Outcomes After Preoperative Chemoradiation With or Without Pazopanib in Non-Rhabdomyosarcoma Soft Tissue Sarcoma: A Report From Children's Oncology Group and NRG Oncology

Weiss, Aaron R.; Chen, Yen-Lin; Scharschmidt, Thomas J.; Xue, Wei; Gao, Zhengya; Black, Jennifer O.; Choy, Edwin; Davis, Jessica L.; Fanburg-Smith, Julie C.; Kao, Simon C.; Kayton, Mark L.; Kessel, Sandy; Lim, Ruth; Million, Lynn; Okuno, Scott H.; Ostrenga, Andrew; Parisi, Marguerite T.; Pryma, Daniel A.; Randall, R. Lor; Rosen, Mark A.; Shulkin, Barry L.; Terezakis, Stephanie; Venkatramani, Rajkumar; Zambrano, Eduardo; Wang, Dian; Hawkins, Douglas S.; Spunt, Sheri L.

doi:10.1200/jco.23.00045

Cited by 7 publications

(7 citation statements)

References 15 publications

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“…Published 3 years later, 3-year event-free survival and overall survival was not significantly different. But there was a trend towards better OS in the group with higher necrosis [ 27 ]. The authors concluded that pathologic necrosis may not accurately measure treatment response but may reflect the tumor biology itself.…”

Section: Discussionmentioning

confidence: 99%

The Effect of chemo- and radiotherapy on tumor necrosis in soft tissue sarcoma– does it influence prognosis?

Fromm,

Klein,

Kirilova

et al. 2024

BMC Cancer

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Background Soft tissue sarcomas (STSs) are a heterogeneous group of tumors. Wide surgical resection is standard, often combined with neoadjuvant chemotherapy, radiotherapy, or both. Studies have shown the predictive value of tumor necrosis in bone sarcoma (BS); however, the role of necrosis in STS after neoadjuvant therapies is still unclear. This study aimed to investigate the role of chemo- and radiotherapy in the formation of tumor necrosis and to evaluate the influence of tumor necrosis on overall survival and local recurrence-free survival. Data from BS patients and patients who did not receive neoadjuvant therapy were compared. Methods A total of 779 patients with STS or BS were treated surgically. In all patients, tumor-specific factors such as type, size, or grading and the type of adjuvant therapy were documented. Local recurrence (LR), the diagnosis of metastatic disease, and survival during follow-up were evaluated. Results A total of 565 patients with STS and 214 with BS were investigated. In STS, 24.1% G1 lesions, 34.1% G2 lesions, and 41.8% G3 lesions were observed. Two hundred twenty-four of the patients with STS and neoadjuvant therapy had either radiotherapy (RTx) (n = 80), chemotherapy (CTx) (n = 93), or both (n = 51). Three hundred forty-one had no neoadjuvant therapy at all. In STS, tumor necrosis after neoadjuvant treatment was significantly higher (53.5%) than in patients without neoadjuvant therapy (15.7%) (p < 0.001). Patients with combined neoadjuvant chemo-/radiotherapy had substantially higher tumor necrosis than those with radiotherapy alone (p = 0.032). There was no difference in tumor necrosis in patients with combined chemo-/radiotherapy and chemotherapy alone (p = 0.4). The mean overall survival for patients with STS was 34.7 months. Tumor necrosis did not influence survival in a subgroup of G2/3 patients. In STS with no neoadjuvant therapy and grading of G2/3, the correlation between necrosis and overall survival was significant (p = 0.0248). There was no significant correlation between local recurrence (LR) and necrosis. Conclusion STS shows a broad spectrum of necrosis even without neoadjuvant chemo- or radiotherapy. After CTx or/and RTx necrosis is enhanced and is significantly pronounced with a combination of both. There is a trend toward higher necrosis with CTx than with RTx. Grading substantially influences the necrosis rate, but necrosis in soft-tissue sarcoma following neoadjuvant therapy does not correlate with better survival or a lower local recurrence rate, as in bone sarcomas.

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Section: Discussionmentioning

confidence: 99%

The Effect of chemo- and radiotherapy on tumor necrosis in soft tissue sarcoma– does it influence prognosis?

Fromm,

Klein,

Kirilova

et al. 2024

BMC Cancer

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“…Historically, North American pediatric NRSTS studies have used the POG grading system, 7,8,24 although there is widespread acknowledgment among pediatric pathologists that updates are needed given diagnostic advances since its publication nearly 30 years ago. The FNCLCC grading system also has predictive value in pediatric NRSTS, 25 has been used in pediatric NRSTS trials in Europe 2 and North America, 4 and is the de facto grading system for pediatric NRSTS worldwide. However, our analysis suggests that using FNCLCC grading would result in nearly a third of our low‐risk, surgery‐only patients receiving adjuvant radiotherapy and/or chemotherapy using either the ARST0332 5 or the EpSSG NRSTS2005 2 treatment approach.…”

Section: Discussionmentioning

confidence: 99%

“…Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) account for approximately 60% of pediatric soft tissue sarcomas (STS). 1 Histologic grade is a predictor of outcome in pediatric and adult NRSTS, [2][3][4] but prospective data on the clinical features and outcomes of patients with low-grade tumors are limited. Children's Oncology Group (COG) study ARST0332 5 validated a novel risk stratification and therapeutic approach for young NRSTS patients based on metastatic status, tumor diameter, histologic grade, extent of surgical resection, and microscopic margin status.…”

Section: Introductionmentioning

confidence: 99%

Clinical features and outcomes of young patients with low‐grade non‐rhabdomyosarcoma soft tissue sarcomas treated with a risk‐based strategy: A report from Children's Oncology Group study ARST0332

Douglass,

Coffin,

Randall

et al. 2024

Pediatric Blood & Cancer

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BackgroundIn retrospective analyses, the Pediatric Oncology Group [POG) and the Federation National des Centres de Lutte Contre le Cancer (FNCLCC) histologic grade predict outcome in pediatric non‐rhabdomyosarcoma soft tissue sarcoma (NRSTS), but prospective data on grading, clinical features, and outcomes of low‐grade NRSTS are limited.MethodsWe analyzed patients less than 30 years of age enrolled on Children's Oncology Group (COG) study ARST0332 (NCT00346164) with POG grade 1 or 2 NRSTS. Low‐risk patients were treated with surgery alone. Intermediate‐/high‐risk patients received ifosfamide/doxorubicin and radiotherapy, with definitive resection either before or after 12 weeks of chemoradiotherapy.ResultsEstimated 5‐year event‐free and overall survival were 90% and 100% low risk (n = 80), 55% and 78% intermediate risk (n = 15), and 25% and 25% high risk (n = 4). In low‐risk patients, only local recurrence was seen in 10%; none with margins greater than 1 mm recurred locally. Sixteen of 17 intermediate‐/high‐risk patients who completed neoadjuvant chemoradiotherapy underwent gross total tumor resection, 80% with negative margins. Intermediate‐/high‐risk group events included one local and seven metastatic recurrences. Had the FNCLCC grading system been used to direct treatment, 29% of low‐risk (surgery alone) patients would have received radiotherapy ± chemotherapy.ConclusionsMost low‐risk patients with completely resected POG low‐grade NRSTS are successfully treated with surgery alone, and surgical margins greater than 1 mm may be sufficient to prevent local recurrence. Patients with intermediate‐ and high‐risk low‐grade NRSTS have outcomes similar to patients with high‐grade histology, and require more effective therapies. Use of the current FNCLCC grading system may result in overtreatment of low‐risk NRSTS curable with surgery alone.

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“…Pazopanib is approved by the US Food and Drug Administration (USFDA) for patients with metastatic renal cell carcinoma and those with metastatic or locally advanced unresectable soft-tissue sarcoma (STS) who experienced progression after chemotherapy ( 7 ). Several trials in patients with localized high-risk extremity STS have also explored the utility of administering neoadjuvant pazopanib with preoperative radiation therapy (RT) with mixed results ( 8 , 9 ). The patient presented in the current study was consuming elderberry supplements when she started pazopanib.…”

Section: Introductionmentioning

confidence: 99%

Elderberry interaction with pazopanib in a patient with soft‑tissue sarcoma: A case report and literature review

Agarwal,

Mangla

2024

Mol Clin Oncol

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Elderberry flower extract is marketed as an herbal supplement with purported benefits in boosting the immune system. The use of elderberry increased during the coronavirus pandemic. However, the interaction of elderberry with cytotoxic medicines has remained elusive. Pazopanib is a multikinase inhibitor approved for patients diagnosed with soft-tissue sarcoma. The present study reported on the case of a middle-aged woman diagnosed with localized intermediate-grade sarcoma of the left sartorius muscle who received neoadjuvant pazopanib with radiation therapy. The patient had no other medical comorbidities and only took over-the-counter (OTC) elderberry supplements for numerous years to ‘boost’ her immune system. She started pazopanib at 400 mg per os (PO) daily, which was increased to 800 mg PO daily after a week. By week three on pazopanib, the patient reported intense nausea and a number of loose stools, requiring anti-nausea medication. By the fourth week on pazopanib, laboratory tests showed grade 3 liver injury, as demonstrated by a fivefold rise in liver enzymes along with severe nausea and loose stools. All medications, including elderberry supplement, were stopped. Within two weeks of stopping all medicines, the liver enzymes started normalizing within two weeks and were normal by the end of four weeks. Pazopanib treatment was resumed without the recurrence of side effect. Pazopanib is metabolized in the liver via the cytochrome P 450 (CYP)3A4 enzyme pathway. Hence, potent inhibitors of CYP3A4 are avoided for concurrent use with pazopanib. Small in vitro studies on elderberry extracts have shown weak inhibition of CYP3A4. However, considering the wide usage of elderberry and the availability of mixed supplements OTC, it is essential to pursue clinical studies in cancer patients to understand the interactions of elderberry extracts with cytotoxic medicines. In this report, the scientific evidence behind the use of elderberry was reviewed and a hypothesis of its interaction with pazopanib was proposed.

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Outcomes After Preoperative Chemoradiation With or Without Pazopanib in Non-Rhabdomyosarcoma Soft Tissue Sarcoma: A Report From Children's Oncology Group and NRG Oncology

Cited by 7 publications

References 15 publications

The Effect of chemo- and radiotherapy on tumor necrosis in soft tissue sarcoma– does it influence prognosis?

The Effect of chemo- and radiotherapy on tumor necrosis in soft tissue sarcoma– does it influence prognosis?

Clinical features and outcomes of young patients with low‐grade non‐rhabdomyosarcoma soft tissue sarcomas treated with a risk‐based strategy: A report from Children's Oncology Group study ARST0332

Elderberry interaction with pazopanib in a patient with soft‑tissue sarcoma: A case report and literature review

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