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Fourteen-Day Gemcitabine-Docetaxel Chemotherapy Is Effective and Safer Compared to 21-Day Regimen in Patients with Advanced Soft Tissue and Bone Sarcoma.

ABSTRACT: Gemcitabine-docetaxel (G-D) combination is an effective chemotherapy for patients with advanced soft tissue and bone sarcoma, first developed with G administered on days 1 and 8, and D on day 8 every 21 days and later modified to be administered every 14 days in 2012. The 14-day regimen has become increasingly adopted. However, its efficacy and toxicities have not been compared. We identified 161 patients with metastatic or locally advanced soft tissue and bone sarcoma treated with either a 14-day or 21-day regimen within Northern California Kaiser Permanente from 1 January 2017 to 30 July 2020 and compared the outcomes and toxicity profiles of patients treated with the either regimen. Seventy-nine (49%) and 82 (51%) patients received the 14-day and the 21-day regimen, respectively, with similar response rate (22.8% and 15.8%, p = 0.26), median progression-free survival (PFS, 4.0 and 3.2 months, p = 0.15), and median overall survival (OS, 12.6 and 14.7 months, p = 0.55). Subset analysis of the untreated patients (approximately 60% of the entire cohort) as well as the patients with leiomyosarcoma only (approximately 50% of the entire cohort) showed that OS was not significantly different between the two regimens. Febrile neutropenia requiring hospitalization occurred in 10 and one patients (p = 0.006) and intolerance leading to discontinuation of chemotherapy occurred in 12 and two patients (p = 0.006) treated with the 21-day and the 14-day regimens, respectively. CDKN2A deletion/mutation or CDK4 amplification was associated with worse median OS (p = 0.06), while a RB1 deletion/mutation was associated with better median PFS (p = 0.05), and these two genomic alterations were mutually exclusive. Our data demonstrate that, compared to the traditional 21-day G-D regimen, the 14-day G-D regimen is equally effective but safer. In addition, CDKN2A and RB1 pathways play significant role on the outcomes of the patients.

SUBMITTER: Pan M

PROVIDER: S-EPMC8074251 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPediatric bone and soft tissue sarcomas are rare; therefore, national registries are essential tools for orthopedic oncology research. Past studies provide excellent data on long-term prognosis and survival trends but fail to examine treatment-specific morbidity. The aim of this study is to use a national registry to describe patient demographics, comorbidities, and adverse events in the first thirty days following surgical management of pediatric bone and soft tissue sarcomas.MethodsA retrospective review of patients in the American College of Surgeons National Surgical Quality Improvement Program-Pediatrics database (NSQIP-P) was performed. The cohort was partitioned by tumor origin (bone versus soft tissue) and tumor location (axial versus appendicular).ResultsOne-hundred ninety-two patients were identified. Bone sarcomas were more common (71.9%) and predominately appendicular (62.3%), while soft tissue sarcomas were predominately axial (77.8%). The overall complication rate was 8.9%. The most frequent etiologies were wound dehiscence (3.6%) and infectious complications such as surgical site infections (2.6%), pneumonia (1.6%), urinary tract infections (1.6%), and C. diff colitis (1.0%). Twenty-four percent of patients experienced bleeding requiring transfusion. The unplanned readmission rate was 12.5% (3.6% related to principle procedure), and the unplanned reoperation rate was 4.7% (4.2% related to principle procedure). The mortality rate was 1.0%. Neoadjuvant chemotherapy was associated with higher rates of wound dehiscence and infectious complications. There were no differences in adverse events with respect to tumor origin or location.ConclusionApproximately 1 in 11 pediatric patients will experience a complication in the first thirty days following surgery. However, perioperative mortality remains low. This study represents the first comprehensive review of pediatric bone and soft tissue sarcoma surgery in the NSQIP-P database. As the case volume of NSQIP-P continues to grow, NSQIP-P has the potential to become a powerful tool for pediatric orthopedic oncology research.

Project description:Background/aimsDespite enormous effort, anti-angiogenic drugs have not lived up to the promise of globally-enhancing anti-cancer therapies. Clinically, anti-angiogenic drugs have been used to persistently suppress vascular endothelial growth factor (VEGF) in order to "normalize" dysfunctional neo-angiogenic microvasculature and prevent recruitment of endothelial progenitors. Recently, we showed that a 1h pre-treatment with anti-angiogenic drugs prior to ultra-high single dose radiotherapy and specific chemotherapies transiently de-represses acid sphingomyelinase (ASMase), leading to enhanced cancer therapy-induced, ceramide-mediated vascular injury and tumor response. Here we formally decipher parameters of chemotherapy induction of endothelial sphingolipid signaling events and define principles for optimizing anti-angiogenic chemosensitization.MethodsThese studies examine the antimetabolite chemotherapeutic gemcitabine in soft tissue sarcoma (STS), a clinically-relevant combination.ResultsInitial studies address the theoretic problem that anti-angiogenic drugs such as bevacizumab, an IgG with a 3-week half-life, have the potential for accumulating during the 3-week chemotherapeutic cycles currently standard-of-care for STS treatment. We show that anti-angiogenic ASMase-dependent enhancement of the response of MCA/129 fibrosarcomas in sv129/BL6 mice to gemcitabine progressively diminishes as the level of the VEGFR2 inhibitor DC101, an IgG, accumulates, suggesting a short-acting anti-angiogenic drug might be preferable in multi-cycle chemotherapeutic regimens. Further, we show lenvatinib, a VEGFR2 tyrosine kinase inhibitor with a short half-life, to be superior to DC101, enhancing gemcitabine-induced endothelial cell apoptosis and tumor response in a multi-cycle treatment schedule.ConclusionWe posit that a single delivery of a short-acting anti-angiogenic agent at 1h preceding each dose of gemcitabine and other chemotherapies may be more efficacious for repeated sensitization of the ASMase pathway in multi-cycle chemotherapy regimens than current treatment strategies.

Project description:Our results highlight some of the challenges in the management of soft tissue sarcomas, which requires close cooperation between surgeons and medical oncologists and a careful selection of patients. The incidence of hepatotoxicity was a concerning finding and had been previously reported in patients treated with pazopanib.Although pharmacokinetic analysis was not part of this study, concomitant treatment with pazopanib has been recently reported to increase docetaxel exposure, which may explain the increased toxicity of combination regimens. It remains possible that lower doses of combined gemcitabine, docetaxel, and pazopanib may be tolerable. However, caution should be exercised in future trials investigating similar combinations.For extremity soft tissue sarcomas (STS), surgical resection remains the standard of care, and the addition of chemotherapy is controversial. This was a phase Ib/II trial of neoadjuvant therapy for patients with STS.Patients with high grade, extremity STS of >8 cm and amenable to definitive resection were treated with up to four 21-day cycles of 900 mg/m(2) gemcitabine on days 1 and 8, 75 mg/m(2) docetaxel on day 8, and 400 mg of pazopanib daily (GDP), followed by surgery and, if indicated, radiation therapy. Primary and secondary endpoints (phase Ib portion) were the safety and rate of pathologic response.The trial was discontinued because of slow accrual after inclusion of five patients (leiomyosarcoma: two; undifferentiated pleomorphic sarcoma: three). Two patients completed four treatment cycles: one underwent surgery and one had insufficient response and received additional therapies. Three patients discontinued treatment because of toxicity. Grade 3 adverse events included hypertension, fatigue, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation, hoarseness, and myelotoxicity. There were no complete or partial responses. One patient had ? 90% pathologic response. Among four patients who underwent resection, three remain free of disease, and one patient eventually relapsed.GDP combination used in the neoadjuvant setting resulted in significant toxicity; despite pathologic responses, no objective responses occurred.

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Fourteen-Day Gemcitabine-Docetaxel Chemotherapy Is Effective and Safer Compared to 21-Day Regimen in Patients with Advanced Soft Tissue and Bone Sarcoma.

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