Radiation Oncology/Sarcoma/Retroperitoneal sarcoma

Epidemiology

 * 10-15% of all soft tissue sarcomas
 * Median age at diagnosis is 6th decade (but wide range)
 * Most patients present with vague abdominal complaints
 * Tumors typically reach large size, with median diameter ~15 cm

Anatomy

 * 70% occur in abdomen, 30% occur in pelvis
 * 5% likelihood of regional nodal involvement

Retroperitoneal space
 * Potential space posterior to the abdomino-pelvic cavity
 * Superior border: diaphragm
 * Lateral borders: historically at lateral edge of quadratus lumborum, but lateral edge of 12th rib may be considered, since it corresponds to the origin of the transversus abdominous aponeurosis
 * Anterior border: parietal peritoneum
 * Posterior border: psoas, quadratus lumborum muscles in abdomen, iliacus and obturator internus and pyriformis in pelvis
 * Inferior border: pelvic diaphragm
 * Composed predominately of lymphatics and loose connective tissue
 * Retroperitoneal organs: pancreas, kidney, adrenal glands, ureters

Histology

 * Most common pathologies for retroperitoneal sarcoma are liposarcoma and leiomyosarcoma.
 * Most common pathology in children is rhabdomyosarcoma.
 * Tumor grade prognostic for development of distant mets, local recurrence, and decreased time to recurrence.

Staging
Retroperitoneal location is always deep
 * T1 - less than or equal to 5cm (T1a superficial, T1b deep);
 * T2 - greater than 5 cm (T2a superficial, T2b deep);
 * N1 - regional lymph node metastasis;
 * M1 - distant metastasis

AJCC 2002 Staging System
 * Stage I - All low grade, N0, M0
 * Stage II - T1a/b-T2a, N0, high grade
 * Stage III - T2b, N0, high grade
 * Stage IV - N1 or M1, any grade

Dutch/Memorial Sloan Kettering Classification System
 * Stage I - low grade, complete resection, no mets
 * Stage II - high grade, complete resection, no mets
 * Stage III - any grade, incomplete resection, no mets
 * Stage IV - distant mets

Treatment

 * Tumor grade is associated with recurrent and metastatic disease; most series using RT are in intermediate and high grade sarcoma
 * Complete resection is considered the standard treatment (typically en bloc resection of tumor + involved organs)
 * Radical lymphadenectomy generally indicated only if gross nodal involvement
 * However, <70% amenable to complete surgical resection. Positive surgical margins are associated with high local recurrence
 * Furthermore, ~50% of patients with GTR (R0 or R1) experience a recurrence, and overall local recurrence rates may be as high as 95% with sufficient follow-up
 * Locally recurrent disease is associated with lower likelihood of complete resection, and worse survival
 * Since most recurrences are local, there is an increasing interest in the role of RT, partly based on randomized data from extremity and trunk sarcoma and partly based on retrospective institutional series. Surgery alone probably results in 5-year LC <50% while addition of RT >50%
 * Pre-op RT has been proposed as superior to post-op RT due to good tumor volume definition, displacement of normal viscera by tumor, smaller treatment fields, and potential radiobiologic advantage of having normal vasculature/oxygenation in place
 * ACOSOG has an ongoing randomized trial exploring the benefit of pre-op RT
 * Several institutional reports shows improved outcomes for pre-op RT compared with historical controls. Typical dose has been 45-50 Gy, and >50% of patients required intraop or post-op RT boost. But despite aggressive multimodality therapy, local recurrences continue to be a problem, and overall survival is poor compared with extremity/trunk STS
 * For postop RT, evidence is weaker. Based on MD Anderson data (2007), dose should be <60 Gy
 * However, a multi-disciplinary discussion is warranted for most cases as surgical considerations and availability of intra-op RT etc. play a large role in determining whether pre-op or post-op RT is preferred. Pre-op RT has the benefits of potentially reducing bowel toxicity or improving surgical margin status. On the other hand, post-op fields may be preferred for wound healing concerns, confirmation of pathology, acute symptoms, and normal structures can at times be moved/shielded during surgery in anticipation of RT.

Preoperative Radiation
Result: Slow patient accrual, study closed early Unplanned interim analysis available: http://www.biomedcentral.com/1471-2407/14/617
 * ACOSOG Z9031 "A randomized trial of preoperative radiation plus surgery versus surgery alone for localized primary retroperitoneal soft tissue sarcoma"
 * Goal: accrue 370 pts in 4.5 yrs, primary outcome PFS at 5 yrs, closed in 2006. Awaiting results (as of 4/2010)


 * MD Anderson; 2007 PMID 17084545 -- "Retroperitoneal soft tissue sarcoma: an analysis of radiation and surgical treatment." (Ballo MT, Int J Radiat Oncol Biol Phys. 2007 Jan 1;67(1):158-63. Epub 2006 Nov 2.)
 * Retrospective. 83 patients (60 primary, 23 recurrent). Resection R0 in 47%. RT given in 98% (EBRT alone 76%, EBRT + IORT 22%; preop EBRT 60% median dose 50 Gy, postop EBRT median dose 55 Gy; median IORT dose 15 Gy). Median F/U 3.9 years
 * Outcome: Local recurrence 60%; DSS 44%
 * Subgroup: 5-year DSS: Low grade 92% vs intermediate grade 51% vs. high grade 41%. 5-year LC: SM- 62% vs SM+ 33%; primary 58% vs. recurrent 27%. No RT variables (higher dose or IORT) associated with outcome
 * Toxicity: 10% (moderate/severe 8%). Post-op RT 23% vs pre-op RT 0%. Median EBRT dose with complications 60 Gy


 * Toronto Sarcoma Group/MD Anderson; 2006 (1996-2002) PMID 16491338 -- "Long-term results of two prospective trials of preoperative external beam radiotherapy for localized intermediate- or high-grade retroperitoneal soft tissue sarcoma." (Pawlik TM, Ann Surg Oncol. 2006 Apr;13(4):508-17. Epub 2006 Feb 24.)
 * Two prospective trials. 72 patients, intermediate or high grade retroperitoneal sarcoma. 75% primary, 25% recurrent. Median tumor size 15 cm. Preop RT (median dose 45 Gy). All patients at MD Anderson received concurrent low dose doxorubicin. 89% underwent laparotomy with curative intent 4-8 weeks after RT. Intraop or postop RT boost 60%. Median F/U 3.4 years
 * Outcome: GTR 95% (R0 or R1). If GTR, 52% recurrence rate. 5-year LRFS 60%, DFS 46%, OS 61%
 * Conclusion: Outcomes compare favorably with historical data for patients treated


 * MD Anderson; 2003 PMID 12915599 -- "Phase I trial of preoperative concurrent doxorubicin and radiation therapy, surgical resection, and intraoperative electron-beam radiation therapy for patients with localized retroperitoneal sarcoma." (Pisters PW, J Clin Oncol. 2003 Aug 15;21(16):3092-7.)
 * Phase I. 35 patients, potentially resectable, intermediate or high grade retroperitoneal sarcoma. Doxorubicin QW with concurrent RT. Dose escalation 18/10, 30.6/17, 36/20, 41.4/23, 46.8/26, 50.4/28. Then intra-op RT 15 Gy if R0 or R1 resection
 * Outcome: Total laparotomy in 83%. GTR (R0 or R1) in 90%
 * Toxicity: Chemo-RT completed as outpatient in 89%, at 50.4 dose level 18% Grade 3-4 nausea.
 * Outcome: Preop EBRT can be administered to 50.4 Gy with C.I. doxorubicin


 * Princess Margaret; 2002 PMID 11986186 "Initial results of a trial of preoperative external-beam radiation therapy and postoperative brachytherapy for retroperitoneal sarcoma." Ann Surg Oncol, 2002; 9(4): 346-54
 * 55 pts w/ untx'd retroperitoneal sarcoma, 46/55 had complete resection. 41 received preop xrt (45 Gy), 23 received postop brachy.
 * All pts had grade 2 acute toxicity or below. 2 pts died from late toxicity.  2yr OS was 88%, DFS 80%

Intraoperative Radiation

 * Mayo Clinic; 2002 PMID 11872294 "Use of intraoperative electron beam radiotherapy in the management of retroperitoneal soft tissue sarcomas." Int J of Radiat Oncol Biol Phys, 2002; 52(2): 469-75
 * 87 pts (primary or recurrent), median size 10 cm; all received max surgical resection, preop xrt (median 48.6 Gy), IOERT (median 15 Gy)
 * 5 yr OS affected by size >10cm (28% vs 60%), amt of residual tumor (37% gross residual, 52% microscopic or no residual). No diff b/w primary vs recurrent.  Local control 77% at 3yrs, 59% at 5 yrs.  Local control affected by amt of residual dz (41% gross, 60% microscopic, 100% no residual).  12 pts w/ grade 3 toxicity.


 * Mass General Hospital; 2001 PMID 11316555. "Long-term results of intraoperative electron beam radiotherapy for primary and recurrent retroperitoneal soft tissue sarcoma."  Int J Radiat Oncol Biol Phys, 2001; 50(1): 127-31.
 * 29 pts, 16 tx'd w/ IORT, 13 tx'd w/o IORT. IORT consisted of 10-20 Gy delivered via intraop electrons.  All pts received 45 Gy external beam.
 * Local control improved w/ IORT (83% vs 61%).


 * NCI -- Intraop RT + postop RT vs. Postop RT alone
 * Randomized. 35 patients, surgically resected retroperitoneal sarcoma. Arm 1) IORT 20 Gy + Post op EBRT 35-40 Gy vs. Arm 2) Post op EBRT 50-55 Gy. Chemotherapy doxorubicin, cyclophosphamide, MTX.
 * 1993 PMID 8457152 -- "Intraoperative radiotherapy in retroperitoneal sarcomas. Final results of a prospective, randomized, clinical trial." (Sindelar WF, Arch Surg. 1993 Apr;128(4):402-10.) Minimum F/U 5 years
 * Outcome: Median OS IORT 3.7 years vs PORT 4.3 years (NS). Local failure IORT 40% vs. PORT 80%
 * Complications: radiation enteritis IORT 13% vs. PORT 50%, peripheral neuropathy 60% vs. 5%
 * Conclusion: No survival benefit, improved local control with IORT

Adjuvant Radiation

 * University of Florida; 2005 (1974-2003) PMID 15923806 -- "Adjuvant radiation therapy for resectable retroperitoneal soft tissue sarcoma: the University of Florida experience." (Zlotecki RA, Am J Clin Oncol. 2005 Jun;28(3):310-6.)
 * Retrospective. 50 patients treated with surgery + RT (pre-op 38%, post-op 62%). Pre-op 50.4/42 BID @ 1.2 Gy/fx; post-op RT <50 Gy in 1.8 Gy/fx
 * Outcome: 5-year OS SM- 69% vs. SM+ 12% (SS); low grade 77% vs. high grade 34% (SS). Local recurrent pre-op 16% vs. post-op 47% (NS)
 * Toxicity: Post-op RT more frequent complications, though none severe
 * Conclusion: RT appears to improve probability of local control. Pre-op Rt may be preferred


 * French Federation Cancer Sarcoma Group; 2001 (1980-1994) PMID 11466691 "Prognostic factors in retroperitoneal sarcoma: a multivariate analysis of a series of 165 patients of the French Cancer Center Federation Sarcoma Group." (Stoeckle E, Cancer, 2001; 92(2): 359-68.)
 * Retrospective. 145 patients, localized non-metastatic retroperitoneal sarcoma. Median size 15 cm. Liposarcoma/LMS/MFS in 66%. Intermediate/high grade 84%. GTR 65%, post-op RT 41% (50 Gy median dose). Median F/U 3.9 years
 * Outcome: 5-year OS 46%. LRC RT 55% vs surgery alone 23%
 * Conclusion: Randomized trial needed to evaluate place of RT for local control


 * Wayne State; 2002 PMID 12243830 "Long-term outcome of combined modality therapy in retroperitoneal and deep-trunk soft-tissue sarcoma: analysis of prognostic factors." Int J Radiat Oncol Biol Phys, 2002; 54(2): 514-9
 * 60 pts, non-metastatic retroperitoneal sarcoma; all tx'd w/ combined surgery + xrt. Xrt was either given w/ EBRT alone (median 52.2 Gy) or EBRT + brachy boost (42 Gy EB + 16 Gy brachy).
 * 5yr DFS 53%, 10yr DFS 44%. 5yr local control 71%, 10yr 54%.  Margin status significantly correlated w/ local control.
 * Conclusion: margin status and local control very important for RP sarcoma long term outcome.


 * Memorial Sloan Kettering; 1997 (1982-1990) PMID 9256126 -- "Prognostic factors associated with long-term survival for retroperitoneal sarcoma: implications for management." (Heslin MJ, J Clin Oncol. 1997 Aug;15(8):2832-9.)
 * Retrospective. 198 patients with RPSTS
 * Outcome: Recurrence rate 5% per year. Of patients disease-free at 5 years, 40% recurred by 10 years. RT only predictor for low risk of local recurrence. Age <=50 and high grade predictors for distant mets
 * Conclusion: Complete surgical resection necessary; 5-year DFS is not a cure

Treatment Technique

 * Gasthuisberg (Belgium); 2007 (2000-2005) PMID 17084556 -- "Intensity modulated radiation-therapy for preoperative posterior abdominal wall irradiation of retroperitoneal liposarcomas." (Bossi A, Int J Radiat Oncol Biol Phys. 2007 Jan 1;67(1):164-70.)
 * Prospective. 18 patients with RPLS. Pre-op IMRT 50/25. CTV limited to posterior abdominal wall only; planning comparison to standard CTV
 * Outcome: All successfully completed RT and surgery. 2 local recurrences, 1 within high dose region and one marginal which would not have been well covered by standard CTV either
 * Conclusion: Limited CTV to posterior abdominal wall is feasible


 * Emory; 2003 PMID 18521378 -- "Intensity modulated radiation therapy for retroperitoneal sarcoma: a case for dose escalation and organ at risk toxicity reduction." (Koshy M, Sarcoma. 2003;7(3-4):137-48.)
 * Retrospective. 10 patients with RPS and 1 inguinal sarcoma. Prescription 50.4 Gy. Comparison of 3D-CRT and IMRT
 * Outcome: Significantly better dosimetry with IMRT
 * Conclusion: IMRT allowed enhanced tumor coverage and better sparing of organs at risk