Phase I Trial of Neoadjuvant Conformal Radiotherapy Plus Sorafenib for Patients with Locally Advanced Soft Tissue Sarcoma of the Extremity

Abstract

Introduction Despite effective local therapy with surgery and radiation (RT), approximately 50% of patients with high grade soft tissue sarcoma (STS) will relapse and die of disease. Since experimental data suggest a significant synergistic effect when anti-angiogenic targeted therapies, such as sorafenib, are combined with RT, we chose to evaluate preoperative combined modality sorafenib and conformal RT in a Phase I/II trial among patients with extremity STS amenable to treatment with curative intent. Methods For the Phase I trial, eight patients with intermediate or high grade STS > 5 cm in maximal dimension or low grade STS > 8 cm in maximal dimension received concomitant sorafenib (dose escalation cohort 1:200 bid, cohort 2:200/400 daily) and preoperative RT (50 Gy in 25 fractions). Sorafenib was continued during entire period of RT as tolerated. Surgical resection was completed four to six weeks following completion of neoadjuvant sorafenib/RT. Three sorafenib dose levels were planned. Primary endpoints of the Phase I trial were maximal tolerated dose and dose-limiting toxicity (DLT). Results Eight patients were enrolled in the Phase I (5 female, median age 44, 3 high grade pleomorphic, 2 myxoid/round cell liposarcoma, 3 other). Median tumor size was 16 cm (range 8–29), and all tumors were located in the lower extremity. Two of 5 patients treated at dose level 2 developed DLT consisting of grade 3 rash not tolerating drug reintroduction. Other grade 3 side effects included anemia, perirectal abscess, and SVT. Radiation toxicity (grade 1 or 2 dermatitis, N=8) and post-surgical complications (3 grade 3 wound complications) were comparable to historical controls and other series of preoperative RT monotherapy. Complete pathologic reponse (≥ 95% tumor necrosis) was observed in 3 patients (38%). Conclusion Neoadjuvant sorafenib in combination with RT is tolerable and appears to demonstrate activity in locally advanced extremity STS. Further study to determine efficacy at dose level 1 is warranted. (NCT#00805727, ClinicalTrials.gov)

Phase 1 adaptive dose‐finding study of neoadjuvant gemcitabine combined with radiation therapy for patients with high‐risk extremity and trunk soft tissue sarcoma

“…These results compare very favorably with reported complete pathologic response rates with radiation therapy alone (8%‐10%) and with the combination of doxorubicin and radiation therapy (9%‐14%) . Similar complete pathologic response rates have been reported previously with neoadjuvant doxorubicin, ifosfamide, and radiation therapy (48%) and, more recently, with neoadjuvant sorafenib either with radiation therapy alone (38%) or in combination with chemoradiation (44%) . A complete pathologic response in STS has been shown to be significantly associated with improved distant recurrence–free survival, but to our knowledge, it has not been reported for progression‐free or overall survival.…”

HSP90 inhibition as a means of radiosensitizing resistant, aggressive soft tissue sarcomas

“…Whereas for heavy ion irradiation and hyperthermia in combination with photon irradiation the clinical results are promising [33,36], the efficacy of combined radiochemotherapy is controversially discussed and comes at the costs of accumulating side effects [37,38]. Additionally, molecularly targeted approaches of radiosensitization with protein kinase, mammalian target of rapamycin (mTOR), and histone deacetylase (HDAC) inhibitors have been developed in preclinical studies and are currently undergoing clinical evaluation [39][40][41][42][43][44]. HSP90 inhibition in general appears as a very attractive means of radiosensitization, since it can target multiple HSP90 client proteins orchestrating radioresistance and other characteristics of the malignant phenotype, including angiogenesis, invasiveness and metastasis, at the same time [28,30,45,46].…”

Predictors of residual disease after unplanned excision of soft tissue sarcomas

“…Local-recurrence free (LRFS), distant-recurrence free (DRFS), disease-specific (DSS), and overall survival (OS) were calculated as described previously. 13, 14 …”