management of retroperitoneal sarcomas - uphs.upenn.edu · management of retroperitoneal sarcomas...

Management of Retroperitoneal Sarcomas

Giorgos C. Karakousis, M.D.Division of Endocrine and Oncologic Surgery

Department of SurgeryUniversity of Pennsylvania School of Medicine

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

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

Retroperitoneal sarcomas

Background

•Rare tumors accounting for <1% of solid malignancies (0.3-0.4%/100,000 incidence in population)

•Peak incidence in the 5th 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): 89-94.Mullinax et al. Cancer Control 2011; 18(3): 177-87

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


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


Role of BiopsyRetroperitoneal sarcomas

• Generally, percutaneous pre-operative biopsy is not recommended in patients with suspected retroperitoneal sarcomas (concern for peritoneal seeding)

• Indications for biopsy would include1) patients with radiologic findings more suspicious for lymphoma2) patients in which consideration is given to for pre-op systemic therapy or radiotherapy

Contraindications to biopsy

Courtesy of Dr. D.L. Fraker


paraganglioma

• Paragangliomas may look like lymphadenopathy and can release catecholamines with biopsy, and therefore biopsy should be avoided if suspected

Prognostic factors for RP sarcomas: NomogramRetroperitoneal sarcomas

• N=343 patients with resectable non-metastatic RP sarcomas

• 1996-2006 (MD Anderson)• Median f/u: 50 months• Median survival: 59 mo

Anaya, Pollock et al. Ann Oncology 2010; 21: 397-402.


Prognostic factors: Nomogram

• N=192 patients with resectable non-metastatic RP sarcomas

• 1985-2007 (Milan, Italy)• Median f/u 55 months

Ardoino, Gronchi et al. Cancer 2010; 116: 2429-36.

Prognostic factors for RP LiposarcomasRetroperitoneal sarcomas

• N=801 patients with resectable non-metastatic liposarcomas

• 1982-2005 (MSKCC)• Median f/u 45 months

Dalal, Singer et al. Ann Surg 2006; 244: 381-91.

Prognosis: Impact of focality in RP sarcomasRetroperitoneal sarcomas

• 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): 137-42.

N=393

Treatment

Surgery

Radiation Therapy

Systemic Therapy/Chemotherapy



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)


Surgery

• N=200 patients with retroperitoneal sarcomas (1990-2008) 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): 698-706.


Surgery- Royal Marsden Study

Strauss, Thomas et al. Br J Surg 2010; 97 (5): 698-706.

Surgery: Role of compartment resectionRetroperitoneal sarcomas

• 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.


Surgery: Role of compartment resection

Bonvalot et al. JCO 2009; 27 (1): 31-7.

3 year recurrence rate of 10% versus 50% with standard procedures; no difference in overall survival

Retroperitoneal sarcomas Compartment resection for RP sarcoma-controversy

• 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

Value of compartment resection questioned because:

Retroperitoneal sarcomas Surgery-Impact of High Volume Centers on Outcome• N=4205 cases

• Florida Cancer Data System (1981-2001)

• Included soft tissue sarcomas from various locations

Guitierrez et al. Ann Surg 2007; 245: 952-58.

Retroperitoneal sarcomas Surgery-Impact of High Volume Centers on Outcome

Guitierrez et al. Ann Surg 2007; 245: 952-58.

Low volume center found to be negative independent prognostic factor for survival in patients undergoing surgery for soft tissue sarcomas


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

Case presentation: Retroperitoneal liposarcomaRetroperitoneal sarcomas

• 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


Case presentation

• Removed with en bloc with right nephrectomy

• Specimen weighed 18.2 kg

• Final Pathology: 48 cm dedifferentiated liposarcoma

3 months post-op


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


Case presentation # 2• Removed en bloc with

prostate and bladder

• Ileal conduit diversion performed

• Malignant SFT 23.4 cm (resection margins negative)

Treatment

Surgery

Radiation Therapy




Radiotherapy

Mullinax et al. Cancer Control 2011; 18(3): 177-87

•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)


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


Radiotherapy



Radiotherapy-RCT of intra vs. post-op XRT

N=35 patients with resected RP sarcomas

N=15 Intra-op XRT 20 Gy

N=20 No Intra-op XRT

Post-op 35-40 Gy

Post-op high dose XRT (50-

55 GY)

IORT Post-opMedian Survival (mo) 45 52Loco-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): 402-10

• N=1535 patients from 1988-2004 (SEER database)

• 373 patients (23.3%) received XRT

• Median survival 60 months for both patients receiving and not receiving XRT


Radiotherapy-SEER analysis

Tseng et al. Jour Surg Res 2011; 168: 177-87



Overall

Stratified by Grade

High

Intermediate

Low





MFH Histology

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


Radiotherapy with Proton BeamRetroperitoneal sarcomas

• N=28 patients treated with IMRT or proton therapy at Massachusetts General Hospital

Yoon et al. Ann Surg Onc 2010; 17(6): 1515-29

Retroperitoneal sarcomas Radiotherapy with Proton Beam

Roberts Proton Therapy at Penn

Largest facility of its kind affiliated with academic center5 treatment roomsClinical protocol open for patients with RP sarcomas

Retroperitoneal sarcomas 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

Treatment

Surgery

Radiation Therapy




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 combination1

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: 103-12.


Systemic therapy by histologic subtype

Histologic Subtype Systemic Agent

GIST ImatinibDermatofibrosarcomaProtuberans (DFSP)

Imatinib

Angiosarcoma Paclitaxel, sorafenib, pazopanib

Leiomyosarcomas GemcitabineAlveolar soft part VEGF inhibitors

(cediranib or sunitinib)

Retroperitoneal sarcomas 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: 1013-20



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


Adjuvant chemotherapy: EORTC 62931 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


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


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


New Therapies

OlaratumabTrabectedinEribulinImmune checkpoint inhibitors

SarcomatosisRetroperitoneal sarcomas

• 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

Sarcomatosis and HIPEC/IPECRetroperitoneal sarcomas


Intraperitoneal chemotherapy for sarcomatosis-RCTRetroperitoneal sarcomas

No difference in overall survival, local relapse free and metastasis free survival between IPEC+ and IPEC- groupsNo difference between visceral and RP sarcoma groupsMorbidity 21%

Bonvalot et al. Eur J Surg Onc 2005; 31: 917-23.

IP chemotherapy for sarcomatosis: systematic reviewRetroperitoneal sarcomas

Median DFS 2.3 to 22 monthsMedian survival 5.5 to 39.6 monthsMorbidity 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: 207-213.

Metastatectomy for RP sarcomasRetroperitoneal 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

Resection of hepatic metastases for sarcomaRetroperitoneal sarcomas

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: 87-92.Zacherl et al. Langenbecks Arch Surg 2011; 396: 1083-1091.

Retroperitoneal sarcomas 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

: http://anatomytopics.wordpress.com

http://anatomytopics.wordpress.com/2008/12/25/25-the-abdominal-aorta-and-inferior-vena-cava-the-histology-of-the-pineal-body-differentiation-of-the-entoderm-folding-of-the-embryo/


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


• 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

Case Presentation #3: IVC tumor


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: 3877-81.

Retroperitoneal sarcomas 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: 185-90.

Retroperitoneal sarcomas 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

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


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


Conclusions

• Sarcomatosis carries a poor prognosis; cytoreductive surgery may be indicated in selected patients; Intra-peritoneal/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


Thank you for your attention

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