7. Therapy of metastatic disease – Soft Tissue Sarcoma

Version 1.1 · May 2022 · AWMF 032/044OL
Leitlinienprogramm Onkologie · Deutsche Krebsgesellschaft · Deutsche Krebshilfe · AWMF

The heterogeneity of soft tissue sarcomas underscores the need for selection from available drug agents. Table "Sarcoma subgroups considered to be sensitive to chemotherapy" details those soft tissue sarcomas that can be treated with conventional chemotherapy, those for which a targeted therapy is appropriate and those for which no treatment can currently be recommended.

Table 8: Sarcoma subgroups considered to be sensitive to chemotherapy, unless otherwise stated

Sarcoma group	Sarcoma subtype	ICDO code	Remarks
Vascular tumors	Epithelioid hemangioendothelioma	9133/3	No standard chemotherapy, see subtype-specific treatment
	Angiosarcoma	9120/3
Gastrointestinal stromal tumors		8936/3	Subtype-specific treatment (see Chapter 10.1)
Nerve sheath tumors	MPNST	9540/3
	Malignant Triton tumor	9561/3
Tumors of unclear differentiation	Synovial sarcoma	9040/3
	Epithelioid sarcoma	8804/3	No standard chemotherapy, see subtype-specific treatment
	Extraskeletal myxoid chondrosarcoma	9231/3	No standard chemotherapy, see subtype-specific treatment
	Extraskeletal Ewing sarcoma	9364/3	Analogous to therapy for osseous Ewing sarcoma
	Desmoplastic small and round cell tumor	8806/3	No standard chemotherapy, see subtype-specific treatment
Undifferentiated / non-classified sarcomas	Undifferentiated spindle cell sarcoma	8801/3
	Undifferentiated pleomorphic sarcoma	8802/3
	Undifferentiated round cell sarcoma	8803/3
	Undifferentiated epithelioid sarcoma	8804/3
	Undifferentiated sarcoma NOS	8805/3
Adipocytic sarcoma	Dedifferentiated liposarcoma	8858/3
	Myxoid liposarcoma	8852/3
	Pleomorphic liposarcoma	8854/3
Fibroblastic / Myofibroblastic sarcomas	Malignant solitary fibrous tumors	8815/3	No standard chemotherapy, see subtype-specific treatment
	Adult fibrosarcoma	8810/3	Distinct from infantile fibrosarcoma, where NTRK fusion is frequent
	Myxofibrosarcoma	8811/3
Tumors of the smooth musculature	Leiomyosarcoma	8890/3
Tumors with skeletal-muscular differentiation	Embryonal rhabdomyosarcoma	8910/3	analogous to pediatric RMS protocol
	Pleomorphic rhabdomyosarcoma	8901/3	analogous to pediatric RMS protocol, there is discussion whether this subtype does not beong to the group of adult STS an is not particularly sensitive to chemotherapy

A number of approved and non-approved substances are currently available for clinical use in the treatment of these entities. Table"List of recommended substances for drug therapy" lists the substances alphabetically as well as their approvals.

Table 9: List of recommended substances for drug therapy of soft tissue sarcomas according to approval and clinical use.

Substance	Clinical use	Approval	Benefit assessment
Dacarbazine (DTIC)	Pretreated patients*	Soft tissue sarcoma	-
Docetaxel	Only in combination	-	-
Doxorubicin	First-line	Soft tissue sarcoma	-
Liposomal Doxorubicin	First-line	-	-
Eribulin	Pretreated patients	Liposarcoma after anthracycline	Evidence of substantial additional benefit1
Gemcitabine	Pretreated patients	-	-
Ifosfamide	Pretreated patients*	Soft tissue sarcoma	-
Pazopanib	Pretreated patients	Non-adipocytic soft tissue sarcoma after anthracycline	-
Trabectedin	Pretreated patients	Soft tissue sarcomas after anthracycline +/- ifosfamide	-
* Suitable as a combination partner for first-line therapy. 1 For patients for whom dacarbazine is a suitable therapeutic option. For other patients: an additional benefit is not proven (BAnz AT 27.12.2016 B2). [459]

7.1 Systemic therapy

7.1 · Consensus-based Recommendation 2021

Patients with locally untreatable, localized, or metastatic disease should receive guideline-based systemic therapy.

Consensus: Strong consensus

7.2 Objective of drug therapy

7.2.1 First-line therapy

7.2 · Consensus-based Recommendation 2021

The choice of systemic therapy shall be doxorubicin monotherapy or anthracycline-containing combination therapy, taking into account toxicity and goals.

Consensus: Strong consensus

The selection of the appropriate system therapy for locally advanced or metastatic soft tissue sarcoma is subject to the individual therapeutic situation. In the first-line setting, several anthracycline-based options are available and should be selected based on their advantages or disadvantages for the appropriate patient population. Figure"Overview of available options as mono- or combination therapy" shows an overview of the available options as single or combination therapy. Details on the different regimens can be found in the background text.

Overview of available options as monotherapy or combination therapy

After failure of the first-line therapy, a follow-up therapy should be offered. Currently, different follow-up therapies are available, which are shown in Figure"Follow-up therapy". A specific sequence cannot be defined, so that the selection of the appropriate therapy can be selected according to patient-specific factors (Table"Approved Substances" and Table"Approved Substances, Indication and Evaluation of Added Benefit").

Follow-up therapy in advanced or metastatic soft tissue sarcoma.

Table 10: Approved substances for drug therapy and their mechanisms of action (as of 2021)

Substance	Mechanism of action
Dacarbazine (DTIC)	Inhibition of DNA synthesis by alkylating effect
Doxorubicin	Inhibitor of topoisomerase II
Epirubicin	Inhibitor of topoisomerase II, also doing damage to DNA and RNA polymerase via free radical mechanisms, close analogue to doxorubicin
Entrectinib	Inhibitor of tropomyosin receptor kinases (TRK)
Eribulin	Prevention of tumor cell replication by binding to tubulins
Ifosfamide	DNA alkylation: prevention of cell replication
Larotrectinib	Inhibitor of tropomyosin receptor kinases (TRK)
Pazopanib	Inhibitor of multiple tyrosine kinases
Trabectedin	Blocking transcription factor-DNA binding, inhibiting transcrip-tion and interfering with DNA repair mechanisms

Table 11: Approved substances, indication and assessment of added benefit by the G-BA

[459], [460], [461]

Substance	Indication	Added benefit
Entrectinib	Adult and pediatric patients 12 years of age and older with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, in whom locally advanced or metastatic disease is present or disease, for which surgical resection is likely to result in severe morbidity and who have not previously received an NTRK inhibitor inhibitor and for whom no satisfactory satisfactory treatment options are available.	An additional benefit is not proven.
Eribulin	Treatment of adult patients with advanced or metastatic liposarcoma previously treated with anthracycline-containing chemotherapy (if appropriate).	Evidence of substantial added benefit compared with dacarbazine in a clinical trial For other therapy options: No additional benefit proven
Larotrectinib	Adult and pediatric patients with solid tumors with a neurotrophic tyrosine receptor kinase (NTRK) gene fusion who have locally advanced or metastatic disease, or disease for which surgical resection is likely to result in severe morbidity, and for whom there are no satisfactory satisfactory treatment options are available.	No additional benefit has been demonstrated.

7.2.1.1 Monotherapy

7.3 · Evidence-based Recommendation 2021

Patients with an indication for monotherapy shall be treated with doxorubicin.

Recommendation grade

A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht

Level of evidence

⊕⊕⊕⊝

Overall survival (median follow-up: 8.6 months)

⊕⊕⊕⊝

Progression-free survival (re-analysis, median follow-up: 6.2 months)

Consensus

Strong consensus

References

[409] [462] [463] [464] [465] [466] [467] [468]

Background

To date, no improvement in efficacy or overall survival has been achieved by the addition of other chemotherapeutic agents in histology-agnostic studies [409], [462], [463], [464], [465], [466], [467] [468], [469].

No other chemotherapeutic agent has been shown to be superior to doxorubicin [470], [471], [472], [473], [474]. Doxorubicin is furthermore equivalent to the gemcitabine/taxotere combination in grade 2/3 sarcomas in a randomized trial and more favorable in terms of toxicity [475].

In a non-comparative randomized phase II trial, liposomal doxorubicin demonstrated comparable efficacy to doxorubicin in terms of remission rate and progression-free survival (PFS) and appears warranted as an alternative. The study was too small to draw a conclusion regarding overall survival (OS) [476].

Epirubicin was randomized in two papers and showed comparable efficacy data (overall survival, progression-free survival) and toxicity profiles compared with doxorubicin [477], [478]. Epirubicin thus represents an alternative to doxorubicin.

For aldoxorubicin, a randomized phase II trial suggested a PFS advantage over doxorubicin (8.3 vs. 4.6 months) [479], but the phase III trial that followed it, but compared pretreated patients vs. „Physician‘s Choice“, did not confirm this advantage [480].

Olaratumab was randomized in combination with doxorubicin (experimental arm) in a phase II trial compared against doxorubicin as monotherapy. There was a significant overall survival benefit for patients in the experimental arm of 26.5 vs. 14.7 months [481]. In the study, rare sarcoma subgroups were partially included in only one study arm. No significant difference was found in remission rate or progression-free survival. The combination was associated with an increased risk of °IV adverse events (42% vs. 31%). Based on the exceptional significant survival benefit, conditional approval of olaratumab was granted [482]. However, the subsequent phase III trial (ANNOUNCE) failed to meet the primary endpoint of prolonging overall survival in either the overall population or the leiomyosarcoma subpopulation [483]. The marketing authorization for olaratumab as the active ingredient in the drug Lartruvo® was revoked by the European Commission on July 19, 2019, due to proven inefficacy.

When diagnostic evidence for NTRK fusions is established, approved agents larotrectinib and entrectinib are available for metastatic/non-operable stage patients.

7.2.1.2 Combination therapy

7.4 · Consensus-based Recommendation 2021

Patients for combination chemotherapy (high treatment pressure with rapid progression or symptomatic disease) shall receive anthracycline-based chemotherapy combination.

Consensus: Strong consensus

7.5 · Consensus-based Recommendation 2021

In patients with leiomyosarcomas or liposarcomas, combination therapy with doxorubicin and dacarbazine may be administered.

Consensus: Strong consensus

Background

The EORTC 62012 trial [484] which compared doxorubicin plus ifosfamide with single agent docorubicin showed a highly significant advantage of the combination over monotherapy in terms of objective remission rate (26% vs. 14%; p < 0.0006) and improved PFS (HR 0.74, 95% CI 0.60-0.90; p = 0.003) in a range of histologic sarcoma subtypes studied. Therefore, combination therapy should be offered to patients likely to benefit symptomatically from tumor shrinkage or those with rapid disease progression, subject to the usual considerations of toxicity, such as frailty etc.. This is also true for patients with potential resectability (only one organ system affected) of metastases.

A subgroup analysis based on local and central pathology review, central review data suggested that patients with undifferentiated sarcomas (UPS), had a survival benefit with combination regardless of the extent of metastasis (OR 9.90, 95 % CI 1.93-50.7 Combi vs HR 0.44, 95 % CI 0.26-0.79 Mono). ). Although there was a higher response rate with combination therapy in all subgroups studied with the exception of liposarcoma, this was only statistically significant in the case of UPS. This may have been due to small numbers in the subgroups.

Subgroup analysis of a retrospective EORTC study [485] suggests a benefit of adding dacarbazine to doxorubicin treatment for objective remission rate in patients with leiomyosarcoma (55% doxo + DTIC vs 20% doxo mono, p = 0.04). A retrospective analysis of 22 patients each with leiomyosarcoma and liposarcoma showed similar results, which were published as an ab-stract in 2011 [486]. A direct randomized comparison with a doxorubicin/ifosfamide combination has not been performed to date. An EORTC retrospective study did not show an improvement in objective remission rate in leiomyosarcoma and liposarcoma with the addition of ifosfamide [487].

7.2.2 Second-line therapy

7.6 · Consensus-based Recommendation 2021

Selection of follow-up therapy should be individualized based on indica-tions for treatment, histologic subtype, and patient preference.

Consensus: Strong consensus

7.7 · Evidence-based Recommendation 2021

In patients who have received chemotherapy according to the guidelines, follow-up therapy with pazopanib, trabectedin or eribulin shall be offered.

Pazopanib is not approved for liposarcoma and shall therefore not be used in this setting.

Eribulin is only approved in liposarcoma and therefore shall only be used there.

* [490]
**
[493]

Recommendation grade

A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht

Level of evidence

⊕⊕⊕⊝

Overall survival (pazopanib)

⊕⊕⊕⊕

Progression-free survival (pazopanib)

⊕⊕⊕⊝

Health-related QoL (pazopanib).

⊕⊕⊕⊝

Overall survival (trabectedin)*.

⊕⊕⊝⊝

Progression-free survival (trabectedin)*.

⊕⊕⊝⊝

Overall survival (trabectedin)**

⊕⊕⊕⊝

Progression-free survival (trabectedin)**

⊕⊕⊕⊝

Overall survival (eribulin)

⊕⊕⊝⊝

Progression-free survival (eribulin)

⊕⊕⊕⊝

Global health status QoL (eribulin)

Consensus

Consent

References

[488] [489] [490] [491] [492] [493]

7.8 · Evidence-based Recommendation 2021

Gemcitabine can be used as monotherapy or combination with docetaxel or dacarbazine in pretreated patients.

Recommendation grade

0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann

Level of evidence

⊕⊕⊝⊝

Overall survival

⊕⊕⊝⊝

Progression-free survival

Consensus

Strong consensus

References

[494] [495] [496]

Background

The heterogeneity of the disease and the different approved drugs require an individual assessment of the therapy situation. The therapeutic landscape is heterogeneous and the level of evidence for individual therapies varies enormously. The spectrum of side effects, treatment indications, histologic subtype, and patient preference should all factor into drug selection.

A number of drug therapies have been evaluated in pretreated patients with soft tissue sarcoma in randomized trials versus placebo, best-supportive-care, or single agent therapy. Comparative trials between multiple treatment options do not exist, so selection of agents is based on contraindications, histological subtype or patient preference.

Trabectedin was approved in the EU in September 2009 based on a randomized dose comparison study (1.5 mg/m2 vs. 1.2 mg/m2) in 270 patients [497]. The 2016 US pivotal trial demonstrated a significant improvement in PFS compared with active therapy with DTIC in patients with leiomyosarcoma and liposarcoma not further subtyped (HR 0.55; moderate strength of evidence) [493]. However, there was only a trend for OS (HR 0.87; low strength of evidence).

A Japanese study compared trabectedin with best supportive care in patients with previously treated translocation-associated sarcomas (including myxoid liposarcomas, synovial sarcomas, mesenchymal chondrosarcomas, and alveolar soft part sarcomas). This showed significantly improved OS – (CI 12.8 months - not reached) vs. 8 months (CI 7.0 – not reached); HR: 0.42; p = 0.04) in addition to significantly improved PFS (from 0.9 to 5.6 months, HR: 0.07; p < 0.0001). Within randomized trials, the range of different sarcoma subgroups was limited and efficacy data exist almost exclusively from retrospective analyses.

Eribulin was also compared to dacarbazine therapy in a patient population restricted to leiomyosarcomas and liposarcomas. This showed an improvement in OS over dacarbazine (HR 0.77, moderate evidence) [489], while PFS was largely unaffected (HR 0.88). A subgroup analysis for patients with liposarcomas showed a highly significant overall survival benefit for eribulin over dacarbazine (15.6 vs. 8.4 months; HR 0.51; 95% CI 0.35-0.75; p < 0.001). There was also a moderate but also significant benefit in PFS (2.9 vs. 1.7 months, HR 0.52; 95 % CI 0.35-0.78; p=0.0015). A quality of life analysis for this study showed a significant improvement in health-associated quality of life throughout the study period as well as at the time of progression. In particular, dacarbazine patients showed more pronounced symptoms such as nausea, vomiting, insomnia and loss of appetite [488]. Based on the above data, approval was granted only for patients with liposarcoma.

Pazopanib was compared to placebo therapy in 369 patients in a 2:1 randomized phase III trial (PALETTE) including most sarcoma subgroups (except liposarcoma which were excluded due to inadequate efficacy in phase II). Pazopanib improved PFS (4.6 vs. 1.5 months, HR 0.31, p=0.0001) and patient QoL, while overall survival was not significantly imprved (11.9 vs. 10.4 months, HR 0.86, p=0.17) [491], [492]. As a result, follow-up therapy should be offered. A large number of different sarcoma subtypess were treated with only small numbers of cases each, so that no reliable efficacy data can be derived from the study.

In summary, pazopanib is suitable for all subgroups except liposarcomas (PFS advantage). Trabectedin (with PFS advantage in the overall LMS/LPS group) is only optionally recommended for LPS due to available alternatives, but is preferred for LMS. For all other subtypes, the agent is also suitable. Eribulin should only be used in liposarcoma. Here, the drug showed advantages in PFS, OS, and QoL and is thus preferred for this subgroup of soft tissue sarcomas.

The data on comparisons of gemcitabine as single agent compared with the combination of gemcitabine + docetaxel are conflicting. In one study gemcitabine-docetaxel failed to improve PFS (uLMS: HR 1.15; others 0.93) or OS compared to gemcitabine alone, but with an overall low level of evidence [494]. The addition of bevacizumab has no effect, however the study confirmed the principle efficacy of the combination of gemcitabine and docetaxel [496]. It should be noted that this study was first-line data. In another first-line study, the gemcitabine/taxotere combination offered no advantage over monotherapy with doxorubicin [475] (see Chapter 7.2.1.1). In another study, the gemcitabine and docetaxel combination was superior to gemcitabine monotherapy in terms of PFS (HR 0.67), but an overall survival advantage could not be shown [495]. The combination is associated with greater toxicity and should only be used after careful consideration.

Gemcitabine in combination with dacarbazine was superior to dacarbazine alone in a randomized phase II trial [498]. A total of 113 patients with different histologies were randomized, with leiomy-osarcomas and undifferentiated pleomorphic sarcomas predominating. Combination therapy was shown to result in an improvement in PFS from 2.0 to 4.2 months and was associated with a survival benefit (16.8 vs. 8.2 months; p=0.014). Again, an increase in toxicity was reported with combination therapy, so use should be assessed individually in each case.

7.2.3 Follow-up therapy

7.9 · Consensus-based Recommendation 2021

Patients with progression after failure of second-line therapy may receive re-chemotherapy with drugs not yet used.

Consensus: Strong consensus

Background

When making a decision about follow-up therapy considerations are the patient's general condition and organ functions and the patient's wishes. Drugs described in Chapter 7.2.2 can be used. A specific sequence has not been established.

7.3 Metastatic surgery

7.10 · Consensus-based Recommendation 2021

The indication for local therapy of metastases shall be multidisciplinary.

Consensus: Strong consensus

7.11 · Consensus-based Recommendation 2021

Surgical resection of pulmonary metastases shall be performed only under the following conditions:

expected R0 removal of all pulmonary metastases
no evidence of local recurrence that cannot be controlled
previous pulmonary metastasectomies are not a contraindication

In the presence of extrapulmonary metastases, resection shall be performed only after an interdisciplinary case-by-case decision.

Predictive factors for improved survival are a time interval after primary treatment of > 12 months and the radicality of the procedure.

Resection of pulmonary metastases with palliative intent is generally not recommended and should be reserved for exceptional cases with severe symptoms.

Consensus: Strong consensus

7.12 · Consensus-based Recommendation 2021

No additive chemotherapy shall be given for metachronous resected lung metastases.

Consensus: Strong consensus

7.13 · Consensus-based Recommendation 2021

Surgical resection of liver metastases shall only be performed following an interdisciplinary case-by-case decision if the following conditions are met:

expected R0 removal of all liver metastases
No evidence of local recurrence that cannot be controlled.

Predictive factors for improved survival are a time interval after primary treatment of > 24 months and the radicality of the procedure.

Resection of liver metastases with palliative intent is not recommended.

Consensus: Strong consensus

7.14 · Consensus-based Recommendation 2021

Metastases from other sites may be surgically removed on a case-by-case basis.

Consensus: Strong consensus

Background

The decision to resect metastases is often a difficult decision because, firstly, no results from randomized prospective studies are available. Secondly, the decision strongly depends on the subjective assessment and experience of the treating surgeon regarding the extent and radicality of the intervention. Thirdly, under certain conditions, such as in the case of recurrent surgery or when the patient's general condition is significantly impaired, other locally ablative procedures (see Chapter 7.4) should also be considered in addition to a surgical procedure. Therefore, the indication for metastatic surgery should be made on a multidisciplinary basis within the framework of the tumor conference.

20-25% of all patients with soft tissue sarcoma develop pulmonary metastases during the course of the disease, with the frequency of occurrence of pulmonary metastases depending on the grading (G3: 40-60%). The lung represents the organ most commonly affected by soft tissue sarcoma metastases, accounting for 65-80%, and most lung metastases occur within the first two years after resection of the primary tumor [499], [500], [501].

The evidence in favour of resection of pulmonary metastases in metastatic soft tissue sarcoma has been limited to a few large retrospective multicenter studies and a number of smaller observational studies. In 1997, the International Registry of Lung Metastases (IRLM) published a study of 5206 patients after pulmonary metastatic resections. In this cohort, 2173 patients had a diagnosis of sarcoma (soft tissue and osteosarcoma combined). The risk of the pulmonary metastasectomy procedure was acceptable, with a perioperative mortality of 1%. Subgroup analysis from this first large registry study identified incomplete resection (R1), a disease-free interval of less than 36 months from primary diagnosis to the appearance of pulmonary metastases, and an increased number of metastases (>3) as risk factors for less favorable survival in these patients [502].

Subsequent retrospective single enter studies essentially confirmed the above findings and were able to demonstrate a disease-free interval of >12 months from primary diagnosis to the appearance of pulmonary metastases, radicality of surgery (R0), a low number of pulmonary metastases, and extrapulmonary tumor control as predictive factors for improved survival [503], [504], [505], [506], [507], [508], [509], [510], [511], [512], [513].

The best evidence to date, but indirect, that resection of pulmonary metastases provides a survival benefit for patients with metastatic soft tissue sarcoma comes from the French Sarcoma Group METASARC trial, published in 2017. Analysis of 1619 patients with metastatic soft tissue sarcoma only showed a significant increase in survival for patients who had metastases of different sites treated surgically [501]. Since pulmonary metastases were by far the most common metastatic site in this cohort at 65%, these results suggest improved survival for pulmonary metastasectomy for soft tissue sarcoma.

Regarding the surgical procedure, few and hardly robust data exist for a minimally invasive approach to pulmonary metastasectomy [502], [514], [515]. Therefore, the gold standard should still be the open procedure with manual palpation of the entire lung parenchyma. Whether the use of laser technology and mediastinal lymphadenectomy in pulmonary metastasectomy provide benefits for patient survival remains controversial [516], in contrast to renal cell carcinoma, for example, in which the metastatic pathway is via the mediastinal lymph nodes. This is only true for sarcomas in exceptional cases. In contrast, a clear recommendation can be made for pulmonary re-metastasectomies, as surgical treatment of pulmonary recurrence has been shown in several studies to confer a survival benefit for these patients [502], [511], [512], [517], [518].

In 1995, Choong et al postulated that adjuvant chemotherapy after resection of pulmonary metastases was a negative predictive factor for survival [519]. Subsequent studies failed to demonstrate a significant impact of adjuvant chemotherapy on survival in these patients [520], [521]. The French Sarcoma Group registry study of 281 patients with oligometastatic soft tissue and osteosarcoma showed a significant survival benefit for surgical treatment of metastases; however, this was independent of whether chemotherapy was also administered [518].

The liver is the second most commonly affected organ by metastases in soft tissue sarcoma, accounting for 19%. The 5-year survival of these patients is significantly less favorable compared with patients with lung metastases (15% vs. 66%) [501]. Retrospective studies investigated whether resection of liver metastases improves survival in these patients. 5-year survival rates of 27-49% were reported [522], [523], [524], [525], [526]. Prognostic positive factors were defined as a disease-free interval of more than 24 months, calculated from the primary tumor to the appearance of liver metastases, [525], [526], and the radicality of the procedure [524], [526]. However, a problem with these studies is that approximately half of the included patients underwent surgery for liver metastases from GIST. Because drug therapy is highly successful for GIST compared with other soft tissue sarcomas, these survival rates are false positives, and the overall survival of the cohort without GIST is only about 20% [522], [527]. Therefore, only a weak recommendation can be made for resection of liver metastases.

Isolated soft tissue metastases, bone or brain metastases can be resected surgically in terms of individual case decisions. In this case, symptomatic metastases should be considered as the primary indication. In addition to a surgical approach, however, radiotherapy and other locally ablative and less invasive procedures (see Chapter 7.4) should also be considered. Data on improved survival do not exist regarding these indications.

7.4 Locoregional and ablative procedures

7.15 · Consensus-based Recommendation 2021

When surgical therapy of metastases is not an option, local ablative procedures may be used as an interdisciplinary case-by-case decision.

Consensus: Strong consensus

7.16 · Consensus-based Recommendation 2021

The use of SIRT or TACE to control liver metastases is a case-by-case decision to be coordinated on an interdisciplinary basis and should be limited to patients with disseminated metastases in the liver with concomitant low extrahepatic tumor volume.

Consensus: Strong consensus

Background

In the French Sarcoma Group METASARC observational study, 42 patients were treated with radiofrequency ablation out of a total of 1054 patients with locoregional treatment. The data showed a significant positive impact on overall survival in these patients, although the study did not indicate which localizations were treated with radiofrequency ablation [501]. For radiofrequency ablation of lung metastases, positive results have also been reported by other groups, with 3-year survival of 47% and 85%, respectively [528], [529]. This was different in the case of liver metastases; here, the retrospective study by Pawlik et al. showed that radiofrequency ablation as sole therapy or in combination with a surgical approach had a negative impact on overall survival [523].

In contrast to the small number of patients treated with radiofrequency ablation, 254 patients were treated with local radiotherapy in the METASARC study. Despite the larger number of patients with local ablative radiotherapy, there was only a positive trend regarding the impact on survival [501]. In other studies, stereotactic irradiation of pulmonary sarcoma metastases yielded good local control and 2-year survival rates of 85% and 66% with low toxicity [530], [531]. Positive results for sarcoma patients have also been shown for irradiation of spinal metastases [532], irradiation of brain metastases [533], and postradiation of surgically removed brain metastases [534], so radiotherapy can be considered for local control of metastases when surgery is not an option.

The use of transarterial radioembolization (SIRT) [535], [536] and chemoembolization (TACE) for disseminated liver metastases and at the same time low extrahepatic tumor volume, or extrahepatic tumor control, applies to only a few patients but should be considered as an option in such a case. Evidence for this comes from a few retrospective studies in which eradication of liver metastases from soft tissue sarcoma was performed using TACE or SIRT. Patients treated in this way showed a median overall survival of 21-30 months with good tolerability of the method [537]. More favorable results are reported when performing SIRT for liver metastases in GIST with a median overall survival of 29.8 months and a hepatic PFS of 15.9 months [536].

7.5 Supportive measures

Regarding supportive therapy, reference is made to the S3 guidelines „Supportive therapy in oncological patients“, version 1.3, 2020, AWMF registry number: 032/054OL, https://www.leitlinienprogramm-onkologie.de/leitlinien/supportive-therapie/ [538] and „Early detection, diagnosis, therapy and follow-up of breast carcinoma“, version 4.3, 2020 AWMF registry number: 032-045OL, http://www.leitlinienprogramm-onkologie.de/leitlinien/mammakarzinom/ [74]. These are illustrated there in detail.

Special features of supportive therapy in the treatment of soft tissue sarcomas are discussed below.

Addition to moderate emetogenic drug tumor therapy:

Carboplatin, which is only occasionally used to treat soft tissue sarcomas, is among the most potent agents in the moderately emetogenic risk group. Several studies have shown the benefit of 3-fold antiemesis with 5-HT3-RA / NK1-RA / dexamethasone [539], [540], [541]. The updated MASCC/ESMO guidelines [542] therefore recommend prophylaxis with an additional NK1-RA during carboplatin-containing chemotherapy.

7.5.1 Supportive therapy for trabectedin therapy

Trabectedin [497], approved by the EMA since 2007 as a 24-hour infusion (1.5 mg/m2 body surface area), is mainly metabolized hepatically, involving the cytochrome 3A4 system. Therefore, parallel use of potential inhibitors of this enzyme complex (e.g., aprepitant, ritonavir) or cytochrome 3A4 inducers (e.g., rifampicin, phenobarbital, or St. John's wort) should be avoided, as this may lead to additional hepatotoxicity [543], [544]. Studies included patients with renal insufficiency (creatinine clearance < 30 ml/min for monotherapy and < 60 ml/min for combination therapy). Based on pharmacokinetic characteristics, renal elimination of trabectedin plays a minor role, which is why patients on hemodialysis can also be treated with trabectedin [545].

Jordan et al. [546] comprehensively describe supportive strategies in the management of trabectedin.

7.5.1.1 Hepatotoxicity

7.17 · Consensus-based Recommendation 2021

With trabectedin, special attention should be paid to concomitant medications.

Consensus: Strong consensus

Background

Phase II studies have reported that trabectedin treatment is regularly associated with an increase in transaminases as well as bilirubin and alkaline phosphatase [547], [548]. The elevation of liver enzymes is usually reversible and not associated with clinically relevant liver dysfunction [549]. Clinical data suggest that pretreatment with high-dose dexamethasone does not affect trabectedin efficacy, but may protect against trabectedin-induced liver toxicity [550]. According to the EMA approval [551], [552], it is recommended that all patients receive 20 mg of dexamethasone intravenously 30 minutes prior to trabectedin administration.

7.5.1.2 Neutropenia

One of the main side effects of trabectedin during clinical trials is myelosuppression, especially neutropenia. The incidence of all grades of neutropenia varies from 24 to 100 % [550], [553]. The risk of febrile neutropenia varies from 6 to 9 %. According to the national guidelines of the AGIHO (Working Group on Infections in Hematology and Oncology) [554], prophylactic use of G-CSF is recommended only at a risk of febrile neutropenia > 20 %, which is why prophylactic use is not routinely part of the supportive treatment plan in trabectedin monotherapy [553].

7.5.1.3 Nausea and vomiting

Until now, trabectedin is not classified within the emetic risk groups by the national and international guidelines [74], [538], [542]. The incidence of grade III / IV emesis was 9 % in the study by Le Cesne [547]. Because antiemetic prophylaxis is given in most studies, antiemetic risk classification is complicated because it should be done without the use of antiemesis [555]. To date, trabectedin is considered to be moderately emetogenic. Since dexamethasone is already used by default to prevent hepatotoxicity, it is recommended to administer 20 mg of dexamethasone 30 minutes before administration of trabectedin. To prevent the delayed phase of nausea and vomiting, 8 mg of dexamethasone should be given on each of days 2 and 3, according to the guidelines [74], [538], [556]. A 5HT3 receptor antagonist may be used alternatively.

The antiemetic aprepitant, an NK1 receptor antagonist, is metabolized by cytochrome P450 (ZYP 3A4) [557]. The drug represents a moderate inhibitor and inducer of ZYP 3A4 and should be used very cautiously in patients receiving trabectedin for soft tissue sarcoma therapy.

7.5.1.4 Extravasate

After reviewing the guidelines, trabectedin is classified as „Vesican“ according to the national guideline [538] and ASORS expert recommendations [558]. Trabectedin must be administered through a CVC to reduce the risk of extravasation. If extravasation occurs, the infusion must be stopped, aspiration should occur, followed by removal of the cannula [558]. A specific antidote does not exist. The use of sodium thiosulfate is controversial [558], if necessary, a surgeon should be consulted early, especially if there is pain at the extravasation site.

7.5.2 Prophylaxis of ifosfamide-induced encephalopathy.

Ifosfamide-induced encephalopathy is a significant problem in patients receiving high doses of the drug alone or in combination [559], [560]. Ifosfamide represents one of the active agents for the treatment of soft tissue sarcoma. In 10-50% of cases treated with ifosfamide, symptoms such as fatigue, somnolence, tremor, aphasia, auditory or visual hallucinations, and epileptic seizures occur [561]. In 1994, methylene blue was first published for the prophylaxis and treatment of ifosfamide-induced encephalopathy by Küpfer et al. [561]. In 2004, Kasper et al. [562] published the successful prophylaxis of ifosfamide-induced encephalopathy with methylene blue. This was an off-label use. Already on the day before, 50 mg of methylene blue were to be administered i.v. once, on the days of the ifosfamide treatment then 3 x daily. Accompanying thiamine (3 x 100 mg i.v.) was administered and hydration was done with 3 l of a 5% glucose solution [563].

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