Neoadjuvant treatment of soft‐tissue sarcoma: A multimodality approach

Reynoso, David; Subbiah, Vivek; Trent, Jonathan C.; Guadagnolo, B. Ashleigh; Lazar, Alexander J.; Benjamin, Robert S.; Pollock, Raphael E.; Ludwig, Joseph A.

doi:10.1002/jso.21481

Cited by 29 publications

(10 citation statements)

References 43 publications

(33 reference statements)

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“…STS is usually treated using a multidisciplinary approach with surgery, radiation therapy, and chemotherapy (1, 2), but the prognosis of patients with relapsed or metastatic advanced STS remains poor. Cytotoxic chemotherapy has been the mainstay of first- and second-line treatment of these cancers, but patients invariably relapse or become refractory to therapy.…”

Section: Introductionmentioning

confidence: 99%

Phase Ib/II Study of the Safety and Efficacy of Combination Therapy with Multikinase VEGF Inhibitor Pazopanib and MEK Inhibitor Trametinib In Advanced Soft Tissue Sarcoma

Subbiah

Meyer

Zinner

et al. 2017

Clinical Cancer Research

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Purpose Pazopanib, a multi-receptor tyrosine kinase inhibitor targeting primarily vascular endothelial growth factor receptors 1-3 (VEGFRs1-3), is approved for advanced soft tissue sarcoma and renal cell cancer. Downstream of VEGFR, trametinib is an FDA-approved MEK inhibitor used for melanoma. We hypothesized that vertical pathway inhibition using a trametinib would synergize with pazopanib in advanced soft tissue sarcoma (STS). Experimental Design In an open-label, multicenter, investigator-initiated NCCN-sponsored trial, patients with metastatic or advanced STS received pazopanib 800 mg and 2 mg of trametinib continuously for 28-day cycles. The primary endpoint was 4-month progression-free survival (PFS). Secondary endpoints were overall survival, response rate and disease control rate. Results Twenty-five patients were enrolled. The median age was 49 years (range 22–77 years) and 52% were male. Median PFS was 2.27 months (95% confidence interval [CI] 1.9–3.9), and the 4-month PFS rate was 21.1% (95% CI 9.7–45.9%), which was not an improvement over the hypothesized null 4-month PFS rate of 28.3% (p = 0.79). Median overall survival was 9.0 months (95% CI 5.7–17.7). A partial response occurred in 2 (8%) of the evaluable patients (95% CI 1.0–26.0%), one with PIK3CA E542K mutant embryonal rhabdomyosarcoma and another with spindle cell sarcoma. The disease control rate was 14/25 (56%; 95% CI 34.9–75.6%). The most common adverse events were diarrhea (84%), nausea (64%), and fatigue (56%). Conclusion The combination of pazopanib and trametinib was tolerable without indication of added activity of the combination in STS. Further study may be warranted in RAS/RAF aberrant sarcomas.

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Section: Introductionmentioning

confidence: 99%

Phase Ib/II Study of the Safety and Efficacy of Combination Therapy with Multikinase VEGF Inhibitor Pazopanib and MEK Inhibitor Trametinib In Advanced Soft Tissue Sarcoma

Subbiah

Meyer

Zinner

et al. 2017

Clinical Cancer Research

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“…11,12 For localized, high-risk solid tumors, our institution has had a longstanding interest in preoperative or neoadjuvant therapy, which offers several advantages, including the ability to monitor the primary tumor response in vivo and control potential sites of locoregional and distant microscopic disease upfront. 13,14 The safety and efficacy of neoadjuvant gemcitabine plus radiation therapy in patients with STS is unknown. We performed a phase 1 trial to determine the maximum tolerated dose (MTD) of gemcitabine combined with radiation therapy in the neoadjuvant setting for patients with high-risk extremity or trunk STS.…”

Section: Introductionmentioning

confidence: 99%

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

Tseng

Zhou

et al. 2015

Cancer

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BACKGROUND We sought to determine the maximum tolerated dose (MTD) of gemcitabine given concurrently with preoperative, fixed-dose external-beam radiation therapy (EBRT) for patients with resectable, high-risk extremity and trunk soft tissue sarcomas (STS). METHODS Gemcitabine was administered on days 1, 8, 22, 29, 43, and 50 with EBRT (50 Gy, 25 fractions over 5 weeks). The gemcitabine MTD was determined using a toxicity severity weight method (TSWM), incorporating 6 toxicity types. The TSWM is a Bayesian procedure that chooses each cohort’s dose to have posterior mean total toxicity burden closest to a predetermined clinician-defined target. Clinicopathologic and outcome data were also collected. RESULTS Thirty-six patients completed the study. Using the TSWM, the gemcitabine MTD was 700 mg/m2. At this dose level, 4 patients (24%) experienced grade 4 toxicity; no toxicity-related deaths occurred. All tumors were resected with microscopically negative margins. Pathologic responses of >90% tumor necrosis were achieved in 17 patients (47%); 14 (39%) had complete responses. With a median follow-up of 6.2 years, the 5-year locoregional recurrence-free survival, distant metastasis-free survival, and overall survival rates were 85%, 80%, and 86%, respectively. CONCLUSIONS The TSWM combines data from qualitatively different toxicities and can be used to determine the MTD for a drug given as part of multimodality treatment. Neoadjuvant gemcitabine plus radiation therapy is feasible and safe in patients with high-risk extremity and trunk STS. Major pathologic responses can be achieved and after complete resection, long-term clinical outcomes are encouraging.

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“…The pathological response that is induced by the treatment and the subsequent effects on survival have been the subjects of many studies [12-14], such as Gomez et al [15]. This group performed a retrospective study of patients with extremity high-grade sarcomas who underwent neoadjuvant treatment with RT and chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Neoadjuvant Hypofractionated Radiotherapy and Chemotherapy in High-Grade Extremity Soft Tissue Sarcomas: Phase 2 Clinical Trial Protocol

et al. 2017

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BackgroundNeoadjuvant radiotherapy (RT) and chemotherapy are applied to large, high-grade extremity soft tissue sarcomas to treat metastatic disease earlier and sterilize margins to perform R0 surgery. However, preoperative RT increases wound complication rates (rWC), delaying adjuvant chemotherapy or preventing it from being administered altogether. Hypofractionated neoadjuvant RT can be offered in this situation, concomitant to chemotherapy, allowing patients to receive chemotherapy as a preoperative treatment in less time with an acceptable rWC.ObjectiveThe objectives of this protocol are to maintain low rates of morbidity and mortality compared to literature data, improving survival rates and avoiding poor responders from receiving unnecessary adjuvant chemotherapy.MethodsThis noncontrolled, single-arm, phase 2 clinical trial recruited patients aged over 18 years with high-grade soft tissue sarcomas in the girdles or extremities. Three neoadjuvant chemotherapy (ifosfamide and doxorubicin) cycles were administered with 5 days of hypofractionated RT (25 Gy in 5 fractions) in the second cycle of doxorubicin only. Viable cell counts in the surgical specimen were measured, and patients in whom this value was less than 30% continued to receive an additional 3 full chemotherapy cycles as adjuvant treatment.ResultsPrimary endpoint will be disease-specific survival measured by the evaluation of local and distant recurrence after neoadjuvant treatment. The secondary endpoints will be wound complication and amputation rates and chemotherapy toxicity. We also will record the viable cell rates after the schema and correlate this with survival.ConclusionsAs seems with other solid tumors, hypofractionated RT has comparable efficacy and safety as conventional fractionation. This modality of treatment combined with chemotherapy could increase the pathological response rates and improve the outcomes of select patients.Trial RegistrationClinicalTrials.gov NCT02812654; https://clinicaltrials.gov/ct2/show/NCT02812654 (Archived by WebCite at http://www.webcitation.org/6qC3puBOy)

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Neoadjuvant treatment of soft‐tissue sarcoma: A multimodality approach

Cited by 29 publications

References 43 publications

Phase Ib/II Study of the Safety and Efficacy of Combination Therapy with Multikinase VEGF Inhibitor Pazopanib and MEK Inhibitor Trametinib In Advanced Soft Tissue Sarcoma

Phase Ib/II Study of the Safety and Efficacy of Combination Therapy with Multikinase VEGF Inhibitor Pazopanib and MEK Inhibitor Trametinib In Advanced Soft Tissue Sarcoma

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

Neoadjuvant Hypofractionated Radiotherapy and Chemotherapy in High-Grade Extremity Soft Tissue Sarcomas: Phase 2 Clinical Trial Protocol

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