LTX-315 and adoptive cell therapy using tumor-infiltrating lymphocytes generate tumor specific T cells in patients with metastatic soft tissue sarcoma.

LTX-315 is an oncolytic peptide that elicits both local and systemic immune responses upon intratumoral injection. In the present pilot trial, we treated patients with metastatic soft tissue sarcoma with the combination of LTX-315 and adoptive T-cell therapy using in vitro expanded tumor-infiltrating lymphocytes. Six heavily pretreated patients were included in the trial and treated with LTX-315 of which four patients proceeded to adoptive T-cell therapy. Overall, the treatment was considered safe with only expected and manageable toxicity. The best overall clinical response was stable disease for 208 days, and in this patient, we detected tumor-reactive T cells in the blood that lasted until disease progression. In three patients T-cell reactivity against in silico predicted neoantigens was demonstrated. Additionally, de novo T-cell clones were generated and expanded in the blood following LTX-315 injections. In conclusion, this pilot study provides proof that it is feasible to combine LTX-315 and adoptive T-cell therapy, and that this treatment can induce systemic immune responses that resulted in stabilization of the disease in sarcoma patients with otherwise progressive disease. Further optimization of the treatment protocol is warranted to increase clinical activity. ClinicalTrials.gov Identifier: NCT03725605.

Conservatively treated wound for four months turned out to be highly malignant cutaneous angiosarcoma.

Angiosarcomas are rare, highly malignant tumours of vascular origin. They present as fast growing, haematoma-like and diffuse lesions. In this case report, a 71-year-old woman presented with what was assessed as an abscess arising from a traumatic haematoma of the forehead. The lesion was primarily treated conservatively. The condition progressed despite of treatment to a point where the tumour covered a third of her face. After four months, skin biopsies were taken and the diagnosis angiosarcoma was made. This case report should lead to an increased focus on angiosarcomas and the importance of sufficient biopsies.

Transvaginal resection of gastrointestinal stromal tumor in the rectum.

A gastrointestinal stromal tumour (GIST) can occur anywhere in the gastrointestinal tract, though rectal GIST is rare. The primary treatment of GIST is surgical resection. Neoadjuvant imatinib treatment may cause tumor reduction and allow local resection. This is a case report of a 70-year-old woman with a high level of comorbidity who was diagnosed with a low rectal GIST. She was successfully treated with imatinib followed by complete GIST resection using a transvaginal technique.

Occlusive wound closure prevents prolonged wound discharge-A randomised controlled trial in patients undergoing tumour resection and endoprosthetic reconstruction of the proximal femur because of metastatic bone disease.

Prolonged wound discharge is a common postoperative complication of orthopaedic procedures and a risk factor for implant-related infection. Occlusive wound closure methods have previously been suggested to reduce or even prevent this complication. We performed a randomised controlled trial on 70 patients who underwent surgical treatment for metastatic bone disease involving the proximal femur at our centre between January 2017 and August 2018. At conclusion of the tumour resection and endoprosthetic reconstruction procedure, patients were randomised to either occlusive wound closure (n = 35), using the Dermabond Prineo-22 skin closure system, or routine wound closure with conventional skin staples (n = 35). Skin closure with occlusive wound closure resulted in a lesser degree (P < .0001) and shorter duration of postoperative wound discharge (HR 2.89 [95% CI 1.6-5.05], P < .0018). Compared with staples, surgical wounds were already dry after a mean of 3.5 days [95% CI 3.2-3.9] versus 6.1 days [95% CI 4.8-7.3] (P < .0001). Prolonged wound discharge for 7 days or more was observed in 23% of patients (n = 8) in the Staples-group but was entirely absent in the occlusive wound closure group (P < .003). This study provides strong evidence that occlusive wound closure reduces frequency, degree, and duration of wound discharge in a patient population at particularly high risk for this complication.

The Prognostic Value of Plasma Programmed Death Protein-1 (PD-1) and Programmed Death-Ligand 1 (PD-L1) in Patients with Gastrointestinal Stromal Tumor.

BACKGROUND: This study investigates the prognostic value of plasma Programmed Death Protein-1 (PD-1) and Programmed Death-Ligand 1 (PD-L1) concentrations in patients with Gastrointestinal Stromal Tumor (GIST). METHODS: Patients with GIST were included (n = 157) from the two Danish sarcoma centers, independent of disease- and treatment status. The patients were divided into three subgroups; 1: patients with localized disease who underwent radical surgery; 2: patients with local, locally advanced, or metastatic disease; and 3: patients without measurable disease who had undergone radical surgery. Sensitive electrochemiluminescence immune-assays were used to determine PD-1 and PD-L1 concentration in plasma samples. The primary endpoint was the PFS. RESULTS: No patients progressed in group 1 (n = 15), 34 progressed in group 2 (n = 122), and three progressed in group 3 (n = 20). Significantly higher plasma concentrations of PD-1 (p = 0.0023) and PD-L1 (0.012) were found in patients in group 2 compared to PD-1/PD-L1 levels in postoperative plasma samples from patient group 1. Patients with active GIST having a plasma concentration of PD-L1 above the cutoff (225 pg/mL) had a significantly poorer prognosis compared to patients with plasma PD-L1 concentration below the cutoff. CONCLUSIONS: Plasma PD-L1 shows potential as a prognostic biomarker in patients with GIST and should be further evaluated.

The Prognostic Value of Plasma Small Extracellular Vesicles' Phenotype in Patients With Gastrointestinal Stromal Tumor.

BACKGROUND/AIM: For patients with local gastrointestinal stromal tumor (GIST), risk stratification is used to assess the prognosis and identify patients to offer adjuvant treatment. For patients with advanced or metastatic GIST, no such risk stratification exists. This study aimed to investigate the prognostic value of 31 different plasma small extracellular vesicles' (SEVs) surface proteins in GIST patients. MATERIALS AND METHODS: GIST patients from the two sarcoma centers in Denmark were included. Patients were divided into three groups; group 1: patients undergoing radical surgery; group 2: patients with local, locally advanced, or metastatic GIST; and group 3: patients without evidence of disease after radical surgery. Protein microarray technology was used for the analysis of plasma SEVs. The median plasma SEV marker level was used when comparing groups of patients. The primary endpoint was the progression of GIST. Iterative statistical modeling was used to identify a SEV marker profile/model with a prognostic value. RESULTS: A total of 157 patients were included, with a median follow-up time of 2.05 years. In group 2, a high level of carcinoembryonic antigen (CEA) and a low level of glucose transporter 1 (GLUT-1) were found to be poor prognostic factors [univariate analysis; GLUT-1: hazard ratio (HR)=0.47, 95% confidence interval (CI)=0.22-0.98; CEA: HR=2.12, 95%CI=1.02-4.44]. Composing a model consisting of CEA and GLUT-1 adjusted for age at inclusion was found to have a prognostic value (HR=4.93, 95%CI=2.30-10.57, p<0.0001). CONCLUSION: Plasma SEVs in GIST showed that CEA and GLUT-1 might be of prognostic value. However, external validation is needed.

Pre-and Postoperative Circulating Tumour DNA in Patients With Gastrointestinal Stromal Tumour - A Methodological Assessment Study.

BACKGROUND/AIM: Gastrointestinal stromal tumours (GISTs) harbour genetic aberrations in receptor tyrosine kinase KIT (KIT) or platelet-derived growth factor receptor A (PDGFRA) in 85-90% of the patients. Circulating tumour DNA (ctDNA) is a potential biomarker in patients with GIST. Previous studies investigating ctDNA around surgery in patients with GIST presented divergent results regarding the proportion of patients with detectable ctDNA. This study aimed to 1) investigate the feasibility of detecting and monitoring ctDNA pre-and postoperative, 2) compare two different circulating free DNA (cfDNA) extraction methods, and validate results obtained by next-generation sequencing (NGS) using Real-Time PCR technology. PATIENTS AND METHODS: Eight patients planned for immediate surgery or surgery after neoadjuvant oncological treatment were included in the study, from whom blood collection was performed pre- and postoperatively for ctDNA analysis. Furthermore, blood samples from six patients with GIST harbouring a point mutation in KIT or PDGFRA in tissues from primary tumours were used for comparison and validation sub-study. RESULTS: In this explorative study, none of the patients with very low to intermediate risk GIST harboured KIT, or PDGFRA mutated ctDNA in pre-or postoperative blood samples. The methods used for cfDNA extraction gave similar output, and the two methods for ctDNA analysis gave identical results. CONCLUSION: There is no benefit in analysing ctDNA around surgery in very low to intermediate-risk GIST patients. Larger studies investigating ctDNA in patients with high-risk GIST around surgery are warranted.

Real-life incidence of cardiotoxicity and associated risk factors in sarcoma patients receiving doxorubicin.

BACKGROUND: Anthracycline induced cardiotoxicity is well recognized but only few data exist in sarcoma patients. This study retrospectively aimed to analyze sequential Cadmium Zinc Telluride (CZT)-multigated equilibrium radionuclide angiography (ERNA) for monitoring left ventricular ejection fraction (LVEF) and to assess the real-life incidence of cardiotoxicity in sarcoma patients receiving doxorubicin based chemotherapy. MATERIALS AND METHODS: A retrospective analysis was performed on all sarcoma patients referred to Herlev University Hospital between 2012 and 2015. Cardiotoxicity was defined as a decline in LVEF of > 10% percentage point to a LVEF < 50% as compared to baseline. Early cardiotoxicity was defined as < 1 year and late cardiotoxicity as ≥ 1 year. Recovery of cardiotoxicity was defined as a LVEF ≥ 50%. RESULTS: A total of 149 patients were referred, 75 (50%) sarcoma patients were included. The main reason for exclusion was that only one CZT-ERNA had been performed in 50 (68%) of the patients. Twenty-three (31%) of the patients experienced cardiotoxicity, 11 (48%) were female, mean age was 56.9 years. Early cardiotoxicity was observed in 16 (70%) of the patients and 11 (48%) experienced clinical symptoms of cardiotoxicity at diagnosis. Recovery of LVEF was seen in 12 (55%) of the patients and persistent recovery in 10 (45%). The diastolic blood pressure at baseline was positively and significantly associated with a higher risk of developing cardiotoxicity (Relative Risk (RR): 1.039 (95% CI= 1.001 - 1.079; p = 0.042)). The median survival was 1.4 years (range 0.5 - 2.2 years) for patients with metastatic disease versus 3.9 years (range 1.5 - 6.4 years) (p = 0.009) for localized disease at baseline. CONCLUSION: Cardiotoxicity is a relative frequent complication in sarcoma patients treated with doxorubicin based chemotherapy and the diastolic blood pressure at baseline was significantly associated with a higher risk of developing cardiotoxicity.

Quality of life of patients with soft tissue sarcoma treated with doxorubicin in the ANNOUNCE phase III clinical trial.

BACKGROUND: Patient-reported outcomes (PROs), including health-related quality of life, are recommended to be routinely collected in clinical trials, but data are limited from trials of sarcoma patients. In this analysis, pooled PRO data are reported from patients with advanced or metastatic soft tissue sarcoma (STS) enrolled to the ANNOUNCE phase III trial of doxorubicin-based therapy. METHODS: ANNOUNCE was a phase III trial that randomized 509 patients with STS to receive up to eight cycles of doxorubicin with olaratumab or placebo, followed by single-agent olaratumab or placebo. Dexrazoxane was allowed at any cycle of treatment. Participants completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30, which is scored 0-100), and Brief Pain Inventory Short Form Modified (mBPI-sf, scored from 0-10) at each treatment cycle. A descriptive analysis of the longitudinal data was conducted overall and by cumulative dose of doxorubicin received to inform the clinical care of patients with STS. Worsening on the QLQ-C30 was defined as a change of 10 points or more at any post-baseline assessment. Worsening on the mPBI-sf was defined as an increase of ≥2 points from baseline. RESULTS: The majority of participants completed the baseline and at least one subsequent PRO assessment within the trial (n = 460, 90.4% EORTC QLQ-C30; n = 454, 89.2%, mBPI-sf). Patients with STS enrolled to the ANNOUNCE trial had clinically meaningful problems with physical function and pain before initiating doxorubicin. Overall, those with fewer symptoms or better function at baseline received higher cumulative doxorubicin dose throughout the study. At baseline, mean QLQ-C30 fatigue was 29.9 with a median time to first worsening of 0.9 months, and mean nausea/vomiting was 6.5 with 1.4 months until worsening; mean physical function was 78.3 with median time to worsening of 2.1 months and mean health status was 66.8 with median time to first worsening of 1.6 months. Median time to worsening of pain was 7.9 months. CONCLUSION: Patients with advanced or metastatic sarcoma reported a relatively rapid decline in PROs during doxorubicin-based treatment, with patients with poorer symptoms at baseline (specifically fatigue), subsequently receiving less doxorubicin therapy. The availability of detailed summary data from the patient perspective during doxorubicin-based treatment may inform future care of these patients and can provide a resource for the development of PRO endpoints in future trials.

Medical oncological treatment for patients with Gastrointestinal Stromal Tumor (GIST) - A systematic review.

BACKGROUND: Chemotherapy is ineffective in treating patients with Gastrointestinal Stromal Tumor (GIST). However, several types of tyrosine kinase inhibitors have been investigated since the approval of imatinib in 2001. The purpose of this report was to systematically review studies on the efficacy of neoadjuvant, adjuvant, and lifelong medical oncological treatment of GIST. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed throughout the review process. The protocol was submitted to the International prospective register of systematic reviews database (ID 251724). A systematic literature search was performed, including phase II- and III studies of biological treatment, reporting on treatment effect in patients with GIST. RESULTS: Of 308 identified publications, 42 studies were included in this review. CONCLUSION: This review gives an overview of the existing evidence for approved lines of oncological treatments and potential alternatives for patients with GIST in the neoadjuvant-, adjuvant- and life-long setting.

Outstanding Response to Sorafenib in a Patient with Metastatic Gastrointestinal Stromal Tumour.

Gastrointestinal stromal tumour (GIST) is the most common sarcoma and can be seen in any part of the gastrointestinal tract. The effect of tyrosine kinase inhibitors varies with mutation status in receptor tyrosine kinase KIT and in platelet-derived growth factor receptor A (PDGFRA). This case presents a 61-year-old man, diagnosed with an 11-cm GIST located at the stomach with a high risk of recurrence. The patient showed intolerance to imatinib shortly after introduction and subsequently progressed on sunitinib and nilotinib. The patient started fourth-line treatment with sorafenib with an impressive response to a point at which metastases intra-abdominally and in the liver could be resected. After surgery, sorafenib was restarted. Due to toxicity, sorafenib dose was reduced over time. The dose was insufficient to control the disease since a new recurrence was detected. Mutation analyses revealed a GIST harbouring a deletion of codon p.I843_D846del, located at PDGFRA exon 18, right next to the codon D842 where mutations are known leading to imatinib resistance. In this case, the GIST was highly sensitive to sorafenib, and the response was dose related. It is mandatory to perform mutation analyses on primary tumour and at recurrence in the decision-making of the correct treatment for the patient. In March 2021, the patient had been in treatment with sorafenib for 12.5 years and was still without signs of recurrence. A multidisciplinary approach was essential for the long-term survival of the patient in this case.

In vitro 4-1BB stimulation promotes expansion of CD8+ tumor-infiltrating lymphocytes from various sarcoma subtypes.

Tumor-specific tumor-infiltrating lymphocytes (TILs) can be in vitro expanded and have the ability to induce complete and durable tumor regression in some patients with melanoma following adoptive cell therapy (ACT). In this preclinical study, we investigated the feasibility of expanding TIL from sarcomas, as well as performing functional in vitro analyses on these. TILs were expanded in vitro by the use of IL2 stimulation with or without the addition of 4-1BB and CD3 antibodies. Phenotypical and functional analyses were mainly performed by flow cytometry. TILs were expanded from 25 of 28 (89%) tumor samples from patients with 9 different sarcoma subtypes. TILs were predominantly αß T-cells of effector memory subtype with CD4+ dominance. In particular, CD8+ TIL highly expressed LAG3 and to a lesser degree PD-1 and BTLA. In total, 10 of 20 TIL cultures demonstrated in vitro recognition of autologous tumor. In some cases, the fraction of tumor-reactive T cells was more than 20%. 4-1BB stimulation augmented expansion kinetics and favored CD8+ occurrence. In conclusion, TIL expansion from sarcoma is feasible and expanded TILs highly express LAG3 and comprise multifunctional tumor-reactive T-cells.

Effect of Doxorubicin Plus Olaratumab vs Doxorubicin Plus Placebo on Survival in Patients With Advanced Soft Tissue Sarcomas: The ANNOUNCE Randomized Clinical Trial.

Importance: Patients with advanced soft tissue sarcoma (STS) have a median overall survival of less than 2 years. In a phase 2 study, an overall survival benefit in this population was observed with the addition of olaratumab to doxorubicin over doxorubicin alone. Objective: To determine the efficacy of doxorubicin plus olaratumab in patients with advanced/metastatic STS. Design, Setting, and Participants: ANNOUNCE was a confirmatory, phase 3, double-blind, randomized trial conducted at 110 sites in 25 countries from September 2015 to December 2018; the final date of follow-up was December 5, 2018. Eligible patients were anthracycline-naive adults with unresectable locally advanced or metastatic STS, an Eastern Cooperative Oncology Group performance status of 0 to 1, and cardiac ejection fraction of 50% or greater. Interventions: Patients were randomized 1:1 to receive doxorubicin, 75 mg/m2 (day 1), combined with olaratumab (n = 258), 20 mg/kg in cycle 1 and 15 mg/kg in subsequent cycles, or placebo (n = 251) on days 1 and 8 for up to 8 21-day cycles, followed by olaratumab/placebo monotherapy. Main Outcomes and Measures: Dual primary end points were overall survival with doxorubicin plus olaratumab vs doxorubicin plus placebo in total STS and leiomyosarcoma (LMS) populations. Results: Among the 509 patients randomized (mean age, 56.9 years; 58.2% women; 46.0% with LMS), all were included in the primary analysis and had a median length of follow-up of 31 months. No statistically significant difference in overall survival was observed between the doxorubicin plus olaratumab group vs the doxorubicin plus placebo group in either population (total STS: hazard ratio, 1.05 [95% CI, 0.84-1.30], P = .69, median overall survival, 20.4 months vs 19.7 months; LMS: hazard ratio, 0.95 [95% CI, 0.69-1.31], P = .76, median overall survival, 21.6 months vs 21.9 months). Adverse events of grade 3 or greater reported in 15% or more of total patients with STS were neutropenia (46.3% vs 49.0%), leukopenia (23.3% vs 23.7%), and febrile neutropenia (17.5% vs 16.5%). Conclusions and Relevance: In this phase 3 clinical trial of patients with advanced STS, treatment with doxorubicin plus olaratumab vs doxorubicin plus placebo resulted in no significant difference in overall survival. The findings did not confirm the overall survival benefit observed in the phase 2 trial. Trial Registration: ClinicalTrials.gov Identifier: NCT02451943.

Improved Survival of Children, Adolescents, and Young Adults With Head and Neck Soft Tissue Sarcomas in Denmark.

AIM: The aim of this study was to estimate nationally the survival of children, adolescents, and young adults with head and neck soft tissue sarcomas. MATERIALS AND METHODS: The authors included patients 0 to 21 years of age and diagnosed with rhabdomyosarcoma (RMS) or nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) located in the head and neck between 1980 and 2014. Survival probabilities were estimated using the Kaplan-Meier method. The authors estimated the effect of covariates with univariate and multivariate Cox regression analyses. The cumulative recurrence in RMS was estimated when considering death as a competing risk. RESULTS: We identified 72 patients (50% male individuals, whereas 72% had RMS). Elder patients (older than 15 y) did worse compared with younger patients (log-rank test P=0.001). Patients diagnosed from 1980 to 1999 did worse than patients diagnosed from 2000 to 2014 (log-rank test P=0.02). Similarly, younger (younger than 15 y) patients did significantly better when diagnosed from 2000 to 2014 with reference to those diagnosed from 1980 to 1999 (log-rank test P=0.026). The multivariate hazard ratio was 0.46 (95% confidence interval, 0.23-0.92) for patients diagnosed from 2000 to 2014 with reference to patients diagnosed from 1980 to 1999. The 1-year cumulative recurrence for RMS was 21.2% (95% confidence interval, 12.3%-35.0%). CONCLUSION: Overall survival has improved throughout the study period, which is attributable to advancement in diagnostics, treatment, and the application of standardized guidelines from international protocols.

Severely Disseminated Kaposi Sarcoma after ABO-Incompatible Kidney Transplantation Treated Successfully with Paclitaxel and Gemcitabine Combined with Hemodialysis.

Kaposi Sarcoma (KS) is driven by human herpes virus 8 causing vascular proliferation which is induced by loss of immune function most often due to HIV or immunosuppressants. KS occurs with increased incidence in kidney transplant recipients, but rarely is disseminated. We report a 64-year-old male who developed severely disseminated KS 5 months after ABO-incompatible kidney-transplantation. No guidelines for chemotherapy exist in this case and reduced kidney function and impaired immune system complicates the use of systemic chemotherapy in kidney transplant recipients. A combination of paclitaxel and gemcitabine followed by two days of hemodialysis treatment was chosen since paclitaxel can be given in full dose independently of kidney function and gemcitabine is metabolised to 2',2'-difluorodeoxyuridine which is found to be highly dialysable. The present treatment was well tolerated by the patient with one episode of leukopenia and elevated alanine transaminase during treatment which resolved. There were no serious adverse events and the patient obtained a complete remission verified by Positron Emission Tomography CT after ending chemotherapy and at one-year follow up.

Patient and Tumour Characteristics of Adult Head and Neck Soft Tissue Sarcomas: A Systematic Review and Meta-Analysis.

BACKGROUND: Head and neck soft tissue sarcomas (HNSTS) constitute a rare and heterogeneous cancer entity. Management remains a challenge due to the rarity and varied biological behaviour among various subtypes. This systematic review examines the characteristics of tumours and patients with HNSTS. MATERIALS AND METHODS: A systematic literature review and meta-analysis were performed using the electronic databases PubMed and Embase. Eight eligible studies were identified, and 13 variables were extracted from each study including 5-year overall survival (OS) rate and 5-year disease-free survival (DFS) rate. RESULTS: We identified eight studies (n = 1,120 patients; 739 males (66%)) from six different countries). In total, 24 histological subtypes were found, and 20% of the sarcomas (n = 215) could not be subclassified. 607 sarcomas (57%) were <5 cm in diameter, and 945 sarcomas (84%) were grade 3. 1,059 patients (90%) underwent surgery. Estimated 5-year OS was 74% (95% CI; 0.63-0.84%) and 5-year DFS was 56% (95% CI; 38-74%). CONCLUSION: HNSTS holds a relative poor prognosis possibly explained by the heterogeneity of the disease. Treatment of HNSTS has shown to be highly diverse, underlining the importance of uniformed treatment guidelines in order to achieve improved survival outcomes.

Eribulin versus dacarbazine in patients with leiomyosarcoma: subgroup analysis from a phase 3, open-label, randomised study.

BACKGROUND: This subgroup analysis of a phase 3 study compares outcomes for eribulin versus dacarbazine in patients with leiomyosarcoma. METHODS: Patients ≥18 years old with advanced liposarcoma or leiomyosarcoma, ECOG PS ≤2, and ≥2 prior treatment regimens were randomly assigned (1:1) to eribulin mesylate (1.4 mg/m² intravenously on day 1 and day 8) or dacarbazine (either 850, 1000, or 1200 mg/m² intravenously) every 21 days until disease progression. The primary end point was OS; additional end points were progression-free survival (PFS) and objective response rate (ORR). RESULTS: 309 Patients with leiomyosarcoma were included (eribulin, n = 157; dacarbazine, n = 152). Median age was 57 years; 42% of patients had uterine disease and 57% had nonuterine disease. Median OS was 12.7 versus 13.0 months for eribulin versus dacarbazine, respectively (hazard ratio [HR] = 0.93 [95% CI 0.71-1.20]; P = 0.57). Median PFS (2.2 vs 2.6 months, HR = 1.07 [95% CI 0.84-1.38]; P = 0.58) and ORR (5% vs 7%) were similar between eribulin- and dacarbazine-treated patients. Grade ≥3 TEAEs occurred in 69% of patients receiving eribulin and 59% of patients receiving dacarbazine. CONCLUSIONS: Efficacy of eribulin in patients with leiomyosarcoma was comparable to that of dacarbazine. Both agents had manageable safety profiles.

Adjuvant Gemcitabine Plus Docetaxel Followed by Doxorubicin Versus Observation for High-Grade Uterine Leiomyosarcoma: A Phase III NRG Oncology/Gynecologic Oncology Group Study.

PURPOSE: We conducted a randomized phase III trial to determine whether adjuvant chemotherapy improves survival in women with uterine leiomyosarcoma. METHODS: Women with uterus-confined, high-grade leiomyosarcoma who were confirmed disease free by imaging were randomly assigned to four cycles of gemcitabine plus docetaxel, followed by four cycles of doxorubicin, or to observation. All were followed for evidence of recurrence. The primary end point was overall survival (OS). RESULTS: With international collaboration, 38 of the targeted accrual of 216 patients were enrolled, after which the study was closed by the National Cancer Institute for accrual futility. Twenty patients were assigned to chemotherapy, 18 to observation. Among the 17 patients treated with at least one cycle of chemotherapy, grade 3 or 4 toxicities were observed in 47%; among the 18 patients assigned to observation, one had grade 3 hypertension. There were six deaths (chemotherapy, n = 5; observation, n = 1), all due to disease. The restricted mean survival time for OS was estimated as 34.3 months (95% CI, 25.3 to 43.3 months) in the chemotherapy arm and as 46.4 months (95% CI, 43.6 to 49.1 months) in the observation arm. There were eight recurrences in each arm. The restricted mean survival time for recurrence-free survival was estimated as 18.1 (95% CI, 14.2 to 22.0) months in the chemotherapy arm and as 14.6 months (95% CI, 10.3 to 19.0 months) in the observation arm. Neither survival outcome comparison was considered statistically robust, due to the small sample size. CONCLUSION: Despite international collaboration to test the role of adjuvant chemotherapy in uterine-confined leiomyosarcoma, this study was closed for accrual futility. Although the sample size precludes robust statistical comparison, observed OS and recurrence-free survival data do not show superior outcomes with adjuvant chemotherapy.