# Radiation Oncology/Sarcoma/Treatment

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
Soft Tissue Sarcoma Treatment Approaches

## Treatment Overview

* Surgery is the primary treatment modality. Historically, patients would undergo amputation for extremity sarcomas
* NCI randomized study demonstrated that high grade lesions could be treated with limb-sparing surgery with concurrent adjuvant chemo-RT; rates of amputation fell to <10% as postop RT became widely used after limb-sparing surgery
* NCI trial evaluated the need for postop EBRT, and found a significant local control benefit but no impact on disease-specific or overall survival
* Similarly, Memorial Sloan Kettering trial found significant local control benefit for postop brachytherapy in high grade lesions (but no local control benefit in low grade lesions), though no impact on disease-specific or overall survival
* Preop RT was advocated for large lesions and high grade tumors, in order to downstage tumor, decrease treatment fields, and allow easier treatment planning. Postop RT was compared to preop RT, and there was no difference in local control or overall survival. However, acute toxicity was worse with preop RT while late toxicity and function was worse with postop RT. A meta-analysis also including 4 retrospective series concluded that local control is better after preop RT, without adversely impacting survival
* Large (>=8 cm) high grade tumors continue to show very high rates of distal failure. Harvard prospective study interdigitating chemotherapy-RT-chemotherapy-RT-chemotherapy prior to surgery showed very good outcomes compared to historical controls. However, a follow-up Phase II RTOG trial (95-14) with more intense chemo was judged to be too toxic for clinical use
* to be continued ...

## Surgery alone

* Historically amputation for extremity, then full compartment resection, now en-bloc resection with ~2 cm margin. Skin and bone need to resected only rarely, as most STS do not initially invade them
* Amputation now reserved for otherwise unresectable tumors, no metastatic disease, and the potential for good long-term functional rehabilitation (e.g. large, low-grade tumors severe cosmetic and/or functional deformity)
* Local recurrence
** 90% after simple excision, 39% after wide excision, 25% after soft-part excision, 7-18% after amputation
** LR has minimal impact on overall survival, which is primarily driven by development of metastatic disease
** Since LR is dependent on size, tumors >5 cm should be referred for discussion of RT

## RT alone

Local recurrence 66% and 2-year DFS 17% (PMID 4203021).
5yLC 45% DFS 24% OS 35%. Median 64Gy (24-82.5Gy). Better LC, DFS, OS with >63Gy. n=112. 43% Extremities, 26% retroperitoneal, 24% head and neck, 7% truncal wall. Massachusetts General Hospital experience of unresected sarcoma receiving RT alone. (PMID: 16199316)

## Amputation vs Limb-Sparing Surgery + Postop Chemo-RT
### Randomized

* National Cancer Institute (1975-1981) -- amputation vs limb-sparing surgery + posto-op Chemo-RT
** Randomized. 43 patients with high grade soft tissue sarcomas of the extremities, without distant mets or LN. Randomized to Arm 1) amputation at the joint proximal to the tumor or Arm 2) limb-sparing resection (wide local excision with several cm of normal tissue, SM+ allowed at critical structures) + postop RT. Randomization 2:1 (limb-sparing vs amp). RT 45-50 Gy followed by a boost to 60-70 Gy. All pts received post-op adriamycin + cytoxan (which was concurrent for those in the RT arm) then high-dose methotrexate. Chemo doses were: ADR (max 70 mg/m^2), CYC (max 700 mg/m^2), MTX (250 mg/kg). SM+ in limb salvage 15% vs amputation 0%
** 1982 PMID 7114936 — "The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy." (Rosenberg SA et al. Ann Surg. 1982 Sep;196(3):305-15.) Median F/U 4.8 years
*** Outcome: Local failure limb-sparing 15% vs amputation 0% (p=0.06); of the 4 LRs, 1 was isolated and 3 combined with DM. 5-year DFS 71% vs 78% (NS); 5-year OS 83% vs 88% (NS)
*** Conclusion: Limb-sparing surgery + postop RT is an effective treatment for most patients

### Retrospective

* MD Anderson; 1981 (1963-77) - PMID 7272893 — "Conservative surgery and postoperative radiotherapy in 300 adults with soft-tissue sarcomas." (Lindberg RD et al. Cancer. 1981 May 15;47(10):2391-7. )
** Retrospective. 300 patients. All gross tumor removed by conservative surgical excision (no attempt at wide margins). Patients received post-operative XRT to tumor bed after healing complete. Excluded pts with < 50 Gy and with sarcoma of organ sites like the uterus. 68 pts required second surgery for residual gross tumor. XRT started when healing complete, usu. 3-4 weeks after surgery. Field included surgical bed + 5-7cm margin. Dose prior to Sept 1971 was 70-75 Gy with reduced fields after 50 Gy. After Sept 1971, used 60 Gy for low grade and 65-70 Gy for intermediate and high grade.
** Minimum 2 yr follow-up. 137 lower extremity, 63 upper ext, 74 trunk, 26 H&N. 2-yr overall survival 74%, 5-year 61%. 7% died with primary site failure; 18% died with distant mets. 5-year DFS 61% for all, 69% for extremity, 74% for upper ext, 33% for abdomen.
** Local recurrences: LF is 22% (worse for abdomen at 38% and better for UE at 16%). More than half of local recurrences within first 2 years, but continue up to 5 years. 32 of 40 LR in extremities were controlled by surgery. Similar rate of LR for 60 Gy vs 70 Gy. By histology, fewer local recurrences (in lower extremity) for liposarcoma (3.6%) and more for neurofibrosarcoma (50%). 12 of 40 local recurrences in the extremities were outside of the radiation field (geographic miss). By grade, significant difference in local failure for small lesions (<5 cm) between Grade 1 (6%) vs Grade 2 (10%) vs Grade 3 (31%). Size is a factor for Grade 2 lesions for tumors < 5 cm (10% LF) vs tumors 5-8cm (30% LF), but size does not matter for Grade 3 lesions.
** Lymph node metastases: infrequent, 2.7%.
** Distant metastases: 27% developed DM; 80% to lung. DM appear earlier than LF. Similar to with LF, worse for abdomen and better for UE. By histology, higher DM frequency in neurofibrosarcoma than liposarcoma and fibrosarcoma. By grade and size, higher for lesions > 5 cm.
** Disease free survival: correlates with grade and size. Fibrosarcoma and liposarcoma have the best survival; neurofibrosarcoma has the worst. Grade 2 lesions < 5 cm have similar prognosis to grade 1 lesions.
** Complications, except for fibrosis, infrequent at 6.5%.
** Conclusion: Limb-sparing treatment with good outcome is possible using post-operative XRT. Limb preservation rate 84%. Has similar survival and local recurrence to surgical series. Do not recommend elective treatment of the lymph nodes.
** Comment: This was one of the studies that gave impetus to the NCI randomized trial of amputation vs limb-sparing + RT

## Surgery + Postop EBRT vs Surgery Alone
### Randomized

* National Cancer Institute (1983-1991) -- RT (or chemo-RT) vs observation (or chemo)
** Randomized. 141 patients with extremity sarcoma (allowed desmoid and DFSP). Limb-sparing surgery, allowed SM+. High-grade (n=91) randomized to Arm 1) Postop RT 63 Gy with concurrent chemo (doxorubicin + cyclophosphamide) x5 cycles vs Arm 2) Chemo alone. Low-grade (n=50) randomized to Arm 1) Same RT without chemo vs Arm 2) observation
** 1998 PMID 9440743 — "Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity." (Yang JC et al. J Clin Oncol. 1998 Jan;16(1):197-203.) Median F/U 9.6 years
*** High grade: local recurrence chemo-RT 0% vs chemo 19% (SS); 10-year DSS (NS), 10-year OS 75% vs 74% (NS)
*** Low grade tumors: local recurrence RT 4% vs observation 33% (SS); 10-year OS (NS)
*** Toxicity: Decreased muscle strength, joint motion, and worse edema. Little effect on overall satisfaction and daily activities.
*** Conclusions: Postop RT highly effective at preventing local recurrence, though select patients with low risk of LR may not require adjuvant RT

### Retrospective

* U Maryland SEER Analysis (1988-2005) PMID 19679403 — "Improved Survival With Radiation Therapy in High-Grade Soft Tissue Sarcomas of the Extremities: a SEER Analysis" (Koshy M Int J Radiat Oncol Biol Phys. 2010 May 1;77(1):203-9)
** 6,960 pts, 47% received RT; majority postop (86%).
** No benefit on OS in low-grade pts
** In high-grade pts RT associated with improved 3-yr OS (73% vs 63%) (SS)
** Conclusions: Largest population-based study of RT in pts undergoing limb-sparing surgery; suggests OS benefit w/ RT for high-grade tumors

## Preoperative XRT

* Used primarily for patients who would require extensive resection such as disarticulation, amputation, or hemipelvectomy.
* Patients with large (>=8 cm) and high-grade tumors can have good local control with adjuvant RT alone, but experience significant risk of DM (5-10 cm risk 34%, 10-15 cm risk 43%, 15-20 cm risk 58%). Neoadjuvant doxorubicin has been shown to improve DFS, though impact on OS was not clear. This led to MGH developing an aggressive sequential interdigitated chemo-RT regimen, with good results
* However, RTOG 95-14 using a more intense chemo regimen, was felt to be too toxic
* RTOG 95-14 / Intergroup (1997-2000) - Protocol (PDF) - Neoadjuvant sequential chemo-RT-chemo-RT-chemo
** Phase II. 64 patients. Large (≥ 8 cm), high grade (G2-3), in extremities or torso, with expected R0 resection. MFH 44%, leiomyosarcoma 13%. Extremity 88%. High grade 80%. Sandwich course: MAID (mesna, doxorubicin, ifosfamide, dacarbazine) then RT 22/11 then MAID then RT 22/11 then MAID, surgery, MAID x3 additional cycles. If necessary, 14 Gy post-op RT boost. Effort made not to treat entire extremity circumference. 91% had R0 resections. 59% received full chemo course.
** 2006 PMID 16446334, 2006 — "Phase II Study of Neoadjuvant Chemotherapy and Radiation Therapy in the Management of High-Risk, High-Grade, Soft Tissue Sarcomas of the Extremities and Body Wall: Radiation Therapy Oncology Group Trial 9514." (Kraybill WG, J Clin Oncol Vol 24, No 4 (February 1), 2006: pp. 619-625.)
*** Outcome: 3-yr LRF 18% (if amputation is considered a failure), or 10% (if not). 3-yr DFS 57%, DDFS 64%, OS 75%. 92% amputation-free rate
*** Toxicity: 5% treatment-related deaths (most 2ndary AML), 84% Grade 4 toxicity (78% G4 hematologic, 19%)
*** Conclusion: Regimen has activity, but substantial toxicity precludes its use outside of clinical protocols
*** Comment: Used more intense version of MAID than used in MGH protocol, which probably worsened toxicity
* Harvard; 2003 (1989-1999) PMID 12829150 -- "Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas." (DeLaney TF, Int J Radiat Oncol Biol Phys. 2003 Jul 15;56(4):1117-27.)
** Retrospective. 48 patients, large (>=8cm) high grade extremity soft-tissue sarcoma. Interdigitated sequential chemo and RT: MAID - RT 22/11 - MAID - RT 22/11 - MAID, then surgery, then MAID x3. If SM+, 16 Gy post-op
** 5-year LC 92% (NS), DF-free 86% (NS), DFS 75% (SS), OS 44% (SS) compared with historical controls
** Toxicity: wound complications 29%, 2% treatment-related death
** Conclusion: Significant reduction in DM, with significant gain in DFS and OS compared to historical control.
** Comment: Led to RTOG 9514
* University of Florida; 1990 (1978-1987) - PMID 2211257 — "Preoperative irradiation for soft tissue sarcomas of the trunk and extremities in adults." Brant TA. Int J Radiat Oncol Biol Phys. 1990 Oct;19(4):899-906.
** Retrospective. 58 pts with sarcomas of the trunk and extremities treated with XRT followed by wide local excision. XRT minimum 50 Gy. Most treated BID with 1.2-1.25 cGy/fraction.
** Tumor regression in 60%. Preserved functional limb in 47 of 54 pts who otherwise would require amputation. LR in 9%.
* M.D.Anderson; 1988 (1970-1984) - PMID 3350724 — "Treatment of soft tissue sarcomas by preoperative irradiation and conservative surgical resection." Int J Radiat Oncol Biol Phys. 1988 Apr;14(4):693-9.
** Retrospective. 110 pts. Usual dose 50Gy in 25 fractions. 59% were disease free after 5 years, for the 90 pts treated with photons only.

## Preop vs Postop RT

* Acute wound complications worse after preop RT, though majority of these were in lower extremity sites
* Long-term extremity function worse after postop RT. Suggests preop favorable in upper extremity.
* Meta-analysis suggests that preop RT may improve local control, without affecting survival, however there was heterogeneity in studies analyzed
* Additional benefit of preop RT is smaller RT fields

### Meta-Analysis

* Ontario; 2010 (1985-2005) PMID 20217260 -- "A systematic review and meta-analysis of oncologic outcomes of pre- versus postoperative radiation in localized resectable soft-tissue sarcoma." (Al-Absi E, Ann Surg Oncol. 2010 May;17(5):1367-74. Epub 2010 Mar 9.)
** Meta-analysis. 5 studies (1 RCT and 4 retrospective cohort), 1098 patients. Localized, resectable, STS. Comparison of preop and postop RT. Heterogeneity 0.26
** Outcome: Local recurrence better in preop group (HR 0.6, SS). Survival preop 76% vs postop 67%
** Conclusion: Delay in surgical resection for preop RT doesn't increase mortality. Local recurrence lower after preop RT

### Randomized

* NCI Canada (1994-97) -- Preop RT vs Postop RT
** Randomized. Closed early after interim significant difference. Accrued 190 patients out of 266 planned. STS originating in limb without mets, expected to need both surgery and RT. Recurrences allowed. Primary endpoint was major wound complications. Arm 1) Preop RT 50/25, if SM+ additional 16-20 Gy post-op boost vs. Arm 2) Postop RT 66-70 Gy. RT initial field 5 cm proximal/distal margin (50/25), boost 2 cm proximal/distal margin (16-20 Gy). Longitudinal strip of skin/SC tissue untreated for at least half the course, unless margin <2 cm not confined by intact fascial boundary. Timing 3-6 weeks apart
** 3-years; 2002 PMID 12103287 — "Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial." (O'Sullivan B, Lancet. 2002 Jun 29;359(9325):2235-41.) Median F/U 3.3 years
*** Outcome: Wound complications preop RT 35% vs. postop RT 17% (SS); highest rate of complications upper leg (45% vs. 28%). More preop RT patients required non-primary wound closure. 6 week function better in post-op group. No difference in LR, LRR, DMR. OS better after >2.5 years for preop group (but not designed for it)
*** RT field size: median field preop 333 cm2 vs. postop 416 cm2 (SS)
*** Conclusion: Local anatomy should be considered; for arm or if large field needed, consider preop RT, otherwise postop RT better wound healing and comparable outcome
** 5-years; 2004 ASCO Abstract -- "Five-year results of a randomized phase III trial of pre-operative vs post-operative radiotherapy in extremity soft tissue sarcoma." (O'Sullivan B, Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 9007). Median F/U 6.9 years
*** Outcome: 5-year LC preop RT 93% vs. postop RT 92% (NS), RFS 58% vs. 59% (NS), OS 73% vs. 67% (NS). Predictors for outcome SM+ for LC, size and grade for RFS and OS
*** Conclusion: Pre-op and post-op RT equally effective for disease control and survival; different complication profiles should guide treatment by site. No longer a survival difference
** Late effects; 2005 PMID 15948265, 2005 — "Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma." (Davis AM, Radiother Oncol. 2005 Apr;75(1):48-53.
*** Post-op RT associated with worse fibrosis as well as joint stiffness (although not statistically significant).
*** Outcome: Grade 2+ fibrosis pre-op RT 31% vs. post-op RT 48% (p=0.07); edema, and joint stiffness also more severe in post-op arm. Joint stiffness and fibrosis worse with larger field size
*** Conclusion: Post-op RT tended to result in more fibrosis, adversely affecting patient function

### Non-randomized

* Utah "Preoperative Radiotherapy Improves Overall Survival in General Soft-tissue Sarcoma: Multi-institutional Analysis of 3,163 Patients" (Sampath et al. ASTRO abstract #140 2010.)
** Retrospective analysis was conducted using the National Oncology Database
** RT was given with surgery in 1,087 patients. Median f/up was 62 months. The 5- and 10-year OS were 54% and 38%.
** MVA identified that OS and CSS were significantly improved with pre-op-RT vs. postop-RT. No sig differences in patient, tumor characteristics between groups.
** Conclusion: Pre-op RT may have survival benefit compared to post-op RT (as seen in NCI Canada study above).
* MD Anderson PMID 9806516 — "Preoperative vs. postoperative radiotherapy in the treatment of soft tissue sarcomas: a matter of presentation." (Pollack et al. IJROBP 1998.)
** Retrospective analysis of 453 patients with grade 2-3 MFH, synovial, and liposarcoma (retroperitoneal excluded).
** Surgery + RT, 50 Gy if pre-op, 60-66 Gy if post-op
** Overall, local control equivalent (81%) for pre-op vs. post-op
** For those presenting with gross disease, local control better for pre-op RT (88% vs. 67% at 10 years)
** For those presenting after excision at an outside facility, local control better for immediate re-excision and post-op RT (72% vs. 91%)
** More wound-healing problems with pre-op (25% vs. 5%)

## Brachytherapy

* Improves local control in high grade tumors, but has no effect in low grade tumors. No impact on DSS or OS

### Randomized

* Memorial Sloan Kettering (1982-1992) -- Adjuvant brachytherapy vs observation
** Randomized. 164 patients, soft tissue sarcoma of extremity or superficial trunk. Gross total resection (en-bloc) with limb sparing surgery. Arm 1) Adjuvant brachytherapy Ir-192 implant 42-45 Gy over 4-6 days vs. Arm 2) observation. Brachytherapy CTV 2cm around surgical bed, catheters 1 cm apart; no effort to treat surgical scar, drain, or wide margins. Catheters loaded immediately until 1985, then due to complications on postop day 5
** Initial; 1987 PMID 3314794 -- "Local recurrence in adult soft-tissue sarcoma. A randomized trial of brachytherapy." (Brennan MF, Arch Surg. 1987 Nov;122(11):1289-93.)
*** Conclusion: Significant decrease in local recurrence
** 5-years; 1993 (1982-1987) PMID 8407399 -- "Long-term results of a prospective randomized trial of adjuvant brachytherapy in the management of completely resected soft tissue sarcomas of the extremity and superficial trunk." (Harrison LB, Int J Radiat Oncol Biol Phys. 1993 Sep 30;27(2):259-65.)
*** Initial 126 patients. Median F/U 5.5 years
*** Outcome: 5-year local control BT 82% vs observation 67% (SS); high grade tumors 90% vs 65% (SS), no difference low grade. Local recurrence same in high-grade tumors without BT, low-grade tumors without BT, and low-grade tumors with BT, suggesting grade does not impact local recurrence after surgery alone. DM 76% vs 76% (NS), no difference by grade. 6-year DSS BT 81% vs observation 80% (NS), no difference by grade
*** Conclusion: Adjuvant brachytherapy significantly improves local control in high grade histology, without impacting metastases or disease-specific survival. No impact on low grade tumors
** Low-grade; 1994 PMID 8201376 -- "A prospective randomized trial of adjuvant brachytherapy in the management of low-grade soft tissue sarcomas of the extremity and superficial trunk." (Pisters PW, J Clin Oncol. 1994 Jun;12(6):1150-5.)
*** Subset analysis. 45 patients, low-grade STS (liposarcoma 60%). Comparable characteristics. Median F/U 5.6 years
*** Outcome: Local recurrence BT 27% vs observation 22% (NS)
*** Conclusion: Adjuvant brachytherapy does not decrease local recurrence after brachytherapy in low-grade sarcomas
** Long-term; 1996 PMID 8622034 -- "Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma." (Pisters PW, J Clin Oncol. 1996 Mar;14(3):859-68.) Median F/U 6.3 years
*** Outcome: 5-year local control BT 82% vs observation 69% (SS); high-grade 89% vs 66% (SS); no difference low-grade. On MVA, local recurrence predicted only by age >60. If SM-, local recurrence BT 13% vs observation 28% (SS); if SM+ 33% vs 36% (NS). DM 17% vs 24% (NS); 5-year DSS 84% vs 81% (NS)
*** Complications: Catheters initially loaded day 0-5, higher wound complication BT 48% vs observation 16%. In 1985 started loading on day 5, and then no difference in rate of complications (14% vs 10%)
*** Conclusion: Adjuvant brachytherapy improves local control, in high-grade histology, but not distant mets or disease-specific survival

### Retrospective data

* Fox Chase (1983-2001) -- EBRT + BT vs EBRT alone
** 2004: PMID 15145165 -- "Soft tissue sarcomas treated with postoperative external beam radiotherapy with and without low-dose-rate brachytherapy." (Andrews SF, Int J Radiat Oncol Biol Phys. 2004 Jun 1;59(2):475-80.)
** Retrospective, 86 pts -- EBRT alone(61 pts): median 59 Gy. EBRT+BT(25 pts): median 50 Gy EBRT + 16 Gy LDR BT.
** Median f/u 62 months. No diff in OS or FFDM. No diff in 5-yr LC 83% (EBRT) vs 90% (EBRT+BT). Improved LC with BT in Stage III (100% vs 62%) (AJCC 1997 ed, Stg III = T2b high grade), and a trend in high grade tumors (p=0.09). No predictors were found for improved LC on MVA.
** Conclusion: the addition of BT to EBRT may improve LC in high grade and/or Stage III tumors
* MSKCC (1987-92) -- BT alone vs EBRT + BT
** 1996: PMID 8892454 -- "The effect of combined external beam radiotherapy and brachytherapy on local control and wound complications in patients with high-grade soft tissue sarcomas of the extremity with positive microscopic margin." (Alekhteyar KM, Int J Radiat Oncol Biol Phys. 1996 Sep 1;36(2):321-4.)
** Retrospective, 105 pts -- BT alone(87 pts): 45 Gy LDR. EBRT+BT(18 pts): 45-50 Gy EBRT + 15-20 LDR BT. Positive margins in 10 of 18 (56%) EBRT+BT vs 17 of 87 (20%) BT alone.
** Median f/u 22 months. No difference in 2-yr LC between EBRT+BT and BT (90% vs 82%). For positive margins, trend for improved LC with EBRT+BT (90% vs 59%, p=0.08).
** Conclusion: favor the use of EBRT+BT in pts with positive margins.
ABS recommendations (2001) - PMID 11240245 — "The American Brachytherapy Society recommendations for brachytherapy of soft tissue sarcomas." Nag S et al. Int J Radiat Oncol Biol Phys. 2001 Mar 15;49(4):1033-43.

## Neoadjuvant chemotherapy

* No Phase III trials
* An EORTC propective randomized Phase II trial (STBSG 62871) was accruing too slowly, and was not continued to the planned Phase III phase
* EORTC STBSG 62871
** Randomized Phase II. 134 patients with "high risk" STS (>=8 cm or Grade II-III). Arm 1) Surgery alone vs. Arm 2) neoadjuvant doxorubicin/ifosfamide. Post-op RT if marginal surgery, SM+ or local recurrence
** 5-years; 2001 PMID 11378339 -- "A randomised phase II study on neo-adjuvant chemotherapy for 'high-risk' adult soft-tissue sarcoma." (Gortzak E, Eur J Cancer. 2001 Jun;37(9):1096-103.) Median F/U 7.3 years
*** Outcome: 5-year DFS 52% vs. 56% (NS), OS 64% vs. 65% (NS)
*** Conclusion: Not powered for definitive conclusions on benefit, but no likely

## Surgery alone vs Surgery + Adjuvant Chemotherapy

* NCI (1978-1981) -- surgery +/- adjuvant chemotherapy
** Randomized. 65 patients with STS of the extremities. Arm 1) surgery (limb-sparing or amputation) vs Arm 2) surgery + adjuvant chemo (doxorubicin 70 mg/m2 + cytoxan 700 mg/m2, then high dose MTX 250 mg/kg
** 1982 PMID 7114936 -- "The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy." (Rosenberg SA et al. Ann Surg. 1982 Sep;196(3):305-15.) Median F/U 1.8 years
*** Outcome: 3-year DFS observation 60% vs chemotherapy 92% (SS); 3-year OS 74% vs 95% (SS)
*** Conclusion: Adjuvant chemotherapy may be beneficial
** 1988 PMID 3047339 -- "Adjuvant chemotherapy for patients with high-grade soft-tissue sarcomas of the extremity." (Chang AE, J Clin Oncol. 1988 Sep;6(9):1491-500.) Median F/U 7.1 years
*** Outcome: 5-year DFS observation 54% vs chemotherapy 75% (SS); 5-year OS 60% vs 83% (NS)
*** Toxicity: Significant doxorubicin-induced cardiomyopathy
*** Conclusion: Adjuvant chemotherapy improves DFS, but overall survival advantage has diminished. Reduced chemo regimen was found to be comparable
* Metaanalysis -- surgery +/- adjuvant chemotherapy
** 2008 PMID 18521899 -- "A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma." (Pervaiz N, Cancer 2008 Aug 1;113(3):573-81.)
** 18 trials with 1953 patients analyzed.
** Outcome: Doxorubicin alone results into 5% survival benefit (NS), Doxorubicin + Ifosfamid result into 11% survival benefit (SS).
** Conclusion: Marginal effect of adjuvant chemotherapy on STS. Benefit must be weighted against therapy associated toxicity.

## Hyperthermia

* EORTC 62961
** Randomized. 341 patients, large (>=5 cm), Grade II-III, deep and extracompartmental STS. Arm 1) Neoadjuvant EIA vs. Arm 2) Neoadjuvant EIA + deep wave regional hyperthermia (RHT). Primary end-point LRC
** 2007 ASCO Abstract -- "Regional hyperthermia (RHT) improves response and survival when combined with systemic chemotherapy in the management of locally advanced, high grade soft tissue sarcomas (STS) of the extremities, the body wall and the abdomen: A phase III randomised pros." (Issels RD, J Clin Oncol 25 (Suppl 18): A-10009, 547s, 2007). Median F/U 2.1 years
*** Outcome: LRC chemo 2 years vs. chemo + RHT 3.8 years (SS), DFS 1.35 vs. 2.6 years (SS)
*** Conclusion: Neoadjuvant chemo + regional hyperthermia improve LC and DFS in high risk STS

## By location

Inferior vena cava
* Rare, <1% of soft tissue sarcomas at MSKCC; ~300 reported in literature
* More aggressive than other retroperitoneal sarcomas
* Surgery is the primary treatment modality
* Role of adjuvant therapy is unclear, but one small Korean report argues for RT benefit
* Paris, 2006 (1979-2004) PMID 16858193 -- "Leiomyosarcoma of the inferior vena cava: experience in 22 cases." (Kieffer E, Ann Surg. 2006 Aug;244(2):289-95.)
** Retrospective. 22 patients with leiomyosarcoma. Surgery 20/22
** Surgery: 20/22 resection. Resection 19, with ligation 5, PTFE prosthesis 13, cavoplasty 1. Toxicity: 1 intra-op death, and 3 post-op deaths due to multiorgan failure
** Adjuvant therapy: 15/16 patients chemo, 4 RT
** Outcome: 3-year OS 52%, 5-year OS 35%. 50% died to recurrence/distant mets
** Conclusion: Not curative, but recommend aggressive operative management for reasonably long-term survival
* MSKCC, 2003 (1982-2002) PMID 14522326 -- "Surgical treatment and outcomes of patients with primary inferior vena cava leiomyosarcoma." (Hollenbeck ST, J Am Coll Surg. 2003 Oct;197(4):575-9.)
** Retrospective. 25 with primary IVC leiomyosarcoma. Median age 56 years. 84% treated with complete resection
** Surgery: complete resection 21/25 (84%); ligation (11), primary/patch repair (8), PTFE graft 2. Severe post-op edema 11%
** Survival: if complete resection, 3-year 76%, 5-year 33%. If not complete, no 3-year survivors. Recurrence: local 33%, distal 48%
** Conclusion: resection feasible and leads to improved survival
* Seoul, 2003 PMID 12808321 -- "Pararenal leiomyosarcoma of the inferior vena cava." (Kwon TW, J Korean Med Sci. 2003 Jun;18(3):355-9.)
** Retrospective. 4 patients, complete resection, PTFE graft. Post-op RT in 3/4 patients
** Outcome: DM in the 1 patient who didn't get RT, 18 months after surgery
** Conclusion: recommend post-op RT

## Extremity IMRT

* Memorial Sloan Kettering
** 3-years; 2008 (2002-2005) PMID 18612160 -- "Impact of intensity-modulated radiation therapy on local control in primary soft-tissue sarcoma of the extremity." (Alektiar KM, J Clin Oncol. 2008 Jul 10;26(20):3440-4.)
*** Retrospective. Retrospective. 41 adult patients, primary STS of extremity. Treated with limb-sparing surgery; SM close/positive in 51%. IMRT used as preop (n=7, mean 50 Gy) or postop (n=31, mean 63 Gy). Median F/U 2.9 years
*** Outcome: 5-year LC 94% (regardless of margin status), 5-year DM-free 61%, 5-year OS 64%
*** Conclusion: IMRT in STS of the extremity provides excellent local control
** Toxicity; 2007 (2020-2005) PMID 17363186 -- "Intensity modulated radiation therapy for primary soft tissue sarcoma of the extremity: preliminary results." (Alektiar KM, Int J Radiat Oncol Biol Phys. 2007 Jun 1;68(2):458-64. Epub 2007 Mar 23.)
*** Retrospective. 31 adult patients, primary STS of extremity. Treated with limb-sparing surgery; SM close/positive in 55%. IMRT used as preop (n=7, mean 50 Gy) or postop (n=24, mean 63 Gy). Median F/U 1.9 years
*** Outcome: 2-year LC 95%, DM-free 65%, OS 81%
*** Toxicity: Dermatitis Grade 2 16%, Grade 3 10%. Fractures 6%. Neuropathy Grade 2 5%. Joint stiffness Grade 2 19%. Edema Grade 2 13%
*** Conclusion: IMRT provides excellent local control, with favorable toxicity profile
** Dosimetry; 2004 PMID 15183478 -- "Intensity-modulated radiotherapy for soft tissue sarcoma of the thigh." (Hong L, Int J Radiat Oncol Biol Phys. 2004 Jul 1;59(3):752-9.)
*** Dosimetric comparison. Goal to spare femoral dose with IMRT to prevent fractures. 10 patients planned with 3D-CRT and IMRT. CTV = GTV + 1.5 cm margin axially, except at bone where bone interface was used. CTV = GTV + 5-10 cm. PVT = CTV + 0.5 cm
*** Outcome: PTV coverage comparable. Femur V100 decreased by 57% (SS), femur D5 reduced 67% (SS). Ipsilateral soft tissues V100 decreased by 78% (SS), D5 decreased 13%
*** Conclusion: IMRT can reduce dose to femur without compromising target coverage, and can reduce hot spots in bone and surrounding soft tissues and skin

## Other Resources

* ARRO Case- Sarcoma
* ↑ Kepka L, DeLaney TF, Suit HD, Goldberg SI. Results of radiation therapy for unresected soft-tissue sarcomas. Int J Radiat Oncol Biol Phys. 2005 Nov 1;63(3):852-9. doi: 10.1016/j.ijrobp.2005.03.004. PMID: 16199316