- Email: [email protected]
Sarcomas
C H A P T E R
22 Sarcomas SOFT-TISSUE SARCOMAS The estimated incidence in the United States is 13,040 with estimated 5150 deaths in 2018. These tumors are mesenchymally derived and can occur in any part of the body but most commonly in the extremities (60%) and predominantly in muscle groups, although patients can present with head and neck, chest, and retroperitoneal tumors. Sarcomas most commonly metastasize to the lungs and rarely to the lymph nodes (w5%). Angiosarcoma and rhabdomyasarcoma are the most common subtypes associated with lymph node metastases (14%) followed by synovial cell, malignant peripheral nerve sheath tumor, and clear cell sarcoma.
Workup Risk Factors • Inherited disorders: • Hereditary retinoblastomadosteosarcoma, soft-tissue sarcoma, and melanoma • Li Fraumeni syndromedbreast cancer, brain tumors, acute leukemia, softtissue sarcomas, bone sarcomas, and adrenal cortical carcinoma • Neurofibromatosis type Idbenign and malignant nerve sheath tumors and gastrointestinal stromal tumors (GIST) • Radiation (therapeutic, diagnostic, or accidental)dangiosarcoma, osteosarcoma • Environmental toxinsdpolyvinyl chloride, thorium dioxide (Thorotrast)d angiosarcoma, fibrosarcoma, neurofibrosarcomas, spindle cell sarcomas, extraskeletal chondrosarcoma • Human herpesvirus 8detiologic agent responsible for all types of Kaposi sarcoma in immunocompromised patients Symptoms and Signs • Symptoms secondary to effects of pressure or direct invasion by the tumor, such as numbness, edema, and pain and are site specific • Painless lump, growing over time
Copyright © 2019 Elsevier Inc. All rights reserved.
Fundamentals of Radiation Oncology https://doi.org/10.1016/B978-0-12-814128-1.00022-2
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Investigations All suspected soft-tissue sarcomas should be referred to a specialist sarcoma unit. • CBC, chemistry panel, BUN/CR, ESR, LDH • Carefully planned biopsy to reduce risk of seeding at time of surgerydFNA may be adequate for histopathological subtyping or grade assessment, but core needle biopsy, or incisional biopsy, is preferred • Imaging should be performed before biopsy or surgery • CT thorax, CT abdomen for myxoid liposarcomas and retroperitoneal sarcomas • MRI should be performed to locally stage the tumor. Consider angiography if concerned about the vessels • PET-CT if distant metastatic disease has not already been discovered, or where the decision for amputation or mastectomy would be altered by discovery of metastatic disease
TNM STAGING (SOFT-TISSUE SARCOMAS) TRUNK AND EXTREMITIES Tx
Primary tumor cannot be assessed
T0
No evidence of primary tumor
T1
Tumor 5 cm in greatest dimension
T2
Tumor >5 cm in greatest dimension, 10 cm
T3
Tumor >10 cm in greatest dimension, 15 cm
T4
Tumor >15 cm in greatest dimension
N0
No regional lymph node metastasis
N1
Regional lymph node metastasis
M0
No distant metastasis
M1
Distant metastasis
FNCLCC HISTOLOGIC GRADE GX
Grade cannot be assessed
G1
Total differentiation, mitotic count, and necrosis score of 2 or 3
G2
Total differentiation, mitotic count, and necrosis score of 4 or 5
G3
Total differentiation, mitotic count, and necrosis score of 6, 7, or 8
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FNCLCC HISTOLOGIC GRADE
Stage Grouping Stage IA
T1
N0
M0
G1, GX
Stage IB
T2,3,4
N0
M0
G1, GX
Stage II
T1
N0
M0
G2, G3
Stage IIIA
T2
N0
M0
G2, G3
Stage IIIB
T3,4
N0
M0
G2, G3
Stage IV
Any T
N1
M0
Any G
Any T
Any N
M1
Any G
TNM, T (tumor), N (regional lymph nodes), and M (distant metastasis). Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer Science Business Media LLC, www.springer.com.
Treatment Stage 1a/b, Extremity, Superficial Trunk, and H&N Lesions • Surgical wide local excision with oncologically acceptable margins • Patients with positive marginsdrecommendation reresection to obtain negative margins • Stage 1a with clear marginsdobserve • Stage 1b with clear marginsdconsider post-op radiotherapy • Positive margins, or gross residual diseasedperform post-op radiotherapy Stage II, III, Extremity, Superficial Trunk, and H&N Lesions • Preoperative radiotherapy should be considered for all patients, especially for large tumor, or where surgery will provide less than a wide negative resection margin [1e3]. • For positive margins or residual disease, postoperative RT is recommended with EBRT or brachytherapy [4e6]. • The use of adjuvant chemotherapy to treat adults with localized resectable softtissue sarcoma remains controversial. Benefits are further improved with the addition of ifosfamide to doxorubicin-based regimens but must be weighed against associated toxicities [7,8]. Unresectable, Node-Positive, Distant Metastasis • Unresectable diseaseddefinitive RT with consideration for concurrent chemotherapy • Consider regional node dissection and metastasectomy for limited disease followed by localized radiotherapy and chemotherapy
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• Disseminated diseaseetreatment is driven by histology. • For doxorubicin sensitive tumors, treatment with olaratumab and doxorubicin has replaced ifosfamide-doxorubicin. Second line agents in this setting include pegylated liposomal doxorubicin, gemcitabine in combination with other agents or gemcitabine alone. • For patients with dematofibrosarcima protuberant(DMFP) or giant cell tenosynovial tumor, imatinib is recommeded. • For advanced liposarcoma and leiomyosarcoma, trabectin is recommended after doxorubicin-based treatment. Retroperitoneal/Intraabdominal Sarcomas • Preoperative radiation followed by surgery. Potential benefits of using pre-op RT are lower doses; the tumor displaces radiosensitive viscera outside the field of radiation. • Surgery if margin negative observation, margin positive consider reresection or post-op RT. • Adjuvant chemotherapy regimens following surgical resection have demonstrated decreased local recurrence rates, but the effect on overall survival is less clear. • Patients with unresectable or progressive disease, the recommendation is best supportive care. GIST • Resectable disease surgery followed by possible post-op imatinib • Lesions determined not to be resectable, treat with imatinib, then reassess response before evaluating whether suitable for surgery • Metastatic diseasedtreat with imatinib and consider changing to sunitinib depending on response/progression • Disease progressesdconsider regorafenib, or clinical trial or best supportive care Kaposi sarcoma • Optimal control of HIV infection using highly active antiretroviral therapy. • HAART may be tried as the sole modality in nonvisceral disease; for visceral disease, chemotherapy may be added. • For palliation of local symptoms, radiotherapy can be used but caution should be used with regard to local toxicities such as mucositis. RT dose is 200 cGy/fx to 20e40 Gy.
RT Technique CT simulated with extremity in a cast and wire on scar if treating postoperatively. Pre-op CT or MRI can be fused for target delineation. Multifield 3DCRT or IMRT can be used for planning. Use 6 MV photons, nine noncoplanar beams, or two-arc VMAT. A strip of healthy skin/limb circumference is spared, and treatment of whole circumference of bone is avoided. Block growth plates and joint, if possible. Put bolus on the scar. Daily IGRT is recommended (Figs. 22.1 and 22.2).
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FIGURE 22.1 A right upper thigh STS patient DRR of extremity, sarcoma, oblique field, showing 4e5 cm margin on the post-op tumor site and including the entire scar.
FIGURE 22.2 Example of transaxial isodose distribution for a patient with softtissue sarcoma of the thigh treated with (A) 3D-CRT and (B) IMRT techniques showing minimizing dose to the femur and surrounding normal tissue. From Sladoska A, et al. Application of IMRT in adjuvant treatment of soft tissue sarcomas of the thighdPreliminary results. Reports of Practical Oncology & Radiotherapy MayeJune 2011;16(3):110e4.
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Volumes Preoperative GTV ¼ gross disease based on imaging (MRI TI postcontrast) CTV1 ¼ GTV þ 4e5 cm craniocaudally and 1.5 cm radially, respecting anatomical barrier, include peritumoral edema (MRI T2) PTV ¼ CTV þ 0.5 cm Postoperative GTV ¼ none CTV1 ¼ tumor bed, surgical clips þ 4e5 cm craniocaudally and 1.5 cm radially, respecting anatomical barrier CTV2 ¼ tumor bed, surgical clips þ 1.5e2 cm craniocaudally and 1.5 cm radially respecting anatomical barrier PTV ¼ CTV þ 0.5 cm Doses Preoperative: 200 cGy/fx to 50 Gy Postoperative: Negative margin: 180e200 cGy/fx to 50e50.4 Gy, followed by boost dose to 63 Gy (60e66 Gy is acceptable) Microscopic positive margin: 200 cGy/fx to 50 Gy, followed by boost dose to 66e68 Gy Residual gross disease: 200 cGy/fx to 50 Gy, followed by boost dose to 70e76 Gy Brachytherapy boost: Postoperative boost can also be given via low-dose interstitial implant to the tumor bed. Based on the margin status, the radiation dose is 16e18 Gy. The catheters are loaded on or after the sixth post-op day after the wound healing is complete. For boost, use dose rate of 40e60 cGy/h. Start with 1 mCi seeds with 1 cm spacing. For implant >10 cm, use 1 cm spacing; for 10e20 cm, use 1.2 cm spacing; for >20 cm, use 1.5 cm spacing; consider increasing the end seeds by 25%. Constraints Depends on location of treatment site such as retroperitoneal or extremity. Spared healthy strip of limb circumference <20 Gy. Bone V40 < 64%, mean dose <37 Gy, hot spots<59 Gy* Joint space <45 Gy (*Ref: Dickie et al. Bone fractures following external beam radiotherapy and limbpreservation surgery for lower extremity soft tissue sarcoma: relationship to irradiated bone length, volume, tumor location and dose. Int J Radiat Oncol Biol Phys. 2009 Nov 15; 75(4):1119e24)
Complications • Delays wound healing (particularly preoperative radiotherapy, but long-term functional outcomes are better in patients who receive pre-op RT, likely due to higher radiotherapy doses and larger treatment sizes needed in postoperative radiotherapy) • Traumatic fractures, fibrosis with limitation of motion, nerve and vascular injuries, and lymphedema
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PREOPERATIVE RT
• Risk of second malignancy • Reduced fertility, depending on area treated • Site-specific toxicities, depending on site treated such as renal impairment, enteritis, mucositis, etc.
Outcome • The 5-year overall survival rates for localized sarcomas, regional stage sarcomas, and sarcomas with distant metastases are 83%, 54%, and 16%, respectively • For patients with retroperitoneal sarcoma who underwent complete resection, the 5-year survival rate was 58.3%, whereas it was 0% in cases of incomplete or no resection
Follow-up • Consider baseline postoperative and periodic imaging of site unless site is easily followed by physical examination • Follow patients every 3 months for the first 2e3 years and every 6e12 months thereafter • Chest X-ray or CT at each visit
ANNOTATED BIBLIOGRAPHY PREOPERATIVE RT Ref 1. Sampath S et al. (2011). Preoperative versus postoperative radiotherapy in soft-tissue sarcoma: multi-institutional analysis of 821 patients. Int J Radiat Oncol Biol 81(2):498e505. In this retrospective analysis, 821 patients with STS of all major anatomic sites who received definitive surgery and either pre-op or post-op RT were included. The median follow-up time was 63 months and the results were as given below: 5-year (%) CSS Pre-op RT
79
Post-op RT
74
P values
<0.05
The analysis showed preoperative RT is associated with a reduced cancer-specific mortality compared with postoperative RT in STS. Ref 2. O’Sullivan B et al. (2013). Phase 2 study of preoperative image-guided intensity-modulated radiation therapy to reduce wound and combined modalities in lower extremity soft tissue sarcoma. Cancer 15:119(10):1878e84. In this trial, 70 patients with histologically proven LE-STS appropriate for preoperative RT and surgery received 50 Gy in 25 daily fractions. Patients received IMRT using daily
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22. SARCOMAS
CBCT. GTV was delineated per CT or MRI, CTV extended 4 cm superiorly and inferiorly and 1.5 cm radially, restricted at the anatomic barriers, included peritumoral edema. CTV was expanded 0.5 cm to delineate PTV. Data from a median follow-up of 49 months were as follows: Wound (%) Complications
Primary (%) Closure
Local (%) Recurrence
This study
30.5
93.2
6.8
NCIC SR2 trial
No difference
71.4
P value
0.2
0.002
This study revealed that preoperative IG-IMRT significantly diminished the need for tissue transfer RT chronic morbidities and the need for subsequent secondary operations for wound complications was lowered although not significantly. Ref 3. Wang D et al. (2015). Significant reduction of late toxicities in patients with extremity Sarcoma treated with Image-Guided Radiation Therapy to a reduced target volume: Results of Radiation Therapy Oncology Group RTOG-0630 Trial. J Clin Oncol July 2015;33(20):2231e2238. RTOG 0630 Trial. In this trial, 98 patients with extremity STS received IGRT with (cohort A) or without (cohort B) chemotherapy followed by limb-sparing resection. Cohort A was closed for poor accrual. All patients in cohort B received IG-RT to 50 Gy in 25 fractions. For G2/3 tumor <8 cm: CTV sup/inf margins 2 cm, radial 1 cm, also cover edema on T2 MR; for G2/3, tumor > 8 cm: CTV sup/inf margins 3 cm, radial 1.5 cm, also cover edema on T2 MR. RT dose prescribed to reduced targeted volume plus 0.5 cm margin for PTV. IMRT or 3DCRT was used for RT. At a median follow-up of 3.6 years, results were as follows: Toxicity (%) Grade >2
2 year (%) LC
Cohort B
10.5
94
CANeNCICeSR2 trial
37
e
P value
<0.001
The significant reduction of late toxicities in patient with extremity STS who were treated with preoperative IGRT and absence marginal-field recurrences suggests that the target volumes used in the RTOG 0630 study are appropriate for preoperative IGRT for extremity STS.
POSTOPERATIVE RT Ref 4. Beane JD et al. (2014). Efficacy of adjuvant radiation therapy in the treatment of soft tissue sarcoma of the extremity: 20-year follow-up of a randomized prospective trial. Ann Surg Oncol 21(8):2484e9. NCI Trial.
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POSTOPERATIVE RT
In this trial, 141 patients with extremity STS were randomized to limb-sparing surgery (LSS) alone or receiving adjuvant EBRT. The study results at a median follow-up of 17.9 years were as follows:
Local (%) Recurrence
20 year (%) OS
Wound (%) Complication
Edema (%)
LSS
4
64
12.5
12
LSS þ RT
0
71
17
25
P value
0.44
0.22
0.72
0.31
The study results show that adjuvant EBRT following surgery for STS of the extremity provides excellent local control with acceptable treatment-related morbidity and no significant improvement in OS. Ref 5. Folkert MR et al. (2014). Comparison of local recurrence with conventional and intensity-modulated radiation therapy for primary soft-tissue sarcomas of the extremity. J Clin Oncol 32(29):3236e41. In this trial 319, consecutive adult patients with primary nonmetastatic extremity STS were treated with limb-sparing surgery and adjuvant RT. RT dose was generally 50 Gy in 2 Gy fractions for preoperative treatment and was prescribed to the planning target volume (PTV). In the postoperative setting, the PTV is treated to 45 Gy in 1.8 Gy fractions, and then the PTV volume is reduced and treated to an additional 18e21.6 Gy in 1.8 Gy fractions to a total dose of 63e66.6 Gy. Median follow-up data from 90 months were as follows:
LC
5-year (%) Joint Stiffness
Toxicity Gr > 2 Edema
3DCRT
15.1
IMRT (80% post-op)
7.6 ss
14.5
7.9
CANeNCICeSR2 trial
e
17.8
15.1
The study results showed that IMRT was associated with significantly reduced local recurrence compared with 3DCRT for primary STS of the extremity and late toxicity appear to be less with IMRT. Ref 6. Robinson MH et al. (2016). Vortex Trial: A randomized controlled multicenter phase 3 trial of volume of postoperative radiation therapy given to adult patients with extremity soft tissue sarcoma (STS). Int J Radiat Oncol Biol October 1, 2016; 96(2 Suppl.):S1. VORTEX Trial.
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22. SARCOMAS
In this trial, 216 patients with extremity STS after tumor resection were treated either in the control arm (C): 50 Gy in 25 fractions to CTV1 (GTV þ 5 cm craniocaudally and 2 cm axially) followed by 16 Gy in eight fractions to CTV2 (GTV þ 2 cm c-c and axially) or the research arm (R): 66 Gy in 33 fractions to CTV2 alone. No adjuvant chemotherapy was permitted. At a median follow-up of 4.8 years, the results were as follows:
5-year (%) LRFS
5-year (%) OS
Toxicity Gr > 1
bone joint
Arm C
86
72
11
18
Arm R
84
67
15
18
The study results indicated there was no significant difference in limb function at 2 years between the control and research arms. Because of the small number of events, it was not possible to state whether or not the research arm was inferior for LRFS.
NEOADJUVANT AND ADJUVANT CHEMOTHERAPY Ref 7. Cesne Le et al. (2014). Doxorubicin-based adjuvant chemotherapy in soft tissue sarcoma: pooled analysis of two STBSG-EORTC phase III trials. Ann Oncol 25(12): 2425e32. EORTC 627711/62931 Trial. In this study, 819 individual patient’s data from two EORTC trials (EORTC 62771 and EORTC 62931) were pooled. Adjuvant RT was given to both study arms. At a median follow-up of 8.2 years, results were as follows: 1. Adjuvant chemotherapy CYVADIC reduced the local recurrence rate without any impact on survival (EORTC 62771). 2. Adjuvant chemotherapy AI (EORTC 62931) failed to demonstrate any advantage for both RFS and OS. This current study showed that adjuvant CT is not associated with a better OS in young patients or any subgroup and therefore is not recommended for routine standard of care. Ref 8. Pallasini E et al. (2016). Short, full-dose adjuvant chemotherapy (CT) in highrisk adult soft tissue sarcomas (STS): Long-term follow-up of a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group. J Clin Oncol May 2016;34(15 Suppl.):1045e11045. In this trial, 328 patients with high-risk extremity/trunk STS were randomized to receive three preoperative cycles of epirubicin 120 mg/m2 and ifosfamide 9 g/m2 (arm A) or to receive the same three preoperative cycles plus two postoperative cycles (arm B). Radiotherapy (RT) could be either delivered in the preoperative or in the postoperative setting. A total dose of 44e50.4 Gy was given in the preoperative setting and 60e66 Gy in the postoperative setting. Patients treated with preoperative RT could also receive an intraoperative (10e12 Gy) or
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NEOADJUVANT AND ADJUVANT CHEMOTHERAPY
postoperative boost (16e20 Gy) at the discretion of the treating physician. At a median followup of 116 months, results were as follows:
10-year DM (%)
10-year OS (%)
Arm A
34.1
64
Arm B
34.8
59
The study results show that at a longer FU, three cycles of a full-dose conventional CT in comparison with five resulted in about 60% patients alive and disease-free at 10 years.
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22 Sarcomas SOFT-TISSUE SARCOMAS The estimated incidence in the United States is 13,040 with estimated 5150 deaths in 2018. These tumors are mesenchymally derived and can occur in any part of the body but most commonly in the extremities (60%) and predominantly in muscle groups, although patients can present with head and neck, chest, and retroperitoneal tumors. Sarcomas most commonly metastasize to the lungs and rarely to the lymph nodes (w5%). Angiosarcoma and rhabdomyasarcoma are the most common subtypes associated with lymph node metastases (14%) followed by synovial cell, malignant peripheral nerve sheath tumor, and clear cell sarcoma.
Workup Risk Factors • Inherited disorders: • Hereditary retinoblastomadosteosarcoma, soft-tissue sarcoma, and melanoma • Li Fraumeni syndromedbreast cancer, brain tumors, acute leukemia, softtissue sarcomas, bone sarcomas, and adrenal cortical carcinoma • Neurofibromatosis type Idbenign and malignant nerve sheath tumors and gastrointestinal stromal tumors (GIST) • Radiation (therapeutic, diagnostic, or accidental)dangiosarcoma, osteosarcoma • Environmental toxinsdpolyvinyl chloride, thorium dioxide (Thorotrast)d angiosarcoma, fibrosarcoma, neurofibrosarcomas, spindle cell sarcomas, extraskeletal chondrosarcoma • Human herpesvirus 8detiologic agent responsible for all types of Kaposi sarcoma in immunocompromised patients Symptoms and Signs • Symptoms secondary to effects of pressure or direct invasion by the tumor, such as numbness, edema, and pain and are site specific • Painless lump, growing over time
Copyright © 2019 Elsevier Inc. All rights reserved.
Fundamentals of Radiation Oncology https://doi.org/10.1016/B978-0-12-814128-1.00022-2
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Investigations All suspected soft-tissue sarcomas should be referred to a specialist sarcoma unit. • CBC, chemistry panel, BUN/CR, ESR, LDH • Carefully planned biopsy to reduce risk of seeding at time of surgerydFNA may be adequate for histopathological subtyping or grade assessment, but core needle biopsy, or incisional biopsy, is preferred • Imaging should be performed before biopsy or surgery • CT thorax, CT abdomen for myxoid liposarcomas and retroperitoneal sarcomas • MRI should be performed to locally stage the tumor. Consider angiography if concerned about the vessels • PET-CT if distant metastatic disease has not already been discovered, or where the decision for amputation or mastectomy would be altered by discovery of metastatic disease
TNM STAGING (SOFT-TISSUE SARCOMAS) TRUNK AND EXTREMITIES Tx
Primary tumor cannot be assessed
T0
No evidence of primary tumor
T1
Tumor 5 cm in greatest dimension
T2
Tumor >5 cm in greatest dimension, 10 cm
T3
Tumor >10 cm in greatest dimension, 15 cm
T4
Tumor >15 cm in greatest dimension
N0
No regional lymph node metastasis
N1
Regional lymph node metastasis
M0
No distant metastasis
M1
Distant metastasis
FNCLCC HISTOLOGIC GRADE GX
Grade cannot be assessed
G1
Total differentiation, mitotic count, and necrosis score of 2 or 3
G2
Total differentiation, mitotic count, and necrosis score of 4 or 5
G3
Total differentiation, mitotic count, and necrosis score of 6, 7, or 8
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FNCLCC HISTOLOGIC GRADE
Stage Grouping Stage IA
T1
N0
M0
G1, GX
Stage IB
T2,3,4
N0
M0
G1, GX
Stage II
T1
N0
M0
G2, G3
Stage IIIA
T2
N0
M0
G2, G3
Stage IIIB
T3,4
N0
M0
G2, G3
Stage IV
Any T
N1
M0
Any G
Any T
Any N
M1
Any G
TNM, T (tumor), N (regional lymph nodes), and M (distant metastasis). Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer Science Business Media LLC, www.springer.com.
Treatment Stage 1a/b, Extremity, Superficial Trunk, and H&N Lesions • Surgical wide local excision with oncologically acceptable margins • Patients with positive marginsdrecommendation reresection to obtain negative margins • Stage 1a with clear marginsdobserve • Stage 1b with clear marginsdconsider post-op radiotherapy • Positive margins, or gross residual diseasedperform post-op radiotherapy Stage II, III, Extremity, Superficial Trunk, and H&N Lesions • Preoperative radiotherapy should be considered for all patients, especially for large tumor, or where surgery will provide less than a wide negative resection margin [1e3]. • For positive margins or residual disease, postoperative RT is recommended with EBRT or brachytherapy [4e6]. • The use of adjuvant chemotherapy to treat adults with localized resectable softtissue sarcoma remains controversial. Benefits are further improved with the addition of ifosfamide to doxorubicin-based regimens but must be weighed against associated toxicities [7,8]. Unresectable, Node-Positive, Distant Metastasis • Unresectable diseaseddefinitive RT with consideration for concurrent chemotherapy • Consider regional node dissection and metastasectomy for limited disease followed by localized radiotherapy and chemotherapy
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22. SARCOMAS
• Disseminated diseaseetreatment is driven by histology. • For doxorubicin sensitive tumors, treatment with olaratumab and doxorubicin has replaced ifosfamide-doxorubicin. Second line agents in this setting include pegylated liposomal doxorubicin, gemcitabine in combination with other agents or gemcitabine alone. • For patients with dematofibrosarcima protuberant(DMFP) or giant cell tenosynovial tumor, imatinib is recommeded. • For advanced liposarcoma and leiomyosarcoma, trabectin is recommended after doxorubicin-based treatment. Retroperitoneal/Intraabdominal Sarcomas • Preoperative radiation followed by surgery. Potential benefits of using pre-op RT are lower doses; the tumor displaces radiosensitive viscera outside the field of radiation. • Surgery if margin negative observation, margin positive consider reresection or post-op RT. • Adjuvant chemotherapy regimens following surgical resection have demonstrated decreased local recurrence rates, but the effect on overall survival is less clear. • Patients with unresectable or progressive disease, the recommendation is best supportive care. GIST • Resectable disease surgery followed by possible post-op imatinib • Lesions determined not to be resectable, treat with imatinib, then reassess response before evaluating whether suitable for surgery • Metastatic diseasedtreat with imatinib and consider changing to sunitinib depending on response/progression • Disease progressesdconsider regorafenib, or clinical trial or best supportive care Kaposi sarcoma • Optimal control of HIV infection using highly active antiretroviral therapy. • HAART may be tried as the sole modality in nonvisceral disease; for visceral disease, chemotherapy may be added. • For palliation of local symptoms, radiotherapy can be used but caution should be used with regard to local toxicities such as mucositis. RT dose is 200 cGy/fx to 20e40 Gy.
RT Technique CT simulated with extremity in a cast and wire on scar if treating postoperatively. Pre-op CT or MRI can be fused for target delineation. Multifield 3DCRT or IMRT can be used for planning. Use 6 MV photons, nine noncoplanar beams, or two-arc VMAT. A strip of healthy skin/limb circumference is spared, and treatment of whole circumference of bone is avoided. Block growth plates and joint, if possible. Put bolus on the scar. Daily IGRT is recommended (Figs. 22.1 and 22.2).
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FNCLCC HISTOLOGIC GRADE
549
FIGURE 22.1 A right upper thigh STS patient DRR of extremity, sarcoma, oblique field, showing 4e5 cm margin on the post-op tumor site and including the entire scar.
FIGURE 22.2 Example of transaxial isodose distribution for a patient with softtissue sarcoma of the thigh treated with (A) 3D-CRT and (B) IMRT techniques showing minimizing dose to the femur and surrounding normal tissue. From Sladoska A, et al. Application of IMRT in adjuvant treatment of soft tissue sarcomas of the thighdPreliminary results. Reports of Practical Oncology & Radiotherapy MayeJune 2011;16(3):110e4.
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22. SARCOMAS
Volumes Preoperative GTV ¼ gross disease based on imaging (MRI TI postcontrast) CTV1 ¼ GTV þ 4e5 cm craniocaudally and 1.5 cm radially, respecting anatomical barrier, include peritumoral edema (MRI T2) PTV ¼ CTV þ 0.5 cm Postoperative GTV ¼ none CTV1 ¼ tumor bed, surgical clips þ 4e5 cm craniocaudally and 1.5 cm radially, respecting anatomical barrier CTV2 ¼ tumor bed, surgical clips þ 1.5e2 cm craniocaudally and 1.5 cm radially respecting anatomical barrier PTV ¼ CTV þ 0.5 cm Doses Preoperative: 200 cGy/fx to 50 Gy Postoperative: Negative margin: 180e200 cGy/fx to 50e50.4 Gy, followed by boost dose to 63 Gy (60e66 Gy is acceptable) Microscopic positive margin: 200 cGy/fx to 50 Gy, followed by boost dose to 66e68 Gy Residual gross disease: 200 cGy/fx to 50 Gy, followed by boost dose to 70e76 Gy Brachytherapy boost: Postoperative boost can also be given via low-dose interstitial implant to the tumor bed. Based on the margin status, the radiation dose is 16e18 Gy. The catheters are loaded on or after the sixth post-op day after the wound healing is complete. For boost, use dose rate of 40e60 cGy/h. Start with 1 mCi seeds with 1 cm spacing. For implant >10 cm, use 1 cm spacing; for 10e20 cm, use 1.2 cm spacing; for >20 cm, use 1.5 cm spacing; consider increasing the end seeds by 25%. Constraints Depends on location of treatment site such as retroperitoneal or extremity. Spared healthy strip of limb circumference <20 Gy. Bone V40 < 64%, mean dose <37 Gy, hot spots<59 Gy* Joint space <45 Gy (*Ref: Dickie et al. Bone fractures following external beam radiotherapy and limbpreservation surgery for lower extremity soft tissue sarcoma: relationship to irradiated bone length, volume, tumor location and dose. Int J Radiat Oncol Biol Phys. 2009 Nov 15; 75(4):1119e24)
Complications • Delays wound healing (particularly preoperative radiotherapy, but long-term functional outcomes are better in patients who receive pre-op RT, likely due to higher radiotherapy doses and larger treatment sizes needed in postoperative radiotherapy) • Traumatic fractures, fibrosis with limitation of motion, nerve and vascular injuries, and lymphedema
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PREOPERATIVE RT
• Risk of second malignancy • Reduced fertility, depending on area treated • Site-specific toxicities, depending on site treated such as renal impairment, enteritis, mucositis, etc.
Outcome • The 5-year overall survival rates for localized sarcomas, regional stage sarcomas, and sarcomas with distant metastases are 83%, 54%, and 16%, respectively • For patients with retroperitoneal sarcoma who underwent complete resection, the 5-year survival rate was 58.3%, whereas it was 0% in cases of incomplete or no resection
Follow-up • Consider baseline postoperative and periodic imaging of site unless site is easily followed by physical examination • Follow patients every 3 months for the first 2e3 years and every 6e12 months thereafter • Chest X-ray or CT at each visit
ANNOTATED BIBLIOGRAPHY PREOPERATIVE RT Ref 1. Sampath S et al. (2011). Preoperative versus postoperative radiotherapy in soft-tissue sarcoma: multi-institutional analysis of 821 patients. Int J Radiat Oncol Biol 81(2):498e505. In this retrospective analysis, 821 patients with STS of all major anatomic sites who received definitive surgery and either pre-op or post-op RT were included. The median follow-up time was 63 months and the results were as given below: 5-year (%) CSS Pre-op RT
79
Post-op RT
74
P values
<0.05
The analysis showed preoperative RT is associated with a reduced cancer-specific mortality compared with postoperative RT in STS. Ref 2. O’Sullivan B et al. (2013). Phase 2 study of preoperative image-guided intensity-modulated radiation therapy to reduce wound and combined modalities in lower extremity soft tissue sarcoma. Cancer 15:119(10):1878e84. In this trial, 70 patients with histologically proven LE-STS appropriate for preoperative RT and surgery received 50 Gy in 25 daily fractions. Patients received IMRT using daily
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22. SARCOMAS
CBCT. GTV was delineated per CT or MRI, CTV extended 4 cm superiorly and inferiorly and 1.5 cm radially, restricted at the anatomic barriers, included peritumoral edema. CTV was expanded 0.5 cm to delineate PTV. Data from a median follow-up of 49 months were as follows: Wound (%) Complications
Primary (%) Closure
Local (%) Recurrence
This study
30.5
93.2
6.8
NCIC SR2 trial
No difference
71.4
P value
0.2
0.002
This study revealed that preoperative IG-IMRT significantly diminished the need for tissue transfer RT chronic morbidities and the need for subsequent secondary operations for wound complications was lowered although not significantly. Ref 3. Wang D et al. (2015). Significant reduction of late toxicities in patients with extremity Sarcoma treated with Image-Guided Radiation Therapy to a reduced target volume: Results of Radiation Therapy Oncology Group RTOG-0630 Trial. J Clin Oncol July 2015;33(20):2231e2238. RTOG 0630 Trial. In this trial, 98 patients with extremity STS received IGRT with (cohort A) or without (cohort B) chemotherapy followed by limb-sparing resection. Cohort A was closed for poor accrual. All patients in cohort B received IG-RT to 50 Gy in 25 fractions. For G2/3 tumor <8 cm: CTV sup/inf margins 2 cm, radial 1 cm, also cover edema on T2 MR; for G2/3, tumor > 8 cm: CTV sup/inf margins 3 cm, radial 1.5 cm, also cover edema on T2 MR. RT dose prescribed to reduced targeted volume plus 0.5 cm margin for PTV. IMRT or 3DCRT was used for RT. At a median follow-up of 3.6 years, results were as follows: Toxicity (%) Grade >2
2 year (%) LC
Cohort B
10.5
94
CANeNCICeSR2 trial
37
e
P value
<0.001
The significant reduction of late toxicities in patient with extremity STS who were treated with preoperative IGRT and absence marginal-field recurrences suggests that the target volumes used in the RTOG 0630 study are appropriate for preoperative IGRT for extremity STS.
POSTOPERATIVE RT Ref 4. Beane JD et al. (2014). Efficacy of adjuvant radiation therapy in the treatment of soft tissue sarcoma of the extremity: 20-year follow-up of a randomized prospective trial. Ann Surg Oncol 21(8):2484e9. NCI Trial.
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POSTOPERATIVE RT
In this trial, 141 patients with extremity STS were randomized to limb-sparing surgery (LSS) alone or receiving adjuvant EBRT. The study results at a median follow-up of 17.9 years were as follows:
Local (%) Recurrence
20 year (%) OS
Wound (%) Complication
Edema (%)
LSS
4
64
12.5
12
LSS þ RT
0
71
17
25
P value
0.44
0.22
0.72
0.31
The study results show that adjuvant EBRT following surgery for STS of the extremity provides excellent local control with acceptable treatment-related morbidity and no significant improvement in OS. Ref 5. Folkert MR et al. (2014). Comparison of local recurrence with conventional and intensity-modulated radiation therapy for primary soft-tissue sarcomas of the extremity. J Clin Oncol 32(29):3236e41. In this trial 319, consecutive adult patients with primary nonmetastatic extremity STS were treated with limb-sparing surgery and adjuvant RT. RT dose was generally 50 Gy in 2 Gy fractions for preoperative treatment and was prescribed to the planning target volume (PTV). In the postoperative setting, the PTV is treated to 45 Gy in 1.8 Gy fractions, and then the PTV volume is reduced and treated to an additional 18e21.6 Gy in 1.8 Gy fractions to a total dose of 63e66.6 Gy. Median follow-up data from 90 months were as follows:
LC
5-year (%) Joint Stiffness
Toxicity Gr > 2 Edema
3DCRT
15.1
IMRT (80% post-op)
7.6 ss
14.5
7.9
CANeNCICeSR2 trial
e
17.8
15.1
The study results showed that IMRT was associated with significantly reduced local recurrence compared with 3DCRT for primary STS of the extremity and late toxicity appear to be less with IMRT. Ref 6. Robinson MH et al. (2016). Vortex Trial: A randomized controlled multicenter phase 3 trial of volume of postoperative radiation therapy given to adult patients with extremity soft tissue sarcoma (STS). Int J Radiat Oncol Biol October 1, 2016; 96(2 Suppl.):S1. VORTEX Trial.
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22. SARCOMAS
In this trial, 216 patients with extremity STS after tumor resection were treated either in the control arm (C): 50 Gy in 25 fractions to CTV1 (GTV þ 5 cm craniocaudally and 2 cm axially) followed by 16 Gy in eight fractions to CTV2 (GTV þ 2 cm c-c and axially) or the research arm (R): 66 Gy in 33 fractions to CTV2 alone. No adjuvant chemotherapy was permitted. At a median follow-up of 4.8 years, the results were as follows:
5-year (%) LRFS
5-year (%) OS
Toxicity Gr > 1
bone joint
Arm C
86
72
11
18
Arm R
84
67
15
18
The study results indicated there was no significant difference in limb function at 2 years between the control and research arms. Because of the small number of events, it was not possible to state whether or not the research arm was inferior for LRFS.
NEOADJUVANT AND ADJUVANT CHEMOTHERAPY Ref 7. Cesne Le et al. (2014). Doxorubicin-based adjuvant chemotherapy in soft tissue sarcoma: pooled analysis of two STBSG-EORTC phase III trials. Ann Oncol 25(12): 2425e32. EORTC 627711/62931 Trial. In this study, 819 individual patient’s data from two EORTC trials (EORTC 62771 and EORTC 62931) were pooled. Adjuvant RT was given to both study arms. At a median follow-up of 8.2 years, results were as follows: 1. Adjuvant chemotherapy CYVADIC reduced the local recurrence rate without any impact on survival (EORTC 62771). 2. Adjuvant chemotherapy AI (EORTC 62931) failed to demonstrate any advantage for both RFS and OS. This current study showed that adjuvant CT is not associated with a better OS in young patients or any subgroup and therefore is not recommended for routine standard of care. Ref 8. Pallasini E et al. (2016). Short, full-dose adjuvant chemotherapy (CT) in highrisk adult soft tissue sarcomas (STS): Long-term follow-up of a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group. J Clin Oncol May 2016;34(15 Suppl.):1045e11045. In this trial, 328 patients with high-risk extremity/trunk STS were randomized to receive three preoperative cycles of epirubicin 120 mg/m2 and ifosfamide 9 g/m2 (arm A) or to receive the same three preoperative cycles plus two postoperative cycles (arm B). Radiotherapy (RT) could be either delivered in the preoperative or in the postoperative setting. A total dose of 44e50.4 Gy was given in the preoperative setting and 60e66 Gy in the postoperative setting. Patients treated with preoperative RT could also receive an intraoperative (10e12 Gy) or
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NEOADJUVANT AND ADJUVANT CHEMOTHERAPY
postoperative boost (16e20 Gy) at the discretion of the treating physician. At a median followup of 116 months, results were as follows:
10-year DM (%)
10-year OS (%)
Arm A
34.1
64
Arm B
34.8
59
The study results show that at a longer FU, three cycles of a full-dose conventional CT in comparison with five resulted in about 60% patients alive and disease-free at 10 years.
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