Palliative radiation therapy for metastatic Ewing sarcoma

Authors


Abstract

BACKGROUND

Although radiotherapy is an accepted component of curative treatment for Ewing sarcoma (EWS), to the authors' knowledge, there are scant data evaluating its use for palliation. The authors reviewed the Duke University Medical Center experience to evaluate treatment response and response durability.

METHODS

Between 1980 and 2002, 21 patients with metastatic EWS received palliative radiotherapy. Pain was the primary indication for treatment. The majority of patients were male (n = 16 patients), and the median age at diagnosis was 11.6 years (range, 2.7-28.8 yrs). Fifty-two percent of patients had metastases at initial diagnosis. For the others, the median interval from initial diagnosis to metastases was 1.7 years.

RESULTS

Sixty-three metastatic sites were irradiated (median dose, 30 gray [Gy]; range, 4.5-68.5 Gy), and a median of 3 sites were treated per patient (range, 1-16 sites per patient). At the time of last follow-up, 1 patient with a solitary brain metastasis has been disease free for 3.4 years after resection and cranial radiotherapy; all other patients died of their disease. Censoring this survivor, patients lived for a median of 1.0 year after metastatic diagnosis (range, from 17 days to 6.8 years), 41 days of which were spent in treatment (range, 1-93 days). Of all sites, 55% had a complete clinical response of symptoms, and 29% had a partial response. The median response duration was 4.0 months (range, 10 days to 4.8 years). Only the survivor was noted to have a treatment complication (growth hormone insufficiency).

CONCLUSIONS

It was possible to treat metastatic EWS effectively with palliative radiotherapy. Because these patients live a median of 1 year after diagnosis of metastases, providing symptom relief without a protracted treatment course is valuable and appropriate therapy. Cancer 2006. © 2006 American Cancer Society.

Ewing sarcoma is a small, round, blue cell tumor that arises primarily in bone. Treatment for localized disease is multimodal, including a combination of surgery, chemotherapy, and radiation. The 5-year disease-free survival rate with the use of multimodality treatment is approximately 40%,1 and the local control rate with resection and radiation can be as high as 93%.2

Metastatic disease, most commonly in the lung, bone, and bone marrow, is present in 20-25% of patients at diagnosis.1, 3 Although patients with lung as the only site of metastatic disease can be cured, those with other sites of metastatic disease have a worse prognosis.3–5 The Intergroup Ewing Sarcoma Studies (IESS) and others have discussed survival for patients with metastatic Ewing sarcoma when it is treated aggressively with concurrent chemotherapy, radiation, and possible resection.3–12 However, to our knowledge, the role of palliative treatment when curative treatment has failed is discussed infrequently.

The objective of palliative treatment is to ameliorate or prevent symptoms while minimizing the impact of treatment on quality of life. Radiation has been used successfully for the palliation of metastases in many other cancers.13 In the current report, we have reviewed our experience at Duke University Medical Center with palliative radiotherapy for patients with metastatic Ewing sarcoma.

MATERIALS AND METHODS

We reviewed the charts of 59 consecutive patients who were treated for Ewing sarcoma between 1980 and 2002, including 21 patients with distantly metastatic disease (M1 according to the American Joint Committee on Cancer classification) that was treated with radiation. For each patient, the primary site, date of diagnosis, metastatic site, date of metastasis, date of symptoms, radiation dose for each treatment site, response to treatment, and date of recurrence or progression were determined. The length of time spent in treatment was calculated as the time between the first treatment and the last treatment for each metastatic site treated; therefore, this time included weekends during which the patient may have been staying at Duke University Medical Center away from home and family. For each patient, the time spent in treatment and the lifespan after diagnosis of metastasis was used to calculate the percentage of the patient's remaining life spent in palliative radiation treatment. We also calculated the percentage of the patient's remaining lifespan after first symptomatic metastasis by using the day symptoms began or, for asymptomatic metastases, the first day of radiation treatment. The use of chemotherapy within 8 weeks of radiation completion and the presence or absence of radiation recall reactions associated with chemotherapy use also were noted.

Response was coded as a complete response (CR) if the symptom instigating treatment completely resolved. For radiologic findings or a palpable mass, this required complete resolution of the abnormality. Other scored responses included a partial response (PR), stable disease, or no response. This study was performed with approval of the Duke University Medical Center Institutional Review Board.

RESULTS

Patient Characteristics

The majority of patients were male (16 of 21 patients; 76%). The median age was 11.6 years (range, 2.7-28.8 yrs). Approximately 14% of patients had primary extraosseous disease. Ten of 21 patients had metastases at diagnosis. Of those who were diagnosed initially with localized Ewing sarcoma, the median time of the development to metastatic disease was 1.7 years. The median number of metastases irradiated per patient was 3 (range, 1-16 metastases per patient). Overall, 63 sites received palliative radiation. The locations of the primary disease and metastases are shown in Table 1. Pain was the indication for treatment in 40 sites (63%); other indications included neurologic symptoms (6%), palpable mass (3%), and an asymptomatic radiologic finding (29%).

Table 1. Locations of Both Primary and Metastatic Ewing Sarcoma in 21 Patients
Disease LocationNo. of Primary Disease Sites (n = 21)No. of Irradiated Metastatic Disease Sites (n = 63)
Bone  
 Chest wall/sternum/rib26
 Femur/tibia/fibula/knee67
 Humerus25
 Shoulder/scapula/clavicle42
 Pelvis/hips410
 Spine011
 Skull04
 Orbit01
 Hemibody02
Soft tissues  
 Lung18
 Brain05
 Eye10
 Parotid01
 Axillary lymph nodes10
 Cervical lymph nodes03

Treatment and Response

The median palliative radiation dose administered was 30 gray (Gy) (range, 4.5-68.5 Gy) for each site. Patients spent a median of 41 days in treatment (range, 1-93 days). Thirty-five sites (55%) had a CR, and 18 sites (29%) had a PR, for an overall response rate of 84%. Nine sites (14%) did not respond to radiation. Table 2 shows the responses by disease site.

Table 2. Response to Radiation by Metastatic Site
Metastatic SiteNo. of Patients
TotalCRPRNR
  1. CR: complete response; PR: partial response; NR: no response.

Bone    
 Chest wall/sternum/rib651 
 Femur/tibia/fibula/knee7322
 Humerus541 
 Shoulder/scapula/clavicle22  
 Pelvis/hips10613
 Spine11551
 Skull4211
 Orbit1 1 
 Hemibody211 
Soft tissues    
 Lung6312
 Brain5221
 Parotid11  
 Cervical lymph nodes312 

All 21 patients also received chemotherapy. Patients received chemotherapy within 8 weeks after radiotherapy was completed 52% of the time (33 of 63 metastases). Of those patients who did not receive chemotherapy, the overall response rate was 80%. No patient developed a radiation recall reaction during chemotherapy.

The median overall duration of treatment response was 81 days (range, 0-1760 days). The site-specific recurrence-free survival is illustrated in Figure 1. Considering only those patients who responded, the median duration of response was 123 days.

Figure 1.

A complete response or a partial response to treatment was obtained at 53 disease sites. The site-specific, recurrence-free survival (event indicates a recurrence at a treated site; censored for death) is shown. The median duration of response was 123 days (4.1 months).

Survival and Complications

One patient developed a solitary brain metastasis 7 years after diagnosis. She was treated with metastatectomy and cranial radiotherapy and, at the time of last follow-up, had not developed any further recurrences after 3.4 years of follow-up. All of the other 20 patients had died of metastatic Ewing sarcoma. Censoring the single survivor, patients lived for a median of 349 days after they were diagnosed with metastasis (range, 17 days-6.8 years). The median portion of remaining lifespan spent in palliative treatment after diagnosis of metastasis was 10% (range, 0.5-25%). The median portion of remaining lifespan spent in palliative treatment after first symptoms was 12% (range, 2-51%). The distribution of time in palliative treatment is illustrated in Figures 2 and 3. Only the single long-term survivor was noted to have treatment-related complications (growth hormone insufficiency and irregular menses).

Figure 2.

Among 20 patients (the long-term survivor was excluded), the time spent in treatment is illustrated as a percentage of the total lifespan after the diagnosis of metastasis was made (range, 0.5-25.0%; median, 10%).

Figure 3.

Among 20 patients (the long-term survivor was excluded), the time spent in treatment is illustrated as a percentage of the total lifespan after the presentation of first symptomatic metastasis or, for patients with asymptomatic lesions, after the decision to initiate palliative treatment (range, 2-51%; median, 12%).

DISCUSSION

The majority of patients in our series had painful bone metastases. However, we found that other sites of metastasis and causes for palliation included the central nervous system, lung, and painful lymphadenopathy. At the time, using what generally was viewed as an appropriate palliative dose of radiation (median, 30 Gy), we achieved an overall response rate of 84%. This response rate is comparable to that observed for radiation to bone metastases for adult cancers.13

Just greater than 50% of the time, patients were given palliative chemotherapy soon after the completion of radiation. The symptomatic response that we document for these patients may be a combination of efficacy for the radiation and chemotherapy treatments. We documented an 80% response rate for the metastatic sites that did not receive chemotherapy after radiation, suggesting a benefit of radiation in palliation.

The IESS studies of treatment for metastatic disease (MD-I and MD-II) used concurrent chemotherapy and radiation doses from 35 Gy to 45 Gy. Their response rates ranged from 70% to 73%.6, 11 Researchers at St. Jude Children's Research Hospital published a retrospective analysis of 18 patients with metastatic Ewing sarcoma. Thirteen of those patients achieved a CR from chemotherapy, and 2 of the 4 partial responders who received radiation converted to a CR.8

Recently, the use of single-fraction radiotherapy has become more common for palliation of bone metastases in adult cancers. Several studies have been published to date that demonstrated response and control rates similar to those achieved with more conventional fractionated treatment.14, 15 The current series reviewed patients who were treated largely before single-fraction treatment was validated. However, given its effectiveness in the treatment of many adult bony metastases, single-fraction palliation for children also may be effective for palliation in the Ewing sarcoma population.

The patients in the current study survived for a median of 1 year after a diagnosis of metastatic disease. Although the published 5-year and 10-year overall survival rates can be as high as 30%,3, 6, 10 studies that produced those rates included a number of patients who had only pleural or pulmonary metastases, which are known to carry a better prognosis.3–5 Paulussen et al., in a review of results from Cooperative Ewing Sarcoma Study 81 (CESS-81), CESS-86, and European Intergroup Cooperative Ewing Sarcoma Study 92, reported significantly reduced 5-year and 10-year event-free survival (EFS) rates with metastases other than the pleura and lung: The 10-year EFS rate was 30% for patients with only pulmonary/pleural metastases versus 16% for patients with other metastatic sites (P = .0001).3 A review of patients from Saudi Arabia also showed a low survival frequency for patients with metastatic disease.9

Although palliative treatment did not appear to affect overall prognosis, we were able to provide symptom relief for the majority of our patients. In addition, the amount of time expended in the receipt of palliative treatment was not a great percentage of the patients' remaining lifespan. This issue is important in palliation because the emotional needs of the patient and their family and how the length of treatment can affect these needs must be considered. The results of the current study suggest that palliative radiotherapy is worthwhile, particularly in symptomatic patients who have widespread metastases.

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