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(Radiology. 2000;216:197-205.)
© RSNA, 2000

Radiation Oncology

Sarcoma after Radiation Therapy: Retrospective Multiinstitutional Study of 80 Histologically Confirmed Cases1

Jean-Léon Lagrange, MD, PhD, Alain Ramaioli, PhD, Marie-Christine Chateau, MD, Christian Marchal, MD, Michel Resbeut, MD, Pierre Richaud, MD, Philippe Lagarde, MD, Patrice Rambert, MD, Jacques Tortechaux, MD, Sok Hun Seng, MD, Brigitte de la Fontan, MD, Monique Reme-Saumon, MD, Jacqueline Bof, RN, Jean-Pierre Ghnassia, MD and Jean-Michel Coindre, MD, PhD.For the Radiation Therapist and Pathologist Groups of the Fédération Nationale des Centres de Lutte Contre le Cancer

1 From the Radiation Oncology Department, Centre Antoine Lacassagne, 33 avenue de Valombrose, 06189 Nice 2, France (J.L.L.). Statistical Unit, Centre Antoine Lacassagne, Nice, France (A.R., J.B.); Surgical Pathology Department (M.C.C.) and Radiation Oncology Department (B.d.l.F.), Centre Claudius Regaud, Toulouse, France; Radiation Oncology Department, Centre Alexis Vautrin, Nancy, France (C.M.); Radiation Oncology Department, Institut Paoli-Calmettes, Marseille, France (M.R.); Radiation Oncology Department (P.Richaud, P.L.) and Surgical Pathology Department (J.M.C.), Fondation Bergonie, Bordeaux, France; Radiation Oncology Department, Centre René Huguenin, Saint-Cloud, France (P.Rambert); Radiation Oncology Department, Centre Jean-Perrin, Clermond-Ferrand (J.T.); Radiation Oncology Department, Centre Henri Becquerel, Rouen, France (S.H.S.); Radiation Oncology Department, Centre Paul Lamarque–Val D'Aurelle, Montpellier, France (M.R.S.); and Surgical Pathology Department, Centre Paul Strauss, Strasbourg, France (J.P.G.). From the 1998 RSNA scientific assembly. Received January 15, 1999; revision requested March 24; final revision received December 8; accepted December 21. Address correspondence to J.L.L. (e-mail: jean-leon.lagrange@cal.nice.fnclcc.fr).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To evaluate the best strategy for treatment of sarcoma that occurs after radiation therapy.

MATERIALS AND METHODS: Records were retrospectively reviewed for 80 patients with a confirmed histologic diagnosis of sarcoma that occurred after radiation therapy performed during 1975–1995. The patients were treated for breast cancer (n = 33, 42%), non-Hodgkin lymphoma (n = 9, 11%), cervical cancer (n = 9, 11%), benign lesions (n = 4, 5%), or other tumors (n = 25, 31%). Sarcoma occurred after a mean latency of 12 years (range, 3-64 years), with most (70%) developing in the soft tissue. Treatment included surgery (28 patients), surgery and chemotherapy (18 patients), chemotherapy only (15 patients), and radiation therapy (14 patients).

RESULTS: By the end of the study, 51 patients were dead, including 46 due to sarcoma. Median survival was 23 months. Overall survival rates at 2 and 5 years, respectively, were 69% and 39% for patients treated with surgery, 10% and 0% for those treated with chemotherapy, and 52% and 35% for those treated with surgery and chemotherapy (P = .001). The 2- and 5-year rates for survival without recurrence were 54% and 32%, respectively.

CONCLUSION: The results confirm the beneficial effect of surgery. Further study is needed to explore the roles of combined treatments.

Index terms: Histiocytoma, **.322 • Leiomyosarcoma, **.32 • Lymphoma, **.32 • Osteosarcoma, 40.3221, 40.375 • Radiations, injurious effects, complications of therapeutic radiology • Sarcoma, **.32


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The development of sarcoma during the course of cancer is a rare occurrence. The origin of this tumor and the promoting factors that are involved remain controversial (1). There is no doubt that ionizing radiation can induce sarcoma. The poor prognosis associated with such secondary sarcomas has prompted the use of a wide range of therapeutic modalities, but the rarity of these cases has rendered systematic study difficult.

Most published studies on post–radiation therapy sarcoma (hereafter, postradiation sarcoma) have described tumors that occur after treatment for breast cancer. The earliest description of postradiation sarcoma of which we are aware was reported in 1922 by Beck (2), and the earliest description of sarcoma developing after radiation therapy for breast cancer of which we are aware was reported in 1936 by Warren and Sommer (3). Important series were published by Robinson et al (4) and Weatherby et al (5), but the majority of cases were reported separately, often with few details, which makes it difficult to evaluate the prevalence of this tumor and to define an optimal treatment strategy.

Cahan et al (6) defined the criteria for postradiation bone sarcoma: (a) histologic or radiologic proof that there was no previous tumor in the involved bone, (b) development of sarcoma in an irradiated area, (c) a sufficiently long interval between irradiation and development of sarcoma, and (d) histologic proof of sarcoma. These authors suggested an interval of 5 years, although 3–4 years was thought to be sufficient by Arlen et al (7).

The purpose of our study was to determine the best strategy for treatment by reviewing cases treated at the French cancer centers of the Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC).


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
A retrospective study of postradiation sarcoma treated at anticancer centers from 1975 to 1995 was undertaken at nine institutions. To be included, the patients must have undergone radiation therapy for a benign or malignant disease, and the primary diagnosis and the diagnosis of sarcoma must have been confirmed. The investigated parameters included age at diagnosis of the primary tumor, date of radiation therapy, energy used or type of irradiation, dose delivered, histologic type of sarcoma, anatomic location, tropism, age at diagnosis of sarcoma, interval between irradiation and the development of sarcoma, treatment of sarcoma, survival after diagnosis of sarcoma, and cause of death. Only patients in whom a confirmed histologic diagnosis had been established were included in the final analysis. In this respect, the Pathology Group of the FNCLCC reviewed specimens from the primary tumor and from the sarcoma.

Statistical analyses were performed by using the BMDP software package (BMDP Statistical Software, Los Angeles, Calif). Survival times were calculated from the time of the first therapy for the sarcoma. All cases were included in the survival analysis. Survival distributions were performed by using the Kaplan-Meier method (8), and differences between groups were tested with Mantel-Cox (9) and Breslow (10) statistics.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
From 1975 to 1995, sarcoma was recorded for 115 patients. Sarcoma was confirmed in 80 of these patients (60 female and 20 male patients); therefore, only the records for these 80 patients were included in the study. The analytic findings are presented in Table 1. The median age at the time of diagnosis of the primary tumor was 44 years (range, 6–83 years). Primary tumors were breast carcinoma in 33 (42%) patients, non-Hodgkin lymphoma in nine (11%), cervical or endometrial carcinoma in nine (11%), head and neck carcinoma in five (6%), benign disease in four (5%; two with taenia capitis, one with rheumatic inflammatory disease, one with sciatic pain), and other tumors in 20 (25%; five with skin tumors, four with bone or soft-tissue primary tumors, three with testicular tumors, four with ovarian tumors, one with malignant glioma, one with leukemia, one with kidney carcinoma, and one with penile tumor).


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  		TABLE 1. Summary of Study Population Data
 
The patients underwent irradiation with external-beam radiation therapy, brachytherapy, or both. The beam type was known in 69 patients: high-energy x rays in four patients, gamma rays in 33, orthovoltage x rays in 11, electrons alone in two, electrons plus either photons or cobalt in nine, brachytherapy alone in two, and brachytherapy plus either high-energy x rays or gamma rays in eight. All brachytherapy treatments were delivered with a low dose rate. The total dose was known in 65 cases. The median dose was 50 Gy (range, 9–110 Gy), and the distribution of the dose delivered to the primary tumor was 9–20 Gy in four patients, more than 20 Gy to 40 Gy in 14, more than 42 Gy to 50 Gy in 17, more than 50 Gy to 60 Gy in 14, and more than 60 Gy to 110 Gy in 16. There was no correlation between dose and latency until sarcoma or dose and frequency of sarcoma.

At the time of diagnosis of postradiation sarcoma, the median age of the patients was 59 years (range, 18–89 years), and the median interval between irradiation and diagnosis was 12 years (range, 3–64 years). The site of origin, determined clinically, was bone in 30% of the cases and soft tissue in 70%; the initial site was inside the radiation portal in 72 (90%) patients and at the edge of the irradiated area in eight (10%). In this study, it was not possible to analyze the relationship between the dose delivered to the tissue and the development of sarcoma, because the initial location of the secondary tumor could not be determined precisely and it was not possible to review all the dosimetric data. In any case, however, the sarcoma developed in the irradiated volume, which may be larger than the radiation portal (ie, the geometric limits of the beam).

The histologic distribution of sarcomas is reported in Table 2. The tumor was graded according to the FNCLCC grading system (11), which is based on tumor differentiation, mitotic count, and necrosis. Grading of tumors was possible in 54 patients, and these tumors were classified as follows: grade 1 for six tumors, grade 2 for 17 tumors, and grade 3 for 31 tumors.


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  		TABLE 2. Distribution of Histologic Types of Sarcoma
 
With regard to therapy, 75 patients were treated and five were not after biopsy was performed. Sarcoma sites according to initial lesion location and treatment modality are presented in Table 3. No explanation was given in the medical notes for these patients to justify the policy of no treatment. The majority of patients who were treated (58 patients) underwent surgery: surgery alone in 28 patients, surgery plus chemotherapy in 18, or surgery plus radiation therapy with or without chemotherapy in 12. Fifteen patients were treated with chemotherapy alone, and two patients were treated with radiation therapy without chemotherapy. The surgical procedure was classified as "wide" (complete) if all the tumor and surrounding normal tissue were removed (35 patients), "partial" if all the tumor could not be completely removed (15 patients), or amputation (eight patients). Fourteen patients underwent irradiation. The total doses were 20 Gy in one patient, 40–49 Gy in five, 50–59 Gy in four, and more than 60 Gy in three.


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  		TABLE 3. Sarcoma Site according to Initial Lesion Site, Treatment Modality, and Outcome
 
At the time of the analysis, 29 patients were alive, including 18 (62%) without disease and eight (28%) with disease progression; three patients were lost to follow-up. Fifty-one patients had died at the time of our analysis, including 44 (86%) due to the secondary tumor, one (2%) due to iatrogenic causes, four (8%) due to the primary tumor, and two (4%) due to other causes.

Overall survival was determined according to the Kaplan-Meier method. Median survival was 23 months (95% CI: 16, 29 months) for the population (Fig 1). Survival was also stratified into three groups according to treatment: surgery group (28 patients), chemotherapy group (15 patients), and surgery plus chemotherapy group (18 patients) (Fig 2). Median overall survival was 42 months in the patients who underwent surgery alone, 6 months in those who underwent chemotherapy alone, and 28 months in those who underwent surgery plus chemotherapy. There was a significant difference between the three groups (P < .001). Survival among patients treated with surgery was not significantly different from survival among patients treated with surgery plus chemotherapy (Fig 2).



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  		Figure 1. Kaplan-Meier curve shows overall survival in the population of patients with postradiation sarcoma. Median survival was 23 months (95% CI: 16, 29 months).

 


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  		Figure 2. Kaplan-Meier curves show survival according to treatment. Median survival was 42 months in 28 patients who underwent surgery alone ({square}), 28 months in 18 patients who underwent surgery plus chemotherapy ({blacktriangleup}), and 6 months in 16 patients who underwent chemotherapy alone ({diamond}). The differences in survival were significant (P < .001).

 
To try to determine the prognostic factors affecting outcome, we analyzed the roles of different parameters. No relationship was found between age at the time of sarcoma and survival. In the 58 patients treated with surgery, the operation was considered to be complete in 43 patients and partial in 15. Surgery was considered to be complete if total excision of the tumor was mentioned in the pathology report. When the surgeon or the pathologist reported that the limits of the excision were not sufficient, the procedure was considered to be partial. There was no difference in survival between patients who underwent complete and those who underwent partial surgery (P = .18). The tropism of the sarcomas (bone vs soft tissue) did not affect survival (P = .3). Finally, we investigated the role of the site of the primary tumor and found that this variable did not influence patient outcome (P = .14).

Survival was evaluated according to histologic grade of sarcoma. At 2 and 5 years, respectively, the survival rates were 76% and 62% for grade 2 sarcoma (31 patients) and 40% and 19% for grade 3 sarcoma (17 patients). Survival was significantly better in patients with grade 2 sarcoma than in patients with grade 3 sarcoma (P < .01, Mantel-Cox test). There were not enough patients with grade 1 sarcoma (six patients) to compare survival in this group with that in the grade 2 and grade 3 groups.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Because the total number of patients who underwent radiation therapy at the referring institutions could not be determined in this study, it was not possible to evaluate the incidence of secondary sarcoma. A long follow-up is necessary, the number of patients lost to follow-up must be low, and the number of survivors after radiation therapy must be sufficient. Several authors have attempted to determine the incidence in various situations. For example, Phillips and Sheline (12) estimated a 0.23% frequency of sarcoma after irradiation for breast cancer. Others (13–15) have reported similar results. In cases of gynecologic tumors, Mark et al (16) estimated the absolute risk of postradiation sarcoma to be 0.03%–0.8%. Others (17,18), however, have reported a lower incidence if all patients treated with radiation therapy are taken into account. In cases of osteosarcoma, Huvos et al (19,20) and Souba et al (21) estimated that approximately 5% of sarcomas developed after therapeutic or accidental irradiation.

In our series, high-grade malignant fibrous histiocytoma was the most frequent type of secondary sarcoma, followed by high-grade osteosarcoma. This number was a little different from those in the literature (3,22–24), where osteosarcoma was reported to be the most frequent type, followed by fibrosarcoma and malignant fibrous histiocytoma. The fact that malignant fibrous histiocytoma was described relatively recently could help explain this difference (25), and one might expect that some cases would be recognized as malignant fibrous histiocytoma if they were re-reviewed today (3,15,21). In this series, we included only patients with histologically confirmed tumors, and we reported the histologic type as determined by a panel of pathologists. Our results are in agreement with those in the recent report on 42 cases of postradiation sarcoma by Buis and Spiro (26), who found that malignant fibrous histiocytoma was the most frequent histologic type (13 cases), followed by osteosarcoma (11 cases). They also reported that the majority of sarcomas were high grade (grade 2 and 3), as was the case in our study (30% grade 2, 60% grade 3). These numbers differ from the distribution for primary sarcoma. In the report (11) on patients with sarcoma treated at anticancer centers of the FNCLCC, the distribution of soft-tissue sarcomas was 14.5% grade 1, 45.0% grade 2, and 40.5% grade 3 sarcoma.

The prognosis in patients with postradiation sarcoma generally is poor. In our series, the overall survival rate was 48% at 2 years and 29% at 5 years, and the median survival was 23 months (95% CI: 16, 29 months). Eighty-six percent of the patients died of the secondary tumor, whereas only 8% died of the primary tumor. In a review of the literature, we found a reported median survival of 15 months (27), which is similar to results reported later by Robinson et al (4), who found a median survival of 12 months with a survival rate of 22% at 2 years and 11% at 5 years. This poor prognosis was confirmed with results from other series (28–31).

Some authors (26,32) have found a higher survival rate (around 30%) at 5 years. This better result could be related to population characteristics: One study (32) included only those patients whose primary tumor was in the breast and in whom extensive surgery had been performed.

Many factors can help explain the poor prognosis in patients with secondary sarcoma. Such tumors generally are aggressive and have a high potential for local recurrence. Sarcomas also have a high potential for metastasis (21,26,33). The diagnosis is difficult and sometimes is delayed until the tumor is of large volume. Buis and Spiro (26) found that the size of a postradiation sarcoma is predictive of overall survival, disease-free survival, and distant-recurrence–free survival (P < .05) independent of the other studied variables, including tumor margin. They also reported that tumor margin was predictive of disease-free survival independent of size (P = .04). Buis and Spiro found that tumor grade was not predictive of outcome, in contrast to the situation with primary sarcoma (11). In our series, survival was related to tumor grade, with a shorter survival in patients with a grade 3 tumor.

Because secondary sarcomas arise in irradiated areas, surgical procedures are often difficult, and postradiation sarcomas are considered to be radiation resistant. Weatherby et al (5) found that the prognosis was better in patients with a sarcoma of the extremities. In our series, we examined the role of sarcoma origin (soft tissue vs bone) or of primary tumor location (breast vs other) and found no differences among these groups.

The majority of patients in our study were treated with surgery (58 patients), which could help explain the slightly better survival. The important role of surgery has been underlined by many authors (30,34,35); some proposed that patients undergo extensive and aggressive surgery, with amputation or excision of the chest wall. According to Bobin et al (29), only those patients who underwent amputation could hope to be cured. In our study, survival was better in patients treated with surgery or with surgery plus chemotherapy (Fig 2), but there was no difference in survival between complete and partial excision.

In a retrospective study, bias cannot be excluded; our study, however, included all identified cases encountered from 1975 to 1995 at the participating centers. No selection was performed, but only those cases in which a confirmed histologic diagnosis had been established were included in the final analysis. We did not find any factors (age, sex, type of sarcoma) that differed between patients treated with and those treated without surgery.

Some authors have reported that early detection provides a chance for cure, provided that a wide-margin resection is performed. To achieve this result, the diagnosis of postradiation sarcoma must be suspected early, when alterations or symptoms occur in a previously irradiated region (34).

A few authors (21,28–30,33,36–38) have reported on the role of chemotherapy in postradiation sarcoma. This treatment modality can be proposed as part of the strategy in these patients, but its role is difficult to assess. Cefalo et al (39) described a series of five children with postradiation bone sarcoma. These patients were treated with a chemotherapy protocol similar to that used in cases of primary osteogenic sarcoma, and four patients were alive 1–12 years after treatment. Bielack et al (40) and Tabone et al (41) confirmed that, with combined-modality therapy, resectable lesions can be cured or the prognosis can approach that associated with a comparable primary osteosarcoma. In our series, we found no difference between the group treated with surgery alone and the group treated with surgery and chemotherapy. However, survival was longer in both groups than in the group treated with chemotherapy alone. The fact that chemotherapy had no influence on survival could be explained by the variety of chemotherapeutic drugs used, sometimes not in an optimal manner, and limited by the performance status of the patients. Given these possibilities, we can only propose that the role of chemotherapy be evaluated in a prospective study that includes chemotherapeutic protocols similar to those used for treatment of primary sarcoma.

High-dose radiation therapy is limited in cases of postradiation sarcoma because tissue was previously irradiated to nearly the tissue-tolerance dose. In our series, the median dose was 50 Gy. In some rare cases, an apparent cure has been achieved with radiation therapy and hyperthermia (42). Modern conformal radiation therapy has permitted re-treatment in selected cases, and this technique has been proposed for treatment of soft-tissue sarcoma (43), hence this treatment modality should receive special attention.

In conclusion, the results of this retrospective study with a large cohort of patients with postradiation sarcoma confirmed the poor prognosis associated with this tumor. In the majority of patients, postradiation sarcomas were of the high-grade malignant fibrous histiocytoma or osteosarcoma types, and survival was influenced by tumor grade and type of treatment. Our results raise the question of treatment for postradiation sarcoma, which is always difficult because of the suboptimal condition of the patient and the prognosis associated with this tumor. Some investigators consider surgery to be the best solution, although extensive resection may be necessary. Our results confirmed the favorable role of surgery but did not exclude a potential benefit of chemotherapy. Further studies should explore the possibility of the use of aggressive surgery combined with chemotherapy in an attempt to improve patient outcome.


   ACKNOWLEDGMENTS
 
The authors thank A. Benghiat, MD, (Leicester Royal Infirmary, England) for editorial assistance.


   FOOTNOTES
 
**. Multiple body systems Back

Pathologists of the FNCLCC: Gérard Bertrand, MD, Marie-Christine Chateau, MD, Jean-Michel Coindre, MD, Françoise Collin, MD, Michel Fiche, MD, Jean-Pierre Ghnassia, MD, Louis Guillou, MD, Viviane Le Doussal, MD, Anne Leroux, MD, B. Marques, MD, Dominique Ranchere, MD, Xavier Sastre, MD. Philippe Terrier, MD, Martine Trassard, MD, Marie-OdileVilain, MD.

Radiation Therapists of the FNCLCC: Jean-Léon Lagrange, MD, PhD, Christian Marchal, MD, Michel Resbeut, MD, Pierre Richaud, MD, Philippe Lagarde, MD, Patrice Rambert, MD, Sok Hun Seng, MD, Brigitte de la Fontan, MD, Monique Reme-Saumon, MD, Jacques Tortochamp, MD.

Abbreviation: FNCLCC = Fédération Nationale des Centres de Lutte Contre le Cancer

Author contributions: Guarantors of integrity of entire study, J.M.C., J.L.L., A.R. Study concepts, J.M.C., J.L.L., A.R.; study design, A.R., J.L.L.; definition of intellectual content, J.L.L.; literature research, J.L.L., C.M.; clinical studies, J.L.L., C.M., M.R., P. Richaud, P.L., P. Rambert, J.T., S.H.S., B.d.l.F., M.R.S., and all pathologists; M.C.C., J.P.G., J.M.C., and all pathologists; data acquisition, A.R., J.L.L., J.B.; data analysis, C.M., A.R., J.L.L., J.B.; statistical analysis, A.R.; manuscript preparation, J.M.C., J.L.L., A.R.; manuscript editing, J.L.L., A.R.; manuscript review, C.M., J.B., J.L.L., A.R.


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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