The patient is at intermediate risk for recurrence. Numerous studies have demonstrated that tumor size, grade, and location are the most important factors to determine risk of recurrence, with larger size, higher grades, and deeper locations being associated with higher risk of recurrence. In an analysis of 1041 patients with STS of the extremities, high grade was the most important risk factor for distant metastases.39 The highest risk of recurrence is within the first 2 years. Given that the patient’s initial tumor was located in the extremity, he is more likely to have a distant metastasis as his site of recurrence; individuals with retroperitoneal tumors and visceral tumors are more likely to recur locally.40 For STSs of the extremity, distant metastases determine overall survival, whereas patients with retroperitoneal sarcomas can die from complications of local metastases.41 Once a patient develops distant metastases, the most important prognostic factor is the size of the tumor, with tumors larger than 10 cm having a relative risk of 1.5(95% CI 1.0 to 2.0).39
• What are the recommendations for surveillance?
Surveillance recommendations are based on the stage of the sarcoma. Stage I tumors are the least likely to recur either locally or distally. As a result, it is recommended that stage I tumors be followed with history and physical exam every 3 to 6 months for the first 2 to 3 years, and then annually after the first 2 to 3 years. Chest x-rays should be considered every 6 to 12 months.2 For stage II–IV tumors, history and physical exam is recommended every 3 to 6 months for the first 2 to 3 years. Chest and distant metastases imaging should also be performed every 3 to 6 months during this time frame. For the next 2 years, history and physical exam and imaging are recommended every 6 months. After the first 4 to 5 years, annual follow-up is recommended.2
A study that followed 141 patients with primary extremity STSs for a median interval of 49 months found that high-grade tumors were most likely to recur during the first 2 years, with 20% of their patients recurring locally and 40% recurring distally. Chest x-rays performed during surveillance follow-up found distant lung metastases in 36 asymptomatic patients and had a positive predictive value of 92%, a negative predictive value of 97%, and a quality-adjusted life-year of $30,000.40,41 No laboratory testing was found to aid in detection of recurrence.
› Case Continued
The patient does well for 1 year. With physical therapy, he regains most of the strength and coordination of the lower extremity. He is followed every 3 months with chest x-rays and a MRI of the thigh for the first year. On his fourth follow-up clinic visit, he describes increased dysp-nea on exertion over the previous few weeks and is found to have multiple lung metastases in both lungs on chest x-ray. He undergoes further evaluation for metastases and is not found to have any other metastatic lesions. Bronchoscopy and biopsy of 1 of the lung nodules confirms recurrent dedifferentiated liposarcoma.
• Should this patient undergo metastectomy?
An analysis of 3149 patients with STS treated at Memorial Sloan-Kettering who developed lung metastases found that patients with pulmonary metastases have survival rates of 25%. The most important prognostic factor for survival was complete resection of all metastases.42 For stage IV disease, surgery is used only in certain instances. In instances where tumor is more localized or limited, removal of metastases or metastectomy can play a role in management.2
› Case Continued
Because the patient’s metastases are limited to the lungs, he is referred for metastectomy. He undergoes wedge resection for definitive diagnosis but it is not possible to completely resect all of the metastases. He is thus referred to a medical oncologist to discuss his treatment options.
• What are treatment options for unresectable or metastatic disease?
Metastatic Disease
Unlike local and locally advanced disease, chemotherapy forms the backbone of treatment in stage IV disease. Doxorubicin and olaratumab or doxorubicin and ifosfamide in combination are considered first line in metastatic disease. Response rates for single-agent doxorubicin range from 16% to 27%, while phase 2 and phase 3 studies of doxorubicin and ifosfamide have found response rates ranging from 18% to 36%.43 In addition, the effectiveness of doxorubicin and ifosfamide phase 2 and 3 trials varied. Edmonson et al found a tumor regression rate of 34% for doxorubicin and ifosfamide as compared to 20% for doxorubicin alone.44 In comparison, Santoro et al found a response rate of 21.3% for doxorubicin alone and 25.2% for doxorubicin and ifosfamide.45 Neither study found increased survival benefit for doxorubicin and ifosfamide when compared to doxorubicin alone. In a Cochrane review evaluating randomized trials that compared doxorubicin and combination chemotherapy regimens, response rates varied from 14% for doxorubicin in combination with streptomycin to 34% for doxorubicin and ifosfamide. Most trials did not show a significant benefit for combination therapies when compared to doxorubicin alone.43 Mean survival with doxorubicin or doxorubicin and ifosfamide is 12 months. High rates of recurrence highlight the need for additional chemotherapy regimens.
