Postradiation Sarcoma Treatment & Management


Background

A late effect of ionizing radiation is the development of sarcoma within the field of irradiation, referred to as postradiation sarcoma (PRS). Ionizing radiation has had many varied uses in medicine. In early years, besides being employed in the treatment of a variety of malignancies, radiation was used to treat benign conditions, such as acne, fungal infections, eczema, and various bone diseases. [123456789]

Advances in cancer treatment in recent years have included intensive multiagent chemotherapy and irradiation. [10Despite significant medical use of radiation therapy, PRS is an uncommon tumor. The overall incidence of PRS is lower than 1% for patients with cancer who are treated with radiation and survive 5 years. [10Although the implication for individual patients is significant, little doubt exists that the benefits of ionizing radiation therapy far outweigh the potential risks of developing sarcomas.

The diagnosis of PRS generally is based on the following criteria:

  • The histologic features of the original lesion and PRS are completely different
  • PRS is located within the field of irradiation
  • Patients with cancer syndromes such as Li-Fraumeni and Rothmund-Thomson are excluded
  • The latent period (period between initiation of radiotherapy and histologic diagnosis of second neoplasm) is more than 4 years; although 4 years is an arbitrary figure in the light of the wide age range reported in the literature (4-55 years), it has generally been accepted as the lower limit for the latent period

Pathophysiology

PRS can occur with orthovoltage (low-energy) and megavoltage (high-energy) radiation. With orthovoltage radiation, the dosages are lower and the latent periods longer. The threshold dose for PRS is not known, though in most published series, a dose of 40-60 Gy has been reported. [21112Development of PRS also is influenced by other factors, including genetic tendency and influence of chemotherapeutic agents.

Ionizing radiation is thought to act via genetic alterations, including mutations of p53 and retinoblastoma (Rb) genes. Experimental studies revealed p53 gene alterations or increased p53 messenger ribonucleic acid (mRNA) levels in murine PRS. [13]

A study by Mentzel et al used fluorescence in situ hybridization (FISH) to analyze angiosarcomas and atypical vascular lesions occurring after treatment of breast cancer. [14In all postradiation cutaneous angiosarcomas, FISH analysis revealed MYC amplification in a variable number of counted nuclei; MYC amplification was not seen in any of the other cases. The authors concluded that MYC amplification may be an important diagnostic tool for distinguishing postradiation cutaneous angiosarcomas from atypical vascular lesions after radiotherapy.

A study by Laé et al found that C-MYC amplification was able to distinguish postradiation breast angiosarcomas from primary breast angiosarcomas, even though the two lesions were morphologically indistinguishable. [15]

Etiology

Whereas ionizing radiation is the triggering factor (with 40-60 Gy believed to be the threshold dose), other factors (eg, genetic tendency, concomitant use of chemotherapeutic agents, and various factors as yet unknown) appear to be responsible for the development of PRS.

Epidemiology

If the criteria listed above (see Background) are followed strictly, the overall US incidence of PRS in patients who survive longer than 5 years following radiation therapy is about 0.1%. In one large series, the incidence was reported to be 0.11% following orthovoltage radiation therapy and 0.09% following megavoltage radiation therapy. [10]

In earlier published studies, many patients had received radiation therapy for benign bone and soft-tissue conditions. In contrast, other reports have shown larger numbers of patients who have received radiation therapy for malignancies such as breast cancer, lymphoma, and Ewing sarcoma. [561016]

In a large retrospective study from the Mayo Clinic spread over several decades (1933-1992), benign bone conditions were found to be the single largest group of index lesions in patients with PRS, followed by genitourinary malignancies (especially cervical cancers). [10]

Age-, sex-, and race-related demographics

Patients of all ages are affected. In the Mayo study (N = 130), the average age at diagnosis of index lesion was 28.7 years (range, 4 months to 65 years). [10The mean age at diagnosis of PRS was 47.9 years (range, 10.5-80.9). The latent period ranged from 4 years to 55 years (average, 17). Predilection based on sex has not been reported. In the Mayo study,10 although the male-to-female ratio was 8:5, when sex-specific tumors (eg, breast, cervix, testis, ovary) were excluded, no difference was demonstrated on the basis of sex. A racial predilection has not been reported in the literature.

Prognosis

The overall reported 5-year survival rates for patients with PRS have been poor, ranging from 8.7% to 22% in different studies. [111217181920However, patients with resectable peripheral lesions at stage IIB or lower have a relatively better prognosis. In the Mayo Clinic series, the 5-year survival rate was 68%. [10The overall poor prognosis in these patients is thought to be due to a number of interrelated factors, such as the following:

  • Significant delay in diagnosis
  • Large unresectable lesions
  • Older age
  • Anaplastic nature of lesions
  • Lack of effective adjuvant treatment

In a retrospective review of histopathologic features, surgery, and outcome in 67 patients with radiation-induced sarcoma followed for a median of 53 months, Neuhaus et al found that median sarcoma-specific survival was 54 months (2-year survival, 75%; 5-year survival, 45%).23 The local relapse rate was 65%, and negative histopathologic margins were a significant predictor of sarcoma-specific survival. Grade and size of tumor approached, but did not attain, significance.

In a study of the prevalence and outcome of radiation-induced sarcomas in 90 sarcoma patients, Bjerkehagen et al reported a sarcoma-related 5-year crude survival rate of 33%. [19 Unfavorable prognostic factors were metastases at presentation, incomplete surgery, and presence of tumor necrosis. According to the authors, complete surgical resection is mandatory for cure.

In a retrospective study of 52 patients with PRS (45 with bone sarcoma and 7 with soft-tissue sarcoma), Mavrogenis et al reported survival figures of 85% at 1 year, 51% at 2 years, 48% at 3 years, and 45% at 5 years. [21On univariate analysis, sarcoma type was the sole predictor of survival; on multivariate analysis, no variable was a significant predictor of survival.



History and Physical Examination

Pain is the most common complaint in patients with postradiation sarcoma (PRS). This pain is abrupt and rapid in onset, relentless and progressive, constant, and worse at night. It usually is not relieved by aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs). Mass (soft tissue or bone), bleeding, and pathologic fracture also are reported. [2223Clinical factors that favor a diagnosis of PRS include the following:

  • Sarcoma in bone or soft tissue appearing at an unusual age
  • Sarcoma in bone or soft tissue at an unusual site
  • Addition of intensive chemotherapy to irradiation

Physical findings are localized to the irradiated area. These usually are a mass (bony or soft tissue), tenderness, and/or a pathologic fracture.

Complications

PRS is itself a complication of radiation treatment for various bone and soft-tissue malignancies. Complications that arise from PRS are those seen with other soft-tissue and bone tumors, such as pathologic fractures, hemorrhage, metastases, and local complications due to direct invasion.



Diagnostic Considerations

Differential diagnoses for bone pain in a patient with a history of irradiation include the following:

  • Metastatic bone disease
  • Radiation osteopathy
  • Nonneoplastic causes of bone pain, such as rotator cuff impingement syndrome, osteoarthritis, bursitis/tendonitis, gout, and pseudogout

The pain in postradiation sarcoma (PRS) is worse at night. The pain usually is not relieved with aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs). Patients with arthritis also complain of worsening pain at night, but this usually is positional and only occasionally is severe enough to wake the patient. Arthritic pain also usually is exacerbated by activity and relieved by rest.D

Differential Diagnoses


Laboratory Studies

No specific laboratory blood tests are used to diagnose postradiation sarcoma (PRS). Routine laboratory investigations may be ordered.

Cytogenetic studies on PRS tumor cells do not have much value, because the tumor cells can have numerous quantitative (numerical) and qualitative abnormalities that lack specificity. However, the value of cytogenetic analysis lies in excluding other conditions that may have specific anomalies and that may present a challenge in light-microscopic examination.

Imaging Studies

Plain radiographs should be obtained in two planes. Cortical bone destruction is the most common finding. A mineralized soft-tissue mass is seen in most patients. Changes such as osteopenia and sclerosis are seen in a minority of patients.

If plain radiography yields normal findings and the patient has significant pain, computed tomography (CT) and magnetic resonance imaging (MRI) are useful for identifying abnormal areas in the medullary cavity, cortical bone destruction, and the presence of an extramedullary soft-tissue mass. MRI is the best modality for detecting soft-tissue involvement in PRS. Chest CT is performed to detect pulmonary metastases.

Technetium bone scanning is performed to detect bone metastases.

Biopsy

Fine-needle aspiration (FNA) biopsies or Tru-Cut core biopsies can be obtained from the lesion for histopathologic/cytopathologic confirmation of diagnosis and for typing and grading of the lesion. In the case of a deep-seated lesion, CT-guided biopsies can be obtained. The biopsy should be the final diagnostic procedure because it can distort the findings from imaging studies, especially MRI.

Careful preoperative planning is required before biopsy is attempted. Imaging studies aid the surgeon in selecting the best site for tissue diagnosis. Usually, the best diagnostic site is at the interface between the tumor and adjacent normal tissue; this also prevents the occurrence of fracture at the biopsy site, in that biopsy in this location usually does not violate cortical bone.

A frozen section can be obtained to determine whether adequate representative tissue has been obtained. A definitive diagnosis usually is delayed until permanent sections are analyzed.

Olson et al conducted a retrospective review of 13 patients (median age, 61 years) who underwent FNA in the treatment of PRS. [24 Patients generally presented with large tumors (median, 8 cm; range, 3-12 cm), and median survival was 14 months (range, 6-46 months). Nine of the 13 patients died of their disease, and one was lost to follow-up. The tumors were morphologically heterogeneous. The researchers concluded that PRS can be diagnosed by means of FNA and that immunohistochemistry is often required to rule out locally recurrent malignancy.

Histologic Findings

PRS in bone and soft tissue usually is a high-grade lesion, and this partly accounts for the almost uniformly grim prognosis. [47In a study of 130 patients with PRS of bone and soft tissue, osteosarcoma was the most common type, constituting 61.5% of all cases. [10This was followed by fibrosarcoma (23.7%), malignant fibrous histiocytoma (MFH; 9.6%), chondrosarcoma (3.7%), and rare cases of angiosarcoma and Ewing sarcoma. No difference in the histologic type of PRS was demonstrated between orthovoltage and megavoltage groups.

Among soft-tissue PRS lesions, the most common histologic type is MFH (70%), followed by osteosarcomafibrosarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, and angiosarcoma. [25]

Grossly, these tumors are soft and fleshy, with extension into adjacent soft tissue and formation of a soft-tissue mass. Hemorrhagic/necrotic foci and matrix production (osteoid/chondroid) may be seen. Degenerative calcific changes also may be noted. Microscopically, whereas specific characteristics such as osteoid production (in osteosarcomas) may be seen, these tumors generally show pleomorphic high-grade spindle cell features with marked nuclear pleomorphism, mitotic activity, and variable necrosis. (See the image below.)

Light-microscopic appearance of postradiation osteLight-microscopic appearance of postradiation osteosarcoma; tumor is composed of pleomorphic plump spindle cells with focal presence of neoplastic osteoid (pink areas) in between tumor cells. This meningeal tumor occurred 10 years after radiation therapy in patient who had received such therapy for recurrent pituitary neoplasm.

Staging

Careful staging is a prerequisite for appropriate management of PRS. The marrow extent and soft-tissue involvement of PRS should be gauged by using radiologic modalities, of which MRI is the best choice. Biopsies may be obtained to confirm the diagnosis and to type and grade the lesion. CT of the chest is obtained to detect pulmonary metastases. A technetium bone scan is performed to detect bone metastases.

On the basis of the results of imaging and histopathologic/cytopathologic studies, the lesion may be staged. The American Joint Committee on Cancer (AJCC) and Musculoskeletal Tumor Society (MSTS) staging systems generally are used.

AJCC staging system

The AJCC staging system is based on the TNM staging system and uses the following categories:

  • Size and extension of primary tumor (T)
  • Involvement of lymph nodes (N)
  • Presence of metastases (M)
  • Type and grade of sarcoma (G)

T categories in the AJCC TNMG staging system are as follows:

  • T1 - Tumor smaller than 5 cm
  • T2 - Tumor 5 cm or larger

N categories in the AJCC TNMG staging system are as follows:

  • N0 - No histologically verified regional node metastasis
  • N1 - Histologically verified regional node metastasis

M categories in the AJCC TNMG staging system are as follows:

  • M0 - No distant metastasis
  • M1 - Distant metastasis

G categories in the AJCC TNMG staging system are as follows:

  • G1 - Well differentiated
  • G2 - Moderately well differentiated
  • G3 - Poorly differentiated
  • G4 – Undifferentiated

MSTS staging system

The MSTS staging system classifies tumors as follows:

  • Stage IA - Low grade, intracompartmental
  • Stage IB - Low grade, extracompartmental
  • Stage IIA - High grade, intracompartmental
  • Stage IIB - High grade, extracompartmental
  • Stage III - Systemic or regional metastases

In the MSTS staging system, the margins are classified as follows:

  • Intralesional - Margin through tumor tissue
  • Marginal - Margin through reactive zone around tumor consisting of edema, inflammatory cells, fibrous tissue, and tumor cell satellites
  • Wide - Margin through normal tissue outside reactive zone
  • Radical – Removal of entire compartment containing tumor.

Approach Considerations

Postradiation sarcoma (PRS) ideally is managed with a multidisciplinary approach that includes input from the radiation oncologist, the medical oncologist, and the surgeon. Because PRS is high grade and advanced stage or metastatic at the time of diagnosis, patients commonly are not eligible for curative surgery, and their prognosis generally is poor. Chemotherapy is the most common treatment modality and typically is associated with poor response rates.

Inpatient care frequently is required for patients with PRS at different stages of treatment. Inpatient care may be required for diagnostic evaluation to allow surgery with general anesthesia. Most preoperative chemotherapy regimens and palliative chemotherapy regimens for advanced disease require inpatient hospitalization.

Medical Care

The selection of chemotherapy agents used to treat patients with PRS is based largely on data from clinical trials of soft-tissue and bone sarcomas. The two most active single chemotherapy agents are doxorubicin and ifosfamide. These agents have roughly equivalent activity. Dacarbazine has modest single-agent activity. MAID (a combination of mesna, Adriamycin [ie, doxorubicin], ifosfamide, and dacarbazine) has been a commonly used combination chemotherapy regimen for the treatment of soft-tissue sarcoma over the past decade.

Three randomized trials compared doxorubicin plus ifosfamide with doxorubicin alone. Two of these trials showed higher response rates in the treatment arms containing doxorubicin and ifosfamide than in those containing doxorubicin alone. However, the doxorubicin and ifosfamide combinations also were associated with significantly higher myelosuppression (including fatal neutropenic sepsis) but no survival advantage. No standard of care has been established for the choice of chemotherapy agents. Therefore, treatment typically is individualized.

Preoperative chemotherapy can be administered with or without radiation therapy and is administered either intravenously (as a bolus or as a continuous infusion) or regionally (via an intra-arterial infusion to an isolated limb). Preoperative chemotherapy generally is considered in order to facilitate a limb-sparing procedure. This approach is considered for patients who otherwise would require amputation for cure or palliation. In some instances, this approach may be considered to convert a marginally resectable lesion into one that is operable.

Consideration of preoperative chemotherapy for PRS must take into account that response rates to chemotherapy are low and that most long-term survivors with PRS are patients who have undergone successful surgical resection.

Surgical Care

Surgical options for PRS include wide or radical resection (limb salvage) and amputation, and the choice depends on the stage and location of the tumor and the age and performance status of the patient. In patients with peripherally located tumors at Musculoskeletal Tumor Society (MSTS) stage IIB and below (see Workup, Staging), it is feasible to expect resection to provide a reasonable 5-year survival rate. (In one study, the 5-year survival rate for this group approached 68%.) Brachytherapy or postoperative external beam radiation can be added if the margins are close to the tumor.

Chan et al conducted a retrospective study that included 25 patients treated for PRS after radiotherapy for nasopharyngeal carcinoma. [26Of the 25 patients, 20 underwent surgery with curative intent. All 25 received postoperative adjuvant chemoradiation, and six underwent brachytherapy as well. Local recurrence occurred in 71.4%. Median survival was significantly better for surgical patients with clear margins than for those with positive margins. Surgery was found to be effective in symptom palliation, including tumor pain, bleeding, and trismus.

Diet

Nutrition is an important aspect in the care of patients receiving active cancer treatment. [27Surgery, radiation therapy, and chemotherapy may adversely affect the patient's nutritional status and hence may alter quality of life. Cancer treatment can alter the patient's ability to eat, digest, and absorb food. Anticipation of these potential adverse effects, therefore, is necessary.

Intervention, such as with commercially available liquid nutritional supplements, may be required to maintain adequate caloric intake. Consultation with a healthcare provider qualified in nutrition also may be considered.

Activity

The impact of physical activity on treatment outcome in patients with cancer is not well defined in the literature. However, modest levels of physical activity during cancer treatment may provide benefits with respect to increasing appetite, maintaining mobility and muscle tone, and enhancing a sense of emotional well-being.

Prevention

Lowering the dosage of radiation and/or adjuvant chemotherapy is the only preventive measure for PRS; however, such reductions may not be practicable. The discontinuance of radiation for benign bone and soft-tissue diseases has limited PRS to patients receiving radiation treatment for malignancies.

Consultations

A multidisciplinary approach is ideal for PRS. The surgical oncologist, who preferably has experience in treating sarcomas, should be involved at the outset for the diagnostic evaluation. In addition, input from the radiation oncologist and medical oncologist is necessary to achieve a coordinated treatment plan, particularly for patients in whom combined modality treatment is being contemplated.

Long-Term Monitoring

Radiotherapy is delivered in the ambulatory setting. Follow-up of patients who have received definitive treatment for PRS is individualized according to the site of disease. Generally, follow-up should include a posttreatment imaging study to provide a baseline against which subsequent studies may be evaluated.

Subsequent follow-up should include a thorough history and physical examination, with laboratory tests and chest radiographs and other imaging performed regularly for the first 2 years. Assessments may be spaced further apart after the second year to the fifth year following definitive treatment. Annual assessments may be performed thereafter.

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