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Radiotherapy following gross total resection of adult soft tissue sarcoma of the head and neck
Practical Radiation Oncology (2012) 2, e121–e128
www.practicalradonc.org
Original Report
Radiotherapy following gross total resection of adult soft tissue sarcoma of the head and neck Daniel Trifiletti MD a , Robert J. Amdur MD a,⁎, Roi Dagan MD a , Daniel J. Indelicato MD a,b , William M. Mendenhall MD a,b , Jessica M. Kirwan MA a , Anamaria R. Yeung MD a , John W. Werning MD c , Christopher G. Morris MS a a
Department of Radiation Oncology, University of Florida, Gainesville, Florida Department of Otolaryngology, University of Florida, Gainesville, Florida c University of Florida Proton Therapy Institute, Jacksonville, Florida b
Received 14 December 2011; revised 5 January 2012; accepted 10 January 2012
Abstract Purpose: This study reports the outcomes of adults with soft tissue sarcoma (STS) of the head and neck following resection and postoperative radiotherapy (RT), and provides a framework for explaining the issues that radiation oncologists must understand to manage patients with this diverse group of tumors. Methods and Materials: Twenty-four patients met the following inclusion criteria of this study: age ≥19 years, head or neck primary site, STS, with the exception of rhabdomyosarcoma, Ewing, or angiosarcoma variants, and curative-attempt treatment with gross total tumor resection followed by RT. Results: All patients underwent gross total tumor resection followed by adjuvant RT at our institution during the 28-year period between June 1, 1981, and December 31, 2009. This is a mature study with a median follow-up of 11 years (range, 0.6-27 years). No patient was lost to follow-up. All recurrences were at the primary site. No patient developed an isolated regional or distant recurrence. No patient developed synchronous nodal or distant recurrences at the time of local recurrence. Half of the recurrences presented within 1 year of completing RT, but there were 2 cases where we did not detect recurrence until years 6 and 8 after RT. No recurrence was successfully salvaged. The actuarial rate of local control and relapse-free survival was 83% (95% CI [confidence interval], 63%-94%) at 5 years and 73% (95% CI, 51%-87%) at 10 years. The incidence of moderate to severe treatment complications was 4%. Conclusions: Our series documents that gross total resection followed by RT cures most patients (75%) with the most common types of STS of the head and neck. All recurrences were local, meaning near the primary site in tissue that received the full RT prescription dose. For this reason, modifying the approach to treatment of the primary tumor site is the only strategy that will meaningfully improve outcomes for this group of patients. © 2012 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
Conflicts of interest: None. ⁎ Corresponding author. 2000 SW Archer Rd, PO Box 100385, Gainesville, FL 32610-0385. E-mail address: [email protected]fl.edu (R.J. Amdur). 1879-8500/$ – see front matter © 2012 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.prro.2012.01.003
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Introduction Adult soft tissue sarcomas (STSs) that originate in the soft tissues above the clavicles are often managed by headand-neck cancer specialists. Some of the treatment principles for head-and-neck sarcoma are extrapolated from those of extremity lesions, but the proximity of sensitive normal tissues is such that sarcomas of the head and neck present demanding treatment challenges. Our departments have been studying the outcomes of head-and-neck sarcoma patients for many years. 1-3 Our
analyses and publications from other institutions have refined our thinking on how to classify and manage sarcoma patients. This paper will report the long-term outcomes for the largest subgroup of our head-and-neck sarcoma series, adults treated with gross total resection and postoperative radiotherapy (RT), and provide a framework for explaining the issues that radiation oncologists must understand to manage patients with this diverse group of tumors.
Methods and materials Table 1
Characteristics of our study population
Characteristic
Data
Inclusion dates No. of patients Age on day 1 of RT (y) RT for a recurrence Histologic grade Grade 3 Grade 1-2 Histology MFH DFSP Neurosarcoma Leiomyosarcoma Spindle cell sarcoma Fibrosarcoma Alveolar Synovial sarcoma Triton a Site Face/scalp Neck Paranasal sinus Larynx American Joint Committee on Cancer Stage I II III Surgical margin Negative (N20 mm) Close (0.1-20 mm) Microscopically positive RT dose 50-59.9 Gy 60-74.4 Gy Elective nodal RT Chemotherapy Follow-up from day 1 of RT Median, range (y) N5 y N10 y
June 1981-December 2009 24 Median, 46 (range, 20-87) 6 (25%) 15 (63%) 9 (37%) 4 4 4 3 3 2 1 2 1
(17%) (17%) (17%) (13%) (13%) (8%) (4%) (8%) (4%)
14 (58%) 5 (21%) 4 (17%) 1 (4%)
8 (33%) 14 (59%) 2 (8%)
Data for this study were collected as part of an Institutional Review Board-approved protocol. All patients had biopsy-confirmed STS of the head and neck and age of at least 19 years on day 1 of RT. All patients underwent gross total tumor resection followed by adjuvant RT at our institution during the 28-year period between June 1, 1981 and December 31, 2009. The last patient was treated 2.4 years before the date of analysis. No patient was lost to follow-up. This study excludes a small number of patients who were treated with preoperative RT or RT for gross disease because the tumor was unresectable or because the patient was medically inoperable. No patient in this study was known to have a distant metastasis at the time of RT. Table 1 summarizes the major characteristics of the 24 patients in our cohort. In 18 patients (75%), surgery and postoperative RT were the first treatments for their sarcoma. The other 6 patients (25%) were initially treated with at least one curative-intent surgical procedure before referral for the total resection and postoperative RT recorded in this study. All 6 patients experienced gross tumor recurrence before the treatment that qualified them for inclusion in this study. Our series includes various subtypes of STS. This study does not include patients with rhabdomyosarcoma or extraskeletal Ewing sarcoma because they are known to have a different biology than other types of STS and
0 (0%) 19 (79%) 5 (21%) 7 (29%) 17 (71%) 9 (38%) 2 (8%) 11, 0.6-23 83% 54%
DFSP, dermatofibrosarcoma protuberans; MFH, malignant fibrous histiocytoma; RT, radiotherapy. a Triton: a combination of malignant schwannoma cells and malignant rhabdomyoblasts.
Figure 1 Actuarial plot of relapse-free and overall survival for the 24 patients in this series.
Practical Radiation Oncology: October-December 2012 Table 2
Postoperative RT of head-and-neck STS
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Patients with tumor recurrence (all at the primary site); 6 of 24 (25%) patients
Patient
Time after RT
Histology
Site
Stage, grade
Surgical margin
Chemo.
RT dose (Gy)
RT technique
Year of RT
Salvage attempted a
Survival b (y)
1 2 3
b1 y b1 y b1 y
Leiomyo. MFH Fibro.
PNS PNS Face
III, Grade 3 III, Grade 3 IIa, Grade 3
Close Close Positive
No No No
66.6 69.6 60.0
1997 1997 1987
No No No
0.6 1.0 2.0
4 5
3.5 y 6y
Synovial Neuro.
Face Face
IIa, Grade 3 IIa, Grade 3
Positive Positive
Yes c No
74.4 74.4
2005 1985
No Yes
5.2 7.5
6
8y
Spindle
PNS
IIb, Grade 2
Close
No
74.4
3D-CRT 3D-CRT Electrons and 3D-CRT and an Ir192 implant IMRT Electrons and Co60 3D-CRT
2002
No
8.1 (alive)
3D-CRT, 3-dimensional chemoradiotherapy; Fibro., fibrosarcoma; IMRT, intensity modulated radiation therapy; Leiomyo., leiomyosarcoma; MFH, malignant fibrous histiocytoma; Neuro., neurosarcoma; PNS, paranasal sinus; RT, radiotherapy. a All salvage attempts were surgical resections. No patient was successfully salvaged due to repeat local recurrence. b All patients who developed a tumor recurrence died from progressive sarcoma with the exception of patient 6, who is alive with recurrent tumor. c Adriamycin and ifosfamide.
chemotherapy plays a major role in their management. This study also excluded patients with angiosarcoma because almost all of our patients with variants of this histology had large tumors of the scalp that present unique management problems and have an extremely poor prognosis. 4 Patients were retrospectively staged according to the American Joint Committee on Cancer 7th edition STS staging system. 5 Over half the patients in this series had stage II tumors. There is no consensus in the literature on the definition of a “close margin” in this setting. We classified the surgical margin as either microscopically positive (b0.1 mm), close (0.1-20 mm), or wide (N20 mm). We selected 20 mm as the upper limit for the definition of a “close” margin because in several patients this was the only factor that led the tumor conference team to recommend RT. The RT dose schedule and technique varied with clinical scenario and with the availability of new technology during the study period. The primary RT techniques were en face orthovoltage or electron beam (46%), 3-dimensional conformal RT with cobalt-60 or 6to 18-MV photon beams oriented in the axial plane (46%), and intensity-modulated RT with 7 to 9 beam angles (8%). Extending the RT treatment area to treat the clinically negative regional nodes (elective nodal RT) was at the discretion of the treating physician and performed in 38% of the patients. This series begins before magnetic resonance imaging was available at our medical center. Imaging of the head and neck before RT treatment included a computerized tomography (CT) scan in 79% of patients and a magnetic resonance scan in 21%. All patients had their chest imaged with plain film radiography and 29% had a CT scan of the chest that was negative for metastatic disease. Complications from RT were graded with the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE, v4.0). 6 Our
complication analysis is limited by the retrospective nature of this study. We did not attempt to record grade 1 or 2 complications because we know that these are often not documented in our records. The focus of our analysis was on moderate or severe complications, meaning CTC grades 3 to 5.
Table 3
Univariate comparisons a
Variable
Recurrence rate
Surgical margin
Positive: 3/5 (60%) Negative or close: 3/19 (16%) Histologic grade Grade 3: 5/15 (30%) Grade 1-2: 1/9 (11%) Margin and grade Positive and grade 3: 3/3 (100%) combined Negative, close, or grade 1-2: 3/21 (14%) Stage I: 0/7 (0%) American Joint Stage II-III: 6/17 (35%) Committee on Cancer stage Age ≤46 y: 3/13 (23%) ≥47 y: 3/11 (27%) RT for recurrence Yes recurrent: 2/6 (33%) Not recurrent: 4/18 (22%) Elective nodal Yes ENI: 3/9 (33%) irradiation No ENI: 3/15 (20%) RT fractionation Once daily: 1/10 (10%) Twice daily: 5/14 (36%) RT dose 50-59.9 Gy: 0/7 (0%) 60-74.4 Gy: 6/17 (35%) RT year 1981-1995: 2/12 (17%) 1996-2009: 4/12 (33%)
P value b .08 .35 .01
.13
.99 .62 .64 .34 .13 .64
ENI, elective nodal irradiation; RT, radiotherapy. a The distribution of patients and number of subgroups was such that comparisons were not meaningful for histology, site, and RT dose. b Fisher exact test.
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Literature review: Head-and-neck soft tissue sarcoma
Institution Publication
Study dates
No. of patients
Includes Rhabdo, Follow-up Ewings, or Angio Rhabdo: no Ewings: no Angio: 19% Rhabdo: no Ewings: no Angio: 20% None Rhabdo: no Ewings: no Angio: 27% a Rhabdo: 5.8% Ewings: no Angio: 11.5% Rhabdo: 3% Ewings: no Angio: 15% Rhabdo: 6% Ewings: no Angio: 6% Rhabdo: no Ewings: no Angio: 10% None
MGH
Willers 1995 8
1972-1993
57
U. Iowa
Barker 2002 9
1970-2000
44
TMH MSKCC
Dudhat 2000 10 Kraus 1992 11
1981-1995 1982-1989
72 60
PMH
Le Vay 1994 12
1980-1988
52
UCSF
Le 1997 13
1961-1993
65
1969-1983
53
PMH
O'Sullivan 2003 15 1989-1999
40
Current Study
—
24
U. Illinois Greager 1985 14
1981-2009
Recurrent
Median Dose (Gy)
Median 4.3 y 30%
64.8
NS
60
0%
NS 17% Median 4.8 y 32%
NS 60.0
Min. 3.0 y
NS
NS
Median 5.3 y 0%
59.4
NS
NS
NS
Mean 3.6 y
20%
50.0
Median 11.1 y 25%
64.8
(Continued)
All data were analyzed using SAS statistical software (SAS Institute, Cary, NC). Estimates of local control and relapse-free survival were computed using the KaplanMeier product-limit method. 7 For the pattern of failure analysis, we did not code patients who experienced a regional or distant recurrence if they also recurred locally since local recurrence may cause regional or distant metastases as a secondary event.
Results Median follow-up for this study was 11 years (range, 0.6-27 years). The follow-up in patients who were alive at last median follow-up was 13 years (range, 2-23 years). Figure 1 is an actuarial plot of local control, relapse-free and overall survival. Six patients (25%) experienced tumor recurrence. All recurrences were local, meaning near the primary site in tissue that received the full RT prescription dose. No patient developed synchronous nodal or distant recurrence at the time of local recurrence. No patient died of a treatment complication and no patient was successfully
salvaged following tumor recurrence. For these reasons, the rates of local control, local-regional control, relapsefree survival, and cause-specific survival are the same. Table 2 summarizes the characteristics of the 6 patients who developed a tumor recurrence. Most recurrences presented within a year after completing RT but there were 2 late recurrences detected 6 and 8 years after treatment. No patient was successfully salvaged following a recurrence. Five of the 6 patients who recurred died of progressive sarcoma and the remaining patient is living with progressive sarcoma at the skull base. The small number of patients limits our ability to identify prognostic factors so that lack of a correlation in this study does not represent a reliable finding. The study population is too small for multivariate analysis. Table 3 summarizes the univariate comparisons. The recurrence rate was higher in patients treated more recently and with higher doses, but the differences did not approach statistical significance. One patient experienced a moderate-to-severe complication. He was treated with en face electrons to the temporal soft tissue to 64.8 Gy at 1.2 Gy per fraction twice daily. Two and a half years after treatment he developed
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Table 4 (continued) Chemo
ENI
Local Control
DMFS
RFS
CSS
OS
12%
NS
60% (5 y)
77% (5 y)
NS
NS
66% (5 y)
2%
18% a
57% (5 y)
NS
NS
72% (5 y)
61% (5 y)
6% 12%
NS NS
63% a 70% (5 y)
90% a 87% a
45% (5 y) 60% (5 y)
NS NS
60% (5 y) 71% (5 y)
23%
NS
59% (5 y)
69% (5y)
NS
62% (5 y)
NS
22%
0%
66% (5 y)
86% b
NS
60% (5 y)
56% (5 y)
NS
NS
NS
NS
54% (5 y)
NS
NS
3%
NS
80% (2 y)
85% (5 y)
NS
NS
NS
8%
38%
73% (10 y)
100% (10 y)
73% (10 y)
73% (10 y)
87% (5 y) 65% (10 y)
Angio, angiosarcoma; CSS, cause-specific survival; DFS, disease-free survival; DMFS, distant metastasis-free survival; ENI, elective nodal irradiation; MGH, Massachusetts General Hospital; NCI, Netherlands Cancer Institute; MSKCC, Memorial Sloan-Kettering Cancer Center; NS, not specified; OS, overall survival; PMH, Princess Margaret Hospital; Rhabdo, rhabdomyosarcoma; TMH, Tata Memorial Hospital; UCSF, University of California San Francisco. a Crude numbers. b Includes regional metastases.
temporal lobe necrosis and subsequent resection. He is now 23 years out from therapy with no evidence of disease. He works full time yet suffers from depression, which is medically managed. We consider this to represent a grade 4 complication. The grade 3-5 complication rate in our series was 1 of 24 (4%) and 1 of 19 (5%) in patients whose tumors did not recur. As our series has long-term follow-up on most patients, it is noteworthy that we did not observe any radiationassociated second tumors following treatment (benign or malignant) in the brain or near the treatment area in the neck or chest.
Discussion Literature review Table 4 summarizes the major studies of outcomes for head-and-neck sarcoma. 8-15 Comparison between studies is difficult because of heterogeneity in major variables. The control rates in our series are higher than those in most other
series. The likely explanation for this difference is that we excluded patients with gross tumor at the time of RT and patients with the types of angiosarcomas that have a poor prognosis. However, the basic conclusion that follows from our results is supported by other studies; most patients are cured with gross total resection and postoperative RT. Our relapse-free survival rate of 73% is similar to the 60% in the Memorial Sloan-Kettering Cancer Center series. 16 The Princess Margaret Hospital series does not report relapsefree survival but their 80% local control rate and 85% distant metastasis-free survival rate suggest that their relapse-free survival is similar to ours. 15 A finding that deserves specific attention is the low rate of distant failure in patients who are controlled at the primary site. In extremity sarcomas, distant metastasis is a common reason for treatment failure in 35% to 50% of patients. 17 Head-and-neck sarcomas are often detected before they have seeded distant organs. No patient in our series developed an isolated distant failure and the rate of distant metastasis is low in most other series. Many of the other series included patients with rhabdomyosarcoma, Ewing sarcoma, and angiosarcoma, and likely recorded distant failures that were secondary events following a
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Table 5 Treatment guidelines for postoperative radiotherapy following gross total resection of adult soft tissue sarcoma of the head and neck (histologies other than rhabdomyosarcoma, Ewing sarcoma, and angiosarcoma) Indication for RT following gross total resection
Grade 3, positive node, or margin b1-2 cm
Chemotherapy RT dose
No standard role High risk (positive margin): 66-70 Gy at 2 Gy per once-daily fraction or 69.6 Gy at 1.2 Gy per twice-daily fraction. Standard risk (negative margin): 60 Gy at 2 Gy per once-daily fraction or at 1.2 Gy per twice-daily fraction. No ENI: Node negative or when adding ENI significantly increases the risk of acute toxicity or a late complication. Yes ENI: Node positive or when adding ENI does not significantly increase the risk of acute toxicity or a late complication. ENI dose: 50 Gy at 2 Gy per fraction. In patients with a positive node we include the area of positive adenopathy in the high-risk target volume and boost the nodal station adjacent to a positive node to approximately 60 Gy. Individualized based on tumor location and extent. Position is supine with the head extended so that the body of the mandible is perpendicular to the table. Immobilized using a plastic mask or whatever approach optimizes immobilization and setup reproducibility. We use an oral stent to move the tongue inferiorly when the primary site is above the level of the oral cavity. CT simulation with fusion to MR scan. All planning scans done with intravenous contrast. CT: 3-mm contiguous slices from the skull vertex to the mid thorax. MR: 1-mm contiguous slices with T1- and T2-weighted sequences CTV = the resection bed plus 2.0 cm edited for anatomic boundaries to tumor spread. PTV = CTV plus 2 mm because we use daily cone-beam CT and a real-time surface image-guided stereotactic positioning system. These are “hard” constraints that must be met at the expense of normal-tissue dose: 95% of the PTV receives 100% of the prescription dose; 99% of the PTV receives 93% of the prescription dose; no more than 20% of the PTV receives 110% of the prescription dose. Clinical examination monthly until the acute effects of RT have resolved; MR or CT scan (we prefer MR) 3 months after completing RT, then once every 6 months for 5 years, followed by once every 2-5 years.
ENI
RT technique RT simulation
Target definition
Target dose constraints
Follow-up
CT, computed tomography; CTV, clinical target volume; ENI, elective nodal irradiation; MR, magnetic resonance; PTV, planning target volume; RT, radiotherapy.
local recurrence. The literature supports the conclusion that most types of STS of the head and neck are detected at a stage when effective local therapy will be curative.
Histology STS includes many different histologic subtypes. The challenge is to decide if there are histologies that are so unique that they should be analyzed as a separate group in outcome studies and treated differently in clinical practice. In our opinion, 2 histologic subgroups should be analyzed separately from the other STSs: small, round blue-cell tumors (SRBCTs) and angiosarcomas. The main types of SRBCTs that occur in the head and neck are rhabdomyosacroma and extraskeletal Ewing sarcoma. These tumors differ from other sarcoma subtypes in their propensity for distant metastasis and their sensitivity to multi-agent chemotherapy. Chemotherapy is the mainstay of treatment in these tumors and aggressive surgery is usually not indicated.
The angiosarcomas, particularly lymphangiosarcoma, have a more aggressive growth pattern than other sarcoma histologies. In the head and neck these tumors usually present in the scalp, with microscopic tumor extension many centimeters beyond the area of gross disease. When cure is possible these tumors are treated with aggressive resection and RT, but the prognosis is poor. 3,4,9,14 It will be useful for radiation oncologists to think about head-and-neck STS in the following 3 categories: (1) the SRBCTs, like rhabdomyosarcoma and Ewing sarcoma; (2) angiosarcoma; and (3) all others are lumped in the third category. From the standpoint of clinical management, we treat all subtypes within the third category the same.
Preoperative versus postoperative adjuvant RT Gross total resection is the most important component of treatment when the goal is tumor cure. Studies of RT alone for STS or for gross residual tumor are scarce but they suggest that the chance of cure is low. 1,8 The treatment of
Practical Radiation Oncology: October-December 2012
choice for the types of sarcoma that are included in our study is gross total resection and adjuvant RT when gross total resection is likely with acceptable morbidity. The question is if RT should be given preoperatively or postoperatively. There is no study of preoperative versus postoperative RT in head-and-neck sarcomas, but this question has been evaluated in detail in extremity sites. The report of the recent trial by O'Sullivan et al 15 is one of the highestquality data sets and the Discussion section of this paper explains why preoperative versus postoperative RT remains a controversial issue. At our medical center we favor preoperative RT in extremity sarcomas with the usual dose of 50 Gy at 2 Gy per once-daily fraction or 50.4 Gy at 1.2 Gy per twice-daily fraction. We are unsure how to translate this approach to treatment of a sarcoma in the head and neck. When the resection involves violating a mucosal surface, our surgical colleagues are concerned that preoperative RT may increase the risk of fistula; therefore, our standard approach has been to deliver RT 4 to 6 weeks after surgical resection. Today, we are rethinking this policy and plan to use approximately 50 Gy preoperatively when preoperative RT is unlikely to increase the risk of a serious complication.
Indications for postoperative RT following gross total resection There are no published guidelines for RT following resection of a head-and-neck sarcoma. The usual indications for postoperative RT following gross total resection of a head-and-neck STS with one of the histologies included in this study are grade 3 histology, tumor less than 1 to 2 cm from the surgical margin, or metastasis to a regional lymph node. We have no data to support the specific recommendation of 1 to 2 cm as the margin indication as opposed to a smaller distance such as 1.0 or 0.5 cm. Our thinking is that STSs often have microscopic skip metastases well beyond the visible edge of the tumor in soft tissue and many studies show a strong association between treatment margin and tumor control. 18 A recent publication of guidelines for preoperative RT target definition in extremity sarcoma from the Radiation Therapy Oncology Group recommends that the clinical target volume extend at least 3 cm beyond the gross tumor longitudinally, where there are no natural boundaries to tumor spread. 19
RT dose following gross total resection There is no published guideline about the RT dose specifically for head-and-neck sarcoma. Current guidelines from the National Cancer Center Network for postoperative RT for STS of the extremities include 60 to 66 Gy for negative margins, 66 to 70 Gy for
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microscopically positive margins, and 70 to 76 Gy for grossly positive margins. 20 We currently define 2 risk groups for RT dose specification following gross total resection of a head-and-neck STS with one of the histologies included in this study; high risk (positive margin), 66 to 70 Gy at 2 Gy per once-daily fraction or 69.6 Gy at 1.2 Gy per twice-daily fraction, and standard risk (negative margin), 60 Gy at 2 Gy per once-daily fraction or at 1.2 Gy per twice-daily fraction.
Elective nodal irradiation (ENI) Most publications on head-and-neck STS do not specify if they treated the regional nodes electively. In the University of Iowa (Iowa City) series, 18% of the patients received ENI, but the authors do not describe the indications for ENI or the potential benefit of it. 8 The University of California series specifies that they did not use ENI in node-negative patients and they observed only one isolated regional recurrence. 13 In the head-and-neck sarcoma series for Massachusetts General Hospital, Willers et al 9 reported that the rate of simultaneous local and regional recurrence was 9% and the isolated regional failure rate was 5%, with most of the nodal recurrences occurring in patients with angiosarcomas. Other published series on head-and-neck sarcoma report a 2% to 5% rate of isolated regional recurrence. 11,15 Our data are of limited value in determining the need for ENI because our indications for ENI were not standardized during the study period and because the first-echelon nodes were often included in the high-dose volume that we used to treat the primary site. However, that we did not observe a single isolated nodal recurrence adds to the other reports suggesting that ENI is not necessary in most patients with the types of sarcoma that we include in our study. Our current policy is to not deliver ENI following gross total resection of a head-and-neck STS with one of the histologies included in this study (including epithelioid sarcoma) if the patient is node-negative on imaging studies and the biopsy, and if extending the RT target volume to treat the regional nodes would significantly increase the risk of a complication. However, we deliver ENI to the same nodal stations that we would treat with squamous cell carcinoma when the added morbidity of ENI is low and in all patients with a positive node. Our usual dose for ENI is 50 Gy at 2 Gy per fraction. In patients with a positive node we include the area of positive adenopathy in the high-risk target volume and boost the nodal station adjacent to a positive node to approximately 60 Gy.
Chemotherapy There is no study that specifically evaluates the role of chemotherapy in adults with head-and-neck STS.
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Chemotherapy has been studied extensively for adult STS of the extremity or in groups that include patients with all body sites. The bottom line is that the results from prospective randomized trials are conflicting, such that the value of chemotherapy in the management of adult STS is controversial. A recent review article by Blay and Le Cesne 21 gives an excellent summary of the trials and debate about when to add chemotherapy in the adjuvant setting. Our current practice is not to use chemotherapy in the type of head-and-neck sarcoma patients that are included in our study. In our series, chemotherapy was given to only 8% of the patients, yet the cure rate was high (79%) and no patient failed with an isolated distant metastasis. Other series have similar findings, indicating that it is unlikely that the risk/benefit ratio will be favorable from adding aggressive chemotherapy in our patient population.
Follow-up program after RT Based on the propensity for head-and-neck STS to recur in the first few years after RT treatment, we recommend frequent clinic visits during the first few months after completing treatment until the acute effects of RT have resolved, and then a follow-up program with a clinical examination and radiographic imaging to monitor for treatment failure. We do not perform routine CT or positron emission tomography imaging for these patients in light of the low risk of distant metastasis without concurrent local or regional disease.
Recommendations Table 5 summarizes our current guidelines for managing the types of head and neck sarcoma that we included in our study.
Conclusions The chance of cure of the kinds of soft tissue sarcoma of the head and neck that were included in our study is high following gross total resection and postoperative radiotherapy. The great majority of recurrences are local (meaning near the resection site) such that modifying the approach to treatment of the primary tumor site is the only strategy that will improve the outcome of this group of patients to a meaningful degree. Late recurrences are unusual but do occur; therefore, follow-up should continue for many years after treatment. 21
References 1. Chen SA, Morris CG, Amdur RJ, Werning JW, Villaret DB, Mendenhall WM. Adult head and neck soft tissue sarcomas. Am J Clin Oncol. 2005;28:259-263.
Practical Radiation Oncology: October-December 2012 2. Dagan R, Morris CG, Zlotecki RA, Scarborough MT, Mendenhall WM. Radiotherapy in the treatment of dermatofibrosarcoma protuberans. Am J Clin Oncol. 2005;28:537-539. 3. Ward JR, Feigenberg SJ, Mendenhall NP, Marcus Jr RB, Mendenhall WM. Radiation therapy for angiosarcoma. Head Neck. 2003;25:873-878. 4. Mendenhall WM, Mendenhall CM, Werning JW, Reith JD, Mendenhall NP. Cutaneous angiosarcoma. Am J Clin Oncol. 2006; 29:524-528. 5. Soft tissue sarcoma. In: Edge SB, Byrd DR, Compton CC, et al, eds. AJCC Cancer Staging Handbook, 7 Ed. Chicago, IL: Springer; 2010: 345-355. 6. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) v4.0. 2010. Available at: http://www. ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ ctcae_index.pdf#search="commonterminology". Accessed January 5, 2012. 7. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457-481. 8. Barker Jr JL, Paulino AC, Feeney S, McCulloch T, Hoffman H. Locoregional treatment for adult soft tissue sarcomas of the head and neck: An institutional review. Cancer J. 2003;9:49-57. 9. Willers H, Hug EB, Spiro IJ, Efird JT, Rosenberg AE, Wang CC. Adult soft tissue sarcomas of the head and neck treated by radiation and surgery or radiation alone: patterns of failure and prognostic factors. Int J Radiat Oncol Biol Phys. 1995;33:585-593. 10. Dudhat SB, Mistry RC, Varughese T, Fakih AR, Chinoy RF. Prognostic factors in head and neck soft tissue sarcomas. Cancer. 2000;89:868-872. 11. Kraus DH, Sterman BM, Levine HL, Wood BG, Tucker HM, Lavertu P. Factors influencing survival in ethmoid sinus cancer. Arch Otolaryngol Head Neck Surg. 1992;118:367-372. 12. Le Vay J, O'Sullivan B, Catton C, et al. An assessment of prognostic factors in soft-tissue sarcoma of the head and neck. Arch Otolaryngol Head Neck Surg. 1994;120:981-986. 13. Le QT, Fu KK, Kroll S, et al. Prognostic factors in adult soft-tissue sarcomas of the head and neck. Int J Radiat Oncol Biol Phys. 1997;37:975-984. 14. Greager JA, Patel MK, Briele HA, Walker MJ, Das Gupta TK. Soft tissue sarcomas of the adult head and neck. Cancer. 1985;56: 820-824. 15. O'Sullivan B, Gullane P, Irish J, et al. Preoperative radiotherapy for adult head and neck soft tissue sarcoma: assessment of wound complication rates and cancer outcome in a prospective series. World J Surg. 2003;27:875-883. 16. Kraus DH, Dubner S, Harrison LB, et al. Prognostic factors for recurrence and survival in head and neck soft tissue sarcomas. Cancer. 1994;74:697-702. 17. O'Sullivan B, Davis AM, Turcotte R, et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet. 2002;359:2235-2241. 18. Sampo M, Tarkkanen M, Huuhtanen R, Tukiainen E, Böhling T, Blomqvist C. Impact of the smallest surgical margin on local control in soft tissue sarcoma. Br J Surg. 2008;95:237-243. 19. Wang D, Bosch W, Roberge D, et al. RTOG sarcoma radiation oncologists reach consensus on gross tumor volume and clinical target volume on computed tomographic images for preoperative radiotherapy of primary soft tissue sarcoma of extremity in Radiation Therapy Oncology Group studies. Int J Radiat Oncol Biol Phys. 2011;81:e525-e528. 20. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Soft tissue sarcomas. 2011. Available at: http://www.nccn.org/professionals/physician_gls/PDF/sarcoma.pdf. Accessed January 5, 2012. 21. Blay JY, Le Cesne A. Adjuvant chemotherapy in localized soft tissue sarcomas: still not proven. Oncologist. 2009;14:1013-1020.
www.practicalradonc.org
Original Report
Radiotherapy following gross total resection of adult soft tissue sarcoma of the head and neck Daniel Trifiletti MD a , Robert J. Amdur MD a,⁎, Roi Dagan MD a , Daniel J. Indelicato MD a,b , William M. Mendenhall MD a,b , Jessica M. Kirwan MA a , Anamaria R. Yeung MD a , John W. Werning MD c , Christopher G. Morris MS a a
Department of Radiation Oncology, University of Florida, Gainesville, Florida Department of Otolaryngology, University of Florida, Gainesville, Florida c University of Florida Proton Therapy Institute, Jacksonville, Florida b
Received 14 December 2011; revised 5 January 2012; accepted 10 January 2012
Abstract Purpose: This study reports the outcomes of adults with soft tissue sarcoma (STS) of the head and neck following resection and postoperative radiotherapy (RT), and provides a framework for explaining the issues that radiation oncologists must understand to manage patients with this diverse group of tumors. Methods and Materials: Twenty-four patients met the following inclusion criteria of this study: age ≥19 years, head or neck primary site, STS, with the exception of rhabdomyosarcoma, Ewing, or angiosarcoma variants, and curative-attempt treatment with gross total tumor resection followed by RT. Results: All patients underwent gross total tumor resection followed by adjuvant RT at our institution during the 28-year period between June 1, 1981, and December 31, 2009. This is a mature study with a median follow-up of 11 years (range, 0.6-27 years). No patient was lost to follow-up. All recurrences were at the primary site. No patient developed an isolated regional or distant recurrence. No patient developed synchronous nodal or distant recurrences at the time of local recurrence. Half of the recurrences presented within 1 year of completing RT, but there were 2 cases where we did not detect recurrence until years 6 and 8 after RT. No recurrence was successfully salvaged. The actuarial rate of local control and relapse-free survival was 83% (95% CI [confidence interval], 63%-94%) at 5 years and 73% (95% CI, 51%-87%) at 10 years. The incidence of moderate to severe treatment complications was 4%. Conclusions: Our series documents that gross total resection followed by RT cures most patients (75%) with the most common types of STS of the head and neck. All recurrences were local, meaning near the primary site in tissue that received the full RT prescription dose. For this reason, modifying the approach to treatment of the primary tumor site is the only strategy that will meaningfully improve outcomes for this group of patients. © 2012 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
Conflicts of interest: None. ⁎ Corresponding author. 2000 SW Archer Rd, PO Box 100385, Gainesville, FL 32610-0385. E-mail address: [email protected]fl.edu (R.J. Amdur). 1879-8500/$ – see front matter © 2012 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.prro.2012.01.003
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Introduction Adult soft tissue sarcomas (STSs) that originate in the soft tissues above the clavicles are often managed by headand-neck cancer specialists. Some of the treatment principles for head-and-neck sarcoma are extrapolated from those of extremity lesions, but the proximity of sensitive normal tissues is such that sarcomas of the head and neck present demanding treatment challenges. Our departments have been studying the outcomes of head-and-neck sarcoma patients for many years. 1-3 Our
analyses and publications from other institutions have refined our thinking on how to classify and manage sarcoma patients. This paper will report the long-term outcomes for the largest subgroup of our head-and-neck sarcoma series, adults treated with gross total resection and postoperative radiotherapy (RT), and provide a framework for explaining the issues that radiation oncologists must understand to manage patients with this diverse group of tumors.
Methods and materials Table 1
Characteristics of our study population
Characteristic
Data
Inclusion dates No. of patients Age on day 1 of RT (y) RT for a recurrence Histologic grade Grade 3 Grade 1-2 Histology MFH DFSP Neurosarcoma Leiomyosarcoma Spindle cell sarcoma Fibrosarcoma Alveolar Synovial sarcoma Triton a Site Face/scalp Neck Paranasal sinus Larynx American Joint Committee on Cancer Stage I II III Surgical margin Negative (N20 mm) Close (0.1-20 mm) Microscopically positive RT dose 50-59.9 Gy 60-74.4 Gy Elective nodal RT Chemotherapy Follow-up from day 1 of RT Median, range (y) N5 y N10 y
June 1981-December 2009 24 Median, 46 (range, 20-87) 6 (25%) 15 (63%) 9 (37%) 4 4 4 3 3 2 1 2 1
(17%) (17%) (17%) (13%) (13%) (8%) (4%) (8%) (4%)
14 (58%) 5 (21%) 4 (17%) 1 (4%)
8 (33%) 14 (59%) 2 (8%)
Data for this study were collected as part of an Institutional Review Board-approved protocol. All patients had biopsy-confirmed STS of the head and neck and age of at least 19 years on day 1 of RT. All patients underwent gross total tumor resection followed by adjuvant RT at our institution during the 28-year period between June 1, 1981 and December 31, 2009. The last patient was treated 2.4 years before the date of analysis. No patient was lost to follow-up. This study excludes a small number of patients who were treated with preoperative RT or RT for gross disease because the tumor was unresectable or because the patient was medically inoperable. No patient in this study was known to have a distant metastasis at the time of RT. Table 1 summarizes the major characteristics of the 24 patients in our cohort. In 18 patients (75%), surgery and postoperative RT were the first treatments for their sarcoma. The other 6 patients (25%) were initially treated with at least one curative-intent surgical procedure before referral for the total resection and postoperative RT recorded in this study. All 6 patients experienced gross tumor recurrence before the treatment that qualified them for inclusion in this study. Our series includes various subtypes of STS. This study does not include patients with rhabdomyosarcoma or extraskeletal Ewing sarcoma because they are known to have a different biology than other types of STS and
0 (0%) 19 (79%) 5 (21%) 7 (29%) 17 (71%) 9 (38%) 2 (8%) 11, 0.6-23 83% 54%
DFSP, dermatofibrosarcoma protuberans; MFH, malignant fibrous histiocytoma; RT, radiotherapy. a Triton: a combination of malignant schwannoma cells and malignant rhabdomyoblasts.
Figure 1 Actuarial plot of relapse-free and overall survival for the 24 patients in this series.
Practical Radiation Oncology: October-December 2012 Table 2
Postoperative RT of head-and-neck STS
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Patients with tumor recurrence (all at the primary site); 6 of 24 (25%) patients
Patient
Time after RT
Histology
Site
Stage, grade
Surgical margin
Chemo.
RT dose (Gy)
RT technique
Year of RT
Salvage attempted a
Survival b (y)
1 2 3
b1 y b1 y b1 y
Leiomyo. MFH Fibro.
PNS PNS Face
III, Grade 3 III, Grade 3 IIa, Grade 3
Close Close Positive
No No No
66.6 69.6 60.0
1997 1997 1987
No No No
0.6 1.0 2.0
4 5
3.5 y 6y
Synovial Neuro.
Face Face
IIa, Grade 3 IIa, Grade 3
Positive Positive
Yes c No
74.4 74.4
2005 1985
No Yes
5.2 7.5
6
8y
Spindle
PNS
IIb, Grade 2
Close
No
74.4
3D-CRT 3D-CRT Electrons and 3D-CRT and an Ir192 implant IMRT Electrons and Co60 3D-CRT
2002
No
8.1 (alive)
3D-CRT, 3-dimensional chemoradiotherapy; Fibro., fibrosarcoma; IMRT, intensity modulated radiation therapy; Leiomyo., leiomyosarcoma; MFH, malignant fibrous histiocytoma; Neuro., neurosarcoma; PNS, paranasal sinus; RT, radiotherapy. a All salvage attempts were surgical resections. No patient was successfully salvaged due to repeat local recurrence. b All patients who developed a tumor recurrence died from progressive sarcoma with the exception of patient 6, who is alive with recurrent tumor. c Adriamycin and ifosfamide.
chemotherapy plays a major role in their management. This study also excluded patients with angiosarcoma because almost all of our patients with variants of this histology had large tumors of the scalp that present unique management problems and have an extremely poor prognosis. 4 Patients were retrospectively staged according to the American Joint Committee on Cancer 7th edition STS staging system. 5 Over half the patients in this series had stage II tumors. There is no consensus in the literature on the definition of a “close margin” in this setting. We classified the surgical margin as either microscopically positive (b0.1 mm), close (0.1-20 mm), or wide (N20 mm). We selected 20 mm as the upper limit for the definition of a “close” margin because in several patients this was the only factor that led the tumor conference team to recommend RT. The RT dose schedule and technique varied with clinical scenario and with the availability of new technology during the study period. The primary RT techniques were en face orthovoltage or electron beam (46%), 3-dimensional conformal RT with cobalt-60 or 6to 18-MV photon beams oriented in the axial plane (46%), and intensity-modulated RT with 7 to 9 beam angles (8%). Extending the RT treatment area to treat the clinically negative regional nodes (elective nodal RT) was at the discretion of the treating physician and performed in 38% of the patients. This series begins before magnetic resonance imaging was available at our medical center. Imaging of the head and neck before RT treatment included a computerized tomography (CT) scan in 79% of patients and a magnetic resonance scan in 21%. All patients had their chest imaged with plain film radiography and 29% had a CT scan of the chest that was negative for metastatic disease. Complications from RT were graded with the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE, v4.0). 6 Our
complication analysis is limited by the retrospective nature of this study. We did not attempt to record grade 1 or 2 complications because we know that these are often not documented in our records. The focus of our analysis was on moderate or severe complications, meaning CTC grades 3 to 5.
Table 3
Univariate comparisons a
Variable
Recurrence rate
Surgical margin
Positive: 3/5 (60%) Negative or close: 3/19 (16%) Histologic grade Grade 3: 5/15 (30%) Grade 1-2: 1/9 (11%) Margin and grade Positive and grade 3: 3/3 (100%) combined Negative, close, or grade 1-2: 3/21 (14%) Stage I: 0/7 (0%) American Joint Stage II-III: 6/17 (35%) Committee on Cancer stage Age ≤46 y: 3/13 (23%) ≥47 y: 3/11 (27%) RT for recurrence Yes recurrent: 2/6 (33%) Not recurrent: 4/18 (22%) Elective nodal Yes ENI: 3/9 (33%) irradiation No ENI: 3/15 (20%) RT fractionation Once daily: 1/10 (10%) Twice daily: 5/14 (36%) RT dose 50-59.9 Gy: 0/7 (0%) 60-74.4 Gy: 6/17 (35%) RT year 1981-1995: 2/12 (17%) 1996-2009: 4/12 (33%)
P value b .08 .35 .01
.13
.99 .62 .64 .34 .13 .64
ENI, elective nodal irradiation; RT, radiotherapy. a The distribution of patients and number of subgroups was such that comparisons were not meaningful for histology, site, and RT dose. b Fisher exact test.
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Literature review: Head-and-neck soft tissue sarcoma
Institution Publication
Study dates
No. of patients
Includes Rhabdo, Follow-up Ewings, or Angio Rhabdo: no Ewings: no Angio: 19% Rhabdo: no Ewings: no Angio: 20% None Rhabdo: no Ewings: no Angio: 27% a Rhabdo: 5.8% Ewings: no Angio: 11.5% Rhabdo: 3% Ewings: no Angio: 15% Rhabdo: 6% Ewings: no Angio: 6% Rhabdo: no Ewings: no Angio: 10% None
MGH
Willers 1995 8
1972-1993
57
U. Iowa
Barker 2002 9
1970-2000
44
TMH MSKCC
Dudhat 2000 10 Kraus 1992 11
1981-1995 1982-1989
72 60
PMH
Le Vay 1994 12
1980-1988
52
UCSF
Le 1997 13
1961-1993
65
1969-1983
53
PMH
O'Sullivan 2003 15 1989-1999
40
Current Study
—
24
U. Illinois Greager 1985 14
1981-2009
Recurrent
Median Dose (Gy)
Median 4.3 y 30%
64.8
NS
60
0%
NS 17% Median 4.8 y 32%
NS 60.0
Min. 3.0 y
NS
NS
Median 5.3 y 0%
59.4
NS
NS
NS
Mean 3.6 y
20%
50.0
Median 11.1 y 25%
64.8
(Continued)
All data were analyzed using SAS statistical software (SAS Institute, Cary, NC). Estimates of local control and relapse-free survival were computed using the KaplanMeier product-limit method. 7 For the pattern of failure analysis, we did not code patients who experienced a regional or distant recurrence if they also recurred locally since local recurrence may cause regional or distant metastases as a secondary event.
Results Median follow-up for this study was 11 years (range, 0.6-27 years). The follow-up in patients who were alive at last median follow-up was 13 years (range, 2-23 years). Figure 1 is an actuarial plot of local control, relapse-free and overall survival. Six patients (25%) experienced tumor recurrence. All recurrences were local, meaning near the primary site in tissue that received the full RT prescription dose. No patient developed synchronous nodal or distant recurrence at the time of local recurrence. No patient died of a treatment complication and no patient was successfully
salvaged following tumor recurrence. For these reasons, the rates of local control, local-regional control, relapsefree survival, and cause-specific survival are the same. Table 2 summarizes the characteristics of the 6 patients who developed a tumor recurrence. Most recurrences presented within a year after completing RT but there were 2 late recurrences detected 6 and 8 years after treatment. No patient was successfully salvaged following a recurrence. Five of the 6 patients who recurred died of progressive sarcoma and the remaining patient is living with progressive sarcoma at the skull base. The small number of patients limits our ability to identify prognostic factors so that lack of a correlation in this study does not represent a reliable finding. The study population is too small for multivariate analysis. Table 3 summarizes the univariate comparisons. The recurrence rate was higher in patients treated more recently and with higher doses, but the differences did not approach statistical significance. One patient experienced a moderate-to-severe complication. He was treated with en face electrons to the temporal soft tissue to 64.8 Gy at 1.2 Gy per fraction twice daily. Two and a half years after treatment he developed
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Table 4 (continued) Chemo
ENI
Local Control
DMFS
RFS
CSS
OS
12%
NS
60% (5 y)
77% (5 y)
NS
NS
66% (5 y)
2%
18% a
57% (5 y)
NS
NS
72% (5 y)
61% (5 y)
6% 12%
NS NS
63% a 70% (5 y)
90% a 87% a
45% (5 y) 60% (5 y)
NS NS
60% (5 y) 71% (5 y)
23%
NS
59% (5 y)
69% (5y)
NS
62% (5 y)
NS
22%
0%
66% (5 y)
86% b
NS
60% (5 y)
56% (5 y)
NS
NS
NS
NS
54% (5 y)
NS
NS
3%
NS
80% (2 y)
85% (5 y)
NS
NS
NS
8%
38%
73% (10 y)
100% (10 y)
73% (10 y)
73% (10 y)
87% (5 y) 65% (10 y)
Angio, angiosarcoma; CSS, cause-specific survival; DFS, disease-free survival; DMFS, distant metastasis-free survival; ENI, elective nodal irradiation; MGH, Massachusetts General Hospital; NCI, Netherlands Cancer Institute; MSKCC, Memorial Sloan-Kettering Cancer Center; NS, not specified; OS, overall survival; PMH, Princess Margaret Hospital; Rhabdo, rhabdomyosarcoma; TMH, Tata Memorial Hospital; UCSF, University of California San Francisco. a Crude numbers. b Includes regional metastases.
temporal lobe necrosis and subsequent resection. He is now 23 years out from therapy with no evidence of disease. He works full time yet suffers from depression, which is medically managed. We consider this to represent a grade 4 complication. The grade 3-5 complication rate in our series was 1 of 24 (4%) and 1 of 19 (5%) in patients whose tumors did not recur. As our series has long-term follow-up on most patients, it is noteworthy that we did not observe any radiationassociated second tumors following treatment (benign or malignant) in the brain or near the treatment area in the neck or chest.
Discussion Literature review Table 4 summarizes the major studies of outcomes for head-and-neck sarcoma. 8-15 Comparison between studies is difficult because of heterogeneity in major variables. The control rates in our series are higher than those in most other
series. The likely explanation for this difference is that we excluded patients with gross tumor at the time of RT and patients with the types of angiosarcomas that have a poor prognosis. However, the basic conclusion that follows from our results is supported by other studies; most patients are cured with gross total resection and postoperative RT. Our relapse-free survival rate of 73% is similar to the 60% in the Memorial Sloan-Kettering Cancer Center series. 16 The Princess Margaret Hospital series does not report relapsefree survival but their 80% local control rate and 85% distant metastasis-free survival rate suggest that their relapse-free survival is similar to ours. 15 A finding that deserves specific attention is the low rate of distant failure in patients who are controlled at the primary site. In extremity sarcomas, distant metastasis is a common reason for treatment failure in 35% to 50% of patients. 17 Head-and-neck sarcomas are often detected before they have seeded distant organs. No patient in our series developed an isolated distant failure and the rate of distant metastasis is low in most other series. Many of the other series included patients with rhabdomyosarcoma, Ewing sarcoma, and angiosarcoma, and likely recorded distant failures that were secondary events following a
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Table 5 Treatment guidelines for postoperative radiotherapy following gross total resection of adult soft tissue sarcoma of the head and neck (histologies other than rhabdomyosarcoma, Ewing sarcoma, and angiosarcoma) Indication for RT following gross total resection
Grade 3, positive node, or margin b1-2 cm
Chemotherapy RT dose
No standard role High risk (positive margin): 66-70 Gy at 2 Gy per once-daily fraction or 69.6 Gy at 1.2 Gy per twice-daily fraction. Standard risk (negative margin): 60 Gy at 2 Gy per once-daily fraction or at 1.2 Gy per twice-daily fraction. No ENI: Node negative or when adding ENI significantly increases the risk of acute toxicity or a late complication. Yes ENI: Node positive or when adding ENI does not significantly increase the risk of acute toxicity or a late complication. ENI dose: 50 Gy at 2 Gy per fraction. In patients with a positive node we include the area of positive adenopathy in the high-risk target volume and boost the nodal station adjacent to a positive node to approximately 60 Gy. Individualized based on tumor location and extent. Position is supine with the head extended so that the body of the mandible is perpendicular to the table. Immobilized using a plastic mask or whatever approach optimizes immobilization and setup reproducibility. We use an oral stent to move the tongue inferiorly when the primary site is above the level of the oral cavity. CT simulation with fusion to MR scan. All planning scans done with intravenous contrast. CT: 3-mm contiguous slices from the skull vertex to the mid thorax. MR: 1-mm contiguous slices with T1- and T2-weighted sequences CTV = the resection bed plus 2.0 cm edited for anatomic boundaries to tumor spread. PTV = CTV plus 2 mm because we use daily cone-beam CT and a real-time surface image-guided stereotactic positioning system. These are “hard” constraints that must be met at the expense of normal-tissue dose: 95% of the PTV receives 100% of the prescription dose; 99% of the PTV receives 93% of the prescription dose; no more than 20% of the PTV receives 110% of the prescription dose. Clinical examination monthly until the acute effects of RT have resolved; MR or CT scan (we prefer MR) 3 months after completing RT, then once every 6 months for 5 years, followed by once every 2-5 years.
ENI
RT technique RT simulation
Target definition
Target dose constraints
Follow-up
CT, computed tomography; CTV, clinical target volume; ENI, elective nodal irradiation; MR, magnetic resonance; PTV, planning target volume; RT, radiotherapy.
local recurrence. The literature supports the conclusion that most types of STS of the head and neck are detected at a stage when effective local therapy will be curative.
Histology STS includes many different histologic subtypes. The challenge is to decide if there are histologies that are so unique that they should be analyzed as a separate group in outcome studies and treated differently in clinical practice. In our opinion, 2 histologic subgroups should be analyzed separately from the other STSs: small, round blue-cell tumors (SRBCTs) and angiosarcomas. The main types of SRBCTs that occur in the head and neck are rhabdomyosacroma and extraskeletal Ewing sarcoma. These tumors differ from other sarcoma subtypes in their propensity for distant metastasis and their sensitivity to multi-agent chemotherapy. Chemotherapy is the mainstay of treatment in these tumors and aggressive surgery is usually not indicated.
The angiosarcomas, particularly lymphangiosarcoma, have a more aggressive growth pattern than other sarcoma histologies. In the head and neck these tumors usually present in the scalp, with microscopic tumor extension many centimeters beyond the area of gross disease. When cure is possible these tumors are treated with aggressive resection and RT, but the prognosis is poor. 3,4,9,14 It will be useful for radiation oncologists to think about head-and-neck STS in the following 3 categories: (1) the SRBCTs, like rhabdomyosarcoma and Ewing sarcoma; (2) angiosarcoma; and (3) all others are lumped in the third category. From the standpoint of clinical management, we treat all subtypes within the third category the same.
Preoperative versus postoperative adjuvant RT Gross total resection is the most important component of treatment when the goal is tumor cure. Studies of RT alone for STS or for gross residual tumor are scarce but they suggest that the chance of cure is low. 1,8 The treatment of
Practical Radiation Oncology: October-December 2012
choice for the types of sarcoma that are included in our study is gross total resection and adjuvant RT when gross total resection is likely with acceptable morbidity. The question is if RT should be given preoperatively or postoperatively. There is no study of preoperative versus postoperative RT in head-and-neck sarcomas, but this question has been evaluated in detail in extremity sites. The report of the recent trial by O'Sullivan et al 15 is one of the highestquality data sets and the Discussion section of this paper explains why preoperative versus postoperative RT remains a controversial issue. At our medical center we favor preoperative RT in extremity sarcomas with the usual dose of 50 Gy at 2 Gy per once-daily fraction or 50.4 Gy at 1.2 Gy per twice-daily fraction. We are unsure how to translate this approach to treatment of a sarcoma in the head and neck. When the resection involves violating a mucosal surface, our surgical colleagues are concerned that preoperative RT may increase the risk of fistula; therefore, our standard approach has been to deliver RT 4 to 6 weeks after surgical resection. Today, we are rethinking this policy and plan to use approximately 50 Gy preoperatively when preoperative RT is unlikely to increase the risk of a serious complication.
Indications for postoperative RT following gross total resection There are no published guidelines for RT following resection of a head-and-neck sarcoma. The usual indications for postoperative RT following gross total resection of a head-and-neck STS with one of the histologies included in this study are grade 3 histology, tumor less than 1 to 2 cm from the surgical margin, or metastasis to a regional lymph node. We have no data to support the specific recommendation of 1 to 2 cm as the margin indication as opposed to a smaller distance such as 1.0 or 0.5 cm. Our thinking is that STSs often have microscopic skip metastases well beyond the visible edge of the tumor in soft tissue and many studies show a strong association between treatment margin and tumor control. 18 A recent publication of guidelines for preoperative RT target definition in extremity sarcoma from the Radiation Therapy Oncology Group recommends that the clinical target volume extend at least 3 cm beyond the gross tumor longitudinally, where there are no natural boundaries to tumor spread. 19
RT dose following gross total resection There is no published guideline about the RT dose specifically for head-and-neck sarcoma. Current guidelines from the National Cancer Center Network for postoperative RT for STS of the extremities include 60 to 66 Gy for negative margins, 66 to 70 Gy for
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microscopically positive margins, and 70 to 76 Gy for grossly positive margins. 20 We currently define 2 risk groups for RT dose specification following gross total resection of a head-and-neck STS with one of the histologies included in this study; high risk (positive margin), 66 to 70 Gy at 2 Gy per once-daily fraction or 69.6 Gy at 1.2 Gy per twice-daily fraction, and standard risk (negative margin), 60 Gy at 2 Gy per once-daily fraction or at 1.2 Gy per twice-daily fraction.
Elective nodal irradiation (ENI) Most publications on head-and-neck STS do not specify if they treated the regional nodes electively. In the University of Iowa (Iowa City) series, 18% of the patients received ENI, but the authors do not describe the indications for ENI or the potential benefit of it. 8 The University of California series specifies that they did not use ENI in node-negative patients and they observed only one isolated regional recurrence. 13 In the head-and-neck sarcoma series for Massachusetts General Hospital, Willers et al 9 reported that the rate of simultaneous local and regional recurrence was 9% and the isolated regional failure rate was 5%, with most of the nodal recurrences occurring in patients with angiosarcomas. Other published series on head-and-neck sarcoma report a 2% to 5% rate of isolated regional recurrence. 11,15 Our data are of limited value in determining the need for ENI because our indications for ENI were not standardized during the study period and because the first-echelon nodes were often included in the high-dose volume that we used to treat the primary site. However, that we did not observe a single isolated nodal recurrence adds to the other reports suggesting that ENI is not necessary in most patients with the types of sarcoma that we include in our study. Our current policy is to not deliver ENI following gross total resection of a head-and-neck STS with one of the histologies included in this study (including epithelioid sarcoma) if the patient is node-negative on imaging studies and the biopsy, and if extending the RT target volume to treat the regional nodes would significantly increase the risk of a complication. However, we deliver ENI to the same nodal stations that we would treat with squamous cell carcinoma when the added morbidity of ENI is low and in all patients with a positive node. Our usual dose for ENI is 50 Gy at 2 Gy per fraction. In patients with a positive node we include the area of positive adenopathy in the high-risk target volume and boost the nodal station adjacent to a positive node to approximately 60 Gy.
Chemotherapy There is no study that specifically evaluates the role of chemotherapy in adults with head-and-neck STS.
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Chemotherapy has been studied extensively for adult STS of the extremity or in groups that include patients with all body sites. The bottom line is that the results from prospective randomized trials are conflicting, such that the value of chemotherapy in the management of adult STS is controversial. A recent review article by Blay and Le Cesne 21 gives an excellent summary of the trials and debate about when to add chemotherapy in the adjuvant setting. Our current practice is not to use chemotherapy in the type of head-and-neck sarcoma patients that are included in our study. In our series, chemotherapy was given to only 8% of the patients, yet the cure rate was high (79%) and no patient failed with an isolated distant metastasis. Other series have similar findings, indicating that it is unlikely that the risk/benefit ratio will be favorable from adding aggressive chemotherapy in our patient population.
Follow-up program after RT Based on the propensity for head-and-neck STS to recur in the first few years after RT treatment, we recommend frequent clinic visits during the first few months after completing treatment until the acute effects of RT have resolved, and then a follow-up program with a clinical examination and radiographic imaging to monitor for treatment failure. We do not perform routine CT or positron emission tomography imaging for these patients in light of the low risk of distant metastasis without concurrent local or regional disease.
Recommendations Table 5 summarizes our current guidelines for managing the types of head and neck sarcoma that we included in our study.
Conclusions The chance of cure of the kinds of soft tissue sarcoma of the head and neck that were included in our study is high following gross total resection and postoperative radiotherapy. The great majority of recurrences are local (meaning near the resection site) such that modifying the approach to treatment of the primary tumor site is the only strategy that will improve the outcome of this group of patients to a meaningful degree. Late recurrences are unusual but do occur; therefore, follow-up should continue for many years after treatment. 21
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