Durable complete response for oligometastatic renal cell carcinoma with immune checkpoint inhibition and cytoreductive nephrectomy in a Jehovah's witness: A case report.

The role of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma is a subject of debate. We report a durable complete response in a 62-year-old man Jehovah's Witness with metastatic clear cell renal cell carcinoma who received two cycles of nivolumab/ipilimumab followed by radical nephrectomy and metastasectomy of known pulmonary disease site, both without a clinical need for perioperative blood transfusions. The patient continues to be without evidence of disease and without additional need for systemic therapy over a year after his radical nephrectomy. The case highlights that cytoreductive nephrectomy continues to play a role in the era of immune checkpoint inhibitors.

Combination Immune Checkpoint Blockade Regimens for Previously Untreated Metastatic Renal Cell Carcinoma: The Winship Cancer Institute of Emory University Experience.

Introduction: There are three combination immune checkpoint inhibitor (ICI)-based regimens in the first-line setting for metastatic renal cell carcinoma (mRCC). Currently, there is limited real-world data for clinical outcomes and toxicity in mRCC patients treated with first-line ICI-based regimens. Methods: We performed a retrospective review of 49 mRCC patients treated with ICI-based combination regimens in the standard of care setting at the Winship Cancer Institute of Emory University from 2015-2020. We collected baseline data from the electronic medical record including demographic information and disease characteristics. Immune-related adverse events (irAEs) were collected from clinic notes and laboratory values. The primary clinical outcomes measured were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Results: The median age was 65 years, and most patients (80%) were males. The majority were White (86%) and had clear cell RCC (83%). Most patients had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 (43%) or 1 (45%). Approximately one-half (49%) had at least three sites of distant metastatic disease. Most patients (88%) received nivolumab and ipilimumab. More than one-half (53%) of patients experienced an irAE, with 13 (27%) patients having treatment delayed and 18% discontinuing treatment for toxicity. The median OS was not reached, and the median PFS was 8.0 months per a Kaplan-Meier estimation. More than half of patients (53%) had a PFS > 6 months, and 22% had PFS > 1 year. The ORR was 33% for the entire cohort, and 7% of patients had a complete response. Conclusion: We presented real-world efficacy and toxicity data for front-line ICI combination treatment regimens. The ORR and median PFS were lower in our cohort of patients compared to the available data in the clinical trial setting. This was likely because of more advanced disease in this study. Future studies should provide additional data that will allow comparisons between different ICI combination regimens for untreated mRCC.

Metastatic Clear-Cell Renal Cell Carcinoma in the Era of Immune Checkpoint Inhibitors: Therapies and Ongoing Trials.

Immune checkpoint inhibitors (ICI) are now the bedrock for the treatment of metastatic renal cell carcinoma (RCC). Clear cell RCC (ccRCC) represents the most common subtype of this malignancy. Herein, we explore the therapeutic landscape of ccRCC by discussing the standard of care whose backbone consists of immune checkpoint inhibitors (ICI) and vascular endothelial growth factor inhibitors (VEGF). For ccRCC, pembrolizumab-axitinib, pembrolizumab-lenvatinib, and avelumab-axitinib or nivolumab-cabozantinib are now FDA-approved frontline options for all risk groups while nivolumab-ipilimumab is reserved for intermediate- and poor-risk groups. Monotherapy with pembrolizumab or nivolumab is a potential option for patients who are unable to take VEGFR-tyrosine kinase inhibitors. While outcomes have improved with the adoption of ICI therapies, many patients develop therapy-resistant disease, creating an unmet need for further investigation. The efficacy of novel therapies as well as novel combinations in the post-ICI era is unclear. This review summarizes the most significant clinical trials involving dual ICI/ICI and ICI/VEGFR therapies, in addition to other selected combination therapies that are likely to inform management in the near future.

Blood-Based Next-Generation Sequencing in Adrenocortical Carcinoma.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and heterogeneous malignancy with poor prognosis. We aimed to evaluate the feasibility of next-generation sequencing (NGS) testing of circulating cell-free tumor DNA (ctDNA) in patients with ACC, to characterize the genomic landscape of alterations, and to identify potential clinically actionable mutations. METHODS: Retrospective analysis of genomic data from 120 patients with ACC who had ctDNA testing between 12/2016 and 10/2021 using Guardant360 (Guardant Health, CA) was performed. ctDNA NGS analysis interrogated single nucleotide variants, fusions, indels, and copy number amplifications of up to 83 genes. The frequency of genomic alterations, landscape of co-occurring mutations, and pathogenic/likely pathogenic alterations with potential targeted therapies was identified. The prevalence of alterations identified in ctDNA was compared to those detected in tissue using a publicly available database (cBioPortal). RESULTS: The median age of this cohort was 53 years (range 21-81), and 56% of patients were female. Ninety-six patients (80%) had ≥1 somatic alteration detected. TP53 (52%), EGFR (23%), CTNNB1 (18%), MET (18%), and ATM (14%) were found to be the most frequently altered genes in ACC samples. Pathogenic and/or likely pathogenic mutations in therapeutically relevant genes were observed in 56 patients (47%) and included EGFR, BRAF, MET, CDKN2A, CDK4/6, and ATM. The most frequent co-occurring mutations were EGFR + MET (9%), MET + CDK4 (7%), EGFR + CDK4 (7%), and BRAF + MET (7%). The frequencies of mutations detected in ctDNA were similar to those detected in tissue. CONCLUSIONS: Utilizing blood-based NGS to characterize genomic alterations in advanced ACC is feasible in over 80% of patients. Almost half of the patients had actionable mutations with approved therapies in other cancers. This approach might inform the development of personalized treatment options or identify clinical trials available for this aggressive malignancy.

Analysis of Toxicity and Clinical Outcomes in Full Versus Reduced Starting Dose Cabozantinib in Metastatic Renal Cell Carcinoma Patients.

BACKGROUND: Full dose cabozantinib for metastatic renal cell carcinoma (mRCC) is 60 mg, but adverse events (AEs) may require dose reductions. Limited data exist comparing efficacy among cabozantinib doses. We compared AEs and clinical outcomes in mRCC patients treated with full vs. reduced starting cabozantinib dose. METHODS: We performed a retrospective analysis of 87 mRCC patients treated with cabozantinib at Winship Cancer Institute from 2016 to 2019. Overall survival (OS), progression-free survival (PFS), and objective response (OR) rate measured clinical outcomes. AEs were collected from clinic notes and the most common were hypertension, mucositis/hand-foot skin reaction (HFSR), or gastrointestinal toxicity. Univariate analysis (UVA) between starting doses and AEs with clinical outcomes was performed using logistic regression model. Multivariable analysis was also performed using Cox proportional hazard model. RESULTS: Most patients were men (71%) with clear-cell RCC (72%). The majority were IMDC intermediate (58%) or poor (35%) risk. One third received first-line cabozantinib and 64% had ≥3 baseline metastatic sites. Most patients (68%) required dose reduction from 60 mg or started at reduced dose without escalation. Reduced dose patients were more likely to have ≥3 distant metastatic sites (70% vs. 58%) and ≥2 prior lines of systemic therapy (50% vs. 40%) compared to full dose patients. UVA revealed a trend towards shorter OS (HR: 1.78, P = .095), PFS (HR: 1.50, P = .107), and lower chance of OR (HR:0.42, P = .149) among reduced dose patients. This trend did not hold in Multivariable analysis (OS HR: 1.20, P = .636; PFS HR: 1.23, P = .4662). Mucositis/HFSR and hypertension were significantly associated with improved outcomes in UVA. CONCLUSIONS: Although we found a trend favoring full dose cabozantinib, this is likely due to worse baseline disease characteristics among patients starting on a reduced dose. Hypertension and mucositis/HFSR may be associated with improved outcomes. Larger studies are warranted to validate these findings.

Body Composition as an Independent Predictive and Prognostic Biomarker in Advanced Urothelial Carcinoma Patients Treated with Immune Checkpoint Inhibitors.

BACKGROUND: Several immune checkpoint inhibitors (ICIs) are approved for the treatment of advanced urothelial carcinoma (UC). There are limited biomarkers for ICI-treated patients with UC. We investigated the association between body composition and clinical outcomes in ICI-treated UC patients. MATERIALS AND METHODS: We conducted a retrospective analysis of 70 ICI-treated patients with advanced UC at Winship Cancer Institute from 2015 to 2020. Baseline computed tomography images within 2 months of ICI initiation were collected at mid-L3 and muscle and fat compartments (subcutaneous, intermuscular, and visceral) were segmented using SliceOMatic v5.0 (TomoVision, Magog, Canada). A prognostic body composition risk score (high: 0-1, intermediate: 2-3, or low-risk: 4) was created based on the ß coefficient from the multivariate Cox model (MVA) following best-subset variable selection. Our body composition risk score was skeletal muscle index (SMI) + 2 × attenuated skeletal muscle (SM) mean + visceral fat index (VFI). Concordance statistics (C-statistics) were used to quantify the discriminatory magnitude of the predictive model. RESULTS: Most patients (70%) were men and the majority received ICIs in the second- (46%) or third-line (21%) setting. High-risk patients had significantly shorter overall survival (OS; hazard ratio [HR], 6.72; p < .001), progression-free survival (HR, 5.82; p < .001), and lower chance of clinical benefit (odds ratio [OR], 0.02; p = .003) compared with the low-risk group in MVA. The C-statistics for our body composition risk group and myosteatosis analyses were higher than body mass index for all clinical outcomes. CONCLUSION: Body composition variables such as SMI, SM mean, and VFI may be prognostic and predictive of clinical outcomes in ICI-treated patients with UC. Larger, prospective studies are warranted to validate this hypothesis-generating data. IMPLICATIONS FOR PRACTICE: This study developed a prognostic body composition risk scoring system using radiographic biomarkers for patients with bladder cancer treated with immunotherapy. The study found that the high-risk patients had significantly worse clinical outcomes. Notably, the study's model was better at predicting outcomes than body mass index. Importantly, these results suggest that radiographic measures of body composition should be considered for inclusion in updated prognostic models for patients with urothelial carcinoma treated with immunotherapy. These findings are useful for practicing oncologists in the academic or community setting, particularly given that baseline imaging is routine for patients starting on treatment with immunotherapy.

Racial Differences in Clinical Outcomes for Metastatic Renal Cell Carcinoma Patients Treated With Immune-Checkpoint Blockade.

BACKGROUND: Immune-checkpoint-inhibitors (ICIs) have become the cornerstone of metastatic renal-cell-carcinoma (mRCC) therapy. However, data are limited regarding clinical outcomes by race. In this study, we compared the real-world outcomes between African American (AA) and Caucasian mRCC patients treated with ICIs. METHODS: We performed a retrospective study of 198 patients with mRCC who received ICI at the Emory Winship Cancer Institute from 2015-2020. Clinical outcomes were measured by overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) defined as a complete or partial response maintained for at least 6 months per response evaluation criteria in solid tumors version 1.1. Univariate and multivariable analyses were carried out for OS and PFS by Cox proportional-hazard model and ORR by logistical-regression model. Descriptive statistics compared rates of immune-related adverse events (irAEs) and non-clear-cell-RCC (nccRCC) histology were assessed using Chi-square test. RESULTS: Our cohort was comprised of 38 AA and 160 Caucasian patients. Most were diagnosed with clear-cell-RCC (ccRCC) (78%) and more than half received (57%) PD-1/PD-L1 monotherapy. Most patients were intermediate or poor-risk groups (83%). Comparing to Caucasians, our AA cohort contained more females and nccRCC cases. Kaplan-Meier method showed AAs had no statistically different median OS (17 vs 25 months, p=0.368) and PFS (3.1 vs 4.4 months, p=0.068) relative to Caucasian patients. On multivariable analysis, AA patients had significantly shorter PFS (HR=1.52, 95% CI: 1.01-2.3, p=0.045), similar ORR (OR=1.04, 95% CI: 0.42-2.57, p=0.936) and comparable OS (HR=1.09, 95% CI: 0.61-1.95, p=0.778) relative to Caucasians. CONCLUSIONS: Our real-world analysis of ICI-treated mRCC patients showed that AAs experienced shorter PFS but similar OS relative to Caucasians. This similarity in survival outcomes is reassuring for the use of ICI amongst real-world patient populations, however, the difference in treatment response is poorly represented in early outcomes data from clinical trials. Thus, the literature requires larger prospective studies to validate these findings.

Body Composition Variables as Radiographic Biomarkers of Clinical Outcomes in Metastatic Renal Cell Carcinoma Patients Receiving Immune Checkpoint Inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of metastatic renal cell carcinoma (mRCC). Biomarkers for mRCC patients treated with ICI are limited, and body composition is underutilized in mRCC. We investigated the association between body composition and clinical outcomes in ICI-treated mRCC patients. METHODS: We performed a retrospective analysis of 79 ICI-treated mRCC patients at Winship Cancer Institute from 2015-2020. Baseline CT images were collected at mid-L3 and segmented using SliceOMatic v5.0 (TomoVision). Density of skeletal muscle (SM), subcutaneous fat, inter-muscular fat, and visceral fat were measured and converted to indices by dividing by height(m)2 (SMI, SFI, IFI, and VFI, respectively). Total fat index (TFI) was defined as the sum of SFI, IFI, and VFI. Patients were characterized as high versus low for each variable at gender-specific optimal cuts using overall survival (OS) as the primary outcome. A prognostic risk score was created based on the beta coefficient from the multivariable Cox model after best subset variable selection. Body composition risk score was calculated as IFI + 2*SM mean + SFI and patients were classified as poor (0-1), intermediate (2), or favorable risk (3-4). Kaplan-Meier method and Log-rank test were used to estimate OS and PFS and compare the risk groups. Concordance statistics (C-statistics) were used to measure the discriminatory magnitude of the model. RESULTS: Most patients were male (73%) and most received ICI as first (35%) or second-line (51%) therapy. The body composition poor-risk patients had significantly shorter OS (HR: 6.37, p<0.001), PFS (HR: 4.19, p<0.001), and lower chance of CB (OR: 0.23, p=0.044) compared to favorable risk patients in multivariable analysis. Patients with low TFI had significantly shorter OS (HR: 2.72, p=0.002), PFS (HR: 1.91, p=0.025), and lower chance of CB (OR: 0.25, p=0.008) compared to high TFI patients in multivariable analysis. The C-statistics were higher for body composition risk groups and TFI (all C-statistics ≥ 0.598) compared to IMDC and BMI. CONCLUSIONS: Risk stratification using the body composition variables IFI, SM mean, SFI, and TFI may be prognostic and predictive of clinical outcomes in mRCC patients treated with ICI. Larger, prospective studies are warranted to validate this hypothesis-generating data.

Immune-Related Adverse Events as Clinical Biomarkers in Patients with Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are an important treatment for metastatic renal cell carcinoma (mRCC). These agents may cause immune-related adverse events (irAEs), and the relationship between irAEs and outcomes is poorly understood. We investigated the association between irAEs and clinical outcomes in patients with mRCC treated with ICIs. METHODS: We performed a retrospective study of 200 patients with mRCC treated with ICIs at Winship Cancer Institute from 2015 to 2020. Data on irAEs were collected from clinic notes and laboratory values and grades were determined using Common Terminology Criteria in Adverse Events version 5.0. The association with overall survival (OS) and progression-free survival (PFS) was modeled by Cox proportional hazards model. Logistic regression models were used to define odds ratios (ORs) for clinical benefit (CB). Landmark analysis and extended Cox models were used to mitigate lead-time bias by treating irAEs as a time-varying covariate. RESULTS: Most patients (71.0%) were male, and one-third of patients (33.0%) experienced at least one irAE, most commonly involving the endocrine glands (13.0%), gastrointestinal tract (10.5%), or skin (10.0%). Patients who experienced irAEs had significantly longer OS (hazard ratio [HR], 0.52; p = .013), higher chance of CB (OR, 2.10; p = .023) and showed a trend toward longer PFS (HR, 0.71; p = .065) in multivariate analysis. Patients who had endocrine irAEs, particularly thyroid irAEs, had significantly longer OS and PFS and higher chance of CB. In a 14-week landmark analysis, irAEs were significantly associated with prolonged OS (p = .045). Patients who experienced irAEs had significantly longer median OS (44.5 vs. 18.2 months, p = .005) and PFS (7.5 vs. 3.6 months, p = .003) without landmark compared with patients who did not. CONCLUSION: We found that patients with mRCC treated with ICIs who experienced irAEs, particularly thyroid irAEs, had significantly improved clinical outcomes compared with patients who did not have irAEs. This suggests that irAEs may be effective clinical biomarkers in patients with mRCC treated with ICIs. Future prospective studies are warranted to validate these findings. IMPLICATIONS FOR PRACTICE: This study found that early onset immune-related adverse events (irAEs) are associated with significantly improved clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICIs). In this site-specific irAE analysis, endocrine irAEs, particularly thyroid irAEs, were significantly associated with improved clinical outcomes. These results have implications for practicing medical oncologists given the increasing use of ICIs for the treatment of mRCC. Importantly, these results suggest that early irAEs and thyroid irAEs at any time on treatment with ICIs may be clinical biomarkers of clinical outcomes in patients with mRCC treated with ICIs.

Novel risk scoring system for metastatic renal cell carcinoma patients treated with cabozantinib.

BACKGROUND: Cabozantinib is an effective treatment for metastatic renal cell carcinoma (mRCC). The international mRCC database consortium (IMDC) criteria is the gold standard for risk stratification in mRCC. We created a risk scoring system specific for mRCC patients treated with cabozantinib. METHODS: We conducted a retrospective review of 87 patients with mRCC treated with cabozantinib at Winship Cancer Institute from 2015 to 2019. Overall survival (OS) and progression free survival (PFS) were used to measure clinical outcomes. Upon variable selection in multivariable analysis (MVA), elevated baseline monocyte-to-lymphocyte ratio (MLR), sarcomatoid histologic component, ECOG PS > 1, and absence of bone metastases were each assigned 1 point. A three-group risk scoring system was then created: low (score=0-1), intermediate (score=2), and high risk (score=3-4). The Cox proportional hazard model and Kaplan-Meier method were used for survival analyses. RESULTS: The median age was 62 years-old and the majority were males (71%) with clear-cell RCC (75%). Most (67%) received at least 1 prior line of systemic therapy. High risk and intermediate risk pts had significantly shorter OS (high risk HR: 13.84, p<0.001; intermediate risk HR: 3.50, p = 0.004) and PFS (high risk HR: 7.31, p<0.001; intermediate risk HR: 1.87, p = 0.053) compared to low risk patients in MVA. CONCLUSIONS: RCC patients treated with cabozantinib may benefit from specific risk stratification criteria using RCC histology, ECOG PS, sites of metastatic disease, and MLR. These variables are easily accessible in the clinical setting and may be helpful to determine which mRCC patients may benefit from treatment with cabozantinib.

Symptomatic methemoglobinemia in a patient with metastatic clear cell renal cell carcinoma treated with pembrolizumab and axitinib combination therapy: a case report.

BACKGROUND: Combination regimens that include immune checkpoint (ICI) and vascular endothelial growth factor (VEGF) inhibition have opened the door to new treatment opportunities for patients with metastatic renal cell carcinoma (mRCC). While these treatment options have provided improved tolerability and better outcomes compared to older regimens, many patients still experience a myriad of treatment-related adverse events. Given that these regimens were recently approved for mRCC, the complete side effect profile may not be fully elucidated yet. CASE PRESENTATION: We report a case of a 73-year old White male with mRCC who was managed with an ICI-VEGF inhibitor combination regimen. He experienced a partial response (Fig. 1) but had side effects including symptomatic cyanosis diagnosed as methemoglobinemia which led to treatment discontinuation. Upon holding his therapy, his methemoglobinemia and cyanosis resolved. CONCLUSIONS: Combination VEGF-ICI therapy provide novel regimens for advanced solid tumor malignancies including mRCC. While shown to have improved efficacy in clinical trials, it is crucial that oncologists uncover the full side effect profile of these novel agents especially as their use becomes more standard in the management of advanced malignancies. To our knowledge, this is the first reported case of a patient experiencing symptomatic methemoglobinemia as an adverse event associated with a VEGF-ICI combination regimen. While the cause of this side effect is unclear, in this paper we attempt to elucidate a process that is in line with the mechanism of action of these therapies to explain how these agents, specifically the axitinib, could have caused the methemoglobin to rise to a symptomatic level.

The Role of Chemotherapy in Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors.

Even though the neuroendocrine tumor (NET) field has entered the era of 'targeted therapy', the role of cytotoxic chemotherapy continues to be debated. High response rates, ranging from 30 to 70% depending on the line of therapy, are consistently observed in the treatment of pancreatic NETs, with lesser evidence of activity in other foregut tumors. Activity in midgut carcinoid tumors appears to be negligible. Unfortunately, placebo-controlled randomized controlled trials using modern response criteria are lacking: the bulk of the literature consists of small phase II trials and retrospective series. There are also no completed trials comparing modern chemotherapy regimens, and therefore little data exist to favor the use of streptozocin- versus temozolomide- versus oxaliplatin-based therapies. Due to the absence of high-level evidence, it is difficult to generate data-based guidelines on the appropriate sequencing of cytotoxic drugs versus targeted agents. Although conventional wisdom holds that targeted agents such as everolimus or sunitinib are more tolerable than cytotoxic drugs, there is no evidence to support this perception. As a general principle, chemotherapy may be more appropriate as early-line therapy in patients with bulky and/or symptomatic and/or rapidly progressive tumors, particularly of pancreatic origin. In patients with low-volume disease or slow-growing tumors, noncytotoxic drugs may be preferable in early lines of therapy, reserving chemotherapy for the salvage setting. Validation of predictive factors is imperative in order to appropriately match patients with optimal treatment. Methyl-guanine-methyl-transferase (MGMT) deficiency is likely to be a positive predictive factor for alkylating agents, but needs to be evaluated prospectively. It is also unclear whether immunostaining for MGMT expression, which can be somewhat subjective, is superior to PCR-based techniques, which assess MGMT methylation status. Other basic predictive factors, such as ki-67 index, need to be evaluated in prospective clinical trials. It will also be important to evaluate whether newly discovered mutations in pancreatic NETs, such as DAXX/ATRX, are associated with response to chemotherapy.

BRAF V600E mutations: a series of case reports in patients with non-small cell lung cancer.

We present a series of five patients with BRAF-mutated non-small cell lung cancer (NSCLC) from the Moffitt Cancer Center and a brief literature review. Information utilized included outside medical records, imaging studies, pathology reports in which simultaneous mutation testing was performed, and clinic visit notes. In addition, we conducted a literature search of background information using the following search terms: "BRAF mutations", "non-small cell lung cancer", and "driver mutations". Several retrospective studies on BRAF mutations in patients with NSCLC found that the majority of these mutations occur in adenocarcinomas and are V600E mutations. From our patients and literature search, we found that BRAF-V600E mutations occur predominantly in female smokers with adenocarcinomas.

Vaccine immunotherapy in lung cancer: Clinical experience and future directions.

Lung cancer remains the most common cause of cancer-related deaths in the United States, with SEER data showing lung cancer accounting for 29% of all male-related cancer mortality and 26% of all female-related mortality. Patients with small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) who have localized disease both have 5-year survival rates of 52.2%, whereas patients with metastatic disease have 5-year survival rates of only 3.7%. Traditional anti-cancer therapies (surgery, radiotherapy, and chemotherapy) have limited effectiveness in curbing progression. However, advances in immunology and molecular biology in the past two decades have resulted in improved prognosis for those with SCLC and NSCLC, although novel therapies are still needed to make significant improvements in median overall and progression-free survival rates. Notable progress on the importance of tumor immunology has included work on immune surveillance, antigenic targets, and immune checkpoints. Immunotherapies, including vaccines, which can induce antitumor responses by harnessing the power of the immune system, may help to fill this void, and the cancer vaccine continues to be studied as adjunctive therapy. Here, we review recently reported results from clinical trials as well as the possible future roles of vaccine therapy in the treatment of SCLC and NSCLC patients.

Clinical benefits of above-standard dose of octreotide LAR in patients with neuroendocrine tumors for control of carcinoid syndrome symptoms: a multicenter retrospective chart review study.

BACKGROUND: Octreotide LAR is used in patients for control of carcinoid syndrome (CS) and other symptoms of hormone hypersecretion. The aim of this study was to examine reasons for octreotide LAR dose escalation and observe CS symptom improvement in patients with neuroendocrine tumors (NETs) who underwent octreotide LAR dose escalation at three cancer referral centers. METHODS: Medical records for patients with diagnosis of carcinoid or pancreatic NET who had received one dose or more of octreotide LAR above 30 mg every 4 weeks from 2000 to 2012 were reviewed. Reasons for dose escalation and symptomatic outcomes were abstracted for each patient 3 months prior to and up to 12 months following the dose escalation. RESULTS: Of the evaluated 239 NET patients, 53% were male, mean age at first dose escalation was 60 years (standard deviation [SD]: 11 years), and mean time from octreotide LAR initiation to first dose escalation was 1.7 years (SD: 2.0 years). The primary reasons reported for dose escalation were carcinoid or hormonal syndrome (62%) or radiographic progression (28%). The most common dose changes at the first dose escalation were 40 mg every 4 weeks (71%) and 60 mg every 4 weeks (18%). Of 90 patients in whom flushing was reported prior to first dose escalation, 73 (81%) were reported to have experienced improvement or resolution of their symptoms following the dose escalation. Of 107 patients who were reported to have experienced diarrhea before the first dose escalation, 85 (79%) were reported to have experienced improvement or resolution after first dose escalation. CONCLUSION: The goal of improved symptom control is a common reason for dose escalation of octreotide LAR. This study suggests that escalation to above the standard dose of octreotide LAR of 30 mg every 4 weeks may result in improved CS symptom control.

Above-Label Doses of Octreotide-LAR in Patients With Metastatic Small Intestinal Carcinoid Tumors.

BACKGROUND: Octreotide LAR is indicated for treatment of malignant carcinoid syndrome and has been studied at doses of 10 to 30 mg intramuscularly every 4 weeks. In clinical practice, higher doses are often prescribed for patients who experience refractory carcinoid syndrome (flushing and/or diarrhea) or tumor growth while on the maximum label-recommended dose. METHODS: We performed a retrospective, longitudinal review of octreotide LAR administration at a tertiary institution to determine the frequency of above-label dosing and outcomes. RESULTS: Three hundred thirty-eight patients were considered evaluable, among whom 100 (30%) underwent at least 1 increase in dose or frequency of octreotide-LAR above the standard label dose. The most common maximum doses were 40 mg every 4 weeks (n = 37 patients), 60 mg every 4 weeks (n = 34), and 30 mg every 3 weeks (n = 18). The indications for dose increase were worsening carcinoid syndrome (n = 60), radiographic progression (n = 33), and rising urine 5-HIAA (n = 6). Of the patients whose doses were increased for refractory carcinoid syndrome, 62% (n = 34) experienced improvement in diarrhea, and 56% (n = 28) experienced improvement in flushing. CONCLUSIONS: In conclusion, octreotide LAR is commonly prescribed in doses or schedules above the recommended dose and frequency. Patients with refractory carcinoid syndrome appear to experience a clinical benefit from this change. Prospective data may be used to further evaluate this strategy.