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10.1245/ASO.2005.03.041
Annals of Surgical Oncology 12:237-245 (2005)
© 2005 Society of Surgical Oncology
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Original Article

Radiation-Induced Sarcoma: A Challenge for the Surgeon

Katja M. J. Thijssens, MD1, Robert J. van Ginkel, MD, PhD1, Albert J. H. Suurmeijer, MD, PhD2, Elisabeth Pras, MD, PhD3, Winette T. A. van der Graaf, MD4, Miranda Hollander, BA1 and Harald J. Hoekstra, MD, PhD1

1 Department of Surgical Oncology, Groningen University Medical Centre, P.O. Box 30.001, 9700, RB Groningen, The Netherlands
2 Department of Pathology, Groningen University Medical Centre, 9700, RB Groningen, The Netherlands
3 Department of Radiation Oncology, Groningen University Medical Centre, 9700, RB Groningen, The Netherlands
4 Department of Medical Oncology, Groningen University Medical Centre, 9700, RB Groningen, The Netherlands

Correspondence: Address correspondence and reprint requests to: Harald J. Hoekstra, MD, PhD; E-mail: h.j.hoekstra{at}chir.umcg.nl.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Treatment of radiation-induced sarcoma (RIS) remains an unsolved problem. To provide more insight into the disease process, its characteristics, outcome, and potential outcome determinants were defined.

Methods: From 1978 to 2003, 27 patients—20 females (74%) and 7 males (26%) with a median age 44 years (range, 1–73 years) at the time of diagnosis of the primary tumor—developed an RIS after a median interval of 8 years (range, 3–41 years). The histology of the RIS was 10 (37%) undifferentiated high-grade pleomorphic sarcomas, 7 (26%) angiosarcomas, 6 (22%) fibrosarcomas, 2 (7%) osteosarcomas, 1 (4%) pleomorphic rhabdomyosarcoma, and 1 (4%) pleomorphic leiomyosarcoma. Surgical resection was performed in 21 patients: 13 (62%) R0 (microscopically radical), 4 (19%) R1 (microscopically irradical), 2 (9.5%) R2 ( macroscopically irradical), and 2 (9.5%) RX (unknown radicality). Six (22%) patients underwent no resection.

Results: The 5-year disease-free and overall survival rates were 27%and 30%, respectively. The local failure rate after R0 resection was 54%. The distant failure rate for the entire group was 41%. Patients with an R0 resection had a significantly better survival rate (P < .05) than patients with an R1, R2, or no resection.

Conclusions: RISs are aggressive malignancies with a high tendency for local recurrence and distant metastases. Previously applied treatment often hampers adequate resection. Therefore, radical surgical resection is the only chance to improve disease-free and overall survival, but it may also have a palliative role. Still, the overall prognosis remains poor.

Key Words: Sarcoma • Surgery • Radiation • Complications • Combined-modality treatment


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In The Netherlands, 69,000 new cases of cancer are diagnosed yearly, and 38,000 patients die from their malignancy.1 The incidence of solid tumors is still increasing. Disease-free (DFS) and overall survival (OS) are increasing because of (1) progress in better preoperative staging by various imaging techniques, such as spiral computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, and positron emission tomography, and (2) appropriate surgery in combination with adjuvant therapies such as chemotherapy, radiotherapy, and hormonal therapy. Therefore, cancer may now be viewed as a "chronic disease."

Because more cancer patients survive, there is an increased risk of a new malignancy or a secondary treatment-induced malignancy. The number of patients with a second malignancy reaches 10% in The Netherlands.1 Types of treatment-induced malignancies may be distinguished between chemotherapy-induced and radiation-induced malignancies.

Surgical experience with radiation-induced sarcoma (RIS) is limited, and the results of RIS treatment are discouraging. With improved preoperative imaging techniques, including CT and MRI, and the increased experience in sarcoma surgery, along with plastic surgical reconstructions, more radical surgical operations are now possible. Whether this aggressive surgical approach has influenced the oncological outcome is yet to be determined. Therefore, a retrospective study and review of the literature was performed to investigate the short- and long-term outcome of surgical treatment of RIS.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
From 1978 to 2003, 27 patients—20 females (74%) and 7 males (26%) with a median age of 52 years (range, 20–83 years)—were diagnosed with RIS at the Groningen University Medical Centre. Patient records were retrieved from the sarcoma database of the Division of Surgical Oncology. To fill the required criteria, all patients must have received previous radiotherapy for a malignant or benign disease. The criteria required to fulfill the definition of RIS were (1) different histopathologic features between the primary lesion (i.e., the indication for initial radiotherapy) and the sarcoma; (2) sarcoma arising within the irradiated field; and (3) a latency period of at least 3 years.2 The latency period was calculated from the initial radiotherapy until the diagnosis of RIS. Sarcomas were reviewed on hematoxylin and eosin–stained sections with additional immunohistochemistry to evaluate tumor differentiation. They were classified with the most recent World Health Organization classification and graded according to the French grading system.3,4 Additional data reviewed were patient demographics, delivered radiation dose, latency period, treatment of RIS, local and distant failure, and survival after diagnosis of RIS.

Treatment for RIS in the absence of distant metastases was surgery. In cases of distant metastases, chemotherapy was considered. In cases of local failure after primary treatment for RIS, re-excision was preferred. Radiotherapy and chemotherapy were given only in select cases. Patient characteristics, tumor data, and treatment schedules are listed in Tables 1Go to 3GoGo. DFS and OS was determined, and a comparison of survival after identifiable resection techniques was performed by using Kaplan-Meier survival curves with the log-rank test. The achieved results were discussed, and the RIS literature was reviewed.


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  		TABLE 1. Development of distant metastases in patients with RIS
 

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  		TABLE 2. Primary lesion and presentation of RIS
 

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  		TABLE 3. Treatment and follow-up for radiation-induced sarcoma
 

   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The median age of the 27 patients at the time of diagnosis of the primary lesion was 44 years (range, 1–73 years). The median latency period between radiotherapy for the primary lesion and RIS was 8 years (range, 3–41 years). The median patient age at diagnosis of RIS was 52 years (range, 20–83 years). The total delivered irradiation dose could be exactly retrieved in 24 cases (89%), and the median radiation dose was 50 Gy (range, 16–70 Gy). All three cases in which information on the irradiation dose was not retrievable involved a prolonged latency period after radiotherapy (>18 years). Eleven patients received adjuvant systemic therapy for the primary tumor: seven patients were treated with cytotoxic agents, and five received hormonal therapy. The shortest latency period was observed for a patient with a fibrosarcoma 40 months after irradiation with a dose of 60 Gy for a squamous cell carcinoma of the floor of the mouth. The longest latency period was seen for a patient who developed an undifferentiated high-grade pleomorphic sarcoma 41 years after a squamous cell carcinoma of the vulva (radiation dose, 30 Gy).

Histology of the RIS was 10 (37%) undifferentiated high-grade pleomorphic sarcomas, 7 (26%) angiosarcomas, 6 (22%) fibrosarcomas, 2 (7%) osteosarcomas, 1 (4%) pleomorphic rhabdomyosarcoma, and 1 (4%) pleomorphic leiomyosarcoma. All patients were staged locally and distantly; three (11%) RIS patients had metastatic disease when the RIS was diagnosed.

There were 24 patients (89%) without distant metastases at the time of diagnosis of RIS. Thirteen underwent an R0 resection with a median survival of 29 months (range, 5–307 months); seven of these patients developed a local failure (54%). In patients who did not develop a local failure after R0 resection, the median survival was 40.5 months (range, 6–88 months). In patients who developed a local recurrence, the median survival was 20 months (range, 5–307 months). Four patients underwent an R1 resection with a survival ranging from 5 to 138 months. Two patients underwent an R2 resection and survived 4 and 14 months. Three patients underwent no resection (two of the three received palliative chemotherapy) and survived 7, 7, and 5 months. In two patients, the radicality of the first resection was not retrievable. In one patient, a local failure was diagnosed after 13 months, and an R0 resection was performed, after which the patient survived 149 months with no evidence of disease. The other patient died after 24 months. The three patients with distant metastases at the time of diagnosis of RIS survived 1, 6, and 15 months; the one who survived 15 months received palliative chemotherapy. During follow-up, eight patients (33%) developed metastases at single and multiple locations after a median of 8 months (range, 2–60 months). Details about the presentation of RIS, treatment, follow-up, and sites of metastasis are listed in Tables 1Go–3GoGo.

DFS and OS were both 44% at 2 years and were 27% and 30%, respectively, at 5 years (Figs. 1Go and 2Go). DFS was calculated by using the time period, in the group of patients with primarily no evidence of metastatic disease (n = 24), from establishment of the RIS diagnosis until the first recurrence (Fig. 1Go). The median OS after diagnosis of RIS was 15 months (range, 1–307 months). At the time of this review, nine patients were still alive with no evidence of disease, with a median follow-up of 66 months (range, 5–307 months). Seventeen patients (63%) died of their RIS, with a median survival of 14 months (range, 1–138 months). In one patient, the final cause of death was not retrievable (24 months). The local failure rate after R0 resection was 54 %, and the overall distant failure rate was 41%.



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  		FIG. 1. Percentage of disease-free survival (DFS) during follow-up of patients with primarily no evidence of metastatic disease (n = 24).

 


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  		FIG. 2. Percentage of overall survival during follow-up after radiation-induced sarcoma diagnosis of all patients (n = 27).

 
Patients who received an R0 resection had a significantly better survival than the patients without metastasis in whom only an R1 or R2 resection, or no resection, could be performed (log-rank, 4.96; df = 1; P = .026; relative risk, 8.6; 95% confidence interval, 8.2–8.9; nonradical resection group compared with the radical surgery group; Fig. 3Go).



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  		FIG. 3. Radicality of resection and survival: a radical resection differed significantly (P = .026) from nonradical and no resection with respect to survival.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The first RIS was described at the beginning of the 20th century, and the earliest comprehensive RIS study was performed by Cahan et al.5 Since 1940, 16 studies have been published. The number of patients in the studies, latency period, survival time, number of patients dead of disease, 2- and 5-year DFS and OS, and percentages of local and distant failure are listed in Table 4Go.


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  		TABLE 4. Studies analyzing RIS
 
Until now, RISs have been considered extremely rare, and the current incidence varies from .03%% to .22%.6–12 In this study, the median latency period between irradiation and diagnosis of RIS was 8 years, which is comparable to the roughly 10 years (range, 3 months to 50 years) in the published literature.8,13–15 The development of RIS may be attributed to ionizing radiation, which may induce genomic instability.16 The precise radiation-induced genetic mechanism is still unknown. The prognosis of RIS is poor and is worse than the usual prognosis for a sarcoma.11,17–23 The question of whether RIS of the soft tissue differs from RIS of the bone with respect to local growth pattern and metastatic potential remains unanswered.

We noticed an increased number of patients diagnosed with RIS over the last three decades (Fig. 4Go). The increase in RIS of soft tissue might be the result of an intensive cancer treatment combining (extensive) surgery with adjuvant or neoadjuvant chemotherapy and preoperative or postoperative radiation. Some chemotherapeutic agents, such as doxorubicin, might have the potential for causing radiation sensitization. A definitive relationship between latency period and radiation dose, with or without chemotherapy, as well as age at the time of RIS diagnosis and survival, could be defined neither in this study nor in the available literature.2,17,24,25 Another problem might be the diTcult detection of a second malignancy within a previously irradiated area, causing a delay in diagnosis and, therefore, a more advanced stage of disease. When alterations occur within a previously irradiated area, the diagnosis of RIS must always be considered.26



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  		FIG. 4. Number of patients diagnosed with radiation-induced sarcoma over the last 3 decades.

 
Because of previously performed (intensive) treatment, RIS requires a so-called "tailored" cancer treatment with an optimal tumor staging, as well as information with respect to the local growth pattern of the RIS and involvement of the surrounding tissues. The current new radiodiagnostic imaging modalities of MRI and spiral CT might provide adequate information, and three-dimensional reconstruction enables excellent preoperative planning of the extent of the surgical resection and the need for reconstruction with plastic surgery, with the ultimate goal of achieving an R0 resection with low morbidity, e.g., primary wound healing. Adequate radical resection is sometimes difficult or even impossible. The reason for this is often the anatomical site of the tumor or extensive ingrowth in surrounding tissue. The important role of surgery has been underlined by many authors and was confirmed in this study.2,11,20,24 The group of patients with an R0 resection had a significantly longer median survival time, even in the group with local failure. The prognosis for sarcoma patients after radical re-excision for a primary nonradical excision has been shown not to differ from that of patients after primary radical excision.27 This study was too small to prove this for RIS as well.

The results of this study are similar to those in the review by Robinson and associates25, which reported a median survival of 12 months with a survival rate at 2 years of 22% and at 5 years of 11% . Unfortunately, the overall results have only slightly improved since the 1940s, and most published studies provide only limited data; this hampers further insight into the described diseases. None of the reviewed studies showed a significantly beneficial effect of adjuvant chemotherapy, irradiation, or both.14,28,29 This is not surprising, because effective reirradiation is impossible, and chemotherapy may have a role. However, the numbers of patients described in the subsequent studies were small. Recently, there has been evidence that most RISs show an extensive expression of the KIT protein. Although treatment with the KIT inhibitor imatinib might be considered for patients in whom radical surgery is not amenable, it is not likely that this will be the final solution to this problem.30

As in previous reports, we found a wide variety in histopathologic subtypes of RIS. With the increasing incidence of angiosarcoma of the breast after breast conserving therapy (BCT), this subgroup needs to be explored much more extensively. A cooperative international study is required to acquire more fundamental insight into this treatment-induced disease. If more information is obtained about these kinds of secondary malignancies and the patients who get them, prevention measures might be undertaken in patients who are candidates for BCT. Will the reduction of doses of intensity-modulated radiotherapy indeed fulfill the new hope in eradicating cancer, or will it, conversely, increase the risk of RIS in the surrounding healthy tissue?

In summary, RISs are aggressive malignancies with a high tendency for local recurrence and distant metastases. Previously delivered treatment hampers adequate resection and administration of radiotherapy. Therefore, RISs are a challenge for the surgical oncologist. A radical surgical approach is the only chance to improve DFS and OS, might offer palliation, and it is the only prognostic factor for long-term survival. Because the prognosis is poor, the options of new treatment strategies are being studied. More insight into the disease, especially angiosarcoma of the breast after BCT, might soon provide preventive measures in patients undergoing extensive combined cancer treatment.

Received for publication March 18, 2004. Accepted for publication November 15, 2004.


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 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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