Publications by authors named "Nicole A Larrier"

14 Publications

  • Page 1 of 1

Extent of tumor fibrosis/hyalinization and infarction following neoadjuvant radiation therapy is associated with improved survival in patients with soft-tissue sarcoma.

Cancer Med 2022 01 27;11(1):194-206. Epub 2021 Nov 27.

Department of Orthopaedics, Duke University, Durham, North Carolina, USA.

Introduction: Current standard of care for most intermediate and high-grade soft-tissue sarcomas (STS) includes limb-preserving surgical resection with either neoadjuvant radiation therapy (NRT) or adjuvant radiation therapy. To date, there have been a few studies that attempt to correlate histopathologic response to NRT with oncologic outcomes in patients with STS.

Methods: Using our institutional database, we identified 58 patients who received NRT followed by surgical resection for primary intermediate or high-grade STS and 34 patients who received surgical resection without NRT but did receive adjuvant radiation therapy or did not receive any radiation therapy. We analyzed four histologic parameters of response to therapy: residual viable tumor, fibrosis/hyalinization, necrosis, and infarction (each ratiometrically determined). Data were stratified into two binary groups. Unadjusted, 5- and 10-year overall survival, and relapsed-free survival (RFS) were calculated using the Kaplan-Meier method.

Results: Analysis of pathologic characteristics showed that patients treated with NRT demonstrate significantly higher tumor infarction, higher tumor fibrosis/hyalinization, and a lower percent viable tumor compared with patients not treated with NRT (p < 0.0001). Based on Kaplan-Meier curve analysis and multivariate cox proportional hazard model for OS and RFS, patients treated with NRT and showing >12.5% tumor fibrosis/hyalinization have significantly higher overall survival and recurrence-free survival at 5 and 10 years.

Discussion And Conclusion: We have identified three histopathologic characteristics-fibrosis, hyalinization, and infarction-that may serve as predictive biomarkers of response to NRT for STS patients. Future prospective studies will be needed to confirm this association.
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http://dx.doi.org/10.1002/cam4.4428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8704179PMC
January 2022

Pediatric Hodgkin Lymphoma, Version 3.2021.

J Natl Compr Canc Netw 2021 06 30;19(6):733-754. Epub 2021 Jun 30.

26National Comprehensive Cancer Network.

Hodgkin lymphoma (HL) is a highly curable form of cancer, and current treatment regimens are focused on improving treatment efficacy while decreasing the risk of late effects of treatment. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for pediatric HL provide recommendations on the workup, diagnostic evaluation, and treatment of classic HL, including principles of pathology, imaging, staging, systemic therapy, and radiation therapy. This portion of the NCCN Guidelines focuses on the management of pediatric classic HL in the upfront and relapsed/refractory settings.
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http://dx.doi.org/10.6004/jnccn.2021.0027DOI Listing
June 2021

The Role of Radiotherapy for Chordoma Patients Managed With Surgery: Analysis of the National Cancer Database.

Spine (Phila Pa 1976) 2020 Jun;45(12):E742-E751

Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC.

Study Design: Retrospective review.

Objective: To determine if adjuvant radiation therapy (RT) improves overall survival (OS) following surgical resection of chordomas.

Summary Of Background Data: The role of RT for the treatment of chordomas remains incompletely described. Previous studies have not found adjuvant RT to improve OS, but these studies did not group patients based on surgical margin status or radiation dose or modality. We used the National Cancer Database to investigate the role of RT in chordomas following surgical resection.

Methods: Patients were stratified based on surgical margin status (positive vs. negative). Utilizing the Kaplan-Meier method, OS was compared between treatment modalities (surgical resection alone, therapeutic RT alone, and surgical resection plus therapeutic RT). OS was subsequently compared between patients treated with palliative dose (<40 Gy), low dose (40-65 Gy), and high dose (>65 Gy) RT. Similarly, OS was compared between advanced RT modalities including proton beam therapy (PBT) and intensity-modulated radiation therapy (IMRT), stereotactic radiosurgery (SRS), and external beam radiation therapy (EBRT). A multivariable model was used to determine adjusted variables predictive of mortality.

Results: One thousand four hundred seventy eight chordoma patients were identified; skull base (n = 567), sacral (n = 551), and mobile spine (n = 360). Surgical resection and therapeutic adjuvant RT improved 5-year survival in patients with positive surgical margins (82% vs. 71%, P = 0.03). No clear survival benefit was observed with the addition of adjuvant RT in patients with negative surgical margins. High dose RT was associated with improved OS compared with palliative and low dose RT (P < 0.001). Advanced RT techniques and SRS were associated with improved OS compared with EBRT. In the multivariate analysis high dose advanced RT (>65 Gy) was superior to EBRT.

Conclusion: Patients with positive surgical margins benefit from adjuvant RT. Optimal OS is associated with adjuvant RT administered with advanced techniques and cumulative dose more than 65 Gy.

Level Of Evidence: 4.
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http://dx.doi.org/10.1097/BRS.0000000000003406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649561PMC
June 2020

Revisiting the Role of Radiation Therapy in Chondrosarcoma: A National Cancer Database Study.

Sarcoma 2019 13;2019:4878512. Epub 2019 Oct 13.

Department of Orthopaedic Surgery, Duke University Medical Center, 2301 Erwin Rd, Durham, NC 27710, USA.

Background: Although chondrosarcomas (CS) are mostly considered radioresistant, advancements in radiotherapy have brought attention to its use in these patients. Using the largest registry of primary bone tumors, the National Cancer Database (NCDB), we sought to better characterize the current use of radiotherapy in CS patients and identify any potential survival benefit with higher radiation doses and advanced radiation therapies.

Methods: We retrospectively analyzed CS patients in the NCDB from 2004 to 2015 who underwent radiotherapy. The Kaplan-Meier method with statistical comparisons was used to identify which individual variables related to dosage and delivery modality were associated with improved 5-year survival rates. Multivariate proportional hazards analyses were performed to determine independent predictors of survival.

Results: Of 5,427 patients with a histologic diagnosis of chondrosarcoma, 680 received a form of radiation therapy (13%). The multivariate proportional hazards analysis controlling for various patient, tumor, and treatment variables, including RT dose and modality, demonstrated that while overall radiation therapy (RT) was not associated with improved survival (HR 0.96, 95% CI 0.76-1.20), when examining just the patient cohort with positive surgical margins, RT trended towards improved survival (HR 0.81, 95% CI 0.58-1.13). When comparing advanced and conventional RT modalities, advanced RT was associated with significantly decreased mortality (HR 0.55, 95% CI 0.38-0.80). However, advanced modality and high-dose RT both trended only toward improved survival compared to patients who did not receive any RT (HR 0.74, 95% CI 0.52-1.06 and HR 0.93, 95% CI 0.71-1.21, respectively).

Conclusions: Despite the suggested radioresistance of CS, modern radiotherapies may present a treatment option for certain patients. Our results support a role for high-dose, advanced radiation therapies in selected high-risk CS patients with tumors in surgically challenging locations or unplanned positive margins. While there is an associated survival rate benefit, further, prospective studies are needed for validation.
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http://dx.doi.org/10.1155/2019/4878512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815626PMC
October 2019

Multifocal iris melanoma in a 2-year-old managed with I-125 plaque brachytherapy.

J AAPOS 2017 Oct 26;21(5):410-412. Epub 2017 Aug 26.

Stanford University Medical Center Department of Ophthalmology, Palo Alto, California. Electronic address:

We report a 23-month-old patient presenting with multifocal iris melanoma who underwent plaque brachytherapy with full corneal coverage. The lesion demonstrated several high-risk clinical and histopathologic features associated with iris melanoma in adults, including growth and angle seeding. The patient has been subsequently followed for 3.5 years with no evidence of recurrence. This report demonstrates the importance of serial examination of suspected melanocytic iris lesions in very young children and the effective treatment option of globe-sparing radiation therapy.
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http://dx.doi.org/10.1016/j.jaapos.2017.03.014DOI Listing
October 2017

Radiation Therapy for Soft Tissue Sarcoma: Indications and Controversies for Neoadjuvant Therapy, Adjuvant Therapy, Intraoperative Radiation Therapy, and Brachytherapy.

Surg Oncol Clin N Am 2016 10 6;25(4):841-60. Epub 2016 Aug 6.

Department of Radiation Oncology, Duke University Medical Center, 450 Research Drive, Durham, NC 27708, USA; Department of Pharmacology & Cancer Biology, Duke University Medical Center, 450 Research Drive, Durham, NC 27708, USA. Electronic address:

Soft tissue sarcomas are rare mesenchymal cancers that pose a treatment challenge. Although small superficial soft tissue sarcomas can be managed by surgery alone, adjuvant radiotherapy in addition to limb-sparing surgery substantially increases local control of extremity sarcomas. Compared with postoperative radiotherapy, preoperative radiotherapy doubles the risk of a wound complication, but decreases the risk for late effects, which are generally irreversible. For retroperitoneal sarcomas, intraoperative radiotherapy can be used to safely escalate the radiation dose to the tumor bed. Patients with newly diagnosed sarcoma should be evaluated before surgery by a multidisciplinary team that includes a radiation oncologist.
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http://dx.doi.org/10.1016/j.soc.2016.05.012DOI Listing
October 2016

A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer.

Sci Transl Med 2016 Jan;8(320):320ra4

Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC 27710, USA.

Local recurrence is a common cause of treatment failure for patients with solid tumors. Intraoperative detection of microscopic residual cancer in the tumor bed could be used to decrease the risk of a positive surgical margin, reduce rates of reexcision, and tailor adjuvant therapy. We used a protease-activated fluorescent imaging probe, LUM015, to detect cancer in vivo in a mouse model of soft tissue sarcoma (STS) and ex vivo in a first-in-human phase 1 clinical trial. In mice, intravenous injection of LUM015 labeled tumor cells, and residual fluorescence within the tumor bed predicted local recurrence. In 15 patients with STS or breast cancer, intravenous injection of LUM015 before surgery was well tolerated. Imaging of resected human tissues showed that fluorescence from tumor was significantly higher than fluorescence from normal tissues. LUM015 biodistribution, pharmacokinetic profiles, and metabolism were similar in mouse and human subjects. Tissue concentrations of LUM015 and its metabolites, including fluorescently labeled lysine, demonstrated that LUM015 is selectively distributed to tumors where it is activated by proteases. Experiments in mice with a constitutively active PEGylated fluorescent imaging probe support a model where tumor-selective probe distribution is a determinant of increased fluorescence in cancer. These co-clinical studies suggest that the tumor specificity of protease-activated imaging probes, such as LUM015, is dependent on both biodistribution and enzyme activity. Our first-in-human data support future clinical trials of LUM015 and other protease-sensitive probes.
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http://dx.doi.org/10.1126/scitranslmed.aad0293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794335PMC
January 2016

Practical radiation oncology for extremity sarcomas.

Surg Oncol Clin N Am 2013 Jul 13;22(3):433-43. Epub 2013 Mar 13.

Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27708, USA.

Soft tissue sarcomas are rare cancers. They should be managed by a multidisciplinary team with experience caring for these diverse malignancies. Local control is frequently achieved with a combination of radiation therapy and surgery. This article reviews the data supporting the role of adjuvant radiotherapy in the care of patients with soft tissue sarcoma and describes the side effects of surgery and radiation therapy. Preoperative radiation therapy increases the risk of wound complication from surgery, but has fewer long-term side effects than postoperative radiation therapy. The timing of radiation therapy can be tailored to each patient.
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http://dx.doi.org/10.1016/j.soc.2013.02.004DOI Listing
July 2013

An image-guided technique for planning and verification of supine craniospinal irradiation.

J Appl Clin Med Phys 2011 Jan 31;12(2):3310. Epub 2011 Jan 31.

Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.

We present a technique for planning and verification of craniospinal treatment with the patient in the supine position. Treatment delivery and verification is streamlined through the use of modern imaging techniques. Treatments use two lateral brain fields abutted to a single or pair of posterior spine fields. Treatment delivery is simplified by aligning all isocenters in the anterior-posterior and lateral directions. Patient positioning is accomplished via on-board kV imaging. Verification of field shape and junctions is accomplished with BB placement and MV portal imaging. Daily treatment is simplified by using only longitundinal couch shifts, which are recorded in the patient chart and RV database. The technique is simple to implement in a clinic that is already using a similar beam arrangement with the patient prone. It requires no additional devices to be fabricated (for immobilization or QA), and it takes advantage of all the existing elements of a modern linac.
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http://dx.doi.org/10.1120/jacmp.v12i2.3310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718685PMC
January 2011

Renal shielding and dosimetry for patients with severe systemic sclerosis receiving immunoablation with total body irradiation in the scleroderma: cyclophosphamide or transplantation trial.

Int J Radiat Oncol Biol Phys 2011 Mar 26;79(4):1248-55. Epub 2010 Aug 26.

Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.

Purpose: To describe renal shielding techniques and dosimetry in delivering total body irradiation (TBI) to patients with severe systemic sclerosis (SSc) enrolled in a hematopoietic stem cell transplant protocol.

Methods And Materials: The Scleroderma: Cyclophosphamide or Transplantation (SCOT) protocol uses a lymphoablative preparative regimen including 800 cGy TBI delivered in two 200-cGy fractions twice a day before CD34(+) selected autologous hematopoietic stem cell transplantation. Lung and kidney doses are limited to 200 cGy to protect organs damaged by SSc. Kidney block proximity to the spinal cord was investigated, and guidelines were developed for acceptable lumbar area TBI dosing. Information about kidney size and the organ shifts from supine to standing positions were recorded using diagnostic ultrasound (US). Minimum distance between the kidney blocks (dkB) and the lumbar spine region dose was recorded, and in vivo dosimetry was performed at several locations to determine the radiation doses delivered.

Results: Eleven patients were treated at our center with an anteroposterior (AP)/posteroanterior (PA) TBI technique. A 10% to 20% dose inhomogeneity in the lumbar spine region was achieved with a minimum kidney block separation of 4 to 5 cm. The average lumbar spine dose was 179.6 ± 18.1 cGy, with an average dkB of 5.0 ± 1.0 cm. Kidney block shield design was accomplished using a combination of US and noncontrast computerized tomography (CT) or CT imaging alone. The renal US revealed a wide range of kidney displacement from upright to supine positions. Overall, the average in vivo dose for the kidney prescription point was 193.4 ± 5.1 cGy.

Conclusions: The dose to the kidneys can be attenuated while maintaining a 10% to 20% dose inhomogeneity in the lumbar spine area. Kidneys were localized more accurately using both US and CT imaging. With this technique, renal function has been preserved, and the study continues to enroll patients.
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http://dx.doi.org/10.1016/j.ijrobp.2010.05.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2995833PMC
March 2011

Stereotactic body radiotherapy for lesions of the spine and paraspinal regions.

Int J Radiat Oncol Biol Phys 2009 Apr 10;73(5):1369-75. Epub 2008 Nov 10.

Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.

Purpose: To describe our experience and clinical strategy for stereotactic body radiotherapy (SBRT) of spinal lesions.

Methods And Materials: Thirty-two patients with 33 spinal lesions underwent computed tomography-based simulation while free breathing. Gross/clinical target volumes included involved portions of the vertebral body and paravertebral/epidural tumor. Planning target volume (PTV) expansion was 6 mm axially and 3 mm radially; the cord was excluded from the PTV. Biologic equivalent dose was calculated using the linear quadratic model with alpha/beta = 3 Gy. Treatment was linear accelerator based with on-board imaging; dose was adjusted to maintain cord dose within tolerance. Survival, local control, pain, and neurologic status were monitored.

Results: Twenty-one patients are alive at 1 year (median survival, 14 months). Median follow-up is 6 months for all patients (7 months for survivors). Mean previous radiotherapy dose to 22 patients was 35 Gy, and median interval was 17 months. Renal (31%), breast, and lung (19% each) were the most common histologic sites. Three SBRT fractions (range, one to four fractions) of 7 Gy (range, 5-16 Gy) were delivered. Median cord and target biologic equivalent doses were 70 Gy(3) and 34.3 Gy(10), respectively. Thirteen patients reported complete and 17 patients reported partial pain relief at 1 month. There were four failures (mean, 5.8 months) with magnetic resonance imaging evidence of in-field progression. No dosimetric parameters predictive of failure were identified. No treatment-related toxicity was seen.

Conclusions: Spinal SBRT is effective in the palliative/re-treatment setting. Volume expansion must ensure optimal PTV coverage while avoiding spinal cord toxicity. The long-term safety of spinal SBRT and the applicability of the linear-quadratic model in this setting remain to be determined, particularly the time-adjusted impact of prior radiotherapy.
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http://dx.doi.org/10.1016/j.ijrobp.2008.06.1949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677601PMC
April 2009

Intensity-modulated radiotherapy for resected mesothelioma: the Duke experience.

Int J Radiat Oncol Biol Phys 2008 Jul 8;71(4):1143-50. Epub 2008 Feb 8.

Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.

Purpose: To assess the safety and efficacy of intensity-modulated radiotherapy (IMRT) after extrapleural pneumonectomy for malignant pleural mesothelioma.

Methods And Materials: Thirteen patients underwent IMRT after extrapleural pneumonectomy between July 2005 and February 2007 at Duke University Medical Center. The clinical target volume was defined as the entire ipsilateral hemithorax, chest wall incisions, including drain sites, and involved nodal stations. The dose prescribed to the planning target volume was 40-55 Gy (median, 45). Toxicity was graded using the modified Common Toxicity Criteria, and the lung dosimetric parameters from the subgroups with and without pneumonitis were compared. Local control and survival were assessed.

Results: The median follow-up after IMRT was 9.5 months. Of the 13 patients, 3 (23%) developed Grade 2 or greater acute pulmonary toxicity (during or within 30 days of IMRT). The median dosimetric parameters for those with and without symptomatic pneumonitis were a mean lung dose (MLD) of 7.9 vs. 7.5 Gy (p = 0.40), percentage of lung volume receiving 20 Gy (V(20)) of 0.2% vs. 2.3% (p = 0.51), and percentage of lung volume receiving 5 Gy (V(20)) of 92% vs. 66% (p = 0.36). One patient died of fatal pulmonary toxicity. This patient received a greater MLD (11.4 vs. 7.6 Gy) and had a greater V(20) (6.9% vs. 1.9%), and V(5) (92% vs. 66%) compared with the median of those without fatal pulmonary toxicity. Local and/or distant failure occurred in 6 patients (46%), and 6 patients (46%) were alive without evidence of recurrence at last follow-up.

Conclusions: With limited follow-up, 45-Gy IMRT provides reasonable local control for mesothelioma after extrapleural pneumonectomy. However, treatment-related pulmonary toxicity remains a significant concern. Care should be taken to minimize the dose to the remaining lung to achieve an acceptable therapeutic ratio.
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http://dx.doi.org/10.1016/j.ijrobp.2007.11.011DOI Listing
July 2008

The impact of induction chemotherapy and the associated tumor response on subsequent radiation-related changes in lung function and tumor response.

Int J Radiat Oncol Biol Phys 2007 Apr 2;67(5):1360-9. Epub 2007 Feb 2.

Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.

Purpose: To assess the impact of induction chemotherapy, and associated tumor shrinkage, on the subsequent radiation-related changes in pulmonary function and tumor response.

Methods And Materials: As part of a prospective institutional review board-approved study, 91 evaluable patients treated definitively with thoracic radiation therapy (RT) for unresectable lung cancer were analyzed. The rates of RT-associated pulmonary toxicity and tumor response were compared in the patients with and without pre-RT chemotherapy. In the patients receiving induction chemotherapy, the rates of RT-associated pulmonary toxicity and tumor response were compared in the patients with and without a response (modified Response Evaluation Criteria in Solid Tumor criteria) to the pre-RT chemotherapy. Comparisons of the rates of improvements in pulmonary function tests (PFTs) post-RT, dyspnea requiring steroids, and percent declines in PFTs post-RT were compared in patient subgroups using Fisher's exact test, analysis of variance, and linear or logistic regression.

Results: The use of pre-RT chemotherapy appears to increase the rate of radiation-induced pneumonitis (p = 0.009-0.07), but has no consistent impact on changes in PFTs. The degree of induction chemotherapy-associated tumor shrinkage is not associated with the rate of subsequent RT-associated pulmonary toxicity. The degree of tumor response to chemotherapy is not related to the degree of tumor response to RT.

Conclusions: Additional study is needed to better clarify the impact of chemotherapy on radiation-associated disfunction.
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http://dx.doi.org/10.1016/j.ijrobp.2006.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1950850PMC
April 2007

What radiation dose is safe in patients with non-small-cell lung cancer?

Nat Clin Pract Oncol 2007 Feb 16;4(2):80-1. Epub 2007 Jan 16.

Department of Radiation Oncology, Duke University Medical Center, Box 3085, Durham, NC 27710, USA.

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http://dx.doi.org/10.1038/ncponc0689DOI Listing
February 2007
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