Soft Tissue Sarcoma Guidelines

Updated: May 18, 2017
  • Author: Steven C Katz, MD, FACS; Chief Editor: Edwin Choy, MD, PhD  more...
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Overview

Overview

The consideration of soft tissue sarcoma (STS) as a single entity is necessary to enable clinical study of these exceedingly rare diseases, yet their wide range of natural history and biologic behavior makes it exceedingly difficult to establish management guidelines that account for the nuances of individual clinical presentations. With over 50 distinct histologic subtypes, STS requires that physicians caring for these patients adapt guidelines to fit the clinical features of each patient’s disease. However, certain principles serve as cornerstones for multimodality management of STS when applied in the context of a highly individualized patient and tumor assessment.

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Genetic Testing

While the overwhelming majority of STS cases are sporadic, rare cases involve a genetic predisposition. The National Comprehensive Cancer Network (NCCN) Soft Tissue Sarcoma Panel specifically identifies Li-Fraumeni syndrome and familial adenomatous polyposis (FAP) as genetic cancer syndromes with a predisposition for the development of STS, along with Carney-Stratakis syndrome, which is associated with gastrointestinal stromal tumors (GISTs). NCCN recommendations for genetic testing include the following [1] :

  • Patients with a personal or family history of Li-Fraumeni syndrome or FAP should be considered for genetic testing and assessment
  • For patients diagnosed with desmoid tumors (aggressive fibromatoses), evaluate for family history of FAP or Gardner syndrome
  • For patients with GISTs lacking KIT or PDGFRA mutations, SDH gene mutational analysis should be considered; loss of SDHB protein expression by immunohistochemistry is a useful screen to identify patients who would be candidates for germline mutation testing, but it is not diagnostic of a germline mutation
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Classification, Grading, and Staging Systems

WHO Classification of Tumors

In 2013 the World Health Organization released an update of its 2002 classification system for tumors of the soft tissue and bone. [4] The update incorporated more detailed cytogenetic and molecular data into the classifications. Tumors are further classified as benign, intermediate, or malignant, and intermediate tumors are designated as either locally aggressive or rarely metastasizing.

Gastrointestinal stromal tumors (GISTs) have been added in the update, with three subtypes:

  • Benign
  • Uncertain malignant potential
  • Malignant

A chapter on undifferentiated/unclassified sarcomas was added and includes the following subtypes:

  • Undifferentiated spindle cell sarcoma
  • Undifferentiated pleomorphic sarcoma (previously classified as malignant fibrous histiocytoma)
  • Undifferentiated round cell sarcoma
  • Undifferentiated epithelioid sarcoma
  • Undifferentiated sarcoma not otherwise specified

Tumor Grading Systems

The French Federation of Cancer Centers Sarcoma Group (FNCLCC) system [5] and the National Cancer Institute system are most commonly used for grading STS. [6] Both are three-grade systems. The FNCLCC is based on tumor differentiation, tumor necrosis, and mitotic activity, while the NCI system bases the evaluation on histology, location, and tumor necrosis. In comparison studies, the FNCLCC has shown slightly better ability to predict metastasis development and mortality.

Tumor Staging

Both NCCN and ESMO follows the tumor-node-metastasis (TNM) classification of the American Joint Cancer Committee/Union for International Cancer Control/ (AJCC/UICC) for staging of STS. Anatomic stage/prognostic groupings for STS are detailed in Table 1, below. [7]

Table 1. Staging of Soft Tissue Sarcomas (Open Table in a new window)

Stage T N M Histologic grade
Stage IA T1a N0 M0 G1, GX
T1b N0 M0 G1, GX
Stage IB T2a N0 M0 G1, GX
T2b N0 M0 G1, GX
Stage IIA T1a N0 M0 G2, G3
T1b N0 M0 G2, G3
Stage IIB T2a N0 M0 G2
T2b N0 M0 G2
Stage III T2a, T2b N0 M0 G3
Any T N1 M0 Any G
Stage IV Any T Any N M1 Any G

For description of TNM designations, see Soft Tissue Sarcoma Staging.

GISTs are staged separately from other sarcomas, with tumors graded as low or high. Anatomic stage/prognostic groupings for GIST are detailed in Table 2, below. [7]

Table 2. Staging of Gastrointestinal Stromal Tumors (Open Table in a new window)

Stage T N M Grade
IA T1 or T2 N0 M0 Low
IB T3 N0 M0 Low
II T1 N0 M0 High
T2 N0 M0 High
T4 N0 M0 Low
IIIA T3 N0 M0 High
IIIB T4 N0 M0 High
IV Any T N1 M0 Any grade
Any T Any N M1 Any grade

For description of GIST TNM designations, see Gastrointestinal Stromal Tumors Staging.

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Extremity/Trunk/Head and Neck

Diagnosis

The National Comprehensive Cancer Network (NCCN) workup for soft tissue sarcomas of the extremities, superficial trunk, or head and neck includes evaluation and management prior to initiation of therapy by a multidisciplinary team with expertise and experience in sarcoma. [1] The ESMO guidelines concur and recommend referral of all patients with any unexplained deep soft tissue mass, or any superficial soft tissue lesion larger than 5 cm, to a center that specializes in the treatment of STS. [2]

The NCCN guidelines recommend the following as essential aspects of the workup [1] :

  • Imaging studies that include cross-sectional imaging MRI, with or without CT scanning for tumor details, including size and contiguity to nearby visceral structures; additional studies may be warranted in individual situations
  • After adequate imaging, a core needle or incisional biopsy to establish grade and histologic subtype; fine needle aspiration is acceptable if the institution has the required clinical and pathologic expertise
  • Ancillary diagnostic methodologies (eg, immunohistochemistry, classical cytogenetics, electron microscopy, molecular genetic testing) as appropriate
  • Chest imaging

Overall, the ESMO guidelines are in agreement with NCCN. [2] It is critical that biopsies be planned in conjunction with an expert surgeon experienced in STS management. A poorly planned needle or incisional biopsy may compromise subsequent definitive surgery, which will require  full resection of the prior biopsy site or tract.

Treatment

NCCN treatment recommendations for localized low-grade disease (stage IA, IB) are as follows [1] :

  • Surgical resection is definitive treatment if margins are >1cm or the fascial plane is intact.
  • Re-resection may be necessary when margins are ≤1 cm and are without an intact fascial plane.
  • Postoperative radiation therapy should be considered if final surgical margins are ≤1 cm and without an intact fascial plane (category 1 for stage IB).
  • Radiation therapy may be unnecessary with low-grade lesions ≤5 cm because local recurrence is infrequent and observation is an option.
  • The patient should undergo evaluation for rehabilitation therapy to achieve maximal function.
  • Follow-up includes a history and physical examination (H&P) every 3-6 months for 2-3 years and then annually thereafter. After 10 years, likelihood of recurrence is small and follow-up should be individualized by subtype.
  • Consider chest imaging and baseline/follow-up imaging of the primary site, based on histology.

Initial resection margins and decisions concerning re-resection should be tailored to individual subtype biologic features. For example, a well-differentiated liposarcoma or atypical lipomatous tumor may be adequately treated with a 1 cm margin or less. In contrast, a widely infiltrative dermatofibrosarcoma protuberans, myxofibrosarcoma, or angiosarcoma would require far wider resection margins to ensure adequate treatment.

For extremity STS, the goal should be preservation of limb function to the extent that is possible without compromising appropriate oncologic resection. Prior to considering an amputation, patients should be evaluated by a multidisciplinary team with expertise in STS. Dissection should be through grossly normal tissue planes not involved with tumor. Radical compartmental approaches are not routinely required. Close margins may be necessary to preserve critical neurovascular structures and hence function and quality of life.

For stage II-III disease, the NCCN recommends that treatment options should be decided on the basis of the patient’s age, performance status, and comorbidities, as well as the location and histologic subtype of the tumor. NCCN treatment recommendations for these cases (with acceptable functional outcomes) are as follows [1] :

  • Surgical resection and preoperative and postoperative radiation therapy (category 1 for stage IIA)
  • Adjuvant chemotherapy in addition to postoperative radiation therapy may be considered for stage IIB/III
  • Stage IIA: Preoperative radiation therapy and surgical resection is an alternative treatment option
  • Stage IIB/III: Preoperative radiation therapy or chemoradiation are options; postoperative radiation therapy boost with or without adjuvant chemotherapy may also be considered; Preoperative chemotherapy and postoperative radiation therapy with or without adjuvant chemotherapy is also an option
  • For high-grade resectable tumors >8 cm, preoperative and postoperative therapy may be considered
  • Regional lymph node dissection for patients with stage III tumors with lymph node involvement
  • Evaluation for rehabilitation therapy to achieve maximal function
  • H&P every 3-6 months for 2-3 years and then annually thereafter; after 10 years, likelihood of recurrence is small and follow-up should be individualized by subtype
  • Consider chest imaging and baseline/follow-up imaging of primary site based on histology

NCCN treatment recommendations for stage II-III disease (without acceptable functional outcomes) and unresectable disease are as follows [1] :

  • Radiation therapy, chemoradiation, or chemotherapy
  • Surgical resection for tumors that become resectable with acceptable functional outcome after neoadjuvant treatment and postoperative radiation therapy (if radiation therapy is not given preoperatively), with or without postoperative chemotherapy
  • Positron emission tomography/computed tomography (PET/CT) may be useful for large (>3 cm), deep tumors to assess response to neoadjuvant chemotherapy
  • For tumors that remain unresectable or without acceptable functional outcome following primary treatment, observation is an option for asymptomatic patients; symptomatic patients may be treated with chemotherapy, palliative surgery, amputation, or best supportive care
  • Limb-sparing regional limb infusion therapy is recommended as an option for unresectable tumors only if treated at a center with experience in isolated limb perfusion or infusion
  • Evaluation for rehabilitation therapy to achieve maximal function
  • H&P every 3-6 months for 2-3 years and then annually thereafter; after 10 years, likelihood of recurrence is small and follow-up should be individualized by subtype.
  • Consider chest imaging and baseline/follow-up imaging of primary site based on histology

The ESMO guidelines differ from NCCN in that they do not recommend adjuvant chemotherapy as a standard treatment option for stage II or III STS. [2] NCCN treatment recommendations for stage IV/metastatic disease and unresectable disease are as follows [1] :

  • Patients should be referred to a multidisciplinary team with extensive experience in the treatment of STS.
  • Treatment options should be based on performance status, patient preferences, specific clinical problems from the metastases and treatment availability.
  • Enrollment in a clinical trial is recommended.
  • For patients with single-organ or resectable stage IV disease, metastasectomy may be considered in conjunction with preoperative or postoperative chemotherapy with or without radiation. Ablative and intra-arterial modalities may be considered as well, depending on disease anatomy and burden.

ESMO recommendations for treatment of metastatic disease include the following: [2]

  • Chemotherapy may be offered for synchronous lung metastases, in the absence of extrapulmonary disease.
  • Surgery is an option for completely resectable residual lung metastases following chemotherapy, especially when a tumor response is achieved.
  • For extrapulmonary metastatic disease, chemotherapy is the treatment of choice.
  • Radiation therapy may be used with palliative intent.
  • Best supportive care alone is acceptable, especially if second-line therapies have been given previously.
  • Enrollment in clinical trials is recommended.

 

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Retroperitoneal/Intra-abdominal Sarcomas

Diagnosis

The National Comprehensive Cancer Network (NCCN) guidelines for intra-abdominal sarcomas recommend evaluation and management prior to initiation of therapy by a multidisciplinary team with expertise and experience in sarcoma. A pretreatment chest/abdominal/pelvic CT scan with intravenous contrast, with or without MRI, is also indicated.

Pre-resection biopsy is not necessarily required, based on degree of suspicion of other malignancies. Biopsy is required for patients receiving preoperative radiation therapy (RT) or chemotherapy, because the treatment regimen is selected on the basis of the histologic subtype. [1]

The ESMO guidelines also include a recommendation for functional assessment of the contralateral kidney. In addition, ESMO considers a pretreatment core biopsy to be required but cautions against open or laparoscopic biopsy. [2]

Treatment

For resectable disease, NCCN recommends surgery with or without intraoperative RT; preoperative therapy with RT and chemotherapy are options. [1] Dissection should be through grossly normal tissue planes not involved with tumor. Radical compartmental approaches are not routinely required. Close margins may be necessary to preserve critical neurovascular structures and hence function and quality of life.

For unresectable disease, the NCCN recommends initial chemotherapy or RT to induce a response, followed by resection if feasible. The NCCN advises always considering resection of resectable metastatic disease if the primary tumor can be controlled. If the disease is still unresectable after neoadjuvant therapy or is progressive, considerations include the following [1]

  • Palliative chemotherapy
  • Palliative RT
  • Palliative surgery for symptom control
  • Observation if the patient is asymptomatic

ESMO offers no recommendations regarding preoperative radiation therapy for resectable retroperitoneal tumors, observing that definitive evidence-based guidance is not available.. ESMO notes that in any case, preoperative treatment is not intended to change the extent of surgery, but to improve the quality of surgical margins.

ESMO concludes that despite the lack of randomized trial data, neoadjuvant therapy (chemotherapy, RT, regional hyperthermia) is safe in well-selected patients and may be considered after careful review by a multidisciplinary sarcoma tumor board, particularly in patients with technically unresectable or borderline resectable retroperitoneal disease. The sensitivity of specific histologic subtypes to chemotherapy or RT should be considered as well when determining the components and sequencing of multimodality treatment plans.

ESMO finds postoperative RT to be of limited value and associated with significant morbidity, while intraoperative RT is of unproven value. The value of adjuvant chemotherapy also has not been established. [2]

Postoperative treatment with RT or reresection, if technically feasible, may be an option depending on surgical outcomes. With R0 disease (negative margins), consider postoperative RT in highly selected patients, such as those with high-grade tumors. With R1 disease (positive margins), consider postoperative RT if no preoperative RT was given or consider a boost (10-16 Gy) if preoperative RT was given. For R2 disease (macroscopic incomplete resection), consider reresection if technically feasible, otherwise consider a postoperative RT boost or follow the course for unresectable disease as described above. [1]

Decisions concerning adjuvant RT and re-resection must be tailored to specific histologic subtypes. Intraoperative placement of radio-opaque markers may assist adjuvant RT planning.

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Gastrointestinal Stromal Tumors

Diagnosis

The NCCN guidelines for gastrointestinal stromal tumors (GISTs) recommend evaluation and management, prior to initiation of therapy, by a multidisciplinary team with expertise and experience in sarcoma. Abdominal/pelvic CT scan with contrast, with or without MRI, is also indicated and chest imaging should be considered. Very small GISTs (<2 cm) may be evaluated with endoscopic ultrasound-guided fine-needle aspiration; for GISTs 2 cm or larger, endoscopy with or without ultrasound may also be indicated in select patients. [1]

Genetic testing for KIT and PDGFRA is a strong recommendation, and in the absence of KIT or PDGFRA mutations, testing for loss of SDHB protein expression by immunohistochemistry should be considered.  If SDHB expression is lost, then genetic counseling and germline mutation testing in SDH genes should be considered. In patients with advanced GISTs, identification of specific KIT and PDGFRA mutations helps predict responsiveness to imatinib and the possible benefit of a higher imatinib dose. [1]

ESMO guidelines recommend that patients with small esophagogastric or duodenal nodules <2 cm undergo endoscopic ultrasound assessment and then annual follow-up, reserving excision for patients whose tumor increases in size or becomes symptomatic. For small rectal nodules, however, the ESMO guidelines recommend biopsy/excision after transrectal ultrasound assessment, regardless of tumor size. In addition, all nodules 2 cm or larger require biopsy. [3]

Treatment

NCCN treatment recommendations for localized resectable disease include the following [2] :

  • Surgical resection is the primary treatment.
  • For tumors <2 cm with no high-risk features, consider periodic endoscopic surveillance.
  • Preoperative treatment with imatinib may prevent accurate assessment of recurrence risk; consider preoperative imatinib only for marginally resectable or initially unresectable tumors, where surgical morbidity could be reduced by downstaging the tumor preoperatively.
  • Testing the tumor to ensure it has a mutation that is likely to respond to imatinib (especially  KIT exon 11) is recommended prior to starting preoperative imatinib.
  • Consider postoperative imatinib for at least 36 months for high-risk tumors.

ESMO guidelines discourage a laparoscopic approach for resection of large tumors. [3]

NCCN treatment recommendations for unresectable or metastatic disease include the following [2] :

  • Imatinib (category 1)
  • After assessment of therapeutic effect, resection may be considered or imatinib may be continued if resection is not feasible
  • Continuous daily dosing of sunitinib for patients with imatinib-resistant GIST
  • Regorafenib (category 1) for patients with disease progression on imatinib and sunitinib
  • Tyrosine kinase inhibitor (TKI) therapy should be continued as long as patients are receiving clinical benefit (response or stable disease)
  • Continuation of TKI therapy lifelong for palliation of symptoms is an essential component of best supportive care
  • Resection or ablative therapy may be considered in cases of focal or limited progression
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United Kingdom Guidelines

Sarcoma specialists from the United Kingdom, including members of the British Sarcoma Group and NHS England Sarcoma Clinical Reference Group, issued guidelines on management of STS in 2016. [8]

Clinical presentation, referral, and assessment

Recommendations are as follows:

  • Any patient with a soft tissue mass that is increasing in size or is >5 cm, whether or not painful, should be referred either for an urgent ultrasound scan or directly to a sarcoma diagnostic center.
  • If the ultrasound scan does not definitively confirm benign pathology, the patient should be referred for further investigation on an urgent suspected cancer referral pathway.
  • Any retroperitoneal or intra-abdominal mass with an imaging appearance suggestive of an STS should be referred to a specialist center before biopsy or surgical treatment.
  • All patients with a suspected STS should be managed by a specialist sarcoma multidisciplinary team, as specified in the National Institute for Health and Clinical Excellence (NICE) guidance.
  • Ultrasound scan by a musculoskeletal radiologist should be considered as the first-line investigation and may be supplemented by ultrasound-guided core biopsy.
  • Magnetic resonance imaging and core needle biopsy are recommended prior to definitive surgery.
  • Imaging of the thorax by computed tomography scan for lung metastases should be done before radical treatment; further staging may be considered depending on subtype and location of the sarcoma.

Management of localized disease

Recommendations are as follows:

  • Surgery is the standard treatment for most patients with localized soft tissue sarcoma.
  • For patients with resectable disease, a wide excision through normal uninvolved tissues is the surgical procedure of choice.
  • The definition of what constitutes a wide margin is controversial, but with the addition of adjuvant radiation therapy (RT), a close but tumor-free margin (R0) may be adequate.
  • Where a wide excision is not possible due to anatomic constraints, a planned marginal or microscopically positive margin against a critical structure, plus radiotherapy, for intermediate- and high-grade tumors, may be an appropriate means of achieving tumor control while maintaining function and quality of life.
  • Occasionally, amputation should be undertaken as the only surgical option to achieve adequate margins.
  • For patients with borderline resectable tumors, preoperative treatment with chemotherapy and/or RT should be considered, depending on histology.
  • Preoperative or postoperative RT is recommended along with surgical resection of the primary tumor for the majority of patients with high-grade tumors and for selected patients with large or marginally excised low-grade tumors.
  • The recommended dose for postoperative radiotherapy is 60–66 Gy.
  • Preoperative radiotherapy provides better long-term functional outcome and equivalent rates of disease control but greater risk of acute postoperative wound complications, compared with postoperative radiotherapy.
  • The recommended dose for preoperative RT is 50 Gy.
  • Adjuvant chemotherapy is not routinely recommended but could be considered in situations where achieving local control is likely to be compromised or where the risk of metastatic disease is particularly high, with a lower threshold for its use in the more chemosensitive sarcoma subtypes.

Prognosis and follow-up for primary disease

For patients with intermediate- or high-grade sarcoma, the recommended follow-up schedule is every 3-4 months during the first 2 years, followed by biannual visits during years 3-5 and annually thereafter for a total of 8-10 years. Patients with low-grade sarcoma should be followed up every 4-6 months for 3-5 years, then annually.

Standard follow-up practice should include the following:

  • Review of any new symptoms reported by the patient
  • Clinical examination to focus on local recurrence, with imaging follow-up where indicated by clinical suspicion
  • Routine chest x-ray to exclude pulmonary metastases
  • Monitoring for late effects of treatment.

Prognosis and treatment of advanced disease

Recommendations are as follows:

  • Systemic anticancer therapy for the majority of cases of advanced STS is not curative; median survival time is 12-18 months, which varies by subtype. Chemotherapy response rates range from 10%-50%, depending on the treatment regimen, patient selection, tumor grade, and histologic subtype.
  • Treatment recommendations should be guided by patient performance status, disease extent, rate of progression, and potential sensitivity to treatment.
  • Standard first-line treatment is single-agent doxorubicin.
  • Ifosfamide may be used as first-line treatment if anthracyclines are contraindicated, and it is a standard option for second-line therapy.
  • Although the combination of doxorubicin and ifosfamide has not been demonstrated to improve survival in comparison to single-agent doxorubicin as first-line treatment, response rates are higher, and it may be considered in individual patients where a response would improve symptoms or facilitate other treatment modalities.
  • Additional second-line agents include trabectedin and the combination of gemcitabine and docetaxel. The choice of agent depends on histology, toxicity profile, and patient preference.
  • A number of other agents, such as dacarbazine and pazopanib, can be considered beyond second-line, depending on patient fitness and funding constraints.
  • Surgical resection of locally recurrent disease should be considered where feasible. For patients with oligometastatic disease, surgery, RT, or ablative therapies should be considered in individual cases, although data on survival benefit are limited.
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Trans-Atlantic Retroperitoneal Sarcoma Working Group Guidelines

The Trans-Atlantic Retroperitoneal Sarcoma Working Group was established in 2013 to address challenging management issues encountered when caring for patients with retroperitoneal soft tissue sarcomas (RPS). [9] The working group mainly addresses primary RPS that is non-visceral in origin. Desmoid tumors and gastrointestinal stromal tumors (GISTs) are not addressed by the working group.

Clinical presentation, referral, and assessment

Recommendations are as follows:

  • Review of cross-sectional imaging by a dedicated tumor board is required.
  • CT of the chest, abdomen, and pelvis with intravenous contrast is the preferred imaging modality. MRI is an option for patients with contrast allergy, for pelvic tumors, or for cases in which detailed anatomic information (eg, sciatic foramen) is required.
  • Functional assessment of the contralateral kidney is generally required prior to resection.
  • Image-guided core needle biopsy is recommended unless the imaging is definitive, such as in the case of well-differentiated/de-differentiated liposarcoma. Fine-needle aspiration biopsy should be avoided, as it is generally unhelpful.
  • Open or laparoscopic surgical biopsy should be avoided. If an RPS is encountered unexpectedly at surgery, management should be deferred until proper imaging and tissue sampling can be performed by an expert soft tissue sarcoma (STS) team.

Management of localized disease

Recommendations are as follows:

  • Surgical therapy of RPS should be undertaken with the primary goal of complete macroscopic (R0/R1) resection. Adherent structures and organs should be resected en bloc with the tumor.
  • Organ and critical structure preservation (eg, kidney, bladder, duodenum, sciatic nerve) should be prioritized on the basis of on anatomic issues, histologic subtype biologic features, and patient physiology.
  • Thorough preoperative planning is required to properly engage and prepare necessary subspecialists. RPS may require involvement of urology, vascular surgery, neurosurgery, and reconstructive surgery, in addition to a surgical oncologist with expertise in STS.
  • The surgical team must be familiar with the consequences of major neurovascular structure sacrifice and patients should be thoroughly counseled about potential functional loss prior to intervention.
  • Neoadjuvant chemotherapy or radiation therapy (RT) may be considered in patients with technically unresectable or borderline resectable disease. Intraoperative RT or brachytherapy are rarely useful.

Prognosis and follow-up for primary disease

For patients with intermediate- or high-grade sarcoma, the recommended follow-up schedule is as follows:

  • Risk of recurrence persists beyond 15-20 years, so patients should be followed indefinitely.
  • The median time to recurrence is less than 5 years; thus, more frequent imaging is indicated during this time frame.
  • Imaging and clinical follow-up for RPS is not strictly evidence based. A reasonable approach is to image patients every 3-6 months for the first 5 years after resection, and annually thereafter.
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