Radiation Oncology/Sarcoma/Randomized

Soft Tissue Sarcoma Randomized Evidence

Amputation vs Limb-sparing surgery + EBRT

 * National Cancer Institute(1975-1981) -- amputation vs limb-sparing surgery + 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 &mdash; "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.) Total of 43 pts with highgrade sarcoma randomized; Size of tumor not mentioned; 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

Surgery Alone vs Surgery + Postop EBRT

 * 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 &mdash; "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

Surgery Alone vs Surgery + Postop Brachytherapy

 * 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 I-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
 * 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

Pre-op EBRT vs. Post-op EBRT

 * NCI Canada (1994-97)
 * Randomized. Closed early after interim significant difference for wound healing. 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 50/25 + 16-20 Gy boost. RT initial field 5 cm proximal/distal margin, boost 2 cm proximal/distal margin. 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
 * Function and health status outcome; 2002 PMID: 12431971, 2002 &mdash; "Function and health status outcomes in a randomized trial comparing preoperative and postoperative radiotherapy in extremity soft tissue sarcoma." (Davis AM, J Clin Oncol. 2002 Nov 15;20(22):4472-7.
 * Conclusion: The timing of RT has minimal impact on the function of STS patients in the first year after surgery. Tumor characteristics and wound complications have a detrimental effect on patient function.
 * 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
 * Late effects; 2005 PMID 15948265, 2005 &mdash; "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
 * Conclusion: Post-op RT tended to result in more fibrosis, adversely affecting patient function

IORT + Postop EBRT vs Postop EBRT

 * 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

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
 * 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

EORTC 62931 Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma : a multicentre randomised controlled trial The Lancet Oncology, Volume 13, Issue 10, October 2012, Pages 1045–1054

Between February, 1995, and December, 2003, 351 patients were randomly assigned to the adjuvant chemotherapy group (175 patients) or to the control group (176). 258 (73%) of 351 patients received radiotherapy, 129 in each group. Overall survival did not differ significantly between groups (hazard ratio [HR] 0·94 [95% CI 0·68–1·31], p=0·72) nor did relapse-free survival (HR 0·91 [0·67–1·22], p=0·51). 5-year overall survival rate was 66·5% (58·8–73·0) in the chemotherapy group and 67·8% (60·3–74·2) in the control group. Chemotherapy was well tolerated, with 130 (80%) of 163 patients who started it completing all five cycles. 16 (10%) patients had grade 3 or 4 fever or infection, but no deaths due to toxic effects were recorded.

However Authors also updated the previous SMAC metaanalysis in the article discussiob part and suggested that Adjuvant CT may have ss benefit in some group of patients.