ABSTRACT
BACKGROUND: Early-Onset (EO) pancreatic neuroendocrine tumor (PanNET) is a rare disease, but whether it is clinically different from late-onset (LO) PanNET is unknown. Our study aimed to evaluate clinical differences and disease outcomes between EO-PanNET and LO-PanNET and to compare sporadic EO-PanNET with those with a hereditary syndrome. METHODS: Patients with localized PanNET who underwent pancreatectomy at Memorial Sloan Kettering between 2000 and 2017 were identified. Those with metastatic disease and poorly differentiated tumors were excluded. EO-PanNET was defined as <50 and LO-PanNET >50 years of age at the time of diagnosis. Family history and clinical and pathology characteristics were recorded. RESULTS: Overall 383 patients were included, 107 (27.9%) with EO-PanNET. Compared with LO-PanNET, EO-PanNET were more likely to have a hereditary syndrome (2.2% vs. 16%, P <0.001) but had similar pathology features such as tumor grade ( P =0.6), size (2.2 Vs. 2.3Ā cm, P =0.5) and stageof disease ( P =0.8). Among patients with EO-PanNET, those with hereditary syndrome had more frequently a multifocal disease (65% vs. 3.3%, P <0.001). With a median follow-up of 70 months (range 0-238), the 5-year cumulative incidence of recurrence after curative surgery was 19% (95% CI 12%-28%) and 17% (95% CI 13%-23%), in EO-PanNET and LO-PanNET ( P =0.3). Five-year disease-specific survival was 99% (95% CI 98%-100%) with no difference with respect to PanNET onset time ( P =0.26). CONCLUSIONS: In this surgical cohort, we found that EO-PanNET is associated with hereditary syndromes but has pathologic characteristics and oncological outcomes similar to LO-PanNET. These findings suggest that patients with EO-PanNET can be managed similarly to those with LO-PanNET.
Subject(s)
Neuroendocrine Tumors , Pancreatic Neoplasms , Humans , Retrospective Studies , Pancreatectomy , IncidenceABSTRACT
BACKGROUND: The benefit of primary tumor resection in distant metastatic small bowel neuroendocrine tumors (SBNETs) is controversial, with treatment-based morbidity not well-defined. We aimed to determine the impact of primary tumor resection on development of disease-specific complications in patients with metastatic well-differentiated SBNETs. PATIENTS AND METHODS: A retrospective analysis was performed of patients diagnosed with metastatic well-differentiated jejunal/ileal SBNETs at a single tertiary care cancer center from 1980 to 2016. Outcomes were compared on the basis of treatment selected at diagnosis between patients who underwent initial medical treatment or primary tumor resection. RESULTS: Among 180 patients, 71 underwent medical management and 109 primary tumor resection. Median follow-up was 116 months. Median event-free survival did not differ between treatment approaches (log-rank p = 0.2). In patients medically managed first, 16/71 (23%) required surgery due to obstruction, perforation, or bleeding. These same complications led to resection at presentation in 31/109 (28%) surgically treated patients. Development of an obstruction from the primary tumor was not associated with disease progression/recurrence (HR 1.14, 95% CI 0.75-1.75) with all patients recovering postoperatively. Ongoing tumor progression requiring secondary laparotomy was associated with worse mortality (HR 7.51, 95% CI 3.3-16.9; p < 0.001) and occurred in 20/109 (18%) primary tumor resection and 7/16 (44%) initially medically treated patients. CONCLUSIONS: Rates of event-free survival among patients with metastatic SBNETs do not differ on the basis of primary tumor management. The development of an obstruction from the primary tumor was not associated with worse outcomes with all patients salvaged. Regardless of initial treatment selected, patients with metastatic SBNET should be closely followed for early signs of primary tumor complications.
Subject(s)
Intestinal Neoplasms , Neuroendocrine Tumors , Pancreatic Neoplasms , Stomach Neoplasms , Humans , Retrospective Studies , Neuroendocrine Tumors/surgery , Intestinal Neoplasms/surgeryABSTRACT
OBJECTIVE: The objective of this study was to describe the pattern of recurrence, treatments received, as well the oncological outcomes, of pancreatic neuroendocrine tumors (PanNETs) following curative surgery. BACKGROUND: PanNETs recur in 10% to 15% of cases following surgery. Information on the natural history and management of recurring disease is lacking. MATERIALS AND METHODS: Patients with PanNET that underwent curative surgery at 4 institutions between 2000 and 2019 were identified. Patients with poorly differentiated tumors, unknown tumor grade and differentiation, hereditary syndromes, unknown margin or R2 status, metastatic, and those that had neoadjuvant treatment or perioperative mortality were excluded. Clinical variables were assessed including first site of recurrence, treatment received, and survival outcomes. RESULTS: A total of 1402 patients were included: 957 (74%) had grade 1, 322 (25%) had grade 2, and 13 (1%) had grade 3 tumors. Median follow-up was 4.8 years (interquartile range: 2-8.2 years). Cumulative incidence of recurrence at 5 years was 13% (95% CI: 11%-15.2%) for distant disease, 1.4% (95% CI: 0.8%-2.3%) for locoregional recurrence, and 0.8% (95% CI: 0.4%-1.5%) for abdominal nodal recurrence. Patients who recurred had 2.89 increased risk of death (95% CI: 2-4.1) as compared with patients who did not recur. Therapy postrecurrence included: somatostatin analogs in 111 (61.0%), targeted therapies in 48 (26.4%), liver-directed therapies in 61 (33.5%), peptide receptor radionuclide therapy in 30 (16.5%), and surgery in 46 (25.3%) patients. Multiple treatments were used in 103 (57%) cases. After the first recurrence, 5-year overall survival was 74.6% (95% CI: 67.4%-82.5%). CONCLUSIONS: Recurrence following surgery is infrequent but reduces survival. Most recurrences are distant and managed with multiple therapies. Prospective studies are needed to establish strategies for surveillance and the sequence of treatment to control the disease and prolong survival.
Subject(s)
Neuroendocrine Tumors , Pancreatic Neoplasms , Humans , Neuroendocrine Tumors/surgery , Neuroendocrine Tumors/pathology , Neoplasm Recurrence, Local/pathology , Pancreatic Neoplasms/surgery , Somatostatin/therapeutic use , Neoadjuvant Therapy , Retrospective StudiesABSTRACT
PURPOSE: Based largely on reports that predate modern reporting standards, mitotane has been considered a systemic treatment option for both hormone control and antitumor control of metastatic adrenocortical cancer (ACC), although the therapeutic window is narrow. METHODS: We searched electronic medical records to identify patients with metastatic ACC treated and prescribed single-agent mitotane at Memorial Sloan Kettering Cancer Center from March 15, 1989-September 18, 2015. Reference radiologists reviewed all imaging and determined efficacy according to Response Evaluation Criteria in Solid Tumors 1.1. Patient demographics, toxicities, and treatment outcomes were reviewed. Next-generation sequencing was performed in selected cases. RESULTS: Thirty-six patients were identified. The mean age was 54 and 50% had functional tumors. Grade 3 or greater toxicities were documented in 16 out of 36 patients (44%) and 17% had documented long term adrenal insufficiency. Progression of the disease as the best response occurred in 30 out of 36 patients (83%) and one patient (3%) experienced clinical progression. Three patients achieved a complete response (CR) (8%), one patient achieved a partial response (3%), and one patient (3%) had stable disease after slow disease progression prior to initiation of therapy (durable for 6 months). All responders had nonfunctional tumors. Next-generation sequencing in two of the three CR patients was performed and failed to identify any novel alterations. CONCLUSION: In this retrospective series, mitotane had a low response rate and low tumor control rate; however, a disproportionately high complete response rate suggested it should be used in selected individuals. Adrenal insufficiency is common with mitotane use and aggressive treatment with steroid supplementation should be considered when appropriate to avoid excess toxicities. Biomarkers are desperately needed to further define this disease. IMPLICATIONS FOR PRACTICE: This is the first objective report of single-agent mitotane using modern objective criteria. Although the vast majority of patients did not respond (and toxicity was high), we identified a remarkable 8% complete response rate (i.e. cure) in biopsy proven stage IV adrenocortical cancer patients. Biomarkers are desperately needed for this rare disease.
Subject(s)
Adrenal Cortex Neoplasms/drug therapy , Adrenocortical Carcinoma/drug therapy , Antineoplastic Agents, Hormonal/therapeutic use , Mitotane/therapeutic use , Adrenal Cortex Neoplasms/pathology , Adrenal Insufficiency/chemically induced , Adrenal Insufficiency/diagnosis , Adrenal Insufficiency/drug therapy , Adrenal Insufficiency/epidemiology , Adrenocortical Carcinoma/pathology , Adult , Aged , Aged, 80 and over , Biomarkers/analysis , Biopsy , Disease Progression , Electronic Health Records/statistics & numerical data , Female , Glucocorticoids/therapeutic use , Humans , Male , Middle Aged , Palliative Care/methods , Remission Induction/methods , Retrospective Studies , Treatment Outcome , Young AdultABSTRACT
OBJECTIVE: To analyze the natural history of small asymptomatic pancreatic neuroendocrine tumors (PanNET) and to present a matched comparison between groups who underwent either initial observation or resection. Management approach for small PanNET is uncertain. METHODS: Incidentally discovered, sporadic, small (<3Ā cm), stage I-II PanNET were analyzed retrospectively between 1993 and 2013. Diagnosis was determined either by pathology or imaging characteristics. Intention-to-treat analysis was applied. RESULTS: A total of 464 patients were reviewed. Observation was recommended for 104 patients (observation group), and these patients were matched to 77 patients in the resection group based on tumor size at initial imaging. The observation group was significantly older (median 63 vs. 59Ā years, pĀ =Ā 0.04) and tended towards shorter follow-up (44 vs. 57Ā months, pĀ =Ā 0.06). Within the observation group, 26 of the 104 patients (25Ā %) underwent subsequent tumor resection after a median observation interval of 30Ā months (range 7-135). At the time of last follow-up of the observation group, the median tumor size had not changed (1.2Ā cm, pĀ =Ā 0.7), and no patient had developed evidence of metastases. Within the resection group, low-grade (G1) pathology was recorded in 72 (95Ā %) tumors and 5 (6Ā %) developed a recurrence, which occurred after a median of 5.1 (range 2.9-8.1) years. No patient in either group died from disease. Death from other causes occurred in 11 of 181 (6Ā %) patients. CONCLUSIONS: In this study, no patient who was initially observed developed metastases or died from disease after a median follow-up of 44Ā months. Observation for stable, small, incidentally discovered PanNET is reasonable in selected patients.
Subject(s)
Neuroendocrine Tumors/surgery , Pancreatic Neoplasms/surgery , Aged , Case-Control Studies , Cross-Sectional Studies , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Staging , Neuroendocrine Tumors/pathology , Pancreatic Neoplasms/pathology , Patient Selection , Prognosis , Retrospective Studies , Survival Rate , Watchful WaitingABSTRACT
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare, generally indolent neoplasms that can arise throughout the gastrointestinal system. Some GEP-NETs, known as functional, secrete hormones that can lead to a complex of symptoms. Classical carcinoid syndrome is associated with flushing, diarrhea, bronchospasm, and symptoms of valvular heart disease. GEP-NETs are classified according to the primary tumor site, functionality of the disease, and histology. Treatment is guided by the resectability of the tumor, the location and extent of metastases, and the presence of clinical symptoms. Typically, first-line treatment of patients with unresectable disease includes the use of somatostatin analogs, such as octreotide LAR depot or lanreotide depot/autogel, which was recently approved by the US Food and Drug Administration for treatment of GEP-NETs. Somatostatin analogs can improve the severe diarrhea/flushing episodes that may be associated with metastatic carcinoid tumors. For patients with pancreatic NETs, additional approved treatment options include the targeted agents everolimus and sunitinib, which have demonstrated antitumor activity. Chemotherapy may also have a selective role, particularly in pancreatic NETs. Localized approaches, including cytoreductive surgery, hepatic arterial embolization, and ablative therapies, may be used for palliative treatment in patients with liver metastases.
Subject(s)
Intestinal Neoplasms/pathology , Intestinal Neoplasms/therapy , Intestines/pathology , Neuroendocrine Tumors/pathology , Neuroendocrine Tumors/therapy , Pancreas/pathology , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/therapy , Stomach Neoplasms/pathology , Stomach Neoplasms/therapy , Stomach/pathology , Antineoplastic Agents/therapeutic use , Everolimus/therapeutic use , Hormones/chemistry , Hormones/therapeutic use , Humans , Indoles/therapeutic use , Intestinal Neoplasms/surgery , Intestines/drug effects , Intestines/surgery , Molecular Targeted Therapy , Neuroendocrine Tumors/surgery , Octreotide/therapeutic use , Pancreas/drug effects , Pancreas/surgery , Pancreatic Neoplasms/surgery , Pyrroles/therapeutic use , Somatostatin/analogs & derivatives , Somatostatin/therapeutic use , Stomach/drug effects , Stomach/surgery , Stomach Neoplasms/surgery , SunitinibABSTRACT
BACKGROUND & AIMS: IGF-IR is implicated in hepatic carcinogenesis. This and preliminary evidence of biological activity of anti-IGF-1R monoclonal antibody cixutumumab in phase I trials prompted this phase II study. METHODS: Patients with advanced HCC, Child-Pugh A-B8, received cixutumumab 6mg/kg weekly, in a Simon two-stage design study, with the primary endpoints being 4-month PFS and RECIST-defined response rate. Tissue and circulating markers plus different HCC scoring systems were evaluated for correlation with PFS and OS. RESULTS: As a result of pre-specified futility criteria, only stage 1 was accrued: N=24: median age 67.5 years (range 49-83), KPS 80% (70-90%), 20 males (83%), 9 stage III (37%)/15 stage IV (63%), 18 Child-Pugh A (75%), 11 HBV (46%)/10 HCV (42%)/11 alcoholic cirrhosis (46%)/2 NASH (8%), 11 (46%) diabetic. Median number of doses: 7 (range 1-140). Grade 3/4 toxicities >10% included: diabetes, elevated liver function tests, hyponatremia, and lymphopenia. Four-month PFS was 30% (95% CI 13-48), and there were no objective responses. Median overall survival was 8 months (95% CI 5.8-14). IGF-R1 staining did not correlate with outcome. Elevated IGFBP-1 correlated with improved PFS (1.2 [95% CI 1-1.4]; p 0.009) and OS (1.2 [95% CI 1.1-1.4]; p 0.003). CONCLUSIONS: Cixutumumab monotherapy did not have clinically meaningful activity in this unselected HCC population. Grade 3-4 hyperglycemia occurred in 46% of patients. Elevated IGFBP-1 correlated with improved PFS and OS.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Carcinoma, Hepatocellular/therapy , Liver Neoplasms/therapy , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized , Biomarkers, Tumor/blood , Biomarkers, Tumor/metabolism , Carcinoma, Hepatocellular/blood , Carcinoma, Hepatocellular/pathology , Female , Humans , Insulin-Like Growth Factor Binding Protein 1/blood , Insulin-Like Growth Factor Binding Protein 3/blood , Insulin-Like Growth Factor I/metabolism , Insulin-Like Growth Factor II/metabolism , Kaplan-Meier Estimate , Liver Neoplasms/blood , Liver Neoplasms/pathology , Male , Middle Aged , Receptor, IGF Type 1/metabolismABSTRACT
Standard therapy for locally advanced rectal cancer (LARC) is preoperative chemoradiotherapy and postoperative chemotherapy. At Memorial Sloan-Kettering Cancer Center (MSKCC) the authors began offering FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) as initial treatment for patients with high-risk LARC to target micrometastases while treating the primary tumor. The purpose of this study is to report the safety and efficacy of initial FOLFOX given before chemoradiotherapy on tumor downsizing and pathologic complete response (pathCR) in LARC. The records of patients with stage II/III rectal cancer treated at MSKCC between 2007 and 2012 were reviewed. Of approximately 300 patients with LARC treated at MSKCC, 61 received FOLFOX as initial therapy. Of these 61 patients, 57 received induction FOLFOX (median 7 cycles) followed by chemoradiation, and 4 experienced an excellent response, declined chemoradiation, and underwent total mesorectal excision (TME). Twelve of the 61 patients did not undergo TME: 9 had a complete clinical response (CCR), 1 declined despite persistent tumor, 1 declined because of comorbidities, and 1 developed metastatic disease. Among the 61 patients receiving initial FOLFOX, 22 (36%) had either a pathCR (n=13) or a CCR (n=9). Of the 49 patients who underwent TME, all had R0 resections and 23 (47%) had tumor response greater than 90%, including 13 (27%) who experienced a pathCR. Of the 28 patients who received all 8 cycles of FOLFOX, 8 experienced a pathCR (29%) and 3 a CCR (11%). No serious adverse events occurred that required a delay in treatment during FOLFOX or chemoradiation. FOLFOX and chemoradiation before planned TME results in tumor regression, a high rate of delivery of planned therapy, and a substantial rate of pathCRs, and offers a good platform for nonoperative management in select patients.
Subject(s)
Adenocarcinoma/therapy , Neoadjuvant Therapy , Rectal Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemoradiotherapy/methods , Digestive System Surgical Procedures , Female , Humans , Male , Middle Aged , Neoadjuvant Therapy/methods , Neoplasm Staging , Rectal Neoplasms/pathology , Retrospective Studies , Treatment OutcomeABSTRACT
Important progress has been made over the last decade in the classification, imaging, and treatment of neuroendocrine neoplasm (NENs), with several new agents approved for use. Although the treatment options available for patients with well-differentiated neuroendocrine tumors (NETs) have greatly expanded, the rapidly changing landscape has presented several unanswered questions about how best to optimize, sequence, and individualize therapy. Perhaps the most important development over the last decade has been the approval of 177Lu-DOTATATE for treatment of gastroenteropancreatic-NETs, raising questions around optimal sequencing of peptide receptor radionuclide therapy (PRRT) relative to other therapeutic options, the role of re-treatment with PRRT, and whether PRRT can be further optimized through use of dosimetry among other approaches. The NET Task Force of the National Cancer Institute GI Steering Committee convened a clinical trial planning meeting in 2021 with multidisciplinary experts from academia, the federal government, industry, and patient advocates to develop NET clinical trials in the era of PRRT. Key clinical trial recommendations for development included 1) PRRT re-treatment, 2) PRRT and immunotherapy combinations, 3) PRRT and DNA damage repair inhibitor combinations, 4) treatment for liver-dominant disease, 5) treatment for PRRT-resistant disease, and 6) dosimetry-modified PRRT.
Subject(s)
Intestinal Neoplasms , Neuroendocrine Tumors , Pancreatic Neoplasms , Humans , Consensus , Intestinal Neoplasms/drug therapy , National Cancer Institute (U.S.) , Neuroendocrine Tumors/pathology , Octreotide/therapeutic use , Pancreatic Neoplasms/drug therapy , United States , Clinical Trials as TopicABSTRACT
PURPOSE: Patients with advanced pancreatic neuroendocrine tumors (NETs) have few treatment options that yield objective responses. Retrospective and small prospective studies suggest that capecitabine and temozolomide are associated with high response rates (RRs) and long progression-free survival (PFS). PATIENTS AND METHODS: E2211 was a multicenter, randomized, phase II trial comparing temozolomide versus capecitabine/temozolomide in patients with advanced low-grade or intermediate-grade pancreatic NETs. Key eligibility criteria included progression within the preceding 12 months and no prior temozolomide, dimethyl-triazeno-imidazole-carboxamide or dacarbazine, capecitabine or fluorouracil. The primary end point was PFS; secondary endpoints were overall survival, RR, safety, and methylguanine methyltransferase (MGMT) by immunohistochemistry and promoter methylation. RESULTS: A total of 144 patients were enrolled between April 2013 and March 2016 to temozolomide (n = 72) or capecitabine and temozolomide (n = 72); the primary analysis population included 133 eligible patients. At the scheduled interim analysis in January 2018, the median PFS was 14.4 months for temozolomide versus 22.7 months for capecitabine/temozolomide (hazard ratio = 0.58), which was sufficient to reject the null hypothesis for the primary end point (stratified log-rank P = .022). In the final analysis (May 2021), the median overall survival was 53.8 months for temozolomide and 58.7 months for capecitabine/temozolomide (hazard ratio = 0.82, P = .42). MGMT deficiency was associated with response. CONCLUSION: The combination of capecitabine/temozolomide was associated with a significant improvement in PFS compared with temozolomide alone in patients with advanced pancreatic NETs. The median PFS and RR observed with capecitabine/temozolomide are the highest reported in a randomized study for pancreatic NETs. MGMT deficiency was associated with response, and although routine MGMT testing is not recommended, it can be considered for select patients in need of objective response (ClinicalTrials.gov identifier: NCT01824875).
Subject(s)
Neuroendocrine Tumors , Pancreatic Neoplasms , Humans , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Capecitabine/therapeutic use , Dacarbazine/therapeutic use , Neuroendocrine Tumors/drug therapy , Pancreatic Neoplasms/drug therapy , Prospective Studies , Retrospective Studies , Temozolomide/therapeutic use , Treatment OutcomeABSTRACT
BACKGROUND: Neuroendocrine tumor (NET) cell lines frequently express both insulin-like growth factor (IGF) ligand and the cognate IGF-1 receptor (IGF-1R) and, as such, potentially depend on the activation of IGF-1R and its downstream effectors for growth and survival. Preclinical studies suggest that somatostatin analogs and mammalian target of rapamycin (mTOR) inhibitors exhibit antitumor activity against NETs through inhibition of IGF-1-dependent signaling, suggesting that IGF-1R inhibition may be a promising therapeutic approach to NETs. Therefore, the authors of this report evaluated the safety and efficacy of MK-0646, a fully human monoclonal antibody (MoAb) that binds to the IGF-1R, as monotherapy in patients with metastatic, well-differentiated NETs. METHODS: A phase 2 study was performed in which patients received intravenous MK-0646 10 mg/kg once weekly over 1 hour. Archived pretreatment tumor tissue was obtained and genotyped for v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), phosphatidylinositol-3-kinase, catalytic, alpha polypeptide (PIK3CA); and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations, and immunohistochemistry was performed to measure the expression IGF-1R. RESULTS: Twenty-five patients received treatment (40% women; median age, 61 years; age range, 37-83 years), including 15 patients with carcinoid tumors and 10 patients with pancreatic NETs. No partial or complete responses were observed. The median progression-free survival was 4.2 months in the pancreatic NET cohort (range, 0.7-6.7 months) and 2.7 months in the carcinoid cohort (range, 2-3 months). Serious adverse events that were potentially related to MK-0646 included grade 3/4 hyperglycemia in 8 of 25 patients (32%), grade 2 hypersensitivity reaction in 1 of 24 patients (4%), and grade 3 lipase elevation in 1 of 25 patients (4%). CONCLUSIONS: Despite a compelling preclinical rationale, MK-0646 was inactive as a single agent in well-differentiated NETs. Further studies of MK-0646 as a monotherapy in unselected NETs are unwarranted.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Neuroendocrine Tumors/drug therapy , Receptor, IGF Type 1/antagonists & inhibitors , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal, Humanized , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Carcinoid Tumor/drug therapy , Disease-Free Survival , Female , Gene Expression Regulation, Neoplastic/drug effects , Genotype , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neuroendocrine Tumors/pathology , Pancreatic Neoplasms/drug therapy , Receptor, IGF Type 1/metabolism , Treatment FailureABSTRACT
Well-differentiated neuroendocrine tumors (NETs) can be subdivided into carcinoid and pancreatic NETs (pancNETs). Although these tumors share many morphologic and clinical characteristics, carcinoid tumors appear to be far less sensitive to therapeutic agents than pancNETs, and recent advances approved for pancNETs have not been submitted for FDA approval in patients with carcinoid tumors. Treatment options for patients with advanced pancNETs are multidisciplinary and include surgical resection, liver-directed therapies, and systemic therapies. Cytotoxic therapies, such as temozolomide, fluorouracil, oxaliplatin, and streptozocin-based chemotherapy regimens, are active against some pancNETs, and can play a role in the palliation of patients with advanced disease and symptoms related to tumor bulk. Two therapies were recently approved for progressive well-differentiated pancNETs: sunitinib and everolimus. Both agents showed improved progression-free survival in patients with progressive pancNETs, but can also result in nontrivial toxicities, and therefore should only be considered in patients with progressing and advanced or symptomatic disease. This article discusses these recent trials and provides an update of systemic treatment options in patients with well-differentiated pancNETs.
Subject(s)
Neuroendocrine Tumors/drug therapy , Neuroendocrine Tumors/pathology , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Humans , Molecular Targeted Therapy , Neoplasm Staging , Neuroendocrine Tumors/genetics , Pancreatic Neoplasms/geneticsABSTRACT
PURPOSE: Traditional oncology care models have not effectively identified and managed at-risk patients to prevent acute care. A next step is to harness advances in technology to enable patients to report symptoms any time, enabling digital hovering-intensive symptom monitoring and management. Our objective was to evaluate a digital platform that identifies and remotely monitors high-risk patients initiating antineoplastic therapy with the goal of preventing acute care visits. METHODS: This was a single-institution matched cohort quality improvement study conducted at a National Cancer Institute-designated cancer center between January 1, 2019, and March 31, 2020. Eligible patients were those initiating intravenous antineoplastic therapy who were identified as high risk for seeking acute care. Enrolled patients' symptoms were monitored using a digital platform. A dedicated team of clinicians managed reported symptoms. The primary outcomes of emergency department visits and hospitalizations within 6 months of treatment initiation were analyzed using cumulative incidence analyses with a competing risk of death. RESULTS: Eighty-one patients from the intervention arm were matched by stage and disease with contemporaneous high-risk control patients. The matched cohort had similar baseline characteristics. The cumulative incidence of an emergency department visit for the intervention cohort was 0.27 (95% CI, 0.17 to 0.37) at six months compared with 0.47 (95% CI, 0.36 to 0.58) in the control (P = .01) and of an inpatient admission was 0.23 (95% CI, 0.14 to 0.33) in the intervention cohort versus 0.41 (95% CI, 0.30 to 0.51) in the control (P = .02). CONCLUSION: The narrow employment of technology solutions to complex care delivery challenges in oncology can improve outcomes and innovate care. This program was a first step in using a digital platform and a remote team to improve symptom care for high-risk patients.
Subject(s)
Antineoplastic Agents , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Palliative Care , Hospitalization , Emergency Service, Hospital , Cohort StudiesABSTRACT
IMPORTANCE: Electronic patient-reported outcomes (ePROs) may have the potential to improve cancer care delivery by enhancing patient quality of life, reducing acute care visits, and extending overall survival. However, the optimal cadence of ePRO assessments is unknown. OBJECTIVE: To determine patient response preferences and the clinical value associated with a daily cadence for ePROs for patients receiving antineoplastic treatment. DESIGN, SETTING, AND PARTICIPANTS: This quality improvement study of adult patients undergoing antineoplastic treatment assessed a remote monitoring program using ePROs that was developed to manage cancer therapy-related symptoms. ePRO data submitted between October 16, 2018 to February 29, 2020, from a single regional site within the Memorial Sloan Kettering Cancer Center network were included. Data were analyzed from April 2020 to January 2022. EXPOSURE: While undergoing active treatment, patients received a daily ePRO assessment that, based on patient responses, generated yellow (moderate) or red (severe) symptom alerts that were sent to clinicians. MAIN OUTCOMES AND MEASURES: The main outcomes assessed included patient response rate, symptom alert frequency, and an analysis of the clinical value of daily ePROs. RESULTS: A total of 217 patients (median [range] age, 66 [31-92] years; 103 [47.5%] women and 114 [52.5%] men) initiating antineoplastic therapy at high risk for symptoms were monitored for a median (range) of 91 (2-369) days. Most patients had thoracic (59 patients [27.2%]), head and neck (48 patients [22.1%]), or gastrointestinal (43 patients [19.8%]) malignant neoplasms. Of 14Ć¢ĀĀÆ603 unique symptom assessments completed, 7349 (50.3%) generated red or yellow symptom alerts. Symptoms commonly generating alerts included pain (665 assessments [23.0%]) and functional status (465 assessments [16.1%]). Most assessments (8438 assessments [57.8%]) were completed at home during regular clinic hours (ie, 9 am-5 pm), with higher response rates on weekdays (58.4%; 95% CI, 57.5%-59.5%) than on weekend days (51.3%; 95% CI, 49.5%-53.1%). Importantly, 284 of 630 unique red alerts (45.1%) surfaced without a prior yellow alert for the same symptom within the prior 7 days; symptom severity fluctuated over the course of a week, and symptom assessments generating a red alert were followed by an acute care visit within 7 days 8.7% of the time compared with 2.9% for assessments without a red alert. CONCLUSIONS AND RELEVANCE: These findings suggest that daily ePRO assessments were associated with increased insight into symptom management in patients undergoing antineoplastic treatment and symptom alerts were associated with risk of acute care.
Subject(s)
Antineoplastic Agents , Neoplasms , Adult , Aged , Antineoplastic Agents/adverse effects , Female , Humans , Male , Neoplasms/drug therapy , Patient Reported Outcome Measures , Quality of Life , Symptom AssessmentABSTRACT
PURPOSE: Oncology patients are vulnerable to adverse outcomes associated with COVID-19, and clinical deterioration must be identified early. Several institutions launched remote patient monitoring programs (RPMPs) to care for patients with COVID-19. We describe patients' perspectives on a COVID-19 RPMP at a National Comprehensive Cancer Center. METHODS: Patients who tested positive for COVID-19 were eligible. Enrolled patients received a daily electronic COVID-19 symptom assessment, and a subset of high-risk patients also received a pulse oximeter. Monitoring was provided by a centralized team and was discontinued 14 days after a patient's positive test result and following 3 days without worsening symptoms. Patients who completed at least one assessment and exited the program were sent a patient engagement survey to evaluate the patient's experience with digital monitoring for COVID-19. RESULTS: The survey was distributed to 491 patients, and 257 responded (52% completion rate). The net promoter score was 85%. Most patients agreed that the RPMP was worthwhile, enabled better management of their COVID-19 symptoms, made them feel more connected to their healthcare team, and helped prevent emergency room visits. Identified themes regarding patient-perceived value of a RPMP included (1) security: a clinical safety net; (2) connection: a link to their clinical team during a period of isolation; and (3) empowerment: an education on the virus and symptom management. CONCLUSION: RPMPs are perceived to be of value to oncology patients with COVID-19. Policymakers should consider how these programs can be reimbursed to keep vulnerable patients at home and out of the acute care setting.
Subject(s)
COVID-19 , Neoplasms , Humans , Medical Oncology , Monitoring, Physiologic , Neoplasms/therapy , SARS-CoV-2ABSTRACT
OBJECTIVES: Pancreatic neuroendocrine neoplasms include well-differentiated tumors (PanNETs) and poorly differentiated carcinomas (PanNECs). Previous reports suggested a role for platinum-based therapy largely in PanNEC. We sought to investigate the role of platinum-based therapy in pancreatic neuroendocrine neoplasms regardless of tumor grade and differentiation. METHODS: Patients with pancreatic neuroendocrine neoplasms treated with platinum-based therapy at Memorial Sloan Kettering (1994-2016) and Verona University Hospital (2008-2016) were retrospectively identified. Response to treatment by RECIST v1.1, overall survival, and progression-free survival were defined. Among patients with available tissue, DAXX, ATRX, Rb, and p53 expression was evaluated to support the histologic grade of differentiation. RESULTS: Fifty PanNETs, 29 PanNECs, and 22 high-grade tumors with undeterminable differentiation were included. No patients achieved complete response. Overall rate of partial response was 31%, 41% for PanNEC, and 20% for PanNETs. Among PanNETs, partial response was achieved in 33% of G1 (2/6), 10% of G2 (2/19), and 24% of G3 (6/25) tumors. Median overall survival was 29.3 months for PanNETs and 10.9 months for PanNEC (P < 0.001). There was no significant difference in median progression-free survival (P = 0.2). CONCLUSIONS: Platinum-based therapies demonstrated increased activity in PanNEC; however, promising efficacy was also observed in PanNETs, irrespective of grade.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Neuroendocrine/drug therapy , Cell Differentiation , Pancreatic Neoplasms/drug therapy , Platinum Compounds/therapeutic use , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Neuroendocrine/mortality , Carcinoma, Neuroendocrine/pathology , Disease Progression , Female , Humans , Male , Middle Aged , Neoplasm Grading , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Platinum Compounds/adverse effects , Progression-Free Survival , Retrospective Studies , Time FactorsABSTRACT
PURPOSE: The prevalence and clinical characteristics of small bowel adenocarcinomas (SBA) in the setting of Lynch syndrome have not been well studied. We characterized SBA according to DNA mismatch repair and/or microsatellite instability (MMR/MSI) and germline mutation status and compared clinical outcomes. EXPERIMENTAL DESIGN: A single-institution review identified 100 SBAs. Tumors were evaluated for MSI via MSIsensor and/or corresponding MMR protein expression via IHC staining. Germline DNA was analyzed for mutations in known cancer predisposition genes, including MMR (MLH1, MSH2, MSH6, PMS2, and EPCAM). Clinical variables were correlated with MMR/MSI status. RESULTS: Twenty-six percent (26/100; 95% confidence interval, 18.4-35.4) of SBAs exhibited MMR deficiency (MMR-D). Lynch syndrome prevalence was 10% overall and 38.5% among MMR-D SBAs. Median age at SBA diagnosis was similar in non-Lynch syndrome MMR-D versus MMR-proficient (MMR-P) SBAs (65 vs. 61; P = 0.75), but significantly younger in Lynch syndrome (47.5 vs. 61; P = 0.03). The prevalence of synchronous/metachronous cancers was 9% (6/67) in MMR-P versus 34.6% (9/26) in MMR-D SBA, with 66.7% (6/9) of these in Lynch syndrome (P = 0.0002). In the MMR-P group, 52.2% (35/67) of patients presented with metastatic disease, compared with 23.1% (6/26) in the MMR-D group (P = 0.008). In MMR-P stage I/II patients, 88.2% (15/17) recurred, compared with 18.2% (2/11) in the MMR-D group (P = 0.0002). CONCLUSIONS: When compared with MMR-P SBA, MMR-D SBA was associated with earlier stage disease and lower recurrence rates, similar to observations in colorectal cancer. With a 38.5% prevalence in MMR-D SBA, germline Lynch syndrome testing in MMR-D SBA is warranted.
Subject(s)
Adenocarcinoma/pathology , Biomarkers, Tumor/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/pathology , DNA Mismatch Repair , Germ-Line Mutation , Intestinal Neoplasms/pathology , Intestine, Small/pathology , Adenocarcinoma/genetics , Adenocarcinoma/therapy , Adult , Aged , Aged, 80 and over , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/therapy , Female , Follow-Up Studies , Humans , Intestinal Neoplasms/genetics , Intestinal Neoplasms/therapy , Male , Microsatellite Instability , Middle Aged , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/therapy , Neoplasms, Multiple Primary/genetics , Neoplasms, Multiple Primary/pathology , Neoplasms, Multiple Primary/therapy , Prognosis , Retrospective StudiesABSTRACT
PURPOSE: Adrenocortical carcinomas (ACC) are rare and aggressive malignancies with limited treatment options. This study was undertaken to evaluate the immunogenicity of ACC. PATIENTS AND METHODS: Patients with advanced ACC were enrolled in a phase II study to evaluate the clinical activity of pembrolizumab 200 mg every 3 weeks, without restriction on prior therapy. The primary end point was objective response rate. Efficacy was correlated with tumor programmed death-ligand 1 expression, microsatellite-high and/or mismatch repair deficient (MSI-H/MMR-D) status, and somatic and germline genomic correlates. RESULTS: We enrolled 39 patients with advanced ACC and herein report after a median follow-up of 17.8 months (range, 5.4 months to 34.7 months). The objective response rate to pembrolizumab was 23% (nine patients; 95% CI, 11% to 39%), and the disease control rate was 52% (16 patients; 95% CI, 33% to 69%). The median duration of response was not reached (lower 95% CI, 4.1 months). Two of six patients with MSI-H/MMR-D tumors responded. The other seven patients with objective responses had microsatellite stable tumors. The median progression-free survival was 2.1 months (95% CI, 2.0 months to 10.7 months), and the median overall survival was 24.9 months (95% CI, 4.2 months to not reached). Thirteen percent of patients (n = 5) had treatment-related grade 3 or 4 adverse events. Tumor programmed death-ligand 1 expression and MSI-H/MMR-D status were not associated with objective response. CONCLUSION: MSI-H/MMR-D tumors, for which pembrolizumab is a standard therapy, are more common in ACC than has been recognized. In advanced ACC that is microsatellite stable, pembrolizumab provided clinically meaningful and durable antitumor activity with a manageable safety profile.
Subject(s)
Adrenal Cortex Neoplasms/drug therapy , Adrenocortical Carcinoma/drug therapy , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Agents, Immunological/administration & dosage , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Adrenal Cortex Neoplasms/diagnostic imaging , Adrenal Cortex Neoplasms/immunology , Adrenocortical Carcinoma/diagnostic imaging , Adrenocortical Carcinoma/immunology , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Agents, Immunological/adverse effects , Drug Administration Schedule , Female , Humans , Male , Middle Aged , Programmed Cell Death 1 Receptor/immunology , Survival Rate , Young AdultABSTRACT
This article is the result of the North American Neuroendocrine Tumor Society consensus conference on the medical management of pancreatic neuroendocrine tumors from July 19 to 20, 2018. The guidelines panel consisted of medical oncologists, pathologists, gastroenterologists, endocrinologists, and radiologists. The panel reviewed a series of questions regarding the medical management of patients with pancreatic neuroendocrine tumors as well as questions regarding surveillance after resection. The available literature was reviewed for each of the question and panel members voted on controversial topics, and the recommendations were included in a document circulated to all panel members for a final approval.
Subject(s)
Neuroendocrine Tumors/diagnosis , Neuroendocrine Tumors/therapy , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/therapy , Practice Guidelines as Topic , Consensus , Consensus Development Conferences as Topic , Humans , Neuroendocrine Tumors/classification , Pancreatic Neoplasms/classification , Societies, Medical , United StatesABSTRACT
PURPOSE: To create a risk prediction model that identifies patients at high risk for a potentially preventable acute care visit (PPACV). PATIENTS AND METHODS: We developed a risk model that used electronic medical record data from initial visit to first antineoplastic administration for new patients at Memorial Sloan Kettering Cancer Center from January 2014 to September 2018. The final time-weighted least absolute shrinkage and selection operator model was chosen on the basis of clinical and statistical significance. The model was refined to predict risk on the basis of 270 clinically relevant data features spanning sociodemographics, malignancy and treatment characteristics, laboratory results, medical and social history, medications, and prior acute care encounters. The binary dependent variable was occurrence of a PPACV within the first 6 months of treatment. There were 8,067 observations for new-start antineoplastic therapy in our training set, 1,211 in the validation set, and 1,294 in the testing set. RESULTS: A total of 3,727 patients experienced a PPACV within 6 months of treatment start. Specific features that determined risk were surfaced in a web application, riskExplorer, to enable clinician review of patient-specific risk. The positive predictive value of a PPACV among patients in the top quartile of model risk was 42%. This quartile accounted for 35% of patients with PPACVs and 51% of potentially preventable inpatient bed days. The model C-statistic was 0.65. CONCLUSION: Our clinically relevant model identified the patients responsible for 35% of PPACVs and more than half of the inpatient beds used by the cohort. Additional research is needed to determine whether targeting these high-risk patients with symptom management interventions could improve care delivery by reducing PPACVs.