2. Introduction – Soft Tissue Sarcoma

The primary goal of the present S3 guideline „Adult soft tissue sarcomas“ is to develop recommendations for evidence-based diagnostics and therapy depending on histology and tumor stage. This applies to adequate imaging, histological confirmation, surgical primary therapy, drug treatment, including the use and timing of different modalities and combinations in the different stages of the disease, and follow-up needs of individual tumour sub-types. The treatment of rare subtypes as well as hereditary variants will also be addressed. The aim is to prolong the overall survival of patients and improve their quality of life. So far, there are expert recommendations for optimal treatment in German-speaking countries and in Europe; however, a guideline supported by the professional societies and other organizations involved in care is not available.

The development of the S3-guideline „Adult soft tissue sarcoma“ is intended to improve the quality and standardization of procedures for adult soft tissue sarcoma and to standardize the necessary and required diagnostic measures, surgical and medical or other local therapy measures. In particular, the histopathological and molecular biological workup of the tumors must be standardized for the best possible therapy. Furthermore, it is necessary to provide uniform therapy and to use quality specifications. The different available components of therapy and their best possible combination will be comparatively evaluated.

Some treatment procedures are almost exclusively available for soft tissue sarcoma patients, such as isolated limb perfusion with recombinant human tumor necrosis factor alpha, regional deep hyperthermia or liposomal cytostatics. It is the aim of the guidelines to describe the significance of these procedures and to formulate recommendations for their use or non-use. For patients with soft tissue sarcoma, this should result in optimized comprehensive care. Another specific goal of this guideline is to report and rate the postoperative mortality of different treatment options in patients with retroperitoneal sarcoma (RPS).

By implementing the S3-guideline „Adult Soft Tissue Sarcoma“ a better quality oriented care for patients, also considering health economic aspects, should be achieved.

This S3 guideline examines the following clinical questions:

• Epidemiology, risk factors and prevention.
• How frequently does soft tissue sarcoma occur in Germany, broken down by gender?
• What is the frequency distribution in relation to age?
• What is the frequency of the different subtypes of soft tissue sarcoma?
• What is the proportion of secondary sarcomas after another malignancy, especially after radiotherapy?
• Are there validated risk factors for the occurrence of soft tissue sarcoma? Does this pertain to specific histologic subtypes?
• Which hereditary tumor syndromes are associated with an increased risk of soft tissue sarcoma occurrence?
• Are there validated measures (regarding diet, addictive habits, exercise) that prevent the occurrence of soft tissue sarcoma? 

• Diagnostics, prognostic markers and scores
• Which imaging techniques should be used for diagnosis?
• In which cases should a biopsy be performed (recommended procedure, technique)?
• Which histopathological diagnostic procedures are necessary to confirm the diagnosis (minimum requirements for accurate findings)?
• Are there clinical parameters that influence the prognosis of the disease?
• Are there validated clinical prognosis scores?
• Which molecular markers are identified as prognostic or predictive markers, depending on the histological subtype? (Significance in clinical practice)

• Therapy of the localized soft tissue tumor
• What is the standard procedure for surgery of localized soft tissue sarcomas (e.g., extremities, trunk, retroperitoneal, visceral, etc.)?
• What are the standards to be followed prior for histopathologic evaluation?
• What standards apply to resection margins?
• What plastic/reconstructive measures, if any, are required in the treatment of localized disease?
• What is the value of radiotherapy in localized soft tissue sarcoma?
• Which radiation dose and which radiation field are indicated depending on tumor type and localization (neoadjuvant, intraoperative, adjuvant)?
• What is the importance of neoadjuvant/adjuvant systemic therapy?
• What is the value of hyperthermia and isolated limb perfusion?
• Patient education

• Therapy of isolated local recurrence
• What is the incidence and prognosis of local recurrence?
• What is the value of systemic therapy?
• What is the procedure for patients who have undergone surgery alone?
• What measures apply if radiotherapy has already been performed?

• Therapy of metastatic disease
• What first-line/second-line agents are available for the treatment of metastatic soft tissue sarcoma?
• Are there recommended therapy sequences or therapy combinations?
• What is the value, depending on the different metastatic sites, of local ablative procedures (surgery, radiotherapy, RFA, SIRT, etc.)? Which techniques should be used?
• What supportive measures are useful in the context of therapy for metastatic soft tissue sarcoma?

• Rehabilitation and aftercare
• What is the role of physiotherapy and rehabilitation in completing therapy for patients?
• What long-term toxicities (e.g., cardiovascular toxicity) need to be considered and how are they treated/controlled?
• At what intervals and over how many years should follow-up be performed in the localized stage?
• At what intervals should follow-up be performed in the metastatic stage?
• What measures are included in follow-up (localized/metastatic)? What imaging should be performed (CT, MRI)? How often is imaging indicated?

• Psycho-oncological, psychosocial and palliative medical aspects
• What psycho-oncological services should be available to a patient with soft tissue sarcoma?

• Gastrointestinal stromal tumors
• What are the diagnostic requirements for GIST?
• What are the requirements for pathological diagnostics?
• What is the significance of the imatinib-sensitive mutation?
• What is the standard procedure for gastrointestinal stromal tumor surgery?
• What standards apply to resection margins?
• What is the value of adjuvant imatinib therapy (400 mg/day) in GIST?
• What agents are available in first-line/second-line/third-line and for specific GIST subtypes to treat the metastatic setting?

Primary addressees of the guideline are physicians and members of other health care professions involved in the diagnosis, therapy and follow-up of patients with soft tissue sarcoma (all stages; outpatient and inpatient care as well as rehabilitation). Here, surgeons/surgical oncologists, medical oncologists, hematologists, pathologists, orthopedists/tumor orthopedists, radiologists, nuclear medicine specialists, psycho-oncologists, radiation oncologists, and internists should be mentioned.

In its form as a patient guideline, the guideline is intended to reach both patients and self-help groups. These include primarily the German Sarcoma Foundation (represented in the guideline group by Markus Wartenberg and Susanne Gutermuth) but also organizations that are not specifically focused on sarcomas such as the Cancer Information Service, INKA, and others.

The guideline group is composed of an interdisciplinary committee of experts. Thus, all health care providers involved in the provision of care, as well as their patient representatives, were considered in contributing to the content of the guideline. The guideline serves as information for physicians in primary care, physiotherapists and nursing staff.

Further addressees of the guideline are:

• Medical-scientific societies and professional associations
• Health policy institutions and decision-makers at federal and state level
• Patient information and counseling organizations
• Hospitals
• Health insurance companies and contract managers of integrated care contracts
• Quality assurance institutions and projects at federal and state level

The S3 guideline is valid until the next update, the validity period is estimated to be a maximum of 5 years. Regular updates are planned; in case of urgent need for changes, these will be published separately. Comments and suggestions for the update process are explicitly welcome and can be sent to the following address:

weichgewebesarkome@leitlinienprogramm-onkologie.de

To grade the studies analyzed in the external search, the system developed by the GRADE Working Group(http://www.gradeworkinggroup.org) was used in this guideline.

For this purpose, the endpoints for the individual PICO questions were first prioritized by the WG leaders. The quality assessment of the evidence included the end points considered important and relevant to patients (so-called critical end points), for each of which (end point-specific) confidence in the underlying evidence is determined by means of the GRADE system. The system provides for a structured and transparent downgrading and upgrading of the level of evidence depending on relevant factors for the certainty of results of an effect estimator.

The following study or quality characteristics led to the devaluation of the level of evidence [1]:

• A non-randomized study design [1]
• A potentially high risk of bias in the underlying body of evidence [2]
• Heterogeneity or inconsistency of an outcome parameter across the individual studies considered [3]
• An outcome value that is indirectly attributable to the target population or outcome parameter studied [4]
• An imprecisely estimated effect with a wide confidence interval [5]
• An indication of publication bias [6]

 

The following characteristics lead to upgrading the quality of the underlying body of evidence [1], [7]:

• A very pronounced effect
• A dose-response relationship
• Residual confounding 

Downgrading and upgrading of evidence grades are shown in the extraction tables (there with +/- symbolism). The GRADE system provides a four-level scheme of evidence quality (see table below, which is indicated in the recommendation boxes for all evidence-based statements and recommendations in each case by endpoint.

 

Grading of evidence according to GRADE(http://www.gradeworkinggroup.org).

The methodology of the guideline program oncology provides for the assignment of grades of recommendation by the guideline authors within the framework of a formal consensus process. Accordingly, moderated nominal group processes or structured consensus conferences were conducted by the AWMF [8]. Within these processes, the recommendations were formally voted on by the voting mandate holders (see Participating Professional Societies and Organizations). The results of the respective votes (consensus strength) are assigned to the recommendations according to the categories in Table Consensus strength.

In the guideline, the quality of the evidence according to GRADE (see Chapter 2.2.1) and, in the case of recommendations, the strength of the recommendation (degree of recommendation) are shown for all evidence-based statements and recommendations. With regard to the strength of the recommendation, three grades of recommendation are distinguished in this guideline (see Table: Scheme of recommendation grading), which are also reflected in the wording of the recommendations in each case.

Table: Scheme of recommendation grading

Grade of recommendation	Description	Expression
A	Strong recommendation	shall
B	Recommendation	should
0	Recommendation open	can/may

 

Table: Consensus strength

Consensus strength	Percentage consensus
Strong consensus	> 95% of those voting
Consensus	> 75 – 95 % of those entitled to vote
Majority consensus	50 – 75 % of those entitled to vote
Dissent	< 50 % of those entitled to vote

 

The decision criteria for determining the grades of recommendation are explained in the guideline report (see section 5.3.2 there) for this guideline. 

Recommendations

Recommendations are thematically related action guiding core principles of the guideline, which are developed by the guideline group and agreed upon in formal consensus procedures.

 

German Cancer Aid provided the financial resources through the Guidelines Program in Oncology (OL). These funds were used for personnel costs, office supplies, literature procurement, and the consensus conferences (room rentals, technology, catering, moderator fees, travel expenses of participants). The guideline was developed editorially independent from the funding organization.

Obtaining declarations of interest

Declarations of interest were obtained from all guideline group members (coordinators, mandate holders, authors, subject matter experts) at the beginning of the guideline project. For this purpose, the applicable template of the AWMF „Declaration of Interests“, beta version for practice test, as of June 29, 2016, was used. The disclosed information is listed in the guideline report (see Chapter 12) for this guideline (http://leitlinienprogramm-onkologie.de/Leitlinien.7.0.html). Statements from all eligible voters were complete by the first consensus conference (06/28/2018). They are located in the Guideline Secretariat. In cases of a change of mandate by the professional society or a subsequent nomination of a subject matter expert with voting rights, the required conflict of interest declaration was submitted in a timely manner. Third-party funding from industry and advisory boards, as well as owner interests (shareholdings, patents) should be declared. The company name (third-party funds) should be mentioned. In the case of third-party funding, it should also be made transparent from which company it originates and what it was spent on.

Dealing with conflicts of interest

The guideline group members for whom a conflict of interest (CoI, any financial ties to industry) was identified after review of a summary of the declarations of interest on the part of the OL Office were informed of this prior to the first consensus conference (for details, see Guideline Report Chapter 8). During the first consensus conference, the procedure for dealing with conflicts of interest was discussed and it was unanimously agreed that persons entitled to vote with identified CoI should be identified in votes with a corresponding topic reference and counted as abstentions. However, double voting should be done in these cases. One vote with all persons eligible to vote and one vote with abstention of those with conflicts of interest. Control evaluations should be performed (result of the entire group vs. group of persons without CoI). In this case, the result of the group of persons without CoI was decisive.

We would like to point out that possible undue influence by conflicts of interest was reduced by the fact that the evidence-based search, selection, evaluation, and assessment of the literature was performed by IFOM staff. Formal consensus building with external, independent facilitation, interdisciplinary development of the guideline, and public peer review of the guideline provide additional means for reducing bias.

At this point, we would like to thank all participants for their exclusively voluntary contribution to the project.