Publications by authors named "April K S Salama"

42 Publications

Ipilimumab and Radiation in Patients with High-risk Resected or Regionally Advanced Melanoma.

Clin Cancer Res 2021 Mar 10;27(5):1287-1295. Epub 2020 Nov 10.

Department of Radiation Oncology, Duke University, Durham, North Carolina.

Purpose: In this prospective trial, we sought to assess the feasibility of concurrent administration of ipilimumab and radiation as adjuvant, neoadjuvant, or definitive therapy in patients with regionally advanced melanoma.

Patients And Methods: Twenty-four patients in two cohorts were enrolled and received ipilimumab at 3 mg/kg every 3 weeks for four doses in conjunction with radiation; median dose was 4,000 cGy (interquartile range, 3,550-4,800 cGy). Patients in cohort 1 were treated adjuvantly; patients in cohort 2 were treated either neoadjuvantly or as definitive therapy.

Results: Adverse event profiles were consistent with those previously reported with checkpoint inhibition and radiation. For the neoadjuvant/definitive cohort, the objective response rate was 64% (80% confidence interval, 40%-83%), with 4 of 10 evaluable patients achieving a radiographic complete response. An additional 3 patients in this cohort had a partial response and went on to surgical resection. With 2 years of follow-up, the 6-, 12-, and 24-month relapse-free survival for the adjuvant cohort was 85%, 69%, and 62%, respectively. At 2 years, all patients in the neoadjuvant/definitive cohort and 10/13 patients in the adjuvant cohort were still alive. Correlative studies suggested that response in some patients were associated with specific CD4 T-cell subsets.

Conclusions: Overall, concurrent administration of ipilimumab and radiation was feasible, and resulted in a high response rate, converting some patients with unresectable disease into surgical candidates. Additional studies to investigate the combination of radiation and checkpoint inhibitor therapy are warranted.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2452DOI Listing
March 2021

The utility of initial staging PET-CT as a baseline scan for surveillance imaging in stage II and III melanoma.

Surg Oncol 2020 Dec 2;35:533-539. Epub 2020 Nov 2.

Department of Surgery, Duke University Medical Center, Durham, NC, USA. Electronic address:

Background: This study evaluates the utility of whole-body PET-CT for the initial staging and subsequent surveillance imaging of patients with completely resected stage II and stage III melanoma.

Methods: A single-center, retrospective review of patients who received perioperative whole-body PET-CT from January 1, 2005 to December 1, 2019 within three months of initial melanoma diagnosis was performed.

Results: Of 258 total patients with completely resected melanoma who had a PET-CT within 3 months after their melanoma diagnosis, 113 had stage II and 145 had stage III melanoma. PET-CT detected distant metastasis in 3 (2.7%) of 113 stage II patients and 7 (4.8%) of 145 stage III patients. 179 of 258 patients had adequate follow-up time to determine whether they received surveillance cross-sectional imaging and whether they had a melanoma recurrence. 143 (79.9%) received subsequent surveillance imaging, 74 of whom developed a recurrence. In 64 (86.5%) of 74 cases, recurrence was detected by routine surveillance. 26 (34.2%) of 76 stage II and 65 (63.1%) of 103 stage III patients developed a recurrence. The median time to recurrence among the 179 patients for stage II and III was 16.3 and 13.0 months, respectively.

Conclusions: These findings indicate that baseline staging with whole-body PET-CT rarely provides information that changes initial management. Rather, the value of the initial PET-CT is as a baseline for subsequent surveillance scans. Therefore, it may be premature to discourage cross-sectional imaging for patients with stage II and III melanoma without supportive evidence or a reliable biomarker of recurrent disease.
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http://dx.doi.org/10.1016/j.suronc.2020.10.018DOI Listing
December 2020

Higher BMI, But Not Sarcopenia, Is Associated With Pembrolizumab-related Toxicity in Patients With Advanced Melanoma.

Anticancer Res 2020 Sep;40(9):5245-5254

Department of Surgery, Duke University Medical Center, Durham, NC, U.S.A.

Background/aim: To determine whether BMI and sarcopenia were related to treatment-limiting toxicity or efficacy of pembrolizumab treatment in melanoma patients.

Patients And Methods: Medical records for melanoma patients undergoing pembrolizumab treatment at Duke University from January 2014 to September 2018 were reviewed. Pre-treatment measurements such as BMI were collected. Pre-treatment CT imaging was used to determine psoas muscle index (PMI). Patients in the lowest sex-specific tertile of PMI were sarcopenic. Logistic regression measured associations with treatment toxicity and response. Kaplan-Meier analysis assessed progression-free survival (PFS) and overall survival (OS).

Results: Among 156 patients, the overall objective response rate was 46.2% and 29 patients (18.6%) experienced treatment-limiting toxicity. Sarcopenia was not significantly associated with toxicity, response, or survival. However, obese patients (BMI >30) experienced higher rates of toxicity (p=0.0007).

Conclusion: Sarcopenia did not appear to predict clinically relevant outcomes. Obesity, however, represents a readily available predictor of pembrolizumab toxicity.
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http://dx.doi.org/10.21873/anticanres.14528DOI Listing
September 2020

Dabrafenib and Trametinib in Patients With Tumors With Mutations: Results of the NCI-MATCH Trial Subprotocol H.

J Clin Oncol 2020 11 6;38(33):3895-3904. Epub 2020 Aug 6.

Massachusetts General Hospital, Boston, MA.

Purpose: mutations are commonly found in melanoma and thyroid cancers and to a lesser degree in other tumor types. Subprotocol H (EAY131-H) of the NCI-MATCH platform trial sought to investigate the selective BRAF inhibitor dabrafenib and the MEK1/2 inhibitor trametinib in patients with solid tumors, lymphomas, or multiple myeloma whose tumors harbored a mutation.

Patients And Methods: EAY131-H is an open-label, single-arm study. Patients with melanoma, thyroid, or colorectal cancer were excluded; patients with non-small-cell lung cancer were later excluded in an amendment. Patients received dabrafenib 150 mg twice per day and trametinib 2 mg per day continuously until disease progression or intolerable toxicity. The primary end point was centrally assessed objective response rate (ORR); secondary end points included progression-free survival (PFS), 6-month PFS, and overall survival.

Results: Thirty-five patients were enrolled, and 29 were included in the primary efficacy analysis as prespecified in the protocol. Median age was 59 years, and 45% of the patients had received ≥ 3 lines of therapy. The confirmed ORR was 38% (90% CI, 22.9% to 54.9%) with < .0001 against a null rate of 5%, and PFS was 11.4 months (90% CI, 8.4 to 16.3 months); responses were seen in 7 distinct tumor types. Seven patients had a duration of response of > 12 months, including 4 patients with a duration of response of > 24 months. An additional 8 patients had a PFS > 6 months. The median overall survival was 28.6 months. Reported adverse events were comparable to those noted in previously reported profiles of dabrafenib and trametinib.

Conclusion: This study met its primary end point, with an ORR of 38% ( < .0001) in this mixed histology, pretreated cohort. This promising activity warrants additional investigations in -mutated tumors outside of currently approved indications.
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http://dx.doi.org/10.1200/JCO.20.00762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676884PMC
November 2020

Overall Survival Improved for Contemporary Patients with Melanoma: A 2004-2015 National Cancer Database Analysis.

Oncol Ther 2020 Dec 28;8(2):261-275. Epub 2020 May 28.

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

Introduction: Since 2011, encouraging clinical trial results have led to approval of multiple new therapies for advanced melanoma, but the impact of these therapies outside of trial populations is largely unknown. This study examines use of novel therapies and survival in contemporary patients with melanoma.

Methods: Stage I-IV melanoma patients were identified in the 2004-2015 National Cancer Database and grouped into historic (2004-2010) and contemporary (2011-2015) cohorts. Overall survival (OS) was compared using Kaplan-Meier and Cox proportional hazard modeling adjusting for patient, tumor, and facility characteristics.

Results: Of 268,668 patients, 136,828 were classified as historic and 131,840 as contemporary. Among all stages, immunotherapy utilization was significantly higher among contemporary patients (5.3% vs. 5.1%, p = 0.006). Adjusted OS was improved in the contemporary cohort (hazard ratio [HR]: 0.90 p < 0.001). There was no difference in OS among stage I/II patients between groups (HR: 0.99, p = 0.63), while OS was significantly improved for contemporary stage III/IV patients (HR: 0.85, p < 0.001). Among stage III/IV patients who received immunotherapy, OS was improved for the contemporary cohort (HR: 0.87, p = 0.014).

Conclusions: Adjusted overall survival for contemporary melanoma patients is improved. This effect is driven by improvements for those with advanced stage disease, particularly those that received immunotherapy and BRAF/MEK targeted therapies.
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http://dx.doi.org/10.1007/s40487-020-00117-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683754PMC
December 2020

A Review of Immune-Mediated Adverse Events in Melanoma.

Oncol Ther 2019 Dec 8;7(2):101-120. Epub 2019 Jul 8.

Division of Medical Oncology, Duke University, Durham, NC, USA.

The use of checkpoint inhibitor-based immunotherapy has transformed the treatment landscape for melanoma as well as many other cancer types. With the ability to potentiate tumor-specific immune responses, these agents can result in durable tumor control. However, this activation of the immune system can lead to a unique constellation of side effects, distinct from other cancer therapies, collectively termed immune-mediated adverse events (irAEs). This review will focus on irAEs and guidelines for management related to the most clinically relevant checkpoint inhibitors, those that target programmed death receptor-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4).
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http://dx.doi.org/10.1007/s40487-019-0096-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359990PMC
December 2019

Mind the gap: Gendered publication trends in oncology.

Cancer 2020 Jun 25;126(12):2859-2865. Epub 2020 Mar 25.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: Investigating scientific publication trends in the field of oncology may highlight opportunities for improved representation, mentorship, collaboration, and advancement for women.

Methods: We conducted a bibliometric analysis of Annals of Surgical Oncology; Cancer; International Journal of Radiation Oncology, Biology, Physics (IJROBP); JAMA Oncology; and Journal of Clinical Oncology in 1990, 2000, 2010, and 2017. Full name and degree credentials per author role (ie, first or senior author), article type, publication year, and citation metrics were collected. First names were used to identify author gender.

Results: Across 9189 articles, female representation rose between 1990 and 2017 (first authors: 17.7% in 1990, 36.6% in 2017; senior authors: 11.7% in 1990, 28.5% in 2017). For the 50 most cited articles per year, women comprised a smaller percent of first (26.5%) and senior (19.9%) authors. The average citation count was higher for male first (44.8 per article) and senior (47.1) authors compared to female first (39.7) and senior (44.1) authors. With male senior authors, the first author was more likely male (71.4% male; 25.0% female); with female senior authors, first authors were 50.2% male and 47.6% female. IJROBP had the lowest total female representation among first (25.1%) and senior (16.7%) authors. Women had more MDs with Masters degrees, whereas men held more MDs only and more MDs with PhDs.

Conclusion: Despite positive trends, substantial gendered differences in oncology publications persist. Fostering more women in oncology research will benefit female representation at many levels of academia and improve productivity, collaboration, and recruitment, especially in technical fields such as radiation and surgical oncology.
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http://dx.doi.org/10.1002/cncr.32818DOI Listing
June 2020

Current multidisciplinary management of brain metastases.

Cancer 2020 04 23;126(7):1390-1406. Epub 2020 Jan 23.

Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.

Brain metastasis (BM), the most common adult brain tumor, develops in 20% to 40% of patients with late-stage cancer and traditionally are associated with a poor prognosis. The management of patients with BM has become increasingly complex because of new and emerging systemic therapies and advancements in radiation oncology and neurosurgery. Current therapies include stereotactic radiosurgery, whole-brain radiation therapy, surgical resection, laser-interstitial thermal therapy, systemic cytotoxic chemotherapy, targeted agents, and immune-checkpoint inhibitors. Determining the optimal treatment for a specific patient has become increasingly individualized, emphasizing the need for multidisciplinary discussions of patients with BM. Recognizing and addressing the sequelae of BMs and their treatment while maintaining quality of life and neurocognition is especially important because survival for patients with BMs has improved. The authors present current and emerging treatment options for patients with BM and suggest approaches for managing sequelae and disease recurrence.
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http://dx.doi.org/10.1002/cncr.32714DOI Listing
April 2020

A review of cancer immunotherapy toxicity.

CA Cancer J Clin 2020 03 16;70(2):86-104. Epub 2020 Jan 16.

Division of Medical Oncology, Duke University, Durham, North Carolina.

Cancer immunotherapies, including checkpoint inhibitors and adoptive cell therapy, manipulate the immune system to recognize and attack cancer cells. These therapies have the potential to induce durable responses in multiple solid and hematologic malignancies and thus have transformed treatment algorithms for numerous tumor types. Cancer immunotherapies lead to unique toxicity profiles distinct from the toxicities of other cancer therapies, depending on their mechanism of action. These toxicities often require specific management, which can include steroids and immune-modulating therapy and for which consensus guidelines have been published. This review will focus on the toxicities of checkpoint inhibitors and chimeric antigen receptor T cells, including pathophysiology, diagnosis, and management.
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http://dx.doi.org/10.3322/caac.21596DOI Listing
March 2020

Operative and peri-operative considerations in the management of brain metastasis.

Cancer Med 2019 11 30;8(16):6809-6831. Epub 2019 Sep 30.

Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA.

The number of patients who develop metastatic brain lesions is increasing as the diagnosis and treatment of systemic cancers continues to improve, resulting in longer patient survival. The role of surgery in the management of brain metastasis (BM), particularly multiple and recurrent metastases, remains controversial and continues to evolve. However, with appropriate patient selection, outcomes after surgery are typically favorable. In addition, surgery is the only means to obtain a tissue diagnosis and is the only effective treatment modality to quickly relieve neurological complications or life-threatening symptoms related to significant mass effect, CSF obstruction, and peritumoral edema. As such, a thorough understanding of the role of surgery in patients with metastatic brain lesions, as well as the factors associated with surgical outcomes, is essential for the effective management of this unique and growing patient population.
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http://dx.doi.org/10.1002/cam4.2577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853809PMC
November 2019

Retrospective analysis of safety and efficacy of anti-PD-1 therapy and radiation therapy in advanced melanoma: A bi-institutional study.

Radiother Oncol 2019 09 25;138:114-120. Epub 2019 Jun 25.

Department of Medicine, Duke University Medical Center, Durham, United States. Electronic address:

Background And Purpose: Antibodies against programmed cell death protein 1 (PD-1) are standard treatments for advanced melanoma. Palliative radiation therapy (RT) is commonly administered for this disease. Safety and optimal timing for this combination for melanoma has not been established.

Materials And Methods: In this retrospective cohort study, records for melanoma patients who received anti-PD-1 therapy at Duke University or Emory University (1/1/2013-12/30/2015) were reviewed. Patients were categorized by receipt of RT and RT timing relative to anti-PD-1.

Results: 151 patients received anti-PD-1 therapy. Median follow-up was 12.9 months. Patients receiving RT (n = 85) had worse baseline prognostic factors than patients without RT (n = 66). One-year overall survival (OS) was lower for RT patients than patients without RT (66%, 95% CI: 55-77% vs 83%, 95% CI: 73-92%). One-year OS was 61% for patients receiving RT before anti-PD-1 (95% CI: 46-76%), 78% for RT during anti-PD-1 (95% CI: 60-95%), and 58% for RT after anti-PD-1 (95% CI: 26-89%). On Cox regression, OS for patients without RT did not differ significantly from patients receiving RT during anti-PD-1 (HR 1.07, 95% CI: 0.41-2.84) or RT before anti-PD-1 (HR 0.56, 95% CI: 0.21-1.45). RT and anti-PD-1 therapy administered within 6 weeks of each other was well tolerated.

Conclusion: RT can be safely administered with anti-PD-1 therapy. Despite worse baseline prognostic characteristics for patients receiving RT, OS was similar for patients receiving concurrent RT with anti-PD-1 therapy compared to patients receiving anti-PD-1 therapy alone.
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http://dx.doi.org/10.1016/j.radonc.2019.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566286PMC
September 2019

Clinical and laboratory features of autoimmune hemolytic anemia associated with immune checkpoint inhibitors.

Am J Hematol 2019 05 13;94(5):563-574. Epub 2019 Mar 13.

Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

Immune checkpoint inhibitors (ICPis) are a novel class of immunotherapeutic agents that have revolutionized the treatment of cancer; however, these drugs can also cause a unique spectrum of autoimmune toxicity. Autoimmune hemolytic anemia (AIHA) is a rare, but often severe, complication of ICPis. We identified 14 patients from nine institutions across the United States who developed ICPi-AIHA. The median interval from ICPi initiation to development of AIHA was 55 days (interquartile range [IQR], 22-110 days). Results from the direct antiglobulin test (DAT) were available for 13 of 14 patients: 8 patients (62%) had a positive DAT and 5 (38%) had a negative DAT. The median pretreatment and nadir hemoglobin concentrations were 11.8 g/dL (IQR, 10.2-12.9 g/dL) and 6.3 g/dL (IQR, 6.1-8.0 g/dL), respectively. Four patients (29%) had a preexisting lymphoproliferative disorder, and two (14%) had a positive DAT prior to initiation of ICPi therapy. All patients were treated with glucocorticoids, with three requiring additional immunosuppressive therapy. Complete and partial recoveries of hemoglobin were achieved in 12 (86%) and 2 (14%) patients, respectively. Seven patients (50%) were rechallenged with ICPis, and one (14%) developed recurrent AIHA. Clinical and laboratory features of ICPi-AIHA were similar in DAT positive and negative patients. ICPi-AIHA shares many clinical features with primary AIHA; however, a unique aspect of ICPi-AIHA is a high incidence of DAT negativity. Glucocorticoids are an effective first-line treatment in the majority of patients with ICPi-AIHA, and most patients who are rechallenged with an ICPi do not appear to develop recurrence of AIHA.
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http://dx.doi.org/10.1002/ajh.25448DOI Listing
May 2019

The Emerging Role of Surgery for Patients With Advanced Melanoma Treated With Immunotherapy.

J Surg Res 2019 04 20;236:209-215. Epub 2018 Dec 20.

Department of Surgery, Duke University, Durham, North Carolina.

Background: The emergence of immune checkpoint inhibitors (ICIs) has improved survival for patients with metastatic melanoma. The types of disease-response patterns to ICI therapy can be more complex relative to traditional chemotherapy and include mixed responses, pseudoprogression, and oligoprogression. The potential benefit of surgery after incomplete response to ICI therapy has not been explored. The purpose of this study was to explore outcomes of surgery after ICI therapy in patients with metastatic melanoma.

Methods: A retrospective study was conducted at two centers and included patients with melanoma who underwent surgery after treatment with monotherapy or combination therapy with anti-programmed cell death protein (PD) 1 and/or anti-cytotoxic T-lymphocyte associated protein (CTLA)-4 checkpoint blockade.

Results: Of 25 patients, nine received anti-CTLA-4 therapy, eight received anti-PD-1 therapy, and eight received both anti-CTLA-4 and anti-PD-1 therapies before surgery. Five patients were treated in the adjuvant setting and developed new lesions, whereas 20 patients were treated for metastatic disease and underwent surgery for persistent disease on imaging after ICI therapy. Twenty-five patients underwent 30 operations without complications. Twenty-seven of 30 masses were confirmed to be melanoma on pathology, one was a desmoid tumor and two were necrosis. At a median follow-up of 14.2 months, 2 patients died, 8 were alive with a known disease, and 15 continued to have no further evidence of disease.

Conclusions: Surgery was well tolerated in this cohort of patients receiving ICI therapy for melanoma. Surgery may benefit select patients with an oligoprogressive disease after ICI therapy. After a mixed response, surgery remains the only definitive method to render some patients free of disease.
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http://dx.doi.org/10.1016/j.jss.2018.11.045DOI Listing
April 2019

Updates in adjuvant systemic therapy for melanoma.

J Surg Oncol 2019 Jan 27;119(2):222-231. Epub 2018 Nov 27.

Department of Surgery, Duke University, Durham, North Carolina.

There has been a rapid increase in adjuvant therapies approved for treatment following surgical resection of stages III/IV melanoma. We review current indications for adjuvant therapy, which currently includes a heterogenous group of stages III and IV patients with melanoma. We describe several pivotal clinical trials of systemic immune therapies, targeted immune therapies, and adjuvant vaccine strategies. Finally, we discuss the evidence for selecting the most appropriate treatment regimen(s) for the individual patient.
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http://dx.doi.org/10.1002/jso.25298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330126PMC
January 2019

Checkpoint inhibitor use in two heart transplant patients with metastatic melanoma and review of high-risk populations.

Melanoma Manag 2018 Dec 26;5(4):MMT10. Epub 2018 Oct 26.

Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.

Due to the unique side-effect profile of immune checkpoint inhibitors (ICIs), groups of patients deemed to be at high risk of complications were excluded from trials that proved the efficacy and safety of these agents in patients with various malignancies. Among these excluded patients were those with prior solid organ transplantation, chronic viral infections and pre-existing autoimmune diseases including paraneoplastic syndromes. We present follow-up on a patient from a previously published case report with an orthotopic heart transplantation who was treated with both cytotoxic T-lymphocyte antigen 4 and PD-1 inhibition safely, without organ rejection. Additionally, we describe the case of a patient with a cardiac allograft who also did not experience organ rejection after treatment with pembrolizumab. Through smaller trials, retrospective analyses, case series and individual case reports, we are accumulating initial data on how these agents are tolerated by the aforementioned groups. Our survey of the literature has found more evidence of organ transplant rejection in patients treated with PD-1 inhibitors than those treated with inhibitors of cytotoxic T-lymphocyte antigen 4. Patients with chronic viral infections, especially hepatitis C, seem to have little to no risk of treatment-related increase in serum RNA levels. The literature contains few documented cases of devastating exacerbations of pre-existing autoimmune disease during treatment with ICIs, and flares seem to be easily controlled by immunosuppression in the vast majority of cases. Last, several cases allude to a promising role for disease-specific antibodies and other serum biomarkers in identifying patients at high risk of developing certain immune-related adverse events, detecting subclinical immune-related adverse event onset, and monitoring treatment response to immunosuppressive therapy in patients treated with ICIs. Though these excluded populations have not been well studied in randomized placebo-controlled trials, we may be able to learn and derive hypotheses from the existing observational data in the literature.
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http://dx.doi.org/10.2217/mmt-2018-0004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240846PMC
December 2018

Delayed onset of neurosarcoidosis after concurrent ipilimumab/nivolumab therapy.

J Immunother Cancer 2018 07 31;6(1):77. Epub 2018 Jul 31.

Division of Medical Oncology, Duke University Medical Center, 2301 Erwin Rd, Durham, NC, 27701, USA.

Background: Immune checkpoint inhibitors have transformed the treatment landscape for many cancers, including metastatic melanoma, but have also opened the door for a diverse variety of immune-related adverse effects.

Case Presentation: We describe the first reported case of presumed neurosarcoidosis as an immune-related adverse effect that developed nearly a year after discontinuation of treatment with combination ipilimumab and nivolumab for recurrent metastatic melanoma. The patient was noted to develop clinical signs consistent with systemic sarcoidosis shortly after the initiation of treatment and underwent a biopsy of hilar lymphadenopathy that confirmed sarcoidosis and after which immunotherapy was discontinued. His melanoma remained stable on surveillance imaging for the next year after which time he developed neurological symptoms and was found to have MRI brain abnormalities without evidence of intracranial metastatic disease, consistent with probable neurosarcoidosis given biopsy-proven systemic sarcoidosis and lack of evidence of CNS infection or malignancy. He underwent treatment with high dose steroids, followed by infliximab, and then methotrexate with both clinical and radiographic improvement within 4 months of starting treatment.

Conclusions: Immune-related adverse effects often occur within 3-6 months of receiving immune checkpoint inhibitor therapy, with some reports of late toxicity. This report highlights a case of probable neurosarcoidosis nearly a year after discontinuation of immune checkpoint therapy. The potential for durable responses after discontinuation of therapy also likely underscores a potential for late toxicity. In patients presenting with new or unexplained symptoms after checkpoint inhibitor therapy, the index of suspicion for an immune-related adverse effect should remain high, irrespective of timing.
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http://dx.doi.org/10.1186/s40425-018-0390-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069826PMC
July 2018

Immune Checkpoint Blockade: The New Frontier in Cancer Treatment.

Target Oncol 2018 02;13(1):1-20

Division of Medical Oncology, Duke University School of Medicine, Duke Cancer Institute, Duke Box 3198, Durham, NC, 27710, USA.

Immune checkpoint blockers have revolutionized cancer treatment in recent years. These agents are now approved for the treatment of several malignancies, including melanoma, squamous and non-squamous non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, and head and neck squamous cell carcinoma. Studies have demonstrated the significant impact of immunotherapy versus standard of care on patient outcomes, including durable response and extended survival. The use of immunotherapy-based combination therapy has been shown to further extend duration of response and survival. Immunotherapies function through modulation of the immune system, which can lead to immune-mediated adverse events (imAEs). These include a range of dermatologic, gastrointestinal, endocrine, and hepatic toxicities, as well as other less common inflammatory events. ImAEs are typically low grade and manageable when identified early and treated with appropriate measures. Identifying the right patient for the right therapy will become more important as new immunotherapies and immunotherapy-based combinations are approved and costs of cancer care continue to rise.
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http://dx.doi.org/10.1007/s11523-017-0549-7DOI Listing
February 2018

Efficacy and Safety of Pembrolizumab in Patients Enrolled in KEYNOTE-030 in the United States: An Expanded Access Program.

J Immunother 2017 Nov/Dec;40(9):334-340

*Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA †The University of Texas MD Anderson Cancer Center, Houston, TX ‡Memorial Sloan Kettering Cancer Center §Weill Cornell Medical College §§NYU Clinical Cancer Center, New York, NY ∥The Angeles Clinic and Research Institute, Los Angeles ¶Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco ††The John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA #Mayo Clinic, Rochester, MN **Mayo Clinic, Jacksonville, FL ‡‡Dana-Farber Cancer Institute, Boston, MA ∥∥Yale Cancer Center, New Haven, CT ¶¶Clinigen, Weybridge, UK ##Merck & Co. Inc., Kenilworth, NJ ***Duke Cancer Institute, Durham, NC.

KEYNOTE-030 (ClinicalTrials.gov ID, NCT02083484) was a global expanded access program that allowed access to pembrolizumab, an antiprogrammed death 1 antibody, for patients with advanced melanoma before its regulatory approval. Patients with unresectable stage III/IV melanoma that progressed after standard-of-care therapy, including ipilimumab and, if BRAF mutant, a BRAF inhibitor, were eligible to receive pembrolizumab 2 mg/kg every 3 weeks. Response was assessed by immune-related response criteria by investigator review. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. In the United States, 979 patients enrolled between April and September 2014. Of the 947 evaluable patients, 621 (65.6%) remained on treatment and transitioned to receive commercial pembrolizumab following approval by the Food and Drug Administration, whereas 326 (34.4%) discontinued, most commonly for disease progression (39.6%) or death (26.4%). Objective response rate was 14.5% (95% confidence interval, 12.2%-16.8%) in the treated population (n=947) and 22.1% (95% confidence interval, 18.8%-25.5%) in patients who had ≥1 response assessment reported (n=619). Twelve patients achieved complete response. One hundred eighty-one (19.1%) patients experienced ≥1 treatment-related AE, most commonly general disorders (8.0%), skin/subcutaneous tissue disorders (7.3%), and gastrointestinal disorders (6.4%); 29 (3.1%) patients experienced ≥1 grade 3/4 treatment-related AE. Immune-mediated AEs were also reported. There were no treatment-related deaths. The safety and efficacy observed in this expanded access program were consistent with those previously reported for similar populations and support the use of pembrolizumab for patients with advanced melanoma.
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http://dx.doi.org/10.1097/CJI.0000000000000186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647109PMC
May 2018

Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma.

Eur J Cancer 2017 11;86:37-45

University of California Los Angeles, Los Angeles, CA, USA.

Aim: To evaluate the protocol-specified final analysis of overall survival (OS) in the KEYNOTE-002 study (NCT01704287) of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory, advanced melanoma.

Methods: In this randomised, phase II study, eligible patients had advanced melanoma with documented progression after two or more ipilimumab doses, previous BRAF or MEK inhibitor or both, if BRAF mutant-positive. Patients were randomised to pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy. Crossover to pembrolizumab was allowed following progression on chemotherapy. The protocol-specified final OS was performed in the intent-to-treat population. Survival was positive if p < 0.01 in one pembrolizumab arm.

Results: A total of 180 patients were randomised to pembrolizumab 2 mg/kg, 181 to pembrolizumab 10 mg/kg and 179 to chemotherapy. At a median follow-up of 28 months (range 24.1-35.5), 368 patients died and 98 (55%) crossed over to pembrolizumab. Pembrolizumab 2 mg/kg (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.67-1.10, p = 0.117) and 10 mg/kg (0.74, 0.57-0.96, p = 0.011) resulted in a non-statistically significant improvement in OS versus chemotherapy; median OS was 13.4 (95% CI 11.0-16.4) and 14.7 (95% CI 11.3-19.5), respectively, versus 11.0 months (95% CI 8.9-13.8), with limited improvement after censoring for crossover. Two-year survival rates were 36% and 38%, versus 30%. Progression-free survival, objective response rate and duration of response improved with pembrolizumab versus chemotherapy, regardless of dose. Grade III-V treatment-related adverse events occurred in 24 (13.5%), 30 (16.8%) and 45 (26.3%) patients, respectively.

Conclusion: Improvement in OS with pembrolizumab was not statistically significant at either dose versus chemotherapy.
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http://dx.doi.org/10.1016/j.ejca.2017.07.022DOI Listing
November 2017

Can binimetinib, encorafenib and masitinib be more efficacious than currently available mutation-based targeted therapies for melanoma treatment?

Expert Opin Pharmacother 2017 Apr 22;18(5):487-495. Epub 2017 Mar 22.

b Department of Surgery , Ohio State University , Columbus , OH , USA.

Introduction: Historically, there were few effective and durable treatments for metastatic melanoma. Recently, mutation based targeted therapies have revolutionized treatment and outcomes for patients with metastatic melanoma. Specifically, inhibitors aimed at BRAF, NRAS, and C-KIT mutations are now commonly used in treatment for patients harboring the specific mutations. Areas covered: A brief review of current BRAF, NRAS, and C-KIT inhibitors provides background for a thorough review of newly developed agents namely binimetinib, a MEK inhibitor, encorafenib a BRAF inhibitor, and masitinib which inhibits C-KIT. Expert opinion: While the 3 novel agents reviewed here have potential for use in melanoma, optimal utilization will occur once a more personalized approach incorporating genomic, proteomic, and immunologic data guides therapeutic decisions.
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http://dx.doi.org/10.1080/14656566.2017.1299710DOI Listing
April 2017

Genetic risk analysis of a patient with fulminant autoimmune type 1 diabetes mellitus secondary to combination ipilimumab and nivolumab immunotherapy.

J Immunother Cancer 2016 20;4:89. Epub 2016 Dec 20.

Department of Medicine, Division of Medical Oncology, Melanoma Program, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710 USA.

Background: Checkpoint inhibitor immunotherapy is becoming an effective treatment modality for an increasing number of malignancies. As a result, autoinflammatory side-effects are also being observed more commonly in the clinic. We are currently unable to predict which patients will develop more severe toxicities associated with these treatment regimens.

Case Presentation: We present a patient with stage IV melanoma that developed rapid onset autoimmune type 1 diabetes (T1D) in response to combination ipilimumab and nivolumab immunotherapy. At the time of the patient's presentation with diabetes ketoacidosis, a confirmed anti-GAD antibody seroconversion was noted. Longer-term follow-up of this patient has demonstrated a durable complete response based on PET CT imaging along with a persistently undetectable C-peptide level. Single nucleotide polymorphism gene sequencing and HLA risk allele analysis has revealed the patient to lack any established genetic predisposition to the development of autoimmune T1D.

Conclusions: While larger studies are necessary to better understand the role of genetic risk factors for the development of autoimmune toxicities in those patients undergoing checkpoint inhibitor immunotherapy, these results suggest that pre-screening patients for known T1D risk alleles may not be indicated. Additional investigation is needed to determine whether an approach such as T cell receptor clonotypic analysis to identify the presence of autoreactive T cell clones may be an effective approach for predicting which patients are at risk for the development of autoinflammatory toxicities while undergoing checkpoint inhibitor immunotherapy.
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http://dx.doi.org/10.1186/s40425-016-0196-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5170902PMC
December 2016

The efficacy of anti-PD-1 agents in acral and mucosal melanoma.

Cancer 2016 Nov 17;122(21):3354-3362. Epub 2016 Aug 17.

Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: Therapeutic antibodies against programmed cell death receptor 1 (PD-1) are considered front-line therapy in metastatic melanoma. The efficacy of PD-1 blockade for patients with biologically distinct melanomas arising from acral and mucosal surfaces has not been well described.

Methods: A multi-institutional, retrospective cohort analysis identified adults with advanced acral and mucosal melanoma who received treatment with nivolumab or pembrolizumab as standard clinical practice through expanded access programs or published prospective trials. Objective responses were determined using investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progression-free survival and overall survival were assessed using the Kaplan-Meier method.

Results: Sixty individuals were identified, including 25 (42%) with acral melanoma and 35 (58%) with mucosal melanoma. Fifty-one patients (85%) had received previous therapy, including 77% who had previously received ipilimumab. Forty patients (67%) received pembrolizumab at a dose of 2 mg/kg or 10 mg/kg, and 20 (33%) received nivolumab at a doses ranging from 0.3 to 10 mg/kg every 2 to 3 weeks. The objective response rate was 32% (95% confidence interval, 15%-54%) in patients with acral melanoma and 23% (95% confidence interval, 10%-40%) in those with mucosal melanoma. After a median follow-up of 20 months in the acral melanoma group and 10.6 months in the mucosal melanoma group, the median progression-free survival was 4.1 months and 3.9 months, respectively. Only 2 patients (3%) discontinued treatment because of toxicity.

Conclusions: Response rates to PD-1 blockade in patients with acral and mucosal melanomas were comparable to the published rates in patients with cutaneous melanoma and support the routine use of PD-1 blockade in clinical practice. Further investigation is needed to identify the mechanisms of response and resistance to therapy in these subtypes. Cancer 2016;122:3354-3362. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5134420PMC
November 2016

Embracing rejection: Immunologic trends in brain metastasis.

Oncoimmunology 2016 Jul 11;5(7):e1172153. Epub 2016 Apr 11.

Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA; Department of Pathology, Duke University Medical Center, Durham, NC, USA.

Brain metastases represent the most common type of brain tumor. These tumors offer a dismal prognosis and significantly impact quality of life for patients. Their capacity for central nervous system (CNS) invasion is dependent upon induced disruptions to the blood-brain barrier (BBB), alterations to the brain microenvironment, and mechanisms for escaping CNS immunosurveillance. In the emerging era of immunotherapy, understanding how metastases are influenced by the immunologic peculiarities of the CNS will be crucial to forging therapeutic advances. In this review, the immunology of brain metastasis is explored.
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http://dx.doi.org/10.1080/2162402X.2016.1172153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006920PMC
July 2016

Phase II study of vemurafenib followed by ipilimumab in patients with previously untreated BRAF-mutated metastatic melanoma.

J Immunother Cancer 2016 16;4:44. Epub 2016 Aug 16.

Dana-Farber Cancer Institute, Boston, MA USA.

Background: Ipilimumab (IPI), an anti-CTLA-4 antibody, and vemurafenib (VEM), a BRAF inhibitor, have distinct mechanisms of action and shared toxicities (e.g., skin, gastrointestinal [GI] and hepatobiliary disorders) that may preclude concomitant administration. Concurrent administration of IPI and VEM previously showed significant dose-limiting hepatotoxicity in advanced melanoma. This single-arm, open-label, phase II study evaluated a sequencing strategy with these two agents in previously untreated patients with BRAF-mutated advanced melanoma.

Methods: This study was divided into two parts. During Part 1 (VEM1-IPI), patients received VEM 960 mg twice daily for 6 weeks followed by IPI 10 mg/kg every 3 weeks for 4 doses (induction), then every 12 weeks (maintenance) beginning at week 24 until disease progression or unacceptable toxicity. During Part 2 (VEM2), patients who progressed after IPI received VEM at their previously tolerated dose. The primary objective was to estimate the incidence of grade 3/4 drug-related skin adverse events (AEs) during VEM1-IPI.

Results: All patients who were initially treated with VEM (n = 46) received IPI induction therapy; 8 received IPI maintenance and 19 were treated during VEM2. During VEM1-IPI, the incidence of grade 3/4 drug-related AEs associated with the skin, GI tract, and hepatobiliary system was 32.6 %, 21.7 %, and 4.3 %, respectively. There were no drug-related deaths. At a median follow-up of 15.3 months, median overall survival was 18.5 months. Median progression-free survival was 4.5 months.

Conclusions: VEM (960 mg twice daily for 6 weeks) followed by IPI 10 mg/kg has a manageable safety profile. The benefits/risks of BRAF inhibitors followed by immunotherapy should be evaluated further in light of continuing developments in treatment options for metastatic melanoma.

Trial Registration: ClinicalTrials.gov identifier: NCT01673854 (CA184-240) Registered 24 August 2012.
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http://dx.doi.org/10.1186/s40425-016-0148-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4986368PMC
August 2016

Safety and Efficacy of Radiation Therapy in Advanced Melanoma Patients Treated With Ipilimumab.

Int J Radiat Oncol Biol Phys 2016 09 21;96(1):72-7. Epub 2016 Apr 21.

Division of Medical Oncology, Duke University Medical Center, Durham, North Carolina. Electronic address:

Purpose: Ipilimumab and radiation therapy (RT) are standard treatments for advanced melanoma; preclinical models suggest the potential for synergy. However, limited clinical information exists regarding safety and optimal timing of the combination.

Methods And Materials: We reviewed the records of consecutive patients with unresectable stage 3 or 4 melanoma treated with ipilimumab. Patients were categorized as having received RT or not. Differences were estimated between these 2 cohorts.

Results: We identified 88 patients treated with ipilimumab. At baseline, the ipilimumab-plus-RT group (n=44) had more unfavorable characteristics. Despite this, overall survival, progression-free survival, and both immune-related and non-immune-related toxicity were not statistically different (P=.67). Patients who received ipilimumab before RT had an increased duration of irradiated tumor response compared with patients receiving ipilimumab after RT (74.7% vs 44.8% at 12 months; P=.01, log-rank test). In addition, patients receiving ablative RT had non-statistically significantly improved median overall survival (19.6 vs 10.2 months), as well as 6-month (95.1% vs 72.7%) and 12-month (79.7% vs 48.5%) survival rates, compared with those treated with conventionally fractionated RT.

Conclusions: We found that both ablative and conventionally fractionated RT can be safely administered with ipilimumab without a clinically apparent increase in toxicity. Patients who received ipilimumab before RT had an increased duration of irradiated tumor response.
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http://dx.doi.org/10.1016/j.ijrobp.2016.04.017DOI Listing
September 2016

Tumor Heterogeneity and Therapeutic Resistance.

Am Soc Clin Oncol Educ Book 2016 ;35:e585-93

From the Department of Medicine, Department of Cancer Biology, Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN; Department of Internal Medicine, Duke University Medical Center, Durham, NC; Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA.

The rapidly changing landscape of oncology has brought new light, and with it, new challenges to optimizing therapeutic strategies for patients. Although the concept of patient heterogeneity is well known to any practicing clinician, a more detailed understanding of the biologic changes that underscore the clinical picture is beginning to emerge. Thus, tumor heterogeneity has come to encompass more than just the clinical picture and can represent both intratumor and intertumor differences. Within the fields of thoracic oncology and melanoma, the discovery of key molecular drivers has resulted in landmark breakthroughs in therapy. However, the complexities of tumor genetics and the interaction within the environment continue to drive the search for better therapies. Ongoing challenges include the accurate and timely assessment of genetic changes as well as the development of resistance and the resultant compensatory mechanisms. Novel technologies, including commercially available next-generation sequencing, have allowed for a greater breadth and depth of information to be gained from a single pathologic specimen, and it is now being incorporated into routine clinical practice. Translational advances have subsequently provided valuable insight into mechanisms of resistance, with the development of novel treatment strategies. Future work will focus on novel diagnostic techniques and adaptive mechanisms that can ultimately drive the development of the next generation of cancer therapy.
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http://dx.doi.org/10.1200/EDBK_158808DOI Listing
January 2017

Irradiation and immunotherapy: From concept to the clinic.

Cancer 2016 Jun 23;122(11):1659-71. Epub 2016 Feb 23.

Department of Radiation Oncology, Duke University, Durham, North Carolina.

In recent years, an increased understanding of T-cell-regulatory mechanisms has led to the development of a novel class of immune-checkpoint inhibitors that have robust clinical activity against a broad array of malignancies-even those that historically were not believed to be sensitive to immune therapy. With this, there has been renewed interest in the potential for synergy with more traditional forms of anticancer therapy like radiation therapy (RT). The role of RT in palliation or as definitive treatment for certain malignancies has been well established. Yet, in recent years, the concept has come to light that RT could be an attractive partner for use in combination with other immunotherapies. The effects of RT include not only control of an irradiated tumor but also multiple immunomodulatory effects on both the tumor and the microenvironment, priming tumors for an immune-mediated response. Herein, the authors summarize relevant preclinical data and rationale supporting the synergy of combined RT and immunotherapy and highlight recent clinical work on promising combination strategies. Cancer 2016;122:1659-71. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.29889DOI Listing
June 2016

Updates in Therapy for Advanced Melanoma.

Cancers (Basel) 2016 Jan 15;8(1). Epub 2016 Jan 15.

Division of Medical Oncology, Department of Internal Medicine, Duke University Medical Center, Durham, NC 27710, USA.

Cutaneous melanoma is one of the most aggressive forms of skin cancer, and is correlated with a large proportion of skin cancer-related deaths. Therapy for cutaneous melanoma has advanced greatly through careful identification of therapeutic targets and the development of novel immunotherapeutic approaches. The identification of BRAF as well as other driver mutations, have allowed for a specialized approach to treatment. In addition, immune checkpoint inhibition has dramatically changed the treatment landscape over the past 5-10 years. The successful targeting of CTLA-4, as well as PD-1/PD-L1, has been translated into meaningful clinical benefit for patients, with multiple other potential agents in development. Systemic therapy for cutaneous melanoma is becoming more nuanced and often takes a multifaceted strategy. This review aims to discuss the benefits and limitations of current therapies in systemic melanoma treatment as well as areas of future development.
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http://dx.doi.org/10.3390/cancers8010017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728464PMC
January 2016

Neoadjuvant use of ipilimumab in locally advanced melanoma.

J Surg Oncol 2015 Dec;112(8):841-3

Division of Medical Oncology, Duke University, Trinity, North Carolina.

Recent advances in immune modulating therapies show great promise for patients with advanced melanoma, however optimal strategies for achieving long-term disease control in locally advanced melanoma are unclear. We present two cases of neoadjuvant ipilimumab, one case in combination with isolated limb infusion (ILI) followed by surgical resection and one followed by surgery alone. Both patients have had durable responses. These cases highlight the ongoing need for prospective trials in the neoadjuvant setting.
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http://dx.doi.org/10.1002/jso.24079DOI Listing
December 2015

Computed Tomography-Based Limb Volume Measurements for Isolated Limb Infusion in Melanoma.

Ann Surg Oncol 2016 Apr 16;23(4):1090-5. Epub 2015 Nov 16.

Division of Advanced Oncologic and GI Surgery, Department of Surgery, Duke University Medical Center, Durham, NC, USA.

Background: Despite advances in cross-sectional imaging, chemotherapeutic dosing for isolated limb infusion (ILI) in melanoma is currently calculated through cumbersome and potentially imprecise manual measurements. The primary objective of this study was to examine the feasibility of using computed tomography (CT) to calculate limb volume, its concordance with manual measurement, and its ability to predict clinical response and toxicity in patients undergoing ILI.

Methods: A retrospective analysis of all patients undergoing lower extremity ILI at Duke University Medical Center between 2003 and 2014 was performed. Data pertaining to manually measured limb volume, chemotherapeutic dosing, and patient outcome was obtained. CT-based measurements of limb volume were performed in all patients for whom imaging was available and subsequently compared with manually measured values.

Results: CT data were sufficient for measurement in 73 patients. The mean measurement time was 4.61 ± 2.13 min. Although average CT-based measurements were 1.20 L higher in the case of lower limbs, they correlated well with those obtained manually (r (2) = 0.90). Unlike manual measurement, patients with complete responses to chemotherapy had smaller limb volumes than those with disease progression as measured by CT (9.3 vs. 10.7 L; p = .038). Patients suffering grade 3 and 4 toxicities also had statistically lower limb volumes as measured by CT than those who did not (p < .05).

Conclusions: CT-based limb volume measurement is feasible for chemotherapy dosing in patients undergoing ILI for melanoma and has predictive value with respect to clinical response and toxicity.
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http://dx.doi.org/10.1245/s10434-015-4972-7DOI Listing
April 2016