Chemotherapy in Soft Tissue Sarcoma


168 Chemotherapy in Soft Tissue Sarcoma


Robert J. Wilson II MD1, Jennifer L. Halpern MD2, Jill Gilbert MD3, Ginger E. Holt MD2, Vicki L. Keedy MD3, and Herbert S. Schwartz MD2


1 University of Pennsylvania Department of Orthopaedic Surgery, Philadelphia, PA, USA


2 Vanderbilt University Medical Center, Vanderbilt Orthopaedic Institute, Nashville, TN, USA


3 Vanderbilt Hematology/Oncology, Nashville, TN, USA


Note: in this chapter, the odds ratio (OR) reported in italics has been calculated by the authors and is not reported as part of the manuscripts referenced. Table 168.1A provides an overall review of studies cited and includes either the reported or calculated hazard ratio (HR) or OR for overall survival as related to chemotherapy administration.


Introduction


The two staging systems used to describe soft tissue sarcoma (STS) are the American Joint Committee on Cancer (AJCC) and the Enneking System (Surgical Staging System of the Musculoskeletal Tumor Society). The AJCC is based upon the tumor–node–metastasis (TNM) system, but also includes histologic grade as a measure. The Enneking system is based upon histopathologic grade, anatomic site and extent, and presence or absence of metastases.


Doxorubicin (Adriamycin) is an anthracycline antibiotic used as a chemotherapeutic agent. It works by intercalating DNA. Toxicities can include nausea, vomiting, and heart arrhythmias. Cumulative doses can lead to cardiotoxicity including congestive heart failure and dilated cardiomyopathy.


Ifosfamide (Ifex) is an alkylating agent whose mechanism of action includes the formation of covalent bonds with DNA, RNA, and proteins thereby impairing cell function. Dosing is limited by genitourinary and neurologic toxicity and is usually administered in conjunction with mesna to reduce the genitourinary toxicity.


Synovial sarcoma comprises 10–15% of adult STSs. Synovial sarcomas contain a characteristic translocation (X;18; p11;q11) representing the fusion of SYT (18q11) with either SSX1 or SSX2 (both at Xp11) resulting in the fusion genes SYT‐SSX1 or SYT‐SSX2.


Clinical scenario



  • A 38‐year‐old vending machine repairman presents for evaluation of left groin pain. Physical examination reveals asymmetric thigh girth (left 67 cm vs right 55 cm).
  • Imaging studies demonstrates a 12.5 × 15 × 20 cm mass within the adductor compartment of the left thigh.
  • There is no evidence of lung parenchymal disease.
  • Open biopsy of the mass is performed.
  • Final pathology is reported as pleomorphic high‐grade sarcoma (Figure 168.1).

Table 168.1A Efficacy of neoadjuvant chemotherapy in the treatment of STS.
























































































Literature Reference Study Design Quality of evidence No. of Patients Results Conclusions Statistical Significance: Overall Survival Related to Intervention
Gronchi et al.3 RCT 328 3 cycles NeoCT not inferior to 3 cycles NeoCT plus 2 adjuvant cycles No control arm of no chemo to compare chemo arms with
Study could not evaluate NeoCT compared to no chemo
N/A – cannot compare NeoCT to no chemo control
Gronchi et al.4 RCT 287 3 cycles of standard NeoCT compared to 3 cycles of histology‐specific chemo regimens for high‐grade myxoid liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, undifferentiated pleomorphic sarcoma At 1‐year follow‐up the histologic‐specific chemo group had statistically worse OS (38% vs 62% in standard NeoCT group, p = 0.006) so the study was halted early Histology‐specific chemo regimens for high‐grade myxoid liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, and undifferentiated pleomorphic sarcoma are worse than standard NeoCT regimen (epirubicin, IF)
Issels et al.5 RCT 329 Regional hyperthermia and NeoCT compared to NeoCT alone had better OS (p = 0.04) and better LRFS (p = 0.002) No control arm of no chemo to compare NeoCT arm and Neo CT plus hyperthermia arms to
Study could not evaluate NeoCT compared to no chemo
N/A – cannot compare NeoCT to no chemo control
Pennington et al.6 Retrospective Low 116 IF‐based NeoCT and radiotherapy for extremity STS
Median follow‐up 5.9 years
No control group of no chemo to compare to OS at 3/6 years was 82/67%
Age over 60 years (p = 0.03; HR = 2.34; 95% CI: 1.10–4.98) and tumor size over 10 cm compared with tumor size ≤5 cm (p = 0.03; HR = 3.32; 95% CI: 1.15–9.61) were associated with worse OS
Mullen et al.7 Retrospective Low 73 48 extremity STS patients treated with NeoCT and radiotherapy followed by three cycles of adjuvant chemo and 16 Gy postoperative radiotherapy was compared to a historical matched‐control 25 patient population at a single center
Median follow‐up was 9.3 years in NeoCT group, 13.2 years in control group
NeoCT plus adjuvant chemo and pre‐ and postoperative radiotherapy conferred significant survival benefits 7‐year DSS and OS rates were 81 and 50% (p = 0.004) and 79 and 45% (p = 0.003) for the NeoCT and control groups, respectively
Meric et al.12 Retrospective
Low
65 Reviewed records of patients treated with NeoCT to determine radiographic response: 34% partial, 9% minor, 31% stable, 26% progressive
In 13%, NeoCT downstaged the operation, 78% had no change, and 9% progressed
However, radiographic response was the most significant predictor of overall survival
Although only a few NeoCT patients had smaller surgery, radiographic response did correlate to improved survival N/A – correlates radiographic response to survival
Eilber et al.8 Retrospective
Low
496 The percentage of patients who achieved ≥95% necrosis increased from 13% to 48% with the addition of IF to doxorubicin.
5‐year survival in patients with >95% necrosis = 80% vs 62% in patients with <95% necrosis
In patients who received neoadjuvant therapy and had evidence of treatment induced necrosis, patients with >95% necrosis demonstrated improved OS and LRFS N/A – correlates % necrosis to overall survival
Menendez et al.9 Retrospective
Low
82 The overall five year survivorship for patients with <95% or >95% necrosis were 20 and 33%, respectively Tissue necrosis from NeoCT did not seem to predict outcome N/A – correlates % necrosis to overall survival
Gortzak et al.10 RCT 134 Chemotherapy did not interfere with planned surgery and did not affect postoperative wound healing
Trial closed after phase II because of poor patient accrual
Median follow‐up of 7.3 years, five‐year disease‐free survival was 52% for no neoadjuvant chemo and 56% for neoadjuvant chemo groups, and 64 and 65%, respectively, for overall survival
Although chemotherapy did not compromise surgical intervention, there was not a major survival benefit observed with administration of neoadjuvant chemotherapy Calculated OR overall survival at mean of 7.3 years:
OR = 0.68; 95%CI: 0.34–1.38; p = 0.29
Pisters et al.11 Retrospective
Low
76 Responding patients had rates of LRFS, DMFS, DFS, OS similar to nonresponders NeoCT associated with response, DFS, OS rates similar to reported adjuvant chemotherapy
Responding patients had rates of LRFS, DMFS, DFS, OS similar to nonresponders
N/A – correlates radiographic response to survival
Italiano et al.24 Retrospective
Low
237 (SS) Median follow‐up 58 months
Neither neoadjuvant or adjuvant chemotherapy (IF‐containing regimen) had significant impact on DSS, LRFS, DRFS
Wide surgical excision of SS with adjuvant radiotherapy are accepted treatments
Chemotherapy shows no statistically significant benefit
Reported:
HR = 0.91; 95% CI: 0.56–1.49; p = 0.725

IF: ifosfamide, DSS: disease‐specific survival, DFS: disease free survival, DRFS: distant recurrence free survival, LRFS: local recurrence free survival, OR: odds ratio, SS: synovial sarcoma, OS: overall survival, NeoCT: neoadjuvant chemotherapy, Reported: authors reported OR/CI in published manuscripts, Calculated: authors of this review calculated OR/CI to improve statistical validity of analysis, N/A – did not address overall survival reported between control (no chemo) and experimental (chemo group), DMFS: distant metastasis‐free survival

Photos depict the clinical images of patient presented embody the inherent difficulty in treatment of high-risk STS. Pretreatment MRI scans revealed a large 20 × 15 × 12 cm mass in the left medial thigh (A, B). Following neoadjuvant radiation therapy, the patient is taken to the operating room for a wide excision of the tumor (C). Post resection, the sciatic nerve is skeletonized, tagged with a vessi-loop (D). Despite negative margins, no prior evidence of lung involvement on staging studies, and no evidence of local recurrence, the patient developed radiographically detectable lung metastases on CT scan nine months following definitive resection (E). Following treatment with adjuvant chemotherapy (adriamycin and ifosfamide/mesna), the patient underwent pulmonary metastatectomies (F).

Figure 168.1 Clinical images of patient presented embody the inherent difficulty in treatment of high‐risk STS. Pretreatment MRI scans revealed a large 20 × 15 × 12 cm mass in the left medial thigh (A, B). Following neoadjuvant radiation therapy, the patient is taken to the operating room for a wide excision of the tumor (C). Post resection, the sciatic nerve is skeletonized, tagged with a vessi‐loop (D). Despite negative margins, no prior evidence of lung involvement on staging studies, and no evidence of local recurrence, the patient developed radiographically detectable lung metastases on CT scan nine months following definitive resection (E). Following treatment with adjuvant chemotherapy (adriamycin and ifosfamide/mesna), the patient underwent pulmonary metastatectomies (F). Source: Robert J. Wilson, Jennifer L. Halpern, Jill Gilbert, Ginger E. Holt, Vicki L. Keedy, Herbert S. Schwartz.


Table 168.1B Efficacy of adjuvant chemotherapy in the treatment of STS.


























































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Nov 28, 2021 | Posted by in ORTHOPEDIC | Comments Off on Chemotherapy in Soft Tissue Sarcoma
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Literature Reference Study Design Quality of evidence No. of Patients Results Conclusions Statistical Significance: Overall Survival Related to Intervention
Sarcoma Meta‐analysis Group16 Meta‐analysis
High
1568 HRs of 0.73 for LRFS, 0.70 for DRFS, 0.75 for DFS correspond to absolute benefits from adjuvant chemotherapy of 6, 10, and 10%, respectively at 10 years
For OS, the hazard ratio of 0.89 was not significant
Adjuvant doxorubicin‐based chemotherapy (statistically) significantly improves time to local and distant recurrence and overall recurrence‐free survival Reported:
HR = 0.89; 95% CI: 0.76–1.03; p = 0.12
Frustaci et al.17 RCT
High
104 Median follow‐up of 59 months
Median DFS 48 months in treatment group and 16 months in control group
DSS was 75 months for treated group and 46 months for control
Absolute benefit in OS was 13% at two years and 19% at four years
Intensified adjuvant chemotherapy had a positive impact on DFS and OS in patients with high‐risk extremity STS Calculated OR overall survival to four years: OR = 0.54; 95% CI: 0.25–1.18; p = 0.12
Frustaci et al.18 RCT
High
104 Further follow‐up of prior experimental group showed that DFS and OS differences in treatment arm vs control group no longer statistically different The previously observed overall survival benefit loses statistical significance at later time points
Therefore, time to recurrence may be lengthened, but overall survival at further follow up is the same
Calculated OR overall survival to 89.6 months: OR = 0.538; 95% CI: 0.25–1.17; p = 0.12
Cormier et al.19 Retrospective
Low
674 Median follow‐up 6.1 years
Use of chemotherapy is associated with time‐varying clinical effects
Clinical benefits associated with doxorubicin‐based chemotherapy are not sustained beyond 1 year Reported HR DSS at 12 months: HR = 0.37; 95% CI: 0.20–0.69; p = 0.002
Reported HR after 12 months: HR = 1.36; 95% CI: 1.02– 1.81; p = 0.04
Pervaiz et al.20 Meta‐analysis
High
1953 OR for local recurrence was 0.73 in favor of chemotherapy
For distant and overall recurrence, OR 0.67 in favor of chemotherapy
Regarding survival, OR for doxorubicin with IF was 0.56 in favor of chemotherapy
Analysis confirms marginal efficacy of chemotherapy with respect to LRFS, DRFS, and DSS Reported:
OS doxo‐alone based therapies:
OR = 0.84; 95% CI: 0.68–1.03; p = 0.09
OS doxo+ifos based therapies:
OR = 0.56; 95% CI: 0.36– 0.85; p = 0.01
Cochrane Gynaecological Cancer Group15 Cochrane Systematic Review
High
1568◻ LRFS R with chemo was 0.73. DRFS was 0.70
Overall survival was 0.75
Those correspond to significant absolute benefits of 6–10% at 10 years
For OS, HR of 0.89 not statistically significant but does potentially represent absolute benefit of 4%
Doxorubicin‐based chemo appears to significantly improve LRFS, DRFS, DFS, and trends toward improved OS Reported HR = 0.89; 95% CI: 0.76–1.03; p = 0.12
Eilber et al.23 Prospective Observation
Low
101 4‐year DSS of IF treated patients was 88% compared to 67% in no treatment group
Treatment with IF associated with improved DRFS but not LRFS