SEARCH

SEARCH BY CITATION

Keywords:

  • soft tissue sarcoma;
  • radiation-induced;
  • limb salvage surgery;
  • functional outcome;
  • postirradiation

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

BACKGROUND:

Radiation-induced soft tissue sarcomas (RI-STS) are rare, and it is believed that they are associated with a poor prognosis.The authors of this report compared the clinical and functional outcomes of adults who had extremity RI-STS with the outcomes of adults with sporadic STS.

METHODS:

Forty-four patients who were diagnosed with RI-STS from 1989 to 2009 were identified from 4 prospectively collected databases. Patient demographics, surgical and adjuvant treatment parameters, and oncologic and functional outcomes were evaluated.

RESULTS:

The median latent period from irradiation of the primary condition to RI-STS diagnosis was 16 years. The median radiotherapy dose used for the index condition was 45 gray. The median age at RI-STS diagnosis was 56 years. The most common primary diagnoses were breast cancer (36.4%) and lymphoma (34.1%). The most common RI-STS histologies were malignant fibrous histiocytoma (36.4%) and angiosarcoma (18.2%). Forty-two patients underwent surgery, 13 patients received adjuvant radiotherapy, and 8 patients received adjuvant chemotherapy. Systemic metastases occurred in 50% of treated patients (n = 21), and 26% (n = 11) developed local recurrence, the risk of which was lower among patients who received reirradiation (P = .043). The 5-year disease-free interval (DFI) and overall survival (OS) rates for patients with RI-STS who presented without metastasis were 36% and 44%, respectively. Patients who had International Union Against Cancer TNM stage III RI-STS had a significantly worse DFI compared with patients who had stage III sporadic STS (multivariate analysis, P = .051). Eighteen patients with RI-STS underwent functional assessment after surgery, and their results were comparable to those of patients with sporadic STS.

CONCLUSIONS:

Despite aggressive surgical treatment, patients who have RI-STS remain at greater risk of both local and systemic recurrence compared with patients who have sporadic STS, but they can anticipate similar functional outcomes. Reirradiation can be relatively safe and effective if used properly. Cancer 2011. © 2011 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

Radiation therapy plays an important role in the treatment of patients with various types of cancer, either as a preoperative or postoperative component of multidisciplinary, curative treatment or for symptom management in the palliative setting. Although it is effective in helping to maintain local control of many tumors and frequently permits less extensive surgical resections, radiation therapy is not without potential side effects. Radiation toxicity, as part of the multidisciplinary management of soft tissue sarcoma (STS), includes fibrosis, joint stiffness, lymphedema, bone toxicity, and impaired wound healing.1-3 Although it is uncommon, 1 of the most devastating side effects of radiotherapy that usually occurs late after treatment is the development of radiation-induced STS (RI-STS). RI-STS is rare4-6 but can be problematic to treat, because its occurrence in a previously irradiated field limits the therapeutic options compared with the management of de novo STS. RI-STS also reportedly is associated with a worse prognosis than sporadic STS.4, 7-9 The objective of the current study was to review a multi-institutional experience treating patients with RI-STS and compare their clinical and functional outcomes with the outcomes of patients with sporadic STS.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

Patients

This was a multicenter study between Mount Sinai Hospital/Princess Margaret Hospital in Toronto, Canada; Ottawa General Hospital in Ottawa, Canada; McGill University Health Centre in Montreal, Canada; and Vanderbilt Medical Center, Nashville, Tennessee. After obtaining approval from the Institutional Research Ethics Board at each center, we retrospectively reviewed our prospectively collected databases and, when combined, identified 5046 patients with STS who received treatment between 1989 and 2009. Forty-four patients (0.9%) with RI-STS were identified from these 4 centers. The diagnosis of RI-STS was based on the criteria published by Cahan et al,10 which included the previous receipt of radiation treatment for different types of tumors (benign or malignant), development of the sarcoma in the radiation field, sarcoma that was histologically different from the primary cancer, and a minimum latent period of 5 years between the index radiation and development of the sarcoma. However, we followed a more recent modified definition suggesting that a latent period of 3 years was sufficient for the diagnosis of RI-STS.11

The database records and patient charts were reviewed to determine sex, age at diagnosis, location of the tumor, tumor size, tumor grade, tumor depth, tumor histology, index radiation dose, primary cancer type, latency period between the 2 tumors, adjuvant sarcoma treatment, resection margins (with positive margins defined as tumor cells at the inked resection margin12), complications of treatment, local recurrence, systemic recurrence, and functional outcome.

Patients with RI-STS of the extremity who underwent limb salvage surgery had a functional assessment using 2 evaluation methods. The Toronto Extremity Salvage Score (TESS)13 is a patient-completed measure of disability/activity limitations that was developed specifically for patients with extremity sarcoma. The Musculoskeletal Tumor Society Rating Scale 1987 (MSTS-87)14 is a clinician-completed measure of impairment that assesses range of motion, strength, stability, pain, deformity, functionality, and emotional acceptance. The maximum functional scores are 35 for MSTS-87 and 100 for TESS, with higher scores indicating higher levels of function for both measures. The patients who had RI-STS were matched 1:2 with patients who had sporadic STS based on age, location, tumor size, tumor depth, radiation treatment, and no metastasis at diagnosis. All patients underwent functional assessment at least 1-year after surgery using both TESS and MSTS-87 evaluations.

Statistics

The primary outcome was disease-free interval (DFI), which was estimated from the date of surgery to the date of first relapse (either local recurrence or metastasis). Patients who did not experience a relapse were censored at the time of last follow-up or death. The secondary outcome measure was overall survival (OS), which was estimated from the date of surgery to death. The Kaplan-Meier method was used to estimate the probabilities of survival.15 Functional outcome scores were compared for patients with RI-STS and sporadic STS using the Wilcoxon rank-sum test.

To evaluate the prognostic importance of radiation induction in the development of STS, the oncologic outcomes of patients who had RI-STS were compared with the outcomes of patients who had sporadic STS treated at Mount Sinai Hospital/Princess Margaret Hospital. Cox proportional hazards regression models16 were used to estimate the effect of radiation induction on DFI and OS. The effect of radiation induction was estimated first in univariate models and then in multivariate models to adjust for other relevant covariates.17 Because of the limited effective sample size, the multivariable regression models were performed on a subset of patients with International Union Against Cancer (UICC) TNM stage III (ie, large, deep, high grade, and no regional lymph node metastasis) disease.17, 18 Therefore, the variables used for adjustment in the models included adjuvant radiation, chemotherapy, surgical margins, and histologic subtype (angiosarcoma, leiomyosarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, fibrosarcoma, and other sarcoma). Other pretreatment variables were not included in the models, because the patients were comparable at the time of surgery (ie, similar UICC TNM stage). All tests were 2-sided and were conducted at the 5% significance level. Estimates are provided with their 95% confidence intervals (CIs).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

There were 26 women and 18 men, and the median patient age was 56 years (range, 27-85 years) at the time of sarcoma diagnosis. The primary diagnoses for which patients previously received radiotherapy included breast cancer (n = 16), Hodgkin lymphoma (n = 13), non-Hodgkin lymphoma (n = 2), uterine cancer (n = 2), malignant fibrous histiocytoma (n = 2), and 1 each of rhabdomyosarcoma, undifferentiated sarcoma, ovarian cancer, cervical cancer, keloids, anorectal cancer, pineal dysgerminoma, testicular seminoma, and lymphangioma. The median latent period from irradiation of the primary disease to the diagnosis of RI-STS was 16 years (range, 3-56 years), and the median radiation dose for the primary condition for the 25 patients with available radiation data was 45 gray (Gy) (range, 15-74 Gy). The histologic subtypes of RI-STS varied (Fig. 1), but the most common diagnoses included malignant fibrous histiocytoma (36.4%), followed by angiosarcoma (18.2%), liposarcoma and soft tissue osteosarcoma (9% each), and leiomyosarcoma (7%). Most RI-STS were high grade (70%; n = 31), with 12 grade 2 sarcomas and only 1 grade 1 sarcoma. Most of the RI-STS tumors were deep (91%; n = 40) and large (ie, >5.0 cm; 70%; n = 31), and the mean tumor size was 7.1 cm (range, 1.2-19.0 cm). Twenty-five tumors were located in the upper extremity (56.8%), 10 were located in the lower-extremity (22.7%), and 9 involved the trunk or chest wall (20.5%). No patients had regional lymph node metastasis at diagnosis, but 2 patients presented with lung metastases.

thumbnail image

Figure 1. Histologic subtypes of radiation-induced soft tissue sarcoma are illustrated. MPNST indicates malignant peripheral nerve sheath tumor.

Download figure to PowerPoint

Forty-two patients underwent surgical resection of the RI-STS, and 2 patients did not undergo surgery because of disease progression in 1 patient and medical comorbidities in the other. Thirty-eight patients underwent limb salvage surgery, and only 4 patients required an amputation. The patients with RI-STS who required amputation all had very large or multifocal tumors with extensive neurovascular, bone, and soft tissue involvement. Soft tissue reconstruction commonly was required after limb salvage procedures: Seven patients 7 (18.4%) patients had free-flaps, 13 patients (34.2%) had rotational flaps, and 2 patients (5.3%) had split-thickness skin grafts. Eight patients received neoadjuvant chemotherapy (18.2%), including 2 patients who had lung metastases at diagnosis.

Thirteen of the patients who underwent surgery received adjuvant radiation therapy (31%): Ten of those patients received external-beam radiation therapy (7 preoperatively and 3 postoperatively), including 1 patient who received intensity-modulated radiation therapy (IMRT), and 3 received brachytherapy (Table 1). Six patients (46%) had early complications: One patient who was diagnosed with bilateral deep vein thrombosis and another who had a pulmonary embolus received anticoagulation. Four patients developed wound complications, including 1 patient who required a rotational flap, 1 who required surgical debridement and dressing changes, 1 who was treated nonoperatively with dressing changes, and 1 who required percutaneous drainage of an infected seroma and intravenous antibiotics. Seven of thirteen patients (54%) who received reirradiation as part of their RI-STS management exhibited evidence of late radiation effects,19, 20 including 2 patients with upper extremity STS who had lymphedema, 1 patient with an upper extremity STS and 1 patient with a lower extremity STS who had fibrosis, 2 patients with lower limb STS who had both lymphedema and fibrosis, and 1 patient with late-onset radiation-induced colitis. Most late treatment effects did not occur suddenly but developed gradually after treatment and reached their maximal state between 6 months and 18 months after reirradiation (Table 1).

Table 1. Patients With Radiation-Induced Soft Tissue Sarcoma who Received Reirradiation
Patient No.RI-STS SiteRI-STS Radiation Dose (Gy)Local RecurrenceEarly ComplicationsTreatment of Early ComplicationsLate Treatment EffectsaDetection of Maximal Late Treatment Effects After ReirradiationMSTS-87 ScoreTESS Score
  • Abbreviations: Brachy, brachytherapy; Gy, gray; IMRT, intensity-modulated radiotherapy; MSTS-87, Musculoskeletal Tumor Society Rating Scale 1987; Preop, preoperative; Postop, postoperative; RI-STS, radiation-induced soft tissue sarcoma; TESS, Toronto Extremity Salvage Score.

  • a

    Fibrosis was graded according to European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group Late Radiation Toxicity Criteria (see Cox 199519). Edema was measured according to previously reported criteria (see Stern 196420).

1AdductorPrep (49.5)NoPulmonary embolusAnticoagulationModerate lymphedema and grade 3 fibrosis1.5 y3172
2AxillaPostop (50)NoNo No --
3ButtockPreop (28)NoWound necrosisIrrigation and debridement, rotation flapGrade 1 fibrosisPresent since treatment2971
4AxillaBrachy (40)NoNo Mild lymphedema6 mo2378.5
5TrapeziusBrachy (40)NoNo Grade 3 fibrosis6 mo3390.2
6InguinalPreop IMRT (50)NoBilateral deep vein thrombosisAnticoagulationMild lymphedema and grade 1 fibrosis1 y3177.6
7Anterior upper armPreop (50)NoNo No --
8TrapeziusBrachy (28)NoWound necrosisDressing changes onlyNo --
9ButtockPreop (25)NoWound necrosisIrrigation and debridement, dressing changesNo 2371.2
10TrapeziusPostop (45)NoNo No 2775
11ShoulderPostop (45)NoNo No 2989.3
12AxillaPreop (25)YesNo Mild-moderate lymphedemaPresent since treatment--
13InguinalPreop (45)NoInfected seromaPercutaneous drainage and intravenous antibioticsRadiation-induced colitisColitis at 12 y

Of the 42 patients who underwent surgical resection, 29 patients (69%) developed some form of malignant relapse (Fig. 2). Fifty percent of patients (n = 21) developed systemic metastasis, 12% (n = 5) had lymph node metastasis, and 26% (n = 11) developed a local recurrence of the RI-STS. Surgical resection margins were negative in 35 patients (83%), whereas 6 patients had microscopically positive martins, and 1 patient had macroscopically positive margins. Three of 7 patients (43%) with positive resection margins developed a locally recurrent RI-STS versus 8 of 35 patients (23%) with negative resection margins (P = .52). Only 1 of 13 patients (7.7%) who received radiation for their RI-STS had a local recurrence compared with 10 of 29 patients (34.5%) who underwent surgery alone (P = .043) (Fig. 3). After treatment for their RI-STS, 4 patients (9.5%) had a local recurrence of their primary cancer, whereas 11 patients (26%) developed a new cancer or, in some patients, multiple different new cancers unrelated to their primary cancer or RI-STS (Table 2). Three of these patients died from the new cancer. It is noteworthy that, in 9 of these 11 patients, the new unrelated cancers developed within the radiation field.

thumbnail image

Figure 2. This chart illustrates oncologic relapses after treatment for radiation-induced soft tissue sarcoma (RI-STS). Mets indicates metastases.

Download figure to PowerPoint

thumbnail image

Figure 3. The local recurrence-free interval is illustrated for patients with radiation-induced soft tissue sarcoma who underwent surgery with (solid line) or without (dashed line) adjuvant radiation. Vertical bars represent censored observations. Patients who received reirradiation (n = 13) had a better local recurrence-free interval (P = .043) than patients who did not receive radiation (n = 29).

Download figure to PowerPoint

Table 2. New Cancers Unrelated to the Index Cancer or Radiation-Induced Soft Tissue Sarcoma
Patient No.New Type of CancerNew Cancer in the Radiation Field
1MelanomaYes
2Lung cancerYes
3Breast cancerYes
4Prostate cancer, melanoma, myeloma, thyroid cancerYes
5Malignant gliomaYes
6LeiomyosarcomaNo
7Bladder cancerYes
8Thyroid cancerNo
9Colon cancer, bladder cancerYes
10Basal cell cancerYes
11Thyroid cancer, lung cancer, leukemia, basal cell cancerYes

The median follow-up of the 42 patients who underwent surgery was 29 months (range, 2-227 months). Currently, 15 of these patients are alive with no evidence of disease, 4 are alive with evidence of disease, 20 have died of disease, and 3 have died from unrelated causes (Table 3). Overall, the DFI for the 42 patients who underwent surgery was 46% (95% CI, 33%-66%), 36% (95% CI, 23%-57%), and 22% (95% CI, 9%-50%) at 2 years, 5 years, and 10 years, respectively (Fig. 4). The OS rate for patients who underwent surgery was 63% (95% CI, 50%-81%), 44% (95% CI, 30%-65%), and 25% (95% CI, 12%-53%) at 2 years, 5 years, and 10 years, respectively (Fig. 5). We compared the oncologic outcomes between patients who presented with UICC TNM stage III RI-STS(ie, large, deep, high grade, and no regional lymph node metastasis;n = 26) and patients who presented with stage III sporadic STS (n = 550) using multivariate analysis. Radiation induction was associated with a significantly worse DFI (hazard ratio [HR], 1.69; 95% CI, 1-2.86; P = .051) (Table 4, Fig. 6), although the effect of radiation induction was less pronounced on OS (HR, 1.08; 95% CI, 0.58-1.98; P = .81; data not shown). Positive surgical margins also predicted for worse DFI (HR, 1.51; 95% CI,1.13-2.01), whereas the receipt of adjuvant radiation had a beneficial effect (HR, 0.54; 95% CI, 0.40-0.72). There was no significant interaction between adjuvant radiotherapy and the etiology of the sarcoma (P = .27). Histology also was an important predictor, with malignant fibrous histiocytoma and malignant peripheral nerve sheath tumor being associated with significantly worse outcomes.

thumbnail image

Figure 4. The disease-free interval is illustrated for patients with radiation-induced soft tissue sarcoma who underwent surgery. The estimated 5-year disease-free survival rate was 36% (95% confidence interval, 23%-57%). The Kaplan-Meier estimate of probable disease-free survival (solid line) is shown with 95% confidence intervals (dashed lines); vertical bars represent censored observations.

Download figure to PowerPoint

thumbnail image

Figure 5. Overall survival is illustrated for patients with radiation-induced soft tissue sarcoma who underwent surgery. The estimated 5-year overall survival rate was 44% (95% confidence interval, 30%-65%). The Kaplan-Meier estimate of probable survival (solid line) is shown with 95% confidence interval (dashed lines); vertical bars represent censored observations.

Download figure to PowerPoint

thumbnail image

Figure 6. The disease-free interval is illustrated for patients with stage III radiation-induced soft tissue sarcoma (RI-STS) (dashed line) and for patients with stage III sporadic STS (solid line) who underwent surgery. Vertical bars represent censored observations. Patients with stage III RI-STS (n = 26) had a worse disease-free interval (P = .01) than patients with stage III sporadic STS (n = 550).

Download figure to PowerPoint

Table 3. Follow-Up Status of Patients who Underwent Surgery for Radiation-Induced Soft Tissue Sarcoma
StatusNo. of Patients (%)aMedian Survival [Range], months
  • Abbreviations: ANED, alive with no evidence of disease; AWED, alive with evidence of disease; Died, cause of death unrelated to radiation-induced soft tissue sarcoma; DOD, dead of disease.

  • a

    Note that 2 patients did not undergo curative treatment.

ANED15 (36)48 [2-227]
AWED4 (6)21 [6-100]
DOD20 (48)15 [4-92]
Died3 (7)27 [10-90]
Table 4. Regression Model Estimating Disease-Free Interval for Patients With International Union Against Cancer TNM Stage III Radiation-Induced Soft Tissue Sarcoma and Sporadic Soft Tissue Sarcoma
 Univariable ModelMultivariable Model
VariableHR (95% CI)PHR (95% CI)P
  1. Abbreviations: CI, confidence interval; HR, hazard ratio; MFH, malignant fibrous histiocytoma; MPNST, malignant peripheral nerve sheath tumor.

Etiology    
 Radiation-induced1.83 (1.15-2.93).011.69 (1-2.86).051
Surgical margins    
 Positive1.37 (1.04-1.82).031.51 (1.13-2.01).0052
Radiotherapy    
 Yes0.57 (0.43-0.76)<.0010.54 (0.4-0.72)<.001
Chemotherapy    
 Yes1.08 (0.35-3.38).890.58 (0.18-1.95).38
Histology    
 Other sarcoma1.001.00
 Angiosarcoma2.39 (1.05-5.45).0381.42 (0.59-3.42).44
 Fibrosarcoma1.00 (0.47-2.16).991.01 (0.47-2.16).99
 Leiomyosarcoma1.56 (1.02-2.37).0381.34 (0.87-2.05).18
 MFH1.45 (1.1-1.91).00781.45 (1.1-1.92).0083
 MPNST2.3 (1.5-3.53)<.0012.65 (1.72-4.1)<.001

For functional assessment, a 2:1 match was used to identify a group of 36 patients who had sporadic STS comparable to the 18 patients who had RI-STS and who underwent a functional evaluation at least 1 year postoperatively. There was no significant difference between the TESS scores (P = .5) or the MSTS-87 scores (P = .61) for the RI-STS and sporadic STS groups (Table 5). The mean TESS score for the RI-STS cohort was 74 (range, 27-100), and the mean MSTS-87 score was 26.6 (range, 9-33). Six of 13 patients who received irradiation for their RI-STS developed late complications of fibrosis and/or lymphedema, and 5 underwent functional assessment. It is noteworthy that, for these 5 patients, the mean TESS score was 77.8 (range, 71-90), and the mean MSTS-97 was 29.4 (range, 23-33).

Table 5. Comparison of Functional Outcomes for Patients With Radiation-Induced Soft Tissue Sarcoma and Sporadic Soft Tissue Sarcoma
 Mean Score (Range) 
TestRI-STS, n = 18Sporadic STS, n = 36P
  1. Abbreviations: MSTS-87, Musculoskeletal Tumor Society Rating Scale 1987; RI-STS, radiation-induced soft tissue sarcoma; STS, soft tissue sarcoma; TESS, Toronto Extremity Salvage Score.

TESS74.02 (27-100)77.94 (36-98).50
MSTS-8726.63 (9-33)27.25 (14-35).61

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

It has been reported that patients who develop RI-STS have worse outcomes compared with those with de novo STS.21 In the current study, the RI-STS group had all the prognostic factors that would predict for poor survival: patients were older with a median age at diagnosis of 56 years, 70% of tumors were high grade, 91% were deep, and 70% were large.21-23 Overall, 62% of patients presented with UICC TNM stage III disease, and this likely accounted, at least in part, for the high incidence of systemic metastasis in the study (50%).24-26 Kaplan-Meier analysis revealed that, at 5 years, the DFI was 36%, and the OS rate was 44% for these patients.

By comparing the outcomes of patients who were treated for UICC TNM stage III STS, we were able to show more conclusively that patients with RI-STS, in fact, do have a worse prognosis. Comparison by Kaplan-Meier survival analysis revealed that the 5-year DFI for patients with stage III RI-STS was only 27% compared with 55% for those with similar stage sporadic STS (Fig. 6). The results of multivariate regression analysis also support the finding that RI-STS have a significantly inferior outcome compared with sporadic STS (HR, 1.69; 95% CI, 1-2.86; P = .051) (Table 4). Although patients with RI-STS also had poorer OS than patients with sporadic STS, that difference was not statistically significant, and this may be because of the limited effective sample size. Our results confirm the recent findings of Gladdy et al, who studied 130 patients with RI-STS and demonstrated that they had inferior disease-specific survival compared with patients who had sporadic STS.21 Both studies also associated malignant fibrous histiocytoma and malignant peripheral nerve sheath tumor with particularly bad outcomes.

The findings of the current study in RI-STS are similar to what is reflected in much of the literature pertaining to radiation-induced sarcoma of bone (RISB), which also has been associated with a very poor outcome. However in our previous study of RISB, we identified a subgroup of patients (10 of 24) who presented with localized disease and, after aggressive management with both surgery and chemotherapy, actually had a prognosis approaching that of patients with primary osteosarcoma.27 Other recent investigations also identified improved outcomes for patients with RISB who were able to undergo combined-modality treatment.28-30 This improved curability for patients with RISB is largely attributable to the effective nature of chemotherapy in the management of bone sarcomas,31, 32 whereas it is not as effective for STS, in which its role remains controversial.33 A major limitation to further improvements in outcome for RISB is that only a minority of patients can actually tolerate the intensive chemotherapy regimens because of advanced age, medical comorbidities, and previous chemotherapy treatment.

RI-STS may differ genetically and biologically from their sporadic counterparts, and this may account in part for their more aggressive clinical features. RI-STS accumulate additional and specific genetic mutations compared with sporadic tumors because of prior radiation exposure.34, 35 For example, 1 study identified tumor protein 53 (TP53) mutations in 58% of radiation-induced sarcomas compared with approximately 20% in sporadic tumors, whereas another investigation indicated that every postradiation sarcoma had at least 1 TP53 mutation.34, 35 In addition, radiation-induced sarcomas exhibit evidence of biallelic inactivation of TP53, high rates of short deletions (52%), lack of “hot spot” and CpG dinucleotide mutations, and new recurrent sites of mutations, findings that are considered the consequences of ionizing radiation.35 Some of these patients have an underlying genetic predisposition to develop second tumors, such as neurofibromatosis type 1 or Li-Fraumeni syndrome, which also may affect the biologic behavior.36, 37

Three recent studies have documented the difficulties associated with surgical management of patients with RI-STS. Cha et al reported that 46% of 111 patients who underwent surgical resection for RI-STS had gross or microscopically positive margins, and 41% developed local recurrences.38 Thijssens et al23 observed that 38% of their 21 surgically treated patients with RI-STS had positive margins; and even, after achieving negative margin resections, 54% developed local recurrences. After 34 curative resections, Neuhaus et al39 reported 25% with positive margins and 65% with local recurrences. These rates are much higher than what we observed in our study, in which only 7 of 42 patients (17%) had positive resection margins, and 26% (n = 11) developed local recurrences. Despite our lower rate of local recurrence compared with previous studies, it still is worse than our outcomes after management of sporadic STS at Mount Sinai Hospital/Princess Margaret Hospital, where the rate of local recurrence was recently estimated at 8%. This underscores the necessity for very aggressive surgery to improve local control.

The need for soft tissue reconstruction may be 1 indirect measure of the extent of surgical resection for patients with RI-STS. These patients often have soft tissue fibrosis because of prior irradiation, and this can make it challenging to identify normal tissue planes and to determine the true extent of the tumor radiographically as well as intraoperatively, thus making surgical planning and resection more difficult, which can directly affect local control. Fibrosis also can negatively impair adequate surgical exposure and necessitate resection of large amounts of overlying scarred tissues, which subsequently require the use of local or free flaps for coverage. In our study, 22 of 42 patients (52%) underwent some form of soft tissue reconstruction compared with 12 of 34 (35%) in the investigation by Neuhaus et al.39 By comparison, 29% of 182 patients who were treated for sporadic STS as part of a recent randomized trial of preoperative radiation versus postoperative radiation underwent soft tissue reconstruction.3

Reirradiation as part of the management of RI-STS remains controversial, because radiation is the underlying cause of these malignancies. Normal tissue tolerance suggests that reirradiation of an already treated field raises the risk of additional toxicity, including acute wound-healing complications as well as late occurring problems like fibrosis, joint stiffness, lymphedema, neuropathy, decreased function, and radiation-induced fractures, along with additional RI-STS and other cancers.2, 3, 40 Some authors have gone so far as to state that effective reirradiation is not possible in this situation.23 However, our group and others previously demonstrated that reirradiation can be used selectively as part of combined management for locally recurrent, sporadic STS despite prior receipt of radiotherapy.41-43 The results of the current study also suggest that adjuvant radiation does have a beneficial effect on DFI for RI-STS as well as local recurrence and that it can be used safely in a selected group of patients.

Radiation has certainly been used infrequently as part of RI-STS management, and there is greater reliance on surgical resection alone. However, with reports of higher than usual rates of positive resection margins, it is not surprising that local recurrences develop more commonly after the management of RI-STS compared with sporadic STS. Adjuvant radiation was used in only 2 of 21 patients with RI-STS in the study by Thijssens et al23 and in no patients in the study by Neuhaus et al.39 Gladdy et al21 reported that 22% of 130 patients with RI-STS were received adjuvant radiation compared with 49% of their patients with sporadic high-grade STS. By comparison, 13 patients with RI-STS (31%) in our current study received radiation, and this likely contributed to our overall lower rate of local recurrence. We identified fewer local recurrences in patients who received reirradiation (1 of 13 patients; 7.7%) compared with patients who underwent surgery alone (10 of 29 patients; 34.5%; P = 0.043) (Fig. 3).

The selection of patients for reirradiation must take into consideration the potential added benefit of adjunctive radiotherapy in each clinical situation, particularly relative to surgical margins, the previous radiation dose used, the volume of normal tissue irradiated, the estimated normal tissue recovery after radiotherapy, and the presence of adjacent, critical, radiosensitive structures. Our results suggest that reirradiation can be accomplished in selected patients without too high a risk of serious acute and late complications (Table 1). Four of 13 patients with RI-STS who were reirradiated in our study suffered acute wound-healing complications, and 2 required surgical management. Although 7 of these patients exhibited evidence of late radiation effects, including fibrosis and lymphedema, they still had very good functional results. Furthermore, many of these patients were treated and retreated before the current era of high-precision radiotherapy. Modern radiotherapy techniques, such as image-guided IMRT and brachytherapy, have substantially enhanced the ability to protect normal tissues from the full effects of the prescribed radiation dose, and this is of critical importance in the setting of reirradiation.

The timing of external-beam retreatment also is important, and the advantages of preoperative radiotherapy for patients with RI-STS include superior normal tissue protection through a more conformal treatment plan, a smaller treatment volume, and a lower total dose required compared with the postoperative setting.3 Our group also has used twice-daily fractionation at 1.1 Gy per fraction in an attempt to reduce the impact of fraction size on late tissue effects. These improvements in radiotherapy now provide greater flexibility for the use of reirradiation as a part of the management of RI-STS and should lead to an expanded role for combined therapy in the future.

Functional outcomes were expected to be worse in the RI-STS group compared with the sporadic STS group, although this specific issue has not been investigated previously. We predicted that some patients with RI-STS would present with pre-existent soft tissue radiation toxicity, such as fibrosis, which is known to negatively affect function1; and, after additional radical surgery and possibly repeat irradiation, function would deteriorate further. Surprisingly, however, there was no significant difference between the 2 patient groups based on TESS (P = .50) and MSTS-87 (P = .61) evaluations.

In this multicenter study, the incidence of RI-STS was 0.9%, which is within the range identified by other studies, suggesting that RI-STS accounts for 0.5% to 5.5% of all sarcomas.44, 45 In the past, the large volumes and high doses of radiation therapy used to treat cancer patients led to an increased risk of developing secondary tumors, the most common of which were sarcomas.4, 9 In a cohort study of 295,712 Finnish cancer patients, 147 developed a radiation-induced sarcoma (0.06%), and soft tissue sarcomas accounted for 86%.46 One likely explanation for why RI-STS develops more frequently than RISB is that a larger volume of soft tissue compared with bone is irradiated as part of most radiation treatment plans. Differential radiosensitivity of mesenchymal tissues also may play a role in favoring the development of STS rather than bone sarcoma after prior radiotherapy. In fact, it has been demonstrated that higher doses of radiation are required for the induction of RISB, and the risk is dose-dependent.47-50 Patients with Ewing sarcoma, bilateral retinoblastoma, and other malignant bone tumors who received radiation were at greater risk of developing an RISB as a secondary malignant tumor, probably because of underlying genetic risk as well as the high total radiation dose focused within the bone itself. Despite these well established data relating to RISB, a recent study of atomic bomb survivors of Hiroshima and Nagasaki indicated that RISB sometimes can occur after exposure to much lower doses of ionizing radiation than previously reported.51

The introduction of 3-dimensional conformal radiation meant that smaller volumes of normal tissue surrounding tumors were exposed to high-dose radiation, and this may translate into a lower incidence of RI-STS. However, theoretically, it is possible that radiation-induced tumors, including RI-STS, may increase with more prevalent use of IMRT.52, 53 With IMRT, larger volumes of normal tissues surrounding the tumor are exposed to lower but still potentially mutagenic doses of radiation, and there is also the potential for higher total body radiation exposure because of technical aspects of the treatment.54 Some authors have suggested that IMRT may double the risk of second cancers from a current baseline of approximately 1%, although, currently, this is speculative.52, 53

In conclusion, patients who receive radiation as part of the treatment for their primary tumors should be followed very carefully for long periods of time to detect secondary cancers, which can occur even decades later. Although RI-STS are relatively rare, they are associated with a worse oncologic outcome than sporadic STS in terms of both local and systemic recurrence. Currently, aggressive surgical resection is the mainstay of treatment with the judicious use of reirradiation. Despite these concerns, the majority of patients with RI-STS can anticipate limb salvage with good functional outcomes after treatment.

FUNDING SOURCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

David Biau was supported by the OMeGA Medical Grants Association through the generous support of Zimmer for its oncology fellowship grant.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES