Management of Retroperitoneal Sarcomas
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1 Management of Retroperitoneal Sarcomas Giorgos C. Karakousis, M.D. Division of Endocrine and Oncologic Surgery Department of Surgery University of Pennsylvania School of Medicine
2 Sarcomas General Background Rare tumors accounting for approximately 1% of malignancies in adults; 15% pediatric population Over 50 different histologic subtypes Approximately 50% occur in extremities Most common histologic subtype in adults in liposarcoma Staging is TNGM Stage I: localized low grade tumors; Stage II: localized intermediate grade tumors or high grade tumors small and superficial; Stage III: high grade > 5 cm; Stage IV metastatic disease
3 Sarcomas General Background Core biopsies are reasonable for extremity sarcomas over 2 cm Larger extremity sarcomas can be biopsied with incisional biopsy (longitudinal) Pre-operative evaluation includes cross-sectional imaging and chest imaging (CT scan for higher risk lesions) Most common histologic subtype in adults in liposarcoma Mainstay of treatment is surgical
4 Background Rare tumors accounting for <1% of solid malignancies ( %/100,000 incidence in population) Peak incidence in the 5 th decade of life Account for about 10-20% of sarcomas by location Most common histologic subtypes historically have been liposarcoma, MFH*, and leiomyosarcomas, although many MFH histologies are being reclassified Frequently, these tumors present late or are discovered incidentally Francis, Sondak et al. Cancer Imaging 2005; 5 (1): Mullinax et al. Cancer Control 2011; 18(3):
5 Presentation and diagnosis Often asymptomatic Patients may present with vague abdominal symptoms or abdominal and/or back pain Occasionally, patients may present with GI or ureteral obstructive symptoms, muscle wasting with increasing abdominal girth or palpable abdominal mass Cross-sectional imaging (CT/MRI) can identify the lesion and its anatomic relationship to other structures High resolution, thin-cut CT can usually differentiate between primary a primary visceral retroperitoneal tumor, metastatic lymphadenopathy and a suspected sarcoma
6 Differential Diagnosis Lymphoma Primary tumor of retroperitoneal organ (eg pancreas, renal, adrenal) Metastatic lymphadenopathy (including testicular origin) Clinical symptoms/signs may sometimes be helpful in distinguishing etiology
7 Role of Biopsy Generally, percutaneous pre-operative biopsy is not recommended in patients with suspected retroperitoneal sarcomas (concern for peritoneal seeding) Indications for biopsy would include 1) patients with radiologic findings more suspicious for lymphoma 2) patients in which consideration is given to for pre-op systemic therapy or radiotherapy
8 Contraindications to biopsy Paragangliomas may look like lymphadenopathy and can release catecholamines with biopsy, and therefore biopsy should be avoided if suspected paraganglioma Courtesy of Dr. D.L. Fraker
9 Prognostic factors for RP sarcomas: Nomogram N=343 patients with resectable non-metastatic RP sarcomas (MD Anderson) Median f/u: 50 months Median survival: 59 mo Anaya, Pollock et al. Ann Oncology 2010; 21:
10 Prognostic factors: Nomogram N=192 patients with resectable non-metastatic RP sarcomas (Milan, Italy) Median f/u 55 months Ardoino, Gronchi et al. Cancer 2010; 116:
11 Prognostic factors for RP Liposarcomas N=801 patients with resectable non-metastatic liposarcomas (MSKCC) Median f/u 45 months Dalal, Singer et al. Ann Surg 2006; 244:
12 Prognosis: Impact of focality in RP sarcomas N=393 Unifocality associated with significantly improved survival compared to multifocality (31% versus 60% 5 yr survival) Well-differentiated histology (ALT) associated with improved survival > 7 lesions associated with poor prognosis Anaya, Pollock et al. Ann Surg 2009; 249 (1):
13 Treatment Surgery Radiation Therapy Systemic Therapy/Chemotherapy
14 Surgery Surgery when feasible remains the mainstay of curative treatment in patients with retroperitoneal sarcomas Gross resection of the tumor with negative margins (with resection of adjacent involved structures when feasible) is recommended Most common organs resected en bloc with specimen (kidney, colon, distal pancreas/spleen) Less commonly resected organs/structures (aorta/iliac arteries; IVC for primary IVC sarcomas)
15 Surgery N=200 patients with retroperitoneal sarcomas ( ) from Royal Marsden Complete resection in 170 patients (85%) Adjacent organ resection in N=126 patients (63%) or 75% with complete resection (36% kidney, 22% colon, 14% spleen) Post-operative mortality 3% Strauss, Thomas et al. Br J Surg 2010; 97 (5):
16 Surgery- Royal Marsden Study Strauss, Thomas et al. Br J Surg 2010; 97 (5):
17 Surgery: Role of compartment resection N=382 patients from the French sarcoma group 3 and 5-year survival was 66% and 57% respectively Median survival 6 years 120 patient underwent compartment resection beyond standard resection of gross tumor with adjacent organs Bonvalot et al. JCO 2009; 27 (1): 31-7.
18 Surgery: Role of compartment resection 3 year recurrence rate of 10% versus 50% with standard procedures; no difference in overall survival Bonvalot et al. JCO 2009; 27 (1): 31-7.
19 Compartment resection for RP sarcoma-controversy Value of compartment resection questioned because: Inherent selection bias in which patients can undergo a compartment resection (anatomic limitations eg sarcomas near the aorta or spine) No overall survival benefit observed although compartment resection associated with decreased local recurrence rate Surgeries performed over a long time period introducing potential other confounding variables in different technique methodologies Morbidity/mortality not insignificant: 16% surgical morbidity (50% of those requiring re-operation; mortality 4%) in Bonvalot study
20 Surgery-Impact of High Volume Centers on Outcome N=4205 cases Florida Cancer Data System ( ) Included soft tissue sarcomas from various locations Guitierrez et al. Ann Surg 2007; 245:
21 Surgery-Impact of High Volume Centers on Outcome Low volume center found to be negative independent prognostic factor for survival in patients undergoing surgery for soft tissue sarcomas Guitierrez et al. Ann Surg 2007; 245:
22 Case presentation 55 year male with increasing abdominal girth for 2 years Advised by primary care physician to go on diet; continued to lose muscle mass despite increasing abdominal girth Admitted urgently from clinic with dyspnea from diaphragmatic compression
23 Case presentation: Retroperitoneal liposarcoma Large retroperitoneal sarcoma extending from the liver to the pelvis displacing right sided structures to the midline R kidney (not visualized in nearly midline location with right renal artery nearly vertical (from posterior to anterior) Massive retroperitoneal sarcoma
24 Case presentation Removed with en bloc with right nephrectomy Specimen weighed 18.2 kg Final Pathology: 48 cm dedifferentiated liposarcoma 3 months post-op
25 Case presentation # 2 75 M presented with urinary retention Cross-sectional imaging revealed a large pelvic mass (17 cm) involving the prostate and seminal vesicles Compression of the distal R ureter with R hydronephrosis Invasion of the bladder base
26 Case presentation # 2 Removed en bloc with prostate and bladder Ileal conduit diversion performed Malignant SFT 23.4 cm (resection margins negative)
27 Treatment Surgery Radiation Therapy Systemic Therapy/Chemotherapy
28 Radiotherapy No Level I data on value of radiation therapy in retroperitoneal sarcomas so data largely extrapolated from studies with extremity sarcomas The benefit of XRT on survival in sarcomas has not been shown Decision for pre-operative versus post-operative therapy should consider resectability of tumor keeping in mind however no benefit of survival shown in studies with neo-adjuvant versus adjuvant XRT in patients with sarcoma, but higher incidence of wound complications in the neo-adjuvant group Special consideration must be given to radiotherapy (lower doses) compared to extremity soft-tissue sarcomas because of potential toxicity to adjacent organs (bowel) Mullinax et al. Cancer Control 2011; 18(3):
29 Radiotherapy-Rationale for pre-operative therapy Smaller radiation field when tumor is in situ Tumor serves as a tissue expander thereby displacing viscera and minimizing toxicity to the bowel Tumor periphery is better oxygenated and therefore more radiosensitive
30 Radiotherapy Mullinax et al. Cancer Control 2011; 18(3):
31 Radiotherapy-RCT of intra vs. post-op XRT N=15 Intra-op XRT 20 Gy Post-op Gy N=35 patients with resected RP sarcomas N=20 No Intra-op XRT Post-op high dose XRT (50-55 GY) IORT Post-op Median Survival (mo) Loco-regional relapse 40% (6/15) 80% (16/20) Radiation enteritis 13% (2/15) 50% (10/20) Peripheral/femoral neuropathy 60% (9/15) 5% (1/20) Sindelar,Glatstein et al. Arch Surg 1993; 128 (4):
32 Radiotherapy-SEER analysis N=1535 patients from (SEER database) 373 patients (23.3%) received XRT Median survival 60 months for both patients receiving and not receiving XRT Tseng et al. Jour Surg Res 2011; 168:
33 Radiotherapy-SEER analysis Overall Stratified by Grade High Low Intermediate Tseng et al. Jour Surg Res 2011; 168:
34 Radiotherapy-SEER analysis MFH Histology Tseng et al. Jour Surg Res 2011; 168:
35 Radiotherapy with Proton Beam Use of protons to deliver ionizing radiation Principal advantage is to provide more targeted treatment with less collateral toxicity Due to relatively large particle mass, protons have little lateral scatter and therefore can be used for more focused radiation; tissues also deeper to the planned treatment field also receive little radiation
36 Radiotherapy with Proton Beam N=28 patients treated with IMRT or proton therapy at Massachusetts General Hospital Yoon et al. Ann Surg Onc 2010; 17(6):
37 Radiotherapy with Proton Beam Roberts Proton Therapy at Penn Largest facility of its kind affiliated with academic center 5 treatment rooms Clinical protocol open for patients with RP sarcomas
38 Radiotherapy with Proton Beam Potential advantages of Proton therapy: Less radiation to normal tissue Treating tumors near critical organs (eg spinal cord) Ability to retreat tumors that have already been irradiated Clinical trial at University of Pennsylvania: First Phase: Safety and feasibility of the approach with protons Second phase: Use of proton therapy in the neoadjuvant and adjuvant setting
39 Treatment Surgery Radiation Therapy Systemic Therapy/Chemotherapy
40 Chemotherapy Response rates of approximately 25-25% for STS Most series report on use of doxorubicin based regimen (with or without ifosfamide) or with other combinations Meta-analysis of randomized trials comparing doxorubicin to doxorubicin with other chemotherapeutics show no statistically significant survival benefit but with increased adverse effect to the combination 1 More and more, there is increasing awareness of differential responsiveness of different histologic subtypes of sarcoma to various chemotherapeutics Bramwell et al. Sarcoma 2000; 4:
41 Systemic therapy by histologic subtype Histologic Subtype GIST Dermatofibrosarcoma Protuberans (DFSP) Angiosarcoma Leiomyosarcomas Alveolar soft part Systemic Agent Imatinib Imatinib Paclitaxel, sorafenib, pazopanib Gemcitabine VEGF inhibitors (cediranib or sunitinib)
42 Adjuvant chemotherapy: Randomized controlled trials A few trials demonstrated improved overall survival (OS) with adjuvant chemotherapy HOWEVER, Meta-analysis of these trials showed significantly lower local or metastatic relapse rates but no significant difference in OS with adjuvant chemotherapy (4% at 10 years) Blay et al. Oncologist 2009; 14:
43 Chemotherapy Data include patients with extremity soft tissue sarcomas Little data in subgroup of patients with RP sarcomas Frustaci trial showed initially showed improved OS, with adjuvant chemotherapy for high risk extremity sarcomas but difference was lost with longer follow-up Mullinax et al. Cancer Control 2011; 18(3):
44 Adjuvant chemotherapy: EORTC trial European Organization for Research and Treatment of Cancer (EORTC 62931) Soft Tissue and Bone Sarcoma Group (STBSG) reported on largest adjuvant trial of chemotherapy (Dox+Ifos) for sarcoma at ASCO meeting in 2007 N=351 patients with localized (primary or local recurrence) with grade II (43%) or III Adjuvant XRT for microscopic residual disease, inadequate margins and local recurrence Patients randomized within 4 weeks of surgery This trial failed to demonstrate any significant difference in relapse-free or overall survival (69% OS control arm versus 64% in treatment arm) Woll et al. Proc A, Soc Clin Oncol 2007; 25 (3): 546s
45 Adjuvant chemotherapy: Pooled EORTC trials N=819 patients pooled from the two EORTC trials Median follow-up 8.2 years Large tumor size, histologic grade and R1 resection were independent negative prognostic factors for progression-free and overall survival Adjuvant chemotherapy was an independent prognostic factor for progression-free (PFS) but not overall survival (OS) Patients> 40 years had better PFS in adjuvant chemotherapy arm; adjuvant chemotherapy associated with marginally worse OS in patients <40 years Patients with R1 resection had better PFS and OS in adjuvant chemotherapy arm
46 Adjuvant Chemotherapy: Reasons for Failure Soft tissue sarcomas, because of their rarity, are frequently grouped together in clinical trials despite varying histology and tumor biology Surgical resection is variable depending upon the experience for the surgeons in various participating centers Patient factors (eg advanced age, gender) may influence responsiveness to chemotherapy; therefore sub-groups of patients who may benefit from systemic therapy may not be appreciated in unselected populations in clinical trials
47 New Therapies Olaratumab Trabectedin Eribulin Immune checkpoint inhibitors
48 Sarcomatosis Condition characterized by the presence of multiple sarcomas in the peritoneal cavity Frequently not amenable to surgical resection Poor overall prognosis with median survival of approximately 12 months
49 Sarcomatosis and HIPEC/IPEC Mullinax et al. Cancer Control 2011; 18(3):
50 Intraperitoneal chemotherapy for sarcomatosis-rct No difference in overall survival, local relapse free and metastasis free survival between IPEC+ and IPEC- groups No difference between visceral and RP sarcoma groups Morbidity 21% Bonvalot et al. Eur J Surg Onc 2005; 31:
51 IP chemotherapy for sarcomatosis: systematic review Median DFS 2.3 to 22 months Median survival 5.5 to 39.6 months Morbidity 9% to 44% Mortality 0% to 11% Data at present does not support the use of intraperitoneal chemo for sarcomatosis Munene, Temple et al. AnnSurg Onc 2011; 18:
52 Metastatectomy for RP sarcomas Extrapolating from extremity soft tissue sarcomas, metastatectomy is associated with improved outcomes with reported 5 year survival rates of 25-40% in selected patients from pulmonary metastatectomy Disease free interval, number of metastase, complete resection, and grade of primary tumor are all factors associated with better prognosis in metastatectomy Resection of liver metastases historically was associated with poor outcomes
53 Resection of hepatic metastases for sarcoma Recent literature reporting 5 year survival rates as high as 27-32% following resection of liver metastases Disease free interval, and size of metastases, histologic subtype have been shown to be negative prognostic factors Study results confounded by the inclusion of GIST tumors for which imatinib therapy has significantly impacted on outcomes Marudanayagam et al. Eur J Surg Onc 2011; 37: Zacherl et al. Langenbecks Arch Surg 2011; 396:
54 Primary Tumors of the IVC (Leiomyosarcomas) Arise from the smooth muscle cells of the vena cava Frequently slow growing Frequently limited to the vena cava and can grow intra-or extraluminally :
55 Case Presentation #3: IVC tumor 75 M presented with leg swelling after a boating accident Initially felt to have thrombus in IVC MRI showed enhancement of the lesion suggesting primary IVC sarcoma
56 Case Presentation #3: IVC tumor Patient placed on veno-veno bypass Vena cava resected with R nephrectomy (tumor was invading into right renal vein) Homograft was used to reconstruct the IVC (vascular surgery) Final pathology: 4.3 cm high grade leiomyosarcoma
57 IVC tumors: extent of local resection 120 patients were analyzed in the International Registry of IVC leiomyosarcomas 44% went caval rim resection and 56% underwent segmental caval resection No difference in local or distant metastases or overall survival between the two groups with varying degree of resection 57.3% patients recurred at a median follow-up of 32 months Mortality 2.5% and morbidity 5.8% Mingoli et al. Anticancer research 2011; 17:
58 IVC (Leiomyosarcomas) Recent study suggest IVC caval resection may frequently not be necessary; transient lower extremity edema observed (50%) with no long term sequelae Role of preoperative XRT? Daylami et al. JACS 2011; 210:
59 IVC (Leiomyosarcomas) These tumors should be resected with margin negative resection More extensive caval resections do not appear necessary and may increase the morbidity Caval reconstruction may frequently be avoided with few long-term sequelae
60 Final conclusions Diagnosis of retroperitoneal sarcomas should generally be made on radiographic findings and biopsy should be avoided Complete surgical resection with gross negative margins remains the mainstay of treatment Data for neoadjuvant systemic therapy (chemotherapy) are limited No substantial data to support the routine use of adjuvant doxorubicin based chemotherapy after resection Future systemic therapy trials should acknowledge the tremendous variability among different histologic subtypes
61 Conclusions No level I evidence for the use of radiotherapy for RP sarcomas extrapolation can be made from extremity sarcoma studies Recurrent disease should be managed surgically when feasible with intent of negative margin resection or palliation (when complete resection not feasible), taking into account factors such as location and number of recurrences, disease free interval, tumor grade and patient factors
62 Conclusions Sarcomatosis carries a poor prognosis; cytoreductive surgery may be indicated in selected patients; Intraperitoneal/Chemotherapy/HIPEC does not appear to improve outcomes Sarcoma surgery should be managed at high volume centers by experienced surgeons Primary IVC caval tumors present unique challenges; limited caval resection with negative margin is recommended reconstruction may often be avoided
63 Thank you for your attention
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