localization shall be included.
- Consensus
- Strong consensus
The sending of the surgically removed resection specimen should be accompanied by appropriate radiological imaging with which the sent resection specimen can be correlated. This not only facilitates orientation for the pathologist, but also the macroscopic percentage estimation of the extent of necrosis necessary for grading.
- Consensus
- Strong consensus
Background
Adequate workup of a localized soft tissue/bone tumor requires that the pathologist can orient the ex situ specimen sent by the surgeon in three dimensions. Optimally, the resection specimen should be sent with appropriate imaging with intraoperative digital photographs and radiological images. In practice, this will often not be guaranteed. The minimum requirement is therefore to send the specimen with an appropriately prepared standardized schematic drawing in which the resection specimen is drawn. This should then also explain the corresponding markings of the surgeon, ideally according to an interdisciplinary consensus standard (e.g., for suture markings long-lateral, short-cranial, etc.).
5.3.2 Transfer of the resection specimen to the pathology lab
The immediate transmission of the surgically removed resection specimen shall be sought, ideally in a fresh, unfixed state.
Written consent from the patient shall be obtained in advance for the removal of fresh tissue.
- Consensus
- Strong consensus
If unfixed transmission of the surgically removed resectate in the fresh state is not possible for local reasons, fixation in a sufficient amount of buffered 4% formalin shall be performed.
- Consensus
- Strong consensus
Background
The surgically removed specimen should be transferred to pathology as soon as possible. The unfixed immediate transfer allows the collection of fresh tissue samples for the biobank, which is of considerable advantage for further analysis and research purposes. The preservation of fresh tissue for the biobank requires appropriate written consent from the patient, which, depending on local regulations, should be obtained either at the time of admission (e.g., in the admission contract) or preoperatively together with the surgical information.
If, due to local conditions, immediate transmission of the resectate in the unfixed state is not possible, fixation of the material in a sufficient quantity of buffered 4% formalin must be ensured (sufficient means that the preparation is sent in such a quantity of formalin that the preparation floats in a sufficiently large vessel).
5.3.3 Reconditioning
Before tissue is removed from the surgical resection specimen, the resection margins shall be color-marked so that the R status can be determined later.
- Consensus
- Strong consensus
Background
Upon arrival of the unfixed or fixed specimen, it should be immediately inspected in the pathology department by a pathologist familiar with soft tissue/bone tumor sectioning. At this time, the type of further processing is determined. In the case of fresh tissue, the immediate removal of tumor and normal tissue and the immediate transfer of the specimens to the biobank. For fixed material, the amount of formalin should be checked and modified if necessary. In the case of large specimens, it may be useful to incise them several times according to the institute's internal standards before further fixation to ensure adequate fixation. A prerequisite for this is that the anatomical orientation of the resected specimen is possible through the attached markings and the imaging sent along with the specimen. Before incising the specimen, the corresponding resection margins should be marked in color beforehand so as not to jeopardize the assessment of the resection margins during subsequent processing.
During further processing after adequate fixation (usually overnight), systematic color marking of the clinically relevant resection margins is mandatory. Subsequently, the specimen is lamellated into uniform slices approximately 1 to 1.5 cm thick according to the axis guidance of the attached imaging. This allows correlation of imaging and pathology. Subsequently, photodocumentation of the resulting tumor slices is performed before further systematic embedding takes place. The rule of thumb for the minimum amount of specimens to be embedded is to take at least one block per centimeter of maximum tumor diameter. In addition, the relationships of the tumor to relevant resection margins and clinically marked relevant anatomical structures should be documented by tissue sampling. Also, the extent of tumor necrosis in percent shall be recorded during sectioning.
5.3.4 Workup after preoperative pretherapy
After preoperative radiotherapy and/or chemotherapy, correlation of the resection specimen with imaging is of particular importance, as this is the only way to ensure that the extent of response to therapy can be adequately documented. This is especially true for tumors with bone involvement, where preparation radiography - ideally in pathology - plays a particularly important role. The most precise possible estimation of the percentage of vital residual tumor (e.g., according to Salzer-Kuntschik [307]) is of utmost importance for the prognosis and therapy planning of bone tumors and requires systematic preparation of the specimen. For soft tissue tumors, standards of specimen workup and tumor response assessment have also been proposed by the EORTC-STBSG 2016 [103], in which the percentage of stainable residual tumor cells is estimated. The prognostic and predictive significance of this score remains to be tested in prospective clinical trials.
5.4 Radiotherapy: sarcomas of the extremities and trunk of the body
5.4.1 Radiosensitivity of soft tissue sarcomas.
Contrary to the still widely held belief that soft tissue sarcomas are radioresistant, experimental and clinical data indicate that the radiosensitivity of sarcomas is approximately equivalent to that of HPV-negative squamous cell carcinomas [308], [309], [310]. Soft tissue sarcomas can therefore be controlled locally in the long term with high-dose radiotherapy alone (> 66 Gy), especially in tumors < 10 cm in maximal diameter [311]. However, soft tissue sarcomas shrink very slowly after radiotherapy and residual space-occupying lesions may remain detectable for years. Therefore, tumor shrinkage rarely occurs after preoperative irradiation, although histologically high levels of necrosis are often induced [312], [313]. Differences in radiosensitivity of different histologic subtypes have not been reproducibly demonstrated. Clinical data indicate a lower than average radiosensitivity of malignant peripheral nerve sheath tumors [134] and a higher than average sensitivity of synovial sarcomas. Myxoid liposarcoma is also particularly radiosensitive [314]. For this histotype, neoadjuvant radiotherapy should be considered preferentially. Malignancy grade does not correlate with radiosensitivity.
5.4.2 Postoperative radiotherapy (extremities, trunk, non-retroperitoneal)
In well-differentiated (G1) soft tissue sarcomas resected with healthy tissue on all sides, postoperative radiotherapy should be avoided.
- Consensus
- Consent
For G2 and G3 soft tissue sarcomas, preoperative or postoperative radiotherapy shall be given.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- ⊕⊕⊕⊝
Overall survival (follow-up: 16 months)
⊕⊕⊕⊝Disease-specific survival (follow-up: 76 months).
⊕⊕⊕⊝Overall survival low-grade STS (follow-up: 67 months).
⊕⊕⊕⊝Local recurrence (follow-up: 76 months)
⊕⊕⊕⊝Free of distant metastases (follow-up: 76 months)
⊕⊕⊝⊝Overall survival (follow-up: 240 months)
⊕⊕⊕⊝Local recurrence (follow-up: 232.7 months)
- Consensus
- Strong consensus
- References
- [315] [316] [317] [318]
In the case of unplanned R1 or R2 resection, irradiation does not replace a definitive re-resection.
- Consensus
- Strong consensus
Regardless of the outcome of a re-resection, postoperative radiotherapy shall be given for G2 and G3 soft tissue sarcomas if preoperative radiotherapy has not been given.
- Consensus
- Strong consensus
Postoperative percutaneous radiotherapy should begin within 3-6 weeks after surgery or after completion of adjuvant chemotherapy. In case of postoperative brachytherapy, it should be started 5 days after surgery.
- Consensus
- Strong consensus
Background
In randomized trials treating predominantly R0 (86%) resected soft tissue sarcomas, Yang et al. [189] with adjuvant percutaneous radiotherapy (45 Gy/1.8 Gy single dose + 18 Gy/1.8 Gy single dose boost) and Pisters et al. [316] with adjuvant brachytherapy (45 Gy low dose rate) demonstrated that local recurrence rate can be highly significantly reduced by radiotherapy. In the latter study, in patients with G2/G3 sarcomas, the local control rate with brachytherapy was 89% versus 66% without brachytherapy (p=0.0025). However, radiation had no effect in G1 sarcomas (p=0.49) [316].
No other randomized trials addressing this question have been performed. Analyses from large prospective databases have confirmed the clear effect of adjuvant radiotherapy on local recurrence rate [155]. Only in small (T1), subcutaneous tissue tumors of low grade resected with wide margin, no significant improvement in local tumor control was observed. In a meta-analysis of 3,155 patients predominantly from cohort analyses (only 4.5% randomized), Albertsmeier et al. [319] showed that adjuvant radiotherapy) halved the local recurrence rate (odds ratio 0.49 [95% CI 0.31–0.77]).
A statistically significant survival benefit was not demonstrated in the randomized trials. However, the case numbers in the trials were also too small to demonstrate a survival benefit. There was also no statistically significant survival benefit in the large databases and their meta-analysis [319]. A possible reason for the lack of survival benefit, despite significantly improved local tumor control, could be the so-called „prescription bias“, i.e. the tendency in non-randomized comparisons to use radiotherapy more frequently in patients at high risk of relapse. Qu et al. [320] stratified the available studies according to the „risk of bias“ by quantifying the „risk of bias“ from the rates of R1 resections and G3 tumors in the treatment arms compared with the control arms of the studies. A total of 5 studies with available hazard ratios and a very low „risk of bias“ (0.9–1.1) were identified. For these studies with low bias (n = 2,294), there was a significant survival benefit in favor of adjuvant radiotherapy (hazard ratio 0.65 [95% CI 0.52–0.82], p < 0.001).
In the case of R1 resection, the local recurrence rate is increased by approximately a factor of 2-3 after adjuvant radiotherapy compared with R0 resection, in association with worse overall survival [134]. Therefore, if R1 resection is predictable, neoadjuvant treatment concepts should be discussed on a multidisciplinary basis. A resection is considered reasonable if it is surgically possible with acceptable morbidity. If resection is only possible with significant loss of function, e.g. amputation, risk and benefit should be weighed against each other. After R1 resections in the extremities, local recurrence rates between 15% – 35% are reported, despite additive radiotherapy. DeLaney et al. [321] were able to show in a retrospective evaluation that radiation doses of > 64 Gy after R1 resection reduce the local relapse rate from 29 % to 13 % (p < 0.01).
The subgroup of atypical lipomatous tumors (G1 liposarcoma) represents a special case. The French Sarcoma Group (FSG) retrospectively analyzed 283 patients of whom 132 had received adjuvant radiotherapy [322]. When the entity was localized to the extremities, adjuvant radiotherapy after R0 resection did not significantly reduce the local recurrence rate (HR 1). In contrast, after marginal resection, additive radiotherapy significantly reduced the local recurrence rate (HR 6.49 (1.89–22.25), p<0.003). For localization to the body trunk, the cohort was too small (n=25) to conduct a valid analysis.
The time interval between resection and start of postoperative radiotherapy ranged from 3 weeks to 2 months in the majority of patients registered in the studies and databases. Because residual tumor cells may continue to proliferate postoperatively, a timely start of postoperative radiotherapy is desirable. However, wound healing should be completed to the greatest extent possible, meaning that radiotherapy can begin at the earliest 3 weeks after surgery.
In contrast to other tumor entities, such as breast carcinoma [323] and head and neck tumors [324], the negative effect of a long interval between surgery and the start of radiotherapy is not well established scientifically. This is mainly because this association has only been studied in small cohorts [325], [326], [327], in which few patients had a long interval between surgery and radiotherapy. Given the clear data in other tumor entities and in the absence of a plausible reason why residual soft tissue sarcomas cells should not proliferate postoperatively, prompt initiation of radiotherapy within 6 weeks of resection, if possible, is recommended. Adjuvant brachytherapy was started 5 days after surgery in the randomized trial by Pisters et al. [317]. Earlier initiation was associated with an increased acute complication rate.
5.4.3 Preoperative radiotherapy (extremities, trunk, non-retroperitoneal)
There is evidence that preoperative or postoperative radiotherapy is associated with improved overall survival. There are hints, but no proof, that the survival benefit is greater with preoperative radiotherapy than with postoperative radiotherapy.
- Level of evidence
- ⊕⊕⊕⊝
Overall survival (follow-up: 39.6 months)
⊕⊕⊝⊝Local recurrence (follow-up: 39.6 months)
- Consensus
- Strong consensus
- References
- [328]
Sarcomas of the extremities: preoperative radiotherapy (50 Gy/25 fractions) reduces the local recurrence rate as effectively as higher-dose postoperative radiotherapy (66 Gy/ 33 fractions) despite a lower total dose.
- Level of evidence
- ⊕⊕⊕⊝
Overall survival (follow-up: 39.6 months)
⊕⊕⊝⊝Local recurrence (follow-up: 39.6 months)
- Consensus
- Strong consensus
- References
- [328]
Surgical resection after preoperative radiotherapy shall be performed after the acute radiation response has resolved (no earlier than 3 weeks) and should be performed no later than 8 weeks after completion of radiotherapy.
- Consensus
- Strong consensus
- References
- [328]
Background
Preoperative radiotherapy with or without additional chemotherapy was originally used for large, unresectable or borderline resectable soft tissue sarcomas in case series and phase II trials. In most of the soft tissue sarcomas, necrosis zones occurred in > 90% of the tumor volume. In a smaller proportion of sarcomas, no viablel tumor cells are detectable histopathologically. Studies with additional chemotherapy or 2x daily radiation reported higher average necrosis rates than after conventional fractionated radiotherapy alone [312], [313]. Myxoid liposarcoma in particular often shows a good response to neoadjuvant radiotherapy with significant tumor regression: currently, preoperative radiotherapy with only 36 Gy is being tested in a prospective study (NCT02106312). These observations were the starting point to test preoperative radiotherapy also in well resectable soft tissue sarcomas.
O‘Sullivan et al. [O'Sullivan, B. et al. 2002], [329] randomized patients (n = 188) with resectable soft tissue sarcomas of the extremities to either preoperative radiotherapy with 50 Gy in 25 fractions or postoperative radiotherapy with 64 Gy in 32 fractions. Despite the preoperative dose being just over 20% lower, local tumor control and distant metastasis rates were the same. Overall survival was significantly better in the preoperative arm. This was due to lower mortality from non-sarcoma-related deaths. After preoperative radiotherapy, wound healing problems occurred twice as often as in the control arm (35% vs. 17%, p < 0.001). However, this predominantly affected only patients with soft tissue sarcomas of the lower extremity. Grade III–IV late sequelae of radiotherapy (edema, limitation of joint mobility, or subcutaneous fibrosis) occurred less frequently in the preoperative arm, probably as a consequence of the lower radiation dose and significantly smaller radiation fields due to the preoperatively more definable target volume [330].
Sampath et al. [331] performed a multivariable analysis of a group of 816 well-documented sarcoma patients from several large centers with respect to the effect of pre versus post-operative radiotherapy (50.4 Gy vs. 60 Gy in 1.8 Gy–2.0 Gy single dose). Preoperative radiotherapy was associated with significantly better distant metastasis-free and overall survival with the same effect on local recurrence rate. Gingrich et al. [154] analyzed data on patients with sarcomas of the extremity from the National Cancer Database (USA). 14,263 patients were treated surgically only. Radiotherapy was given preoperatively in 3,309 patients and postoperatively in 10,397. The rate of R0 resection after preoperative radiotherapy was significantly higher than after postoperative radiotherapy (90.1% vs. 74.9%, p < 0.001). The higher rate of R0 resection was associated with significantly better overall survival, as was the use of radiotherapy.
In a meta-analysis based on a series of cohort studies and a randomized trial [319], preoperative radiotherapy was associated with a significantly lower local recurrence rate (n=1663, odds ratio: 0.67, 95% CI 0.49–0.92) and significantly improved overall survival [n = 1486, odds ratio: 0.67, 95% CI 0.47–0.94] compared with postoperative radiotherapy. However, the rate of postoperative wound healing disorders was increased [odds ratio: 2.92, 95 % CI 1.74–4.88]. In summary, evidence from the large data bases suggests that preoperative radiotherapy results in better oncologic outcomes than postoperative radiotherapy, although the data available to date are predominantly for sarcomas greater than 5 cm in diameter with a high malignancy grade. In these tumors, preoperative radiotherapy is a reasonable option.
In the case of a preoperatively probable or intraoperatively proven R1/R2 resection, intraoperative radiation therapy (IORT) may be considered as a boost.
- Consensus
- Strong consensus
Background
If R1 resection is performed despite preoperative radiotherapy, it is scientifically uncertain whether postoperative dose boost improves the therapeutic outcome. Since there is a chance that the remaining residual microscopic tumor cells may still die postmitotically as a result of preoperative radiotherapy, R1 resection after preoperative radiation is not associated with a very high local recurrence risk.
Dagan et al. [332] observed only one local recurrence in a group of 17 patients after preoperative radiotherapy (50 Gy/25 foci) and subsequent R1 resection, which occurred after almost 9 years. Al Yami et al. [333] compared both approaches in a retrospective study of 93 patients with R1 resec-tion after preoperative radiotherapy with 50 Gy in 15 fractions. The local recurrence rate at 7 years was 34% when a boost of 16 Gy was applied (n = 41) and 19% when no boost was given (n = 52, p = 0.13). Known risk factors for local recurrence were approximately equally distributed in both groups. Even assuming a selection bias to the disadvantage of the group treated with a boost, the data do not suggest a benefit from a postoperative boost. R1 resection after preoperative radiation is not associated with a significantly increased local recurrence rate, in contrast to postoperative radiation therapy.
Based on the available data and radiobiologic considerations, a boost cannot be routinely recommended. Intraoperative radiotherapy or brachytherapy starting a few days after surgery is theoretically more effective because of the high local dose and the short time interval from preoperative radiotherapy. However, the available evidence [334] is too limited to prove a clinical advantage.
5.4.4 Radiotherapy for soft tissue sarcomas of the trunk (non-retroperitoneal/visceral).
For soft tissue sarcomas of the trunk (non-RPS), radiotherapy shall be used similarly as for soft tissue sarcomas of the extremities.
- Consensus
- Strong consensus
Background
Randomized studies on the value of pre- or postoperative radiotherapy are not available for soft tissue sarcomas in this location. In the larger prospective case series [155] and a meta-analysis [319] of these case series, the results for soft tissue sarcomas of the trunk were combined with those of the extremities because no different effects were found for the effect of radiotherapy. As with soft tissue sarcomas of the extremities, preoperative or postoperative radiotherapy halved the local recurrence rate. Available data are not adequate to assess a possible effect on overall survival. No significantly increased rate of wound healing complications is described after preoperative radiotherapy [335]. It is considered likely that the effects of additional radiotherapy are not relevantly different from those in the treatment of soft tissue sarcomas of the extremity.
5.4.5 Radiotherapy for unresectable tumors or after R2 resection.
For primary tumors after R2 resection or tumors that are not resectable with acceptable morbidity after neoadjuvant therapy, local radiotherapy alone or in combination with simultaneous chemotherapy and/or hyperthermia should be discussed on an interdisciplinary basis.
- Consensus
- Strong consensus
Background
For non-resectable soft tissue sarcomas or after R2 resection, radiotherapy has also been used in some case series with in a high-dose curative intention. In the largest case series [311] consisting of 112 patients, it was shown that durable local tumor control can be achieved with radiotherapy alone in a significant proportion of patients. If these patients are not eligible for neoadjuvant therapy or if resection with acceptable morbidity is not deemed possible even after neoadjuvant therapy, radiotherapy alone or in combination with chemotherapy and/or local hyperthermia can be successfully used as locally definitive therapy [336], [337], [338].
5.4.6 Preoperative radiotherapy in combination with systemic therapy for primarily unresectable or marginally resectable tumors.
The value of neoadjuvant chemotherapy simultaneously or sequentially with preoperative radiotherapy has been investigated in a total of 17 phase I–II studies and case series for locally advanced soft tissue sarcomas or sarcomas that are not considered completely resectable upfront (for review: [339]). On average, higher necrosis rates were reported than in case series with radiotherapy alone. Local recurrence rates and overall survival were favorable compared with historical controls without radiotherapy. In some case series, these therapies were also combined with deep hyperthermia sometimes with high necrosis rates and better outcomes in indirect comparison to radiotherapy or radiation chemotherapy without hyperthermia [336], [340], [341], [342], [343], [344]. However, in the absence of randomized trials, the superiority of any of the above therapies cannot be clearly demonstrated. The best studied are adriamycin (doxorubicin) and ifosfamide in combination as monosubstances or in combination with dacarbazine. A treatment regimen that can be considered standard therapy has not been established to date. For high grade (G2-G3) soft tissue sarcomas (G2-G3) of approximately > 5cm or larger, these preoperative therapeutic strategies should be discussed within the context of a multidisciplinary tumor board, especially if the soft tissue sarcoma crosses a compartmental boundary, extends to involve larger vessels or nerves, or infiltrates bone or organs.
5.4.7 Radiotherapy for retroperitoneal soft tissue sarcoma (RPS).
Soft tissue sarcomas of the retroperitoneum are often diagnosed only at tumor diameters of > 15 cm, because clinical symptoms develop late. Liposarcomas represent by far the most common entity. Retroperitoneal liposarcomas are characterized by local size growth and metastasize to the lung less frequently than other soft tissue sarcomas. The value of preoperative or postoperative radiotherapy for retroperitoneal soft tissue sarcomas can be assessed from the results of a randomized trial and retrospective and prospective case collections [345], [346], [347], [264] .
In the case of retroperitoneal tumors, which are often very large, it is sometimes not possible to apply a sufficiently effective radiation dose postoperatively with acceptable risk while maintaining the radiation tolerance of the adjacent organs, especially the small intestine. This is particularly relevant to patients who have already undergone resection of their primary RPS, with resultant fixation of the small intestine in the potential irradiation area. The application of new radiation techniques, especially intensity-modulated radiotherapy, has brought improvements in this regard, but has not really solved the problem.
Postoperative radiation of RPS (adjuvant or additive indication) usually results in complex concave target volumes, with difficulty in defining the target volume in relation to the bowel and mesentery, due to the commonly massive changes in anatomy resulting from surgery. The target volume can be much better defined preoperatively. A bowel-sparing radiotherapy plan is typically possible, since the tumor often displaces the bowel to a large extent from the target volume by forming a convexity. More conformal target volume acquisitions can therefore be achieved than with postoperative radiotherapy [348]. Increased wound healing disturbances after preoperative radiotherapy of retroperitoneal soft tissue sarcomas have not been reported in retrospective comparisons [334], [349] and could not be found as a significant difference in the prospectively randomized STRASS study (see also the presentation of the results of the STRASS study on page 92. Together with the results of prospectively accrued case series, it can be considered proven that if radiotherapy is indicated for RPS (tumor recurrence, expected R2 resection) preoperative radiotherapy can lead to a reduction of the local intra-abdominal recurrence rate with low toxicity.
Direct comparisons with other preoperative therapies such as chemotherapy combined with deep hyperthermia (subset of a phase III trial [271] or combined radiochemotherapy (case series, single-arm phase II trials [350], [351] are not available. It should be noted that only high grade (G2, G3) soft tissue sarcomas could be included in the treatment protocols with chemotherapy, so that only for well-differentiated (G1) soft tissue sarcomas are robust data on preoperative radiotherapy alone available. Whether and which neoadjuvant therapy should be performed for RPS remains a matter that should be determined in the context of a multidisciplinary tumor board.
5.4.8 Technique of radiotherapy
Percutaneous, postoperative radiotherapy shall be as conformal as possible. The use of IMRT/VMAT techniques also with integrated boost should be preferred for better conformality.
- Consensus
- Strong consensus
Radiation therapy shall meet defined requirements in terms of target volume, dosage, and safety margins.
- Consensus
- Strong consensus
Background
Pre- or postoperative radiotherapy should usually be delivered as intensity-modulated (IMRT) or volume-adapted radiotherapy (VMAT). In most cases, 3D-planned therapy results in inferior dose distributions even for convex target volumes. IORT or brachytherapy via a multicatheter technique is also used in some institutions. Proton therapy should also be considered for tumors that are not completely resectable. Only therapy with photons will be discussed.
According to the recommendations of the RTOG consensus panel [352], the clinical target volume (CTV) postoperatively comprises the surgical bed. In the case of preoperative irradiation, it comprises the macroscopic tumor (gross tumor volume=GTV) in the extent of the T1 weighting on preoperative MRI with contrast medium with a safety margin of 3 cm in the direction of the muscle fiber course (usually longitudinal) and of 1.5 cm in the transverse direction of the muscle fiber course (usually axial). If postoperative irradiation is performed, the sometimes considerable modifications of the anatomy caused by the resection of the tumor and possible reconstructive measures must be taken into account, which may lead to uncertainties in the definition of the CTV in the case of large tumors. Therefore, the CTV is usually larger postoperatively than it would have been with preoperative therapy, where the CTV is clearly definable.
The longitudinal safety margins of up to 10 cm previously proposed for high grade (G2-G3) soft tissue sarcomas are no longer appropriate in the era of routine, accurate preoperative cross-sectional imaging. No consensus exists as to whether the peritumoral edema zone seen in many patinets on T2 weighted images should be included in the CTV. If the increase in target volume is not expected to significantly increase radiotherapy morbidity, it should be included in the CTV. In the RTOG-0630 trial (phase II), reduced safety margins were prospectively investigated for preoperative radiotherapy with 50 Gy in 25 fractions [353]: For G2-G3 soft tissue sarcomas less than 8 cm in diameter and all G1 sarcomas, safety margins for CTV were reduced to 2 cm longitudinally and 1 cm axially. For G2-G3 tumors > 8 cm in diameter, 3 cm longitudinal and 1.5 cm axial safety margins were used. For Planning Target Volume (PTV), a 5 mm safety margin was used assuming the use of image-guided radiotherapy. After a follow-up period of 4 years, 5 local recurrences (all in G3 tumors) were observed. All recurrences were within the 95% isodose, 3 after R1 resection. This study demonstrates that reduced safety margins should be considered safe for preoperative therapy and should be used clinically. Reported late adverse events were significantly lower than expected.
Clinical target volume (CTV) for postoperative radiotherapy.
The CTV for postoperative percutaneous radiotherapy [352] for high grade (G2-G3) soft tissue sarcomas includes the surgical bed with a 3 cm distance longitudinally from the muscle fiber direction and 1.5 cm axially from the muscle fiber direction. Adaptations to anatomy like bony structures or thick fascia should be considered. Any edema zones present on preoperative MRI should be included in the CTV. In the case of very large edema zones, a clinical decision must be made as to whether the additional morbidity due to expansion of the CTV is in reasonable proportion to the potential benefit.
For low grade (G1) soft tissue sarcomas, safety margins around the surgical bed of 2 cm longitudinally and 1 cm axially are sufficient.
The „Boost“-CTV includes the former tumor region as appreciated on the preoperative MRI, with 1.5 - 2 cm longitudinal and 1.0 - 1.5 cm axial anatomically reasonable modified safety margins.
The additional safety margins for the planning target volume (PTV) depend on the possibility of immobilization of the region to be irradiated in the individual patient and on the availability of imaging available within the linear accelerators. As a rule, distances of 5-10 mm are sufficient. For regions that move with respiration, an ITV concept should be considered, as well as the possibility of respiratory-triggered radiotherapy to minimize PTV.
For postoperative brachytherapy, CTV includes the surgical tumor bed with 2 cm longitudinal (in muscle fiber direction) and 1.5 cm axial safety margins [316], [317]. An additional safety margin for the PTV with good catheter fixation is usually not necessary.
To avoid increased wound healing complications, brachytherapy should not be initiated until postoperative day 5 [316], [317].
Dosage in postoperative radiotherapy
In the postoperative situation after R0 resection, total doses of 60 to 64 Gy (1.8-2.0 Gy single dose) should be considered standard for percutaneous radiotherapy [189], with 45-50.4 Gy given initially with the safety margins described above, followed by a boost of 10-14 Gy with isotropic safety margins of 1.0-1.5 cm with respect to the former tumor extent. The recommended doses with the above safety margins are often not achievable, especially in retroperitoneal soft tissue sarcomas, due to necessary dose restrictions by surrounding organs at risk. Whether sig-nificantly reduced safety margins or total doses reduced to 45-50.4 Gy will still impact the local recurrence risk in this situation is not well established from studies and case series. Since the dose-response relationships for adjuvant radi-otherapy could be assumed to be relatively flat, one might expect it be effective with the lowered doses after R0 resection. In the case of R1 resection, the total dose should be increased to 66 Gy if possible. Dose compromise after R1 resec-tion has been shown [321] to result in a significantly higher local recurrence rate.
For postoperative brachytherapy, either 45 Gy in „low dose rate“ or 36 Gy in „high dose rate“ (10 fractions) was applied within 4-6 days in the studies [317], see also Chapter 5.4.2.
Clinical target volume (CTV) for preoperative radiotherapy.
For preoperative radiotherapy, the macroscopic tumor (GTV) based on the extent of cross-sectional imaging (MRI with contrast agent is recommended first, see recommendation 4.3). Because of possible differences in rotation that are difficult to compensate, it is useful to also perform the planning CT with contrast medium, especially on the upper extremity.
The CTV for preoperative percutaneous radiotherapy includes the GTV with a distance of 3 cm longitudinally to the muscle fiber direction and 1.5 cm axially to the muscle fiber direction for highly malignant soft tissue sarcomas (G2-3) with ≥8 cm extension. For soft tissue sarcomas less than 8 cm in extent and all G2 soft tissue sarcomas, the CTV surrounds the GTV with a distance of 2 cm longitudinally to the muscle fiber direction and of 1 cm axially to the muscle fiber direction. Anatomic modifications due to bony structures or large fascial courses should be considered. Any edema zones present on preoperative MRI should be included in the CTV [353]. In the case of very large edema zones, a clinical decision must be made as to whether the additional morbidity caused by extending the CTV is in reasonable proportion to the potential benefit.
The same recommendations apply to PTV as to postoperative percutaneous radiotherapy (see recommendations 5.69. and 5.76).
Caveat: In approximately 20 % of cases, especially in soft tissue sarcomas larger than 10 cm, significant tumor volume increase occurs during preoperative radiotherapy. Therefore, at least weekly conebeam CT checks a should be performed at least once per week nd, if necessary, adaptation of the target volumes undertaken. This edema-related increase in size is not to be considered as tumor progression.
Dosage during preoperative radiotherapy
For preoperative percutaneous radiotherapy, total doses of 45-50.4 Gy (1.8-2.0 Gy single dose) were predominantly used in the clinical case series. Surgery was performed between 4-8 weeks after preoperative radiotherapy in the studies, which is why other intervals are not recommended. Imaging after completion of radiotherapy to assess the effect of therapy is useful after 3-4 weeks at the earliest [O'Sullivan, B. et al. 2002].
5.5 Additional therapy modalities
5.5.1 Hyperthermia
In these guidelines, hyperthermia is understood to be the application of whole-bodyhyperthermia or regional deep-wave hyperthermia in combination with cytostatic chemotherapy and intratumoral temperature measurement. For other forms of hyperthermia, there is no reviewed evidence for use in soft tissue sarcomas.
5.5.1.1 Systemic whole body hyperthermia
Systemic whole-body hyperthermia has no place in the treatment of patients with soft tissue sarcomas and shall not be used outside of trials.
- Consensus
- Strong consensus
Background
In systemic whole-body hyperthermia (SBHT), the entire patient is heated. There are two forms of hyperthermia: moderate SBHT with temperatures of 40.5 °C and extreme SBHT with 41.8 °C. They pursue the goal of the stimulating the immune system and are mainly in use in complementary medicine approaches. Heating is performed by whole-body infrared irradiation under sedation and intensive monitoring conditions. To date, there are no controlled clinical studies that justify the use of SBHT for patients with soft tissue sarcomas.
5.5.1.2 Regional deep hyperthermia
Technique
Regional deep(-wave) hyperthermia (RHT) involves non-invasive heating of the tumor as well as the surrounding tissue to temperatures of 40-43 °C for 60 minutes by irradiation of electromagnetic waves. It is used in addition to stand-ard therapies because of its chemo- and radiosensitizing properties, but not as the sole treatment method, due to chemo- and radiosensitizing properties. In addition, an immune effect is postulated [354]. RHT is suitable for tumors of the pelvis and abdomen as well as for trunk or extremity tumors. The electromagnetic waves are emitted in the frequency range from 27 MHz to about 120 MHz via antennas arranged in a ring around the patient. To avoid reflections on the body surface, a water bolus is placed between the antennas and the patient. This additionally fulfills the function of cooling the skin surface. The electromagnetic waves can be focused within the target area. Temperature monitoring plays a central role. If possible, it is performed directly by temperature probes inserted into the tumor (CT- or sonography-guided) or, in the case of pelvic tumors, approximately via probes in the rectum, bladder or vagina. Due to the development of hyperthermia systems with integrated MRI imaging (MRI deep hyperthermia hybrid system), non-invasive thermometry via temperature-sensitive MR sequences is increasingly possible.
For patients, RHT represents a form of therapy with few side effects and is generally well tolerated. Possible adverse effects include a sensation of pressure and tightness triggered by the water bolus, as well as local insensations caused by the irradiation of the radio waves. Thermal tissue damage occurs only very rarely in the form of slight skin burns or fatty tissue necrosis. Patients with pacemakers or metal implants in the treatment area cannot be treated with RHT.
Radiative RHT in combination with neo-adjuvant chemotherapy has been evaluated within a randomized phase III trial for the use of locally advanced high-risk soft tissue sarcomas (see below). For the capacitive hyperthermia systems, which are also used for local tumor therapy, there is insufficient experience regarding the temperatures reached in the tumor, so that they cannot be recommended for the therapy of soft tissue sarcomas outside of studies.
Clinical studies
Neo-adjuvant chemotherapy for patients with soft tissue sarcomas of the pelvis, abdomen, and extremities should/can be combined with deep hyperthermia.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- ⊕⊕⊕⊝
Overall survival (follow-up: 98.4 months)
⊕⊕⊝⊝DFS (median follow-up: 99 months)
⊕⊕⊝⊝LPFS (median follow-up: 99 months)
⊕⊕⊕⊝Survival (Follow up: 135.6 months) IT experience
⊕⊕⊕⊝LPFS (follow-up: 135.6 months)
⊕⊕⊕⊝DFS (follow-up: 135.6 months)
- Consensus
- Consent
- References
- [269] [271] [355]
Background
Due to the limited availability of regional deep hyperthermia at only a few specialized hospitals as well as the changed chemotherapy standard (AI vs. EIA) compared to the hyperthermia study, no consensus for a „should“ recommendation was reached despite the positive phase 3 study with a survival benefit in the context of the vote. The compromise proposal „should/can“ on the other hand in the sense of „use of regional deep hyperthermia in the context of neo-adjuvant chemotherapy concepts if available“ found a broad majority.
The value of RHT in combination with systemic chemotherapy was investigated in a randomized phase III trial (EORTC 62961 / ESHO RHT-95) in patients with high-risk soft tissue sarcomas. Patients received 4 neoadjuvant cycles of EIA chemotherapy consisting of etoposide (250 mg/m2), ifosfamide (6 g/m2), and doxorubicin (50 mg/m2) followed by surgery and, if possible, radiation, and 4 adjuvant cycles of EIA chemotherapy. In the experimental arm, patients received 2 RHT treatments in parallel with each cycle of EIA chemotherapy (total maximum of 16 RHT). There were 341 patients randomized to either the hyperthermia arm or the chemotherapy alone arm (1:1). Inclusion criterion was the presence of high-risk soft tissue sarcoma (FNCLCC grade 2–3, tumor diameter > 5 cm, deep location in relation to superficial fascia) or its recurrence. Of note, the study included a large number of patients with retroperitoneal or intra-abdominal soft tissue sarcomas (n=192).
After a median observation period of 34 months, the addition of hyperthermia to neoadjuvant and adjuvant chemotherapy showed a significant improvement in local progression-free survival (LPFS; hazard ratio 0.58; 95 % CI 0.41-0.83; p=0.003), disease-free survival (DFS; hazard ratio 0.70; 95 % CI 0.54-0.92; p=0.011), and a doubling of treatment response (28.8 % vs. 12.7 %). The risk of progression with preoperative chemotherapy was also significantly reduced in the hyperthermia arm (6.8 % vs. 20.6 %) [354]. For patients with retroperitoneal and visceral sarcomas (N=149) with macroscopically complete tumor resection, the benefit in LPFS and DFS with the addition of RHT was also present [269]. After long-term follow-up with a median observation time of 11.3 years, survival was also significantly prolonged for patients additionally treated with RHT (hazard ratio 0.73; 95% CI 0.54-0.98; p=0.04) [355].
The current therapeutic regimen for high-risk soft tissue sarcomas at centers with deep hyperthermia facilities is guided by this study. Due to the risk of developing secondary AML due to etoposide and the expected low priority in the treatment of adults with soft tissue sarcomas, EIA chemotherapy is no longer used and instead doxorubicin and ifosfamide (AI) are combined with RHT.
5.5.2 Isolated limb perfusion
The treatment goal of isolated limb perfusion (ILP) is local tumor control and limb preservation in locally advanced soft tissue sarcomas. There is a different starting point for the indication of limb perfusion (see below). As an alternative to limb perfusion, other multimodal therapies or amputation may be considered. Management is highly dependent on patient and tumor factors as well as previous therapies.
5.5.2.1 Isolated Limb Perfusion (ILP) Technique
Isolated limb perfusion is an approved standard treatment [356], [357]. The technically complex procedure involves surgical, vascular isolation of the limb with establishment of a separate circuit under general anesthesia and full heparinization to target. Within the perfusion circuit, mild tissue hyperthermia of 38-39.5 °C is induced and nuclear medicine procedures are used to ensure that there is no leakage to the systemic circuit. In the perfusion circuit, 3-4 mg rhTNFα-1a („recombinant human necrosis factor α-1a“, Tasonermin) combined with 10 mg melphalan/liter perfused limbvolume is applied over 90 minutes. Other substances are used only in individual cases.
Postoperative complications such as redness, hyperthermia, blistering, and desquamation of the cornea are typical. Rhabdomyolysis up to compartment syndrome as well as cardiac stress with application of rhTNF-α may occur [358]. The toxicity of the procedure is classified according to Wieberdink [359].
5.5.2.2 Recombinant human tumor necrosis factor α
Tumor necrosis factor alpha (TNFα) is a multifunctional cytokine that plays an important role in innate and acquired immunity. TNFα binds to two different receptors and leads to hemodynamic and antitumor effects [360]. Clinical studies in patients with solid tumors have so far failed to demonstrate that effective tumor control can be achieved by systemic administration. The route of administration induces a vital threat to patients from systemic inflammatory response syndrome (SIRS) [361], [362]. Administration of rhTNF-α during ILP avoids the hemodynamic effects and shows a strong synergistic antitumor effect with chemotherapeutic agents in melanoma and sarcoma patients [363]. In the setting of ILP, rhTNF-α has two potentially synergistic antitumor properties: increased uptake of melphalan and selective destruction of tumor vascularization [364].
Limb perfusion without rhTNF-α, is significantly inferior to TNF-ILP in terms of tumor response [365], [366]. ILP with rhTNF-α may only be performed at accredited centers. Tasonermin (Beromun®) is dispensed by the manufacturer only after verification of logistical, technical, and medical competence. Extremity perfusions without rhTNF-α are therefore performed exclusively in clinics where the drug is not available. Therefore, a data comparison of ILP cohorts with or without rhTNF-α cannot be performed because of selection bias.
5.5.2.3 Indication for isolated limb perfusion
The approval of rhTNF-α followed a European multicenter study in 186 patients with locally advanced soft tissue sarcomas (107 primary tumors, 79 local recurrences, median tumor diameter 16 cm, 42/186 multifocal tumors) [367]. Inclusion criterion of the study was the presence of an extremity-threatening tumor or already established amputation indication. Tumor response was observed in 82 % of patients, allowing extremity-preserving resection. Treatment outcome showed 33 complete remissions (CR) (18 %), 106 partial remissions (PR) (57 %), no change (NC) in 42 patients (22 %) and progressive disease (PD) in five cases (3 %). With a median follow-up of 22 (6-58) months, amputation was also avoided in the long term in 82 % of patients. In 23/25 patients with metastatic disease when ILP was indicated, the limb was successfully preserved. Therefore, in patients with locally advanced soft tissue sarcoma, regardless of the status of metastasis, the indication for limb perfusion should be considered when no other effective therapeutic option is available.
Cohort studies after approval of tasonermin reported limbpreservation of 76 to 96 % in locally advanced tumors [365], [368], [369], [370], [371], [372], [373]. Pathologic tumor response rates (vital tumor remnant less than 10 % or [Bonvalot, S. et al. 2011]. Treating institutions have a treatment preference depending on the availability of ILP [374]. Randomization between treatment alternatives is also difficult to justify from the patient's perspective.
In isolated limb perfusion for therapy of locally advanced soft tissue sarcomas, recombinant human tumor necrosis factor-α in combination with melphalan shall be applied as effective substances.
- Consensus
- Strong consensus
Before performing an amputation, the indication for isolated limb perfusion shall be reviewed in the interdisciplinary sarcoma board.
- Consensus
- Strong consensus
Extremity perfusion may be indicated in locally advanced primary tumors or local recurrences of soft tissue sarcomas as a preoperative therapy with the goal of tumor revitalization and avoidance of mutilating and severely function-restricting procedures.
- Consensus
- Strong consensus
Extremity perfusion may be indicated as a palliative measure regardless of tumor stage with the goal of local tumor control.
- Consensus
- Strong consensus
5.6 Chemotherapy
5.6.1 Neoadjuvant chemotherapy
Soft tissue sarcomas smaller than 5 cm (T1) shall not receive neoadjuvant chemotherapy regardless of grading and location. This recommendation does not apply to extraosseous Ewing sarcomas and embryonal rhabdomyosarcomas.
- Consensus
- Consent
For soft tissue sarcomas at high risk of recurrence (> 5cm, deep-seated, G2/3) and chemosensitive subtype, neoadjuvant chemotherapy may be offered regardless of location.
- Recommendation grade
- 0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
- Level of evidence
- ⊕⊕⊝⊝
Overall survival (median follow-up: 7.3 years)
⊕⊕⊝⊝DFS (median follow-up: 7.3 years)
- Consensus
- Strong consensus
- References
- [186]
Neoadjuvant chemotherapy should be anthracycline-based combination therapy.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- ⊕⊕⊕⊝
Overall survival (median follow-up: 12.3 months)
⊕⊕⊕⊝DFS (median follow-up: 12.3 months)
- Consensus
- Strong consensus
- References
- [375]
Background
In individual cases, preoperative chemotherapy may be considered as part of a multimodal therapy concept if this, in combination with marginal resection at critical resection margins (nerves, vessels, etc.), enables function-preserving surgery.
Patients with locally advanced high-risk soft tissue sarcoma (FNCLCC grade 2-3, tumor diameter ≥ 5 cm, deep location) have a high risk of dying from local recurrence or the appearance of distant metastases despite the best possible local therapy, consisting of surgery and, in most cases, additional radiotherapy. The 5-year survival rates are approximately 50-80 % for extremities and 40-60 % for retroperitoneal sarcomas, depending on the location. Nomograms now exist for both soft tissue sarcomas in the extremities [142] and retroperitoneal sarcomas [141], which allow a relatively accurate estimation of the risk of recurrence and, in addition to localization and grading, also take into account the patient's age and histological subtype and, in the case of retroperitoneal sarcomas, any multifo-cality [376].
Neoadjuvant chemotherapy aims both to shrink the primary tumor and thus improve the surgical outcome and to treat radiologically undetectable micrometastases. Surgery is usually performed within 3-4 weeks after completion of chemotherapy. Response rates described to date for this situation range from 16 to 34 % [186], [355], [375], [377], [378].
Results are available for preoperative chemotherapy alone (3 cycles of Adriamycin 50 mg/m2 and ifosfamide 5 g/m2) compared with immediate resection without neoadjuvant chemotherapy from a randomized EORTC phase II trial of 134 patients with resectable soft tissue sarcoma (≥ 8 cm, grade I-III or < 8 cm, grade II/III; or recurrence grade II/III) [186]. The objective tumor response rate to preoperative chemotherapy was 29 % (CR 8 %, PR 21 %) in 49 evaluable patients in the experimental arm. 18 % of patients showed tumor progression during preoperative chemotherapy. This study was stopped early due to insufficient recruitment. Furthermore, due to the open inclusion criteria also for patients with stage IB and IIA and the lack of statistical power due to only 67 evaluable patients per arm, published results on 5-year disease-free survival in both arms (56 % vs. 52 %, n.s.) are not interpretable for the evaluation of preoperative chemotherapy.
After an Italian Sarcoma Group (ISG) study of adjuvant chemotherapy in high-risk patients (104 participants) initially showed a significant survival benefit [379], a follow-up study compared the administration of 3 preoperative cycles with the additional administration of 2 postoperative cycles versus 3 cycles of preoperative chemotherapy alone because of the declining dose intensity in the adjuvant trial for cycles 4-5 and because of the potential benefit of neoadjuvant chemotherapy. The final analysis showed non-inferiority of preoperative chemotherapy alone with a 10-year survival of 64 vs 59 % [380], [381]. The survival curve here resembles that of adjuvant-only patients from the first study, making this study further evidence of the efficacy of neo-/adjuvant chemotherapy.
A randomized phase III trial (ISG-STS 1001) that tested different histology-specific chemotherapy regimens in the neoadjuvant setting in patients with high-risk soft tissue sarcoma of the extremities or trunk versus the standard anthracycline in combination with ifosfamide showed a significant survival advantage for patients treated with three preoperative cycles of epirubicin and ifosfamide within the control arm.
Contrary to the original assumption of the study initiators, superiority for treatment with gemcitabine/docetaxel in undifferentiated pleomorphic sarcomas (UPS), trabectedin in myxoid liposarcomas, high-dose ifosfamide in synovial sarcomas, etoposide/ifosfamide in malignant peripheral nerve sheath tumors (MPNST), and gemcitabine/dacarbazine in leiomyosarcomas, the study had to be stopped early due to the significant superiority of the control arm. For standard therapy, disease-free survival at 46 months was 62 % and overall survival was 89 % versus 38 % and 64 %, respectively, for patients treated with histology-specific therapy. Trabectedin was noninferior in high-grade myxoid liposarcoma in primary therapy, so this study arm will still continue [375]. The results of this study reinforce the recommendation for neoadjuvant chemotherapy consisting of a combination of an anthracycline with ifosfamide in patients with high-risk soft tissue sarcomas.
The addition of regional deep hyperthermia to anthracycline-based neoadjuvant chemotherapy resulted in a significant survival benefit in high-risk patients with extremity and retroperitoneal or abdominal soft tissue sarcomas [271] (see Section Chapter 5.5.1). The current therapeutic approach at centers with deep hyperthermia facilities is guided by this study.
5.6.2 Adjuvant chemotherapy
Soft tissue sarcomas smaller than 5 cm (T1) shall not receive adjuvant chemotherapy regardless of grading and location. This recommendation does not apply to extraosseous Ewing sarcomas and embryonal rhabdomyosarcomas.
- Consensus
- Consent
For soft tissue sarcomas at high risk of recurrence (> 5cm, deep-seated, G2/3) and chemosensitive subtype, adjuvant chemotherapy may be offered regardless of location.
- Consensus
- Strong consensus
Adjuvant chemotherapy should be anthracycline-based combination therapy.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- ⊕⊕⊕⊝
Overall survival (follow-up: 8.1-96 months)
⊕⊕⊕⊝DFS (Follow-up: 8.1-84 months).
- Consensus
- Strong consensus
- References
- [382] [383] [384] [385] [386] [387] [388] [389] [390] [391] [392]
Background
Recommendation 5.87. is subject to adequate histopathological staging. For individual case exceptions see above under chapter Chapter 5.6.1.
Until the end of the 1990s, 14 randomized studies on adjuvant chemotherapy in patients with soft tissue sarcomas were published. These were mostly smaller studies with small numbers of cases. Regarding the inclusion criteria, patients with sarcomas of all localizations and with different grading, i.e. not exclusively high-risk patients from today's point of view, were generally included. The therapeutic regimens used consisted of doxorubicin mono [392], [382], [384], [385], [386], [387], [388], [389], [393], as well as different combinations that today would no longer find use in advanced soft tissue sarcoma [394], [395].
Because of the divergent results and mostly small case numbers, a meta-analysis of all 14 studies published up to that time was performed in 1997. For local relapse-free survival, metastasis-free survival, and overall relapse-free survival, there was a significant improvement with chemotherapy with an absolute advantage of 6-10 %. For overall survival, there was a nonsignificant absolute benefit of 4 % at 10 years. However, it is noteworthy that for the subgroup of patients with extremity sarcomas there was a significant benefit also for overall survival [396].
Based on positive data on ifosfamide-containing combinations in the treatment of advanced soft tissue sarcomas in adults, further studies on adjuvant therapy with corresponding combination therapies were subsequently conducted [383].
In a study of the Italian Sarcoma Group (ISG), only high-risk patients with G3 sarcomas of the extremities were included. It reviewed full-dose adjuvant chemotherapy with 5 cycles of epirubicin 120 mg/m2 and ifosfamide 9 g/m2 versus follow-up alone. The first interim analysis showed a significant survival benefit of 13 % at 2 years and 19 % at 4 years, so the study was stopped early [379]. However, at a median follow-up of 89.6 months, the significance was lost again, so that in conclusion the study could not show a convincing survival benefit. Only per-protocol analysis continued to show a significant survival benefit (5-year survival 66 % vs. 46 %) [397].
In 2008, another meta-analysis was published with now 18 studies [272]. This showed a significant advantage for patients who had received adjuvant chemotherapy in terms of local recurrence-free and metastasis-free survival. For overall survival, significant superiority was found for the subgroup of patients who had received combination therapy with doxorubicin and ifosfamide, with an absolute advantage of 11 % and a „number needed to treat“ of 17 to prevent one death.
The importance of grading was further supported by a retrospective study from France. Thus, for patients with G3 tumors, a highly significant impact on overall survival was found, corresponding to an absolute risk reduction of dying from soft tissue sarcoma of 13 %. In G2 tumors, however, adjuvant chemotherapy did not improve overall survival [398].
Not yet included in the meta-analyses were the results of a large randomized trial by the EORTC Soft Tissue and Bone Sarcoma Group [391]. This included patients with sarcomas of all sites, any size, and grading 2 and 3. Overall, there was no significant difference in 5-year relapse-free survival or overall survival (66.5% for the chemotherapy group vs. 67.8 % for the control group). Of note is the unexpectedly high value for 5-year overall survival, which reflects the patient population. The chemotherapy used, with doxorubicin 75 mg/m² plus ifosfamide 5 g/m², does not appear optimal with regard to ifosfamide dosing.
Thus, overall, adjuvant chemotherapy after resection of localized soft tissue sarcoma should not be considered standard. Possible indications for adjuvant combination chemotherapy are in patients at high risk of recurrence (grade 3, deep-seated, >5 cm) and in retroperitoneal sarcomas in which an increased local recurrence rate must be expected due to limited options for follow-up radiation. Usually, an anthracycline-containing combination therapy should be used. The indication must be made individually in informed consensus together with the patient [399].
5.7 Planning of multimodal therapy concepts
5.7.1 Planned marginal resection/lower recurrence rate.
A marginal resection is a surgical procedure in which resection is performed along the outer tumor border. This shall be communicated to the pathologist.
- Consensus
- Strong consensus
Considering morbidity, complications, and functional failure, marginal resection may be performed at critical sites in low-grade sarcomas. This shall be discussed preoperatively in the interdisciplinary sarcoma board.
- Consensus
- Strong consensus
The atypical lipomatous soft tissue tumor can be resected marginally without a multimodality therapeutic approach.
- Consensus
- Strong consensus
Background
In the literature, different terms are used within studies to describe the resection procedure and the outcome of tumor resection.
The R-classification is a standardized part of the pathological report of resection within the TNM system. The R-classification describes the surgical result with regard to the achieved completeness of tumor resection and the safety distance to the margin of the specimen according to R0, R1 and R2.
Studies focused on surgical technique for tumor resection often use terms such as intralesional, marginal, wide, and radical resection.
Different definitions of marginal resection are used in the literature. For example, a minimum distance of 2 mm from the tumor is required for a marginal resection, but also only a narrowest margin of healthy tissue („no tumor on ink“). In a retrospective study with 643 patients, the patients were divided into 3 groups according to their resection margin: less than 1 mm (“no tumor on ink“), 1-5 mm, >5mm. No difference could be found regarding local recurrence-free (LRFS), disease-specific (DSS), and metastasis-free survival (MFS) [104].
In other retrospective studies, a minimal resection margin of 2 mm is required [400]. Gundle et al. studied 2,217 patients with high-grade sarcoma regarding the effect of surgical resection margin on local recurrence rates at 5 and 10 years. The highest rate of local recurrence was found in the R2 group, followed by the R1 group („tumor on ink“) and the R0 group („no tumor on ink“). The authors formed a subgroup R+1mm in the R0 group, significant that [Gundle, K. R. et al. 2018].
It is important to distinguish between a vital tumor that grows progressively into the surrounding area and a tumor that has devitalized after preoperative therapy with regard to the evaluation of the aforementioned R categories.
Some soft tissue tumors of the extremities grow preferentially in a longitudinal direction. In the literature it is mentioned in many places that tissue such as periosteum, fascia, adventitia or perineurium forms a safer margin with regard to the development of a local recurrence [105], [147]. There is no prospectively evaluated evidence on this. In the presence of a tumor not pretreated with neoadjuvant, the histologic subtype and grading play a crucial role. Liposarcomas usually do not infiltrate the aforementioned structures, allowing them to serve as a safe dissection layer. Synovial sarcomas or leiomyosarcomas do infiltrate surrounding structures, so marginal resection is not expected to provide local tumor control. MPNST originate from a nerve (e.g., femoral nerve, sciatic nerve) that must be resected as well.
This problem is particularly common in large atypical lipomatous tumors (ALT, equivalent to G1 liposarcoma). The incidence of distant metastasis in ALT is very low. The incidence of local recurrence is high, often occurring after many years. Only in rare cases are patients vitally threatened by this.
Several case series exist regarding resection of ALT [166], [401], [402], [403], [404]. The largest case series with 151 patients compares the procedure of two different reference centers in Italy [402]. In one center patients underwent marginal R0 resection, in the second center marginal (R1) resection. The 10-year LRFS was 82 %. Margin-forming resection resulted in an increased recurrence rate. No case of dedifferentiation into high-grade sarcoma was detected in 16 local recurrences in this patient population. Similar results are shown by a German single-center study reporting no recurrence after wide resection and a 7.5 % recurrence rate after marginal resection. None of the 3 patients with recurrence experienced tumor dedifferentiation [166]. A single-center study from Japan with 41 patients showed no recurrence with wide resection of an ALT, and a recurrence rate of 10 % with marginal resection. Among the 3 recurrences, dedifferentiation occurred in one case [403]. In one study with 25 recurrences, one recurrent tumor showed dedifferentiation [404]. In both studies, there was no metastasis in the patients with dedifferentiation during the observation period.
For highly malignant sarcomas (grading 2 and 3), the local recurrence risk is much higher than for G1 sarcomas. These sarcomas require at least adjuvant radiotherapy anyway. In this constellation, consideration of neoadjuvant therapy is indicated (see Section Chapter 5.6.1). In the case of tumor localization at critical sites with expected high functional morbidity, it may be possible to perform a marginal resection with curative (R0) intention in the case of a sarcoma devitalized by neoadjuvant therapy.
With marginal resection, there is a risk of failing to remove tumor cells via the fate of the reactive zone [105], [145], [405]. The reactive zone is characterized by signal enhancement on T2-weighted MRI images and mostly by contrast enhancement on contrast-enhanced T1-weighted images. It is also described as a pseudocapsule and may extend to several centimeters beyond the tumor. It typically consists of surrounding tissue compressed by the expansion pressure of the growing tumor. Tumor cells are detected in this reactive zone up to 4 cm away from the macroscopic sarcoma borders [406].
Grabellus et al. investigated the quality of the pseudocapsule after neoadjuvant therapy. Histologic „improvement“ (fibrosis and widening) of the pseudocapsule was seen with all neoadjuvant therapies, most pronounced after ILP and radio-chemotherapy. The improved capsular integrity of the sarcoma resulted in a lower rate of LR [407]. Without (neo-) adjuvant therapy, marginal resection leads to a higher rate of local recurrence [105], [178]. However, marginal resection shows a similar LR rate to wide resection in the multimodal therapy concept. In particular, the positive effect of radiotherapy in marginal resection on LR rate has been demonstrated in several studies [104], [105]. Analyses of adjuvant chemotherapy trials that included patients with marginal resection (e.g., EORTC 62931 „removal of all grossly visible tumor“) describe a positive effect of adjuvant chemotherapy on LR rate [137]. The addition of hyperthermia to systemic chemotherapy after marginal resection (S3 group in the EORTC 62961-ESHO 95 trial) resulted in improved local recurrence-free and overall survival [271], [355].
5.7.2 Survival improvement
Patients with high-risk soft tissue sarcomas (see also Chapter 4.2) have a high risk of developing metastases in the course of local therapy alone and thus ultimately dying from their disease. From the point of view of improving overall survival, systemic therapy with the aim of treating occult metastases at an early stage is therefore of primary importance. Under this objective, systemic therapy can be given both preoperatively, i.e. neoadjuvant, and postoperatively, adjuvant.
For neoadjuvant therapy, data are available from two randomized phase III trials [355], [375]. From ISG-STS 1001, there is evidence regarding improved survival with standard anthracycline plus ifosfamide therapy versus histology-matched chemotherapy. From EORTC 62961-ESHO 95, evidence regarding improved survival even after 10-year follow-up results from combination chemotherapy with regional deep hyperthermia versus chemotherapy alone [271] (see Section Chapter 5.5.1.2).
For adjuvant chemotherapy, the data situation is much more complex, as positive results regarding survival from phase III trials are lacking. However, retrospective analyses [272], [396] provide evidence that combination chemotherapy of anthracyclines and ifosfamide can improve overall survival in clearly defined risk groups (G3 vs. G2) with a hazard ratio of 0.86 (CI 0.75-0.97).
For the largest adjuvant chemotherapy trial, EORTC 62931 a reanalysis was performed using Sarculator [408] (see also Chapter 4.2). It showed that chemotherapy halved survival and risk of recurrence in the patient group with the most prognostically unfavorable value (HR = 0.46, 95 % CI 0.24-0.89), whereas no benefit was demonstrated in the other prognostic groups.
Overall, therefore, both a revised evidence base, and a more comprehensible definition of patients with high-risk soft tissue sarcomas now exist to recommend individualized education regarding the data and shared treatment decision-making in „informed consent“. The data situation for neoadjuvant therapy (randomized phase III trial [271], remission rate of the doxorubicin+ifosfamide arm in the EORTC 62012 trial [409] and in the ISG1001 trial [375] neoadjuvant phase II trial for therapy with trabectedin [410] is thereby broader than that for the meta-analyses [272] or Re-analyses based on a new prognostic parameter of the EORTC 62931 study [408] so that here there tends to be more in favor of preoperative therapy (see recommendations 5.85 and 5.86).
5.7.3 Patient education
The text including the literature references is adapted from the S3 guidelines
„Diagnostics, therapy and follow-up of malignant ovarian tumors“, version 4.0, March 2020 [411] and „Early detection. Diagnosis, Therapy, and Follow-up of Breast Carcinoma“, version 4.4, September 2021 [74].
Due to the increasing need of patients for information and co-determination in the treatment of their disease, knowledge transfer and patient education play an important role. Their importance for the doctor-patient relationship, the course of the disease and the achievement of the therapeutic goal has been proven by numerous studies [412], [413]. Open-ended patient education with the goal of shared (participatory) decision-making enables sufficient medical action.
Two ethical principles are at work in these interactions: the patient's self-determination (autonomy) and the physician's care [414].
The patient's autonomy is of the highest importance. A patient's decision is always voluntary and binds medical action. Patients can speak out for or against medical measures in diagnostics and therapy or also decide in favor of a „I do not want to know“. In order for patients to be able to make a decision in the sense of effective consent („informed consent“), existing information deficits must be compensated for by the physician as best as possible. The personal discussion between patient and physician is of particular importance as the basis for a trusting and respectful understanding. Participatory decision-making is of great importance („shared decision making“). This applies in particular when the outcome of a possible therapy cannot be well estimated.
Of course, these considerations also apply to patients with soft tissue sarcomas, for whom, however, specific problems must be taken into account. For example, minor differences in tumor location and tumor grading may have significant therapeutic and prognostic implications that require particularly detailed clarification (e.g., functional impairment).
The following recommendation has been adapted from the S3 guideline „Diagnostics, therapy and follow-up of malignant ovarian tumors“, version 4.0, March 2020, AWMF register number 032/035OL, https://www.leitlinienprogramm-onkologie.de/leitlinien/ovarialkarzinom/ [411].
Medical education of the patient shall include:
- information about the disease
- the results of the examination
- the course of treatment so far
- diagnosis and discussed differential diagnoses
- treatment options including expected side effects and late effects as well as
- assessments of the associated prognoses and the impact on the patient's life planning and quality of life.
- Consensus
- Strong consensus
All patients with adult soft tissue sarcoma shall be informed about networking opportunities in self-help/patient groups, due to the rarity of the disease with special consideration also of internet-based information and communication opportunities (see chapter 9.2).
- Consensus
- Consent
The patient's attention should be drawn to the patient guideline on the diagnosis, treatment and follow-up of patients with adult soft tissue sarcomas (see Chapter 9).
- Consensus
- Strong consensus
Background
The information provided by the physician should be comprehensive, truthful, complete with regard to the type of measure, purpose, benefits and risks and, in particular, comprehensible (including information on frequencies instead of relative percentages) [415], [416]. The hope for healing or alleviation should not be blocked. The physician providing the information must ensure that the information is provided in accordance with the course of treatment.
The patient's individual somatic, psychological and social situation, gender, age and comorbidities must be taken into account when conducting the discussion. In this context, the patient's fears and concerns, specific burdens, and in particular his or her need for information, treatment expectations, and preferences are to be addressed directly by the physician [417], [418], [419], [420]. The patient's wish to have the conversation or further conversations together with a trusted person must be complied with.
The prerequisite for this is the patient-centered conversation. According to the following basic principles the switching of information and the clearing-up of the patient are to take place [421], [422], [423], [424], [425]:
- Expression of empathy and active listening.
- Addressing difficult issues directly and empathetically
- If possible, avoidance of medical vocabulary, explanation of technical terms if necessary
- Strategies to improve understanding (repetition, summarizing important information, use of graphics, etc.)
- Encouragement to ask questions
- Request to write down questions that arise later and bring them to the next meeting
- Permission and encouragement to express feelings, especially fears and anxieties
- Offering further help (see chapter 9.1 Psychooncology)
- Offer further help by involving the oncology nurse (or advanced practice nurse)
General information about the treatment
The educating physician should explain the recommendations for a form of treatment, especially if there is a patient-centered and consensus-based treatment recommendation from an interdisciplinary conference, and present the principles of treatment, its benefits and risks. Alternative forms of treatment that may be considered for the patient as part of participation in a clinical trial shall be explained. During the discussion, implications for the patient's lifestyle and quality of life should be discussed. This includes informing patients about „normal and unremarkable“ examination results and the course of treatment (reassurance) and providing prognostic information (life planning) [426], [427], [428].
Specific aspects of information for soft tissue tumors
In any case, the following points should be considered as contents of a therapy clarification discussion:
Surgical therapy:
- Explanation of the extent of muscle resections and their consequence for the function of limbs, joints and organs (control of knee joint function after (partial) resection of the quadriceps muscle, internal rotation of the leg after resection of the obturator nerve.
- Changes in respiratory function and body image after resection on the body cavities (e.g. thoracic wall, abdominal wall relaxation after retroperitoneal resection).
- Information about rehabilitation measures (e.g. functional gait training, muscle building) and provision of assistive devices
- Information about foreseeable limitations in the profession practiced as a result of surgical measures (joint mobility, reduction in gross strength, loss of surface and depth sensitivity)
Multimodal therapies:
- Education about effects of neoadjuvant therapies (e.g., radiationtherapy and wound healing, consequences of isolated limb perfusion such as lymphedema, systemic chemotherapy combined with deep hyperthermia)
- For neoadjuvant therapies, in particular, the intended benefit compared with the primary surgical approach should be explained and weighed against the loss of time until definitive surgery.
- Principles and treatment goals of any adjuvant therapy, duration and implementation of the treatment, its side effects and possible late effects, as well as treatment options for side effects
Radiotherapy:
- Advantages and disadvantages of radiotherapy when given before or after surgery (irradiation field smaller preoperatively, irradiation dose larger postoperatively, delay to surgery by radiotherapy of about 8-12 weeks, effects on joint mobility and lymphedema by radiation dose and irradiation field.
General aspects of therapy:
- Participation in clinical trials: principles and treatment goals sought, explanation especially of development status of new drugs (phase I, II, III) and sponsor of trial (investigator initiated, academic research group, industrial client).
- Duration and implementation of the therapy as a whole: effects and side effects known so far, late effects, special features (monitoring, additional measures, participation, data storage and processing)
- Others: possibilities of prophylaxis and treatment of therapy-related side effects (e.g. premature menopause, vomiting, neurotoxicity, lymphedema, skin changes during radiotherapy, etc.), necessity of follow-up care,
- Possibilities of psycho-oncological support as well as services of self-help groups, aspects of personal responsibility and participation (e.g., communication of symptoms and problems, therapy compliance) [429], [430], [431].
- Clarification of a genetic risk
- Possibility of special nursing support for prophylaxis and complementary nursing measures in case of side effects of the therapy by the Oncological Specialist Nursing (or Advanced Practice Nurse).
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