Local tumor control with limb preservation for patients with high-risk STS has significantly increased through a combination of improved imaging, the multimodality approach of surgery and radiation therapy, and gradual improvements in these techniques. In contrast to local control, overall survival has not significantly changed over time. The risk for developing distant metastases with a high-grade STS is directly proportional to tumor size (34% for 5.1–10
cm, 43% for 10.1–15
cm, and 58% for 15.1–20
]. RTOG 9514 was initiated in 1995 to examine the effects of intensive neoadjuvant MAID chemotherapy interdigitated with split courses of preoperative radiation followed by surgical resection and adjuvant systemic chemotherapy on local control and overall survival for high-risk STS. In this study, limb preservation was achieved in 92.2% of patients despite a median tumor size of 15
]. In addition, the pathologic complete response rate was an impressive 27%. Although there was no direct control group for comparison, the 71.2% estimated 5-year overall survival was much better than historical outcomes for comparable patients. Unfortunately, these results were not achieved without significant morbidity. Grade 4 hematologic toxicity was seen in 78% of patients and there were 3 treatment-related deaths. The significant, cumulative toxicity of this multimodality regimen was also evident by the fact that only 59% of patients completed all 6 planned cycles of MAID chemotherapy (3 preoperative and 3 postoperative) and 25% did not receive any postoperative chemotherapy.
In response to the results and limitations of 9514, the RTOG developed 0330. Thalidomide was chosen as a nontraditional therapeutic agent with antiangiogenic and potentially immunomodulatory properties, oral administration, and well-tolerated use in combination therapy for other malignancies such as multiple myeloma. Similar to 9514, cohort A (large, high-grade tumors) was developed to examine the effect of concurrent thalidomide on preoperative radiation therapy as well as whether or not long-term adjuvant thalidomide would be better tolerated than several cycles of postoperative MAID chemotherapy. RTOG 0330 also included large, low-grade tumors (cohort B) to evaluate similar endpoints, albeit using thalidomide and radiation without cytotoxic chemotherapy.
Prior to initiating 0330, there was concern regarding the association of thalidomide with a high incidence of venous thromboembolic events (VTE), such as deep venous thrombosis (DVT), and pulmonary embolus (PE), when used either alone or in combination therapy. A meta-analysis of 3,322 multiple myeloma patients treated with thalidomide alone, dexamethasone alone, combination therapy, or nonthalidomide/dexamethasone regimens showed that thalidomide was associated with a 2.6-fold increased risk for VTE while thalidomide with dexamethasone had an 8-fold increased risk [5
]. Even more pertinent to 0330 was data by Zangari et al. showing that the incidence of DVT was 2.5% in multiple myeloma patients treated with a dexamethasone/thalidomide combination chemotherapy regimen that did not contain doxorubicin versus 16% percent in patients treated with the same regimen but including doxorubicin [6
]. In the doxorubicin group, 35% of DVTs were associated with central venous access. There was also one nonfatal PE.
Due to the high incidence of VTE with thalidomide treatment for multiple myeloma, there has been interest in whether or not anticoagulation or antiplatelet therapy can reduce this risk. In a phase III study of newly diagnosed multiple myeloma patients randomized to induction doxorubicin containing chemotherapy with or without thalidomide, several cohorts were created based upon whether patients received anticoagulation prophylaxis with low-dose coumadin (1
mg per day) [7
]. The rates of DVT were 14% for chemotherapy alone/no thalidomide or anticoagulation, 34% for chemotherapy with thalidomide/no anticoagulation, and 31% for chemotherapy with thalidomide/coumadin. The majority of DVTs occurred during the first cycle of treatment and coumadin did not reduce the risk (P
= 0.7). Following treatment with systemic anticoagulation and resumption of chemotherapy, the DVT recurrence rate in the chemotherapy alone arm was 5% versus 11% in the thalidomide-containing group. A third cohort of chemotherapy alone versus chemotherapy/thalidomide with low-molecular-weight heparin (enoxaparin 40
mg subcutaneous daily) had equal rates of DVT at 15% (P
= 0.81). The conclusion was that low-molecular-weight heparin, but not low-dose coumadin, was effective in reducing the risk of thalidomide-associated DVT and that thalidomide-containing therapy could be safely reinstituted following DVT treated with anticoagulation. Data supporting an antiplatelet approach includes a study from Baz et al. with an initial VTE incidence of 28.6% in multiple myeloma patients receiving pegylated doxorubicin, vincristine, dexamethasone, and thalidomide [8
]. The protocol was then amended to include 81
mg aspirin daily, producing 3 cohorts: aspirin from the beginning of chemotherapy (group 1), aspirin at some point after starting chemotherapy (group 2), and no aspirin (group 3). The incidence of VTE was 19% in group 1, 15% in group 2, and 58% in group 3. As groups 1 and 2 were not statistically different, the hazard ratio for VTE with any aspirin use as compared to no aspirin was 0.22 (P
< 0.001). There were also no bleeding complications associated with aspirin use.
Given the complexities of administering daily outpatient subcutaneous low-molecular-weight heparin over several weeks, a decision was made to use low-dose aspirin (81
mg) to reduce the VTE risk in 0330. However, the greatest challenge to deciding upon an appropriate VTE prophylaxis regimen for 0330 was the paucity of available data regarding expected baseline VTE rates during STS treatment. One retrospective review of children undergoing sarcoma treatment had a 11.5% VTE rate [9
]. In a study of prophylactic IVC filter placement prior to adult musculoskeletal tumor surgery, the rates of DVT and PE were 11.8% and 0%, respectively, in a subset of 17 STS patients [10
]. A review of VTE after orthopedic surgery in adult cancer patients (including non-STS surgery) noted a DVT rate of 14.2% and a PE rate of 0.6% that were comparable to these other studies [11
]. In the sarcoma subgroup (bone and soft tissue), 15.6% of patients developed a DVT. One of the better assessments of sarcoma VTE risk is a retrospective study of 252 patients with a primary bone or STS (94 bone, 158 STS) [12
]. The rate of DVT was 3.9%, PE was 1.2%, and fatal PE was 0.4%. Similar to our study, their VTE patients had a primary tumor located in the hip or lower extremity. Interestingly, 77% of the VTEs occurred prior to the definitive surgical resection of the sarcoma. In our study, 67% of cohort A VTEs also occurred preoperatively, including one DVT prior to even starting thalidomide therapy. As RTOG 0330 was based upon 9514, a reasonable comparison group for cohort A would also be the original 9514 patients. In 9514, there were only two grade 3 vascular adverse events (including one PE) for a VTE rate of 3.1% [1
]. Although this would suggest that some of the VTE risk in 0330 came from the addition of thalidomide to the neoadjuvant therapy regimen, in retrospect, it may have been more prudent to administer daily low dose aspirin for VTE prophylaxis during all phases of the neoadjuvant therapy, not just the thalidomide.