Retroperitoneal Sarcoma

Retroperitoneal sarcoma is a group of malignant mesenchymal tumours arising in the retroperitoneal space, outside the organs and bone. Management depends on histological subtype, grade and resectability, and complete surgery at an experienced centre is the only curative treatment.

It forms 10% to 15% of soft tissue sarcomas, with an incidence of about 2 to 3 cases in 1,000,000 people each year. Median age is 55 to 65. Tumours are large at diagnosis (median over 15 cm) because the space accommodates growth without symptoms.

Liposarcoma is commonest (50% to 60%, well differentiated and dedifferentiated), then leiomyosarcoma (about 20%), solitary fibrous tumour, undifferentiated pleomorphic sarcoma, malignant peripheral nerve sheath tumour and rarer types. Prior radiotherapy is an uncommon association.

Pathophysiology. Well differentiated and dedifferentiated liposarcomas carry MDM2 and CDK4 amplification. Leiomyosarcoma has a complex karyotype with TP53, RB1 and PTEN loss and expresses smooth muscle markers. Subtype and grade determine the pattern of failure.

Pattern of failure. Well differentiated and low grade dedifferentiated liposarcomas fail locally, with local recurrence of 40% to 80% at 10 years, and death results from uncontrolled local disease. Leiomyosarcoma and high grade dedifferentiated liposarcoma fail by distant metastasis (liver, lung) in 30% to 60%.

Prognosis. Five year survival is about 50% to 60% after complete resection. Grade (three tiers), histology, size, multifocality, completeness of resection and need for multivisceral resection are the main determinants.

• Many tumours are found incidentally on imaging.
• Abdominal distension, vague discomfort or pain, a palpable mass, early satiety, weight loss and change in bowel habit.
• Leg oedema or varicosities (vena cava compression), flank pain or hydronephrosis, femoral or sciatic neuropathy, and inguinal or scrotal swelling.
• Systemic symptoms and metastases are uncommon at presentation.

• CT of the abdomen and pelvis with intravenous contrast, and CT of the chest. MRI for pelvic tumours and vascular involvement.
• Percutaneous core biopsy through a retroperitoneal route (not through the peritoneal cavity), preferably by a coaxial technique, planned with the surgeon. It excludes lymphoma, germ cell tumour and gastrointestinal stromal tumour, and fixes histology before treatment.
• Pathology: MDM2 FISH, smooth muscle markers, STAT6, H3K27me3 and grade.
• Blood tests: AFP, beta-hCG and lactate dehydrogenase (germ cell tumour), plasma metanephrines when paraganglioma is possible, creatinine and eGFR.
• Split renal function (renography) when nephrectomy is anticipated.
• Echocardiography before anthracycline.

Differential diagnosis.

• Lymphoma and germ cell tumour
• Gastrointestinal stromal tumour
• Adrenal cortical carcinoma and paraganglioma
• Retroperitoneal fibrosis and desmoid type fibromatosis
• Lymph node metastases from a carcinoma
• Lipoma, angiomyolipoma and schwannoma
• Castleman disease

Surgery. En bloc compartmental resection by a specialist sarcoma team, with adjacent organs taken as needed (kidney, colon, psoas, adrenal gland, pancreas). Microscopically negative margins and avoidance of tumour rupture are the aims. Vascular reconstruction is done when the vena cava or iliac vessels are involved.

Radiotherapy. Preoperative 50.4 Gy in 28 fractions reduces abdominal recurrence in well differentiated and low grade dedifferentiated liposarcoma. Benefit is not shown for leiomyosarcoma or high grade dedifferentiated liposarcoma. Postoperative radiotherapy is not used for retroperitoneal disease because of toxicity to bowel and kidney.

Preoperative chemotherapy. Doxorubicin with ifosfamide for 3 cycles is considered for high grade leiomyosarcoma or high grade dedifferentiated liposarcoma in fit patients at a specialist centre. Evidence is limited.

Unresectable or metastatic disease.

• Doxorubicin:
  • 75 mg/m2 IV every 3 weeks for up to 6 cycles.
  • Maximum cumulative working ceiling 450 mg/m2.
  • Monitoring: echocardiography at baseline and every 2 cycles, FBC before each cycle.
  • Adjustment: bilirubin 20 to 51 micromol/L reduce by 50%, 53 to 85 micromol/L reduce by 75%, over 85 micromol/L avoid. Consider reduction when eGFR is under 30 mL/min/1.73 m2.
• Doxorubicin with ifosfamide:
  • Doxorubicin 75 mg/m2 total each cycle (25 mg/m2 daily on days 1 to 3) with ifosfamide 10 g/m2 total (2.5 g/m2 daily on days 1 to 4) IV.
  • Mesna at a total of 60% to 100% of the ifosfamide dose and pegfilgrastim 6 mg subcutaneously 24 to 72 hours after chemotherapy, every 3 weeks for up to 6 cycles.
  • Maximum doxorubicin cumulative working ceiling 450 mg/m2 and ifosfamide 10 g/m2 each cycle.
  • Monitoring: FBC, creatinine, urinalysis for haematuria, neurological status (ifosfamide encephalopathy), echocardiography.
  • Adjustment: avoid ifosfamide when eGFR is under 30 mL/min/1.73 m2 and reduce by about 25% to 50% when it is 30 to 59. Stop for grade 2 neurotoxicity. Reduce doxorubicin for hepatic impairment (bilirubin 20 to 51 micromol/L by 50%, 53 to 85 micromol/L by 75%, over 85 micromol/L avoid).
• Gemcitabine with docetaxel (leiomyosarcoma):
  • Gemcitabine 900 mg/m2 IV over 90 minutes on days 1 and 8 with docetaxel 75 mg/m2 IV on day 8, with pegfilgrastim 6 mg subcutaneously on day 9, every 21 days until progression.
  • Maximum gemcitabine 900 mg/m2 and docetaxel 75 mg/m2 each cycle.
  • Monitoring: FBC before each dose, liver tests, creatinine, pneumonitis, oedema.
  • Adjustment: do not give docetaxel when bilirubin exceeds the upper limit or AST or ALT exceeds 1.5 times the upper limit with alkaline phosphatase over 2.5 times. Reduce both agents by 25% for grade 3 to 4 toxicity. Caution when creatinine clearance is under 30 mL/min.
• Trabectedin (after anthracycline):
  • 1.5 mg/m2 IV over 24 hours through a central line every 3 weeks until progression or intolerance.
  • Maximum 1.5 mg/m2 each cycle.
  • Monitoring: ALT, AST, bilirubin, alkaline phosphatase and creatine kinase before each cycle, FBC, LVEF at baseline and every 2 to 3 months.
  • Premedication with dexamethasone 20 mg IV 30 minutes before.
  • Adjustment: do not give when bilirubin exceeds the upper limit. Hold for ALT or AST over 2.5 times the upper limit or creatine kinase over 5 times. Reduce to 0.9 mg/m2 in moderate hepatic impairment. Not studied when creatinine clearance is under 30 mL/min.
• Eribulin (liposarcoma, after anthracycline):
  • 1.4 mg/m2 IV over 2 to 5 minutes on days 1 and 8 of each 21-day cycle until progression.
  • Maximum 1.4 mg/m2 each dose.
  • Monitoring: FBC before each dose, ECG when there is heart failure, bradyarrhythmia or QT-prolonging medicines, neuropathy, liver tests.
  • Adjustment: 1.1 mg/m2 in mild hepatic impairment or when creatinine clearance is 30 to 50 mL/min, 0.7 mg/m2 in moderate hepatic impairment.
• Re-resection of local recurrence when complete resection is feasible, and resection or ablation of limited metastases.

Monitoring. CT of abdomen, pelvis and chest every 3 to 4 months for 2 to 3 years, then every 6 months to year 5, then annually. Lifelong follow up for well differentiated liposarcoma because recurrence continues beyond 10 years.

Referral and escalation.

• Sarcoma centre referral before biopsy or any operation.
• Urgent admission for bowel or ureteric obstruction, haemorrhage, vena cava thrombosis or febrile neutropenia.

Special groups.

• Renal impairment: confirm contralateral function before nephrectomy, and adjust chemotherapy doses.
• Older adults: assess frailty. Prefer surgery alone or single agent doxorubicin.
• Pregnancy: urgent multidisciplinary review, with surgery in the second trimester when needed and radiotherapy deferred.