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.
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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 dyspnea 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.
The newest approved agent is olaratumab, a monoclonal antibody that binds platelet-derived growth factor receptor alpha and prevents receptor activation. A phase 1-b and phase 2 trial evaluated patients with locally advanced and metastatic STS and randomly assigned them to either olaratumab and doxorubicin or doxorubicin alone.46 Progression-free survival for olaratumab/doxorubicin was 6.6 months (95% CI 4.1 to 8.3) compared to 4.1 months (95% CI 2.8 to 5.4) for doxorubicin alone. The objective response rate was 18.2% (95% CI 9.8 to 29.6) for olaratumab/doxorubicin compared to 7.5% (95% CI 2.5 to 6.6) for doxorubicin alone. Furthermore, the median overall survival for olaratumab plus doxorubicin was 26.5 months (95% CI 20.9 to 31.7) compared to 14.7 months for doxorubicin alone (95% CI 5.5 to 26.0). Impressively, this improved response was notable across histological types. Furthermore, patients who had previously been treated with more than 1 regimen and those who were treatment naïve had similar response rates.46
• What are second-line treatment options?
Doxorubicin has been used in combination with several other agents including dacarbazine (DTIC) as well as DTIC and ifosfamide (MAID). Borden et al evaluated patients with metastatic STS and randomly assigned the patients to either doxorubicin or doxorubicin and DTIC. Combination therapy demonstrated better tumor response than doxorubicin alone: 30% complete or partial response for combination therapy and 18% for doxorubicin alone.47 However, Omura et al