ABSTRACT
INTRODUCTION: Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer in the White population. Unfortunately, the prognosis of advanced cSCC is poor, and management can be challenging. Until recently, the choice of systemic medications was limited, and those that were available had modest efficacy. Cemiplimab is an anti-programmed cell-death protein 1 inhibitor and the first immunotherapeutic agent approved for the treatment of metastatic or locally advanced cSCC. The purpose of this study was to evaluate the efficacy of cemiplimab when used as adjuvant or neoadjuvant therapy in patients treated at our institution. METHODS: A retrospective review of patients with locally advanced or metastatic cSCC who were treated with cemiplimab as adjuvant or neoadjuvant therapy at a single institution between February 2019 and November 2022 was performed. Response to treatment was objectively assessed based on Response Evaluation Criteria in Solid Tumors, version 1.1, criteria. The primary end point was objective response rate. Secondary endpoints included time to observed response, disease-control rate, progression-free survival, overall survival, and adverse effects of therapy. RESULTS: A total of 6 patients were identified with a median age of 79 years (range, 51-90 years). Four patients had locally advanced cSCC, and 2 had distant metastasis. Cemiplimab was used as adjuvant therapy in 3 patients and neoadjuvant therapy in 2 patients. There was 1 patient in which it was used for limb salvage, who would have otherwise required an amputation. Objective response rate, complete response, and partial response were 66% (4 of 6), 33% (2 of 6), and 33% (2 pf 6), respectively. Average time to observed response was 2.9 months. Disease-control rate was 83% (5 of 6), and average progression-free survival was 10 months. Toxicity was reported in 2 patients, both of which were grade 1 severity. CONCLUSIONS: Cemiplimab has established its utility in the treatment of advanced cSCC, demonstrating clinical efficacy while generally having a tolerable adverse effect profile. Our preliminary results suggest that cemiplimab has potential as an adjuvant or neoadjuvant therapy in combination with surgery for treatment of cSCC.
Subject(s)
Carcinoma, Squamous Cell , Skin Neoplasms , Humans , Middle Aged , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/pathology , Skin Neoplasms/drug therapy , Skin Neoplasms/pathology , Neoadjuvant Therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/adverse effectsABSTRACT
BACKGROUND: Multiple international organizations have called for exercise to become standard practice in the setting of oncology care. The feasibility of integrating exercise within systemic chemotherapy has not been investigated. METHODS: Patients slated to receive infusion therapy between April 2017 and October 2018 were screened for possible inclusion. The study goal was to establish the acceptability and feasibility of embedding an exercise professional into the chemotherapy infusion suite as a method of making exercise a standard part of cancer care. The exercise prescriptions provided to patients were individualized according to results of brief baseline functional testing. RESULTS: In all, 544 patients were screened, and their respective treating oncologists deemed 83% of them to be medically eligible to participate. After further eligibility screening, 226 patients were approached. Nearly 71% of these patients (n = 160) accepted the invitation to participate in the Exercise in All Chemotherapy trial. Feasibility was established because 71%, 55%, 69%, and 63% of the aerobic, resistance, balance, and flexibility exercises prescribed to patients were completed. Qualitative data also supported the acceptability and feasibility of the intervention from the perspective of patients and clinicians. The per-patient cost of the intervention was $190.68 to $382.40. CONCLUSIONS: Embedding an exercise professional into the chemotherapy infusion suite is an acceptable and feasible approach to making exercise standard practice. Moreover, the cost of the intervention is lower than the cost of other common community programs. Future studies should test whether colocating an exercise professional with infusion therapy could reach more patients in comparison with not colocating. LAY SUMMARY: Few studies have tested the implementation of exercise for patients with cancer by embedding an exercise professional directly into the chemotherapy infusion suite. The Exercise in All Chemotherapy trial shows that this approach is both acceptable and feasible from the perspective of clinicians and patients.
Subject(s)
Antineoplastic Agents/therapeutic use , Exercise , Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Costs and Cost Analysis , Feasibility Studies , Female , Humans , Male , Middle Aged , Neoplasms/drug therapy , Patient Safety , Patient Selection , Physical Functional Performance , Program Development/economicsABSTRACT
BACKGROUND: DNA damage response (DDR) genomic alterations may play an important role in clinical outcomes of patients with urothelial cancer (UC). However, data on the prognostic role of DDR gene alterations in patients with advanced UC remain unclear. MATERIALS AND METHODS: We retrospectively collected data of three independent patient cohorts with relapsed or advanced UC including 81 and 91 patients from four institutions who underwent FoundationOne genomic sequencing as well as 129 patients selected from The Cancer Genome Atlas bladder cohort. Fisher's exact test was used to determine differences of mutation frequency among the three cohorts. Logistic regression analysis was performed to calculate odds ratio (OR) and 95% confidence interval (CI). Overall survival (OS) was measured from time of initial diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% CI. RESULTS: DDR genomic alterations were present in 76.5% (62/81), 40.7% (37/91), and 51.2% (66/129) of the three cohorts. ATM alterations consistently correlated with significantly shorter OS, whereas other DDR alterations (excluding ATM) were associated with better prognosis. In 152 patients treated with platinum pooled from the three cohorts, the prognostic value of alterations in ATM as compared with other predefined DDR genes was substantially different (ATM: adjusted HR [HR], 2.03; 95% CI, 1.03-4; p = .04; other DDR: adjusted HR, 0.49; 95% CI, 0.31-0.8; p = .003). CONCLUSIONS: Genomic alterations in ATM and other DDR genes may have opposite prognostic value in relapsed and/or advanced UC. ATM may have a complex role in UC progression. IMPLICATIONS FOR PRACTICE: Somatic mutations of DNA damage response (DDR) genes are frequently found in urothelial cancer and appear to play an important role in tumorigenesis, progression, treatment response, and outcomes. In a set of DDR genes, ATM alterations were associated with worse survival, while other alterations were associated with better survival in advanced urothelial cancer. The results of this study suggest a complex role of ATM in tumor progression and call for further studies to determine the underlying mechanisms and biomarker clinical utility.
Subject(s)
DNA Damage , Neoplasm Recurrence, Local , DNA Damage/genetics , Genomics , Humans , Mutation , Prognosis , Retrospective StudiesABSTRACT
Drug combinations acting synergistically to kill cancer cells have become increasingly important in melanoma as an approach to manage the recurrent resistant disease. Protein kinase B (AKT) is a major target in this disease but its inhibitors are not effective clinically, which is a major concern. Targeting AKT in combination with WEE1 (mitotic inhibitor kinase) seems to have potential to make AKT-based therapeutics effective clinically. Since agents targeting AKT and WEE1 have been tested individually in the clinic, the quickest way to move the drug combination to patients would be to combine these agents sequentially, enabling the use of existing phase I clinical trial toxicity data. Therefore, a rapid preclinical approach is needed to evaluate whether simultaneous or sequential drug treatment has maximal therapeutic efficacy, which is based on a mechanistic rationale. To develop this approach, melanoma cell lines were treated with AKT inhibitor AZD5363 [4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide] and WEE1 inhibitor AZD1775 [2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one] using simultaneous and sequential dosing schedules. Simultaneous treatment synergistically reduced melanoma cell survival and tumor growth. In contrast, sequential treatment was antagonistic and had a minimal tumor inhibitory effect compared with individual agents. Mechanistically, simultaneous targeting of AKT and WEE1 enhanced deregulation of the cell cycle and DNA damage repair pathways by modulating transcription factors p53 and forkhead box M1, which was not observed with sequential treatment. Thus, this study identifies a rapid approach to assess the drug combinations with a mechanistic basis for selection, which suggests that combining AKT and WEE1 inhibitors is needed for maximal efficacy.
Subject(s)
Forkhead Box Protein M1/metabolism , Multiple Myeloma/drug therapy , Pyrazoles/administration & dosage , Pyrimidines/administration & dosage , Pyrroles/administration & dosage , Tumor Suppressor Protein p53/metabolism , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Administration Schedule , Drug Antagonism , Drug Screening Assays, Antitumor , Drug Synergism , Drug Therapy, Combination , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mice , Multiple Myeloma/metabolism , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Pyrimidinones , Pyrroles/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
Circulating tumor cells (CTCs) are important targets for cancer biology studies. To further elucidate the role of CTCs in cancer metastasis and prognosis, effective methods for isolating extremely rare tumor cells from peripheral blood must be developed. Acoustic-based methods, which are known to preserve the integrity, functionality, and viability of biological cells using label-free and contact-free sorting, have thus far not been successfully developed to isolate rare CTCs using clinical samples from cancer patients owing to technical constraints, insufficient throughput, and lack of long-term device stability. In this work, we demonstrate the development of an acoustic-based microfluidic device that is capable of high-throughput separation of CTCs from peripheral blood samples obtained from cancer patients. Our method uses tilted-angle standing surface acoustic waves. Parametric numerical simulations were performed to design optimum device geometry, tilt angle, and cell throughput that is more than 20 times higher than previously possible for such devices. We first validated the capability of this device by successfully separating low concentrations (â¼100 cells/mL) of a variety of cancer cells from cell culture lines from WBCs with a recovery rate better than 83%. We then demonstrated the isolation of CTCs in blood samples obtained from patients with breast cancer. Our acoustic-based separation method thus offers the potential to serve as an invaluable supplemental tool in cancer research, diagnostics, drug efficacy assessment, and therapeutics owing to its excellent biocompatibility, simple design, and label-free automated operation while offering the capability to isolate rare CTCs in a viable state.
Subject(s)
Acoustics , Cell Separation/methods , Neoplastic Cells, Circulating/pathology , Breast Neoplasms/blood , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation , Cell Survival , Electricity , Female , Fluorescent Antibody Technique , High-Throughput Screening Assays , HumansABSTRACT
BACKGROUND: Breast angiosarcoma is a rare malignancy with limited publications confined to small retrospective case reviews and case reports. Knowledge of this disease is limited because information from previous studies is insufficient and inconsistent. METHODS: We obtained data from the Surveillance, Epidemiology, and End Results Program for non-metastatic primary and secondary breast angiosarcoma, and performed analysis to determine clinicopathological characteristics and estimate their associations with overall survival (OS). RESULTS: Median age was 50-54 years in primary breast angiosarcoma and 70-74 years in secondary breast angiosarcoma, while median OS was 93 and 32 months, respectively. Age, tumor grade and tumor spread were associated with poor survival outcomes. Compared with primary breast angiosarcoma, patients with secondary breast angiosarcoma had a "nominal" increased death risk (HR = 1.89, 95% CI, 1.43-2.50, p < 0.001), which was driven by older age and more aggressive tumor phenotype at presentation. Mastectomy was associated with worse OS compared with breast conservative surgery (BCS) (adjHR = 2.47, 95% CI, 1.29-4.74) in primary angiosarcoma patients. Adjuvant radiation was associated with worse OS in secondary angiosarcoma patients (adjHR =1.77, 95% CI, 1.01-3.12). CONCLUSIONS: There is a "nominal" increased death risk in secondary breast angiosarcoma due to advanced clinicopathological features. Both BCS and mastectomy are feasible in primary and secondary angiosarcoma if R0 can be achieved. Routine radiation in unselected breast angiosarcoma should be cautious because there is no survival benefit in primary AS and appeared to be associated with a worse OS in secondary AS.
Subject(s)
Breast Neoplasms/pathology , Hemangiosarcoma/pathology , Neoplasms, Second Primary/pathology , Aged , Breast Neoplasms/therapy , Combined Modality Therapy , Female , Follow-Up Studies , Hemangiosarcoma/therapy , Humans , Middle Aged , Neoplasm Grading , Neoplasms, Second Primary/therapy , Prognosis , Retrospective Studies , Survival RateABSTRACT
Familial atypical multiple mole melanoma syndrome (FAMMM) is characterised by dysplastic naevi, malignant melanoma and pancreatic cancer. Given that large deletions involving CDKN2A (cyclin-dependent kinase inhibitor 2A) account for only 2% of cases, we describe a family that highlights the co-occurrence of both melanoma and neural system tumours to aid clinical recognition and propose a management strategy. A patient with multiple neurofibromas was referred with a provisional diagnosis of neurofibromatosis type 1 (NF1). Prior molecular testing, though, had failed to identify an NF1 mutation by sequencing and multiplex ligation-dependent probe amplification. His family history was significant for multiple in situ/malignant melanomas at young ages and several different cancers reminiscent of an underlying syndrome. A search of the Familial Cancer Database, FaCD Online, highlighted several families with cutaneous melanoma and nervous system tumours who were subsequently identified to have large deletions spanning CDKN2A Although sequencing of CDKN2A and TP53 failed to identify a mutation, a heterozygous CDKN2A deletion was identified by targeted array comparative genomic hybridisation (CGH). Whole-genome oligonucleotide array CGH and SNP analysis identified an interstitial deletion of at least 1.5 Mb within 9p21.3 and spanning approximately 25 genes. Identification of the underlying molecular abnormality permits predictive testing for at-risk relatives. Given the young cancer diagnoses, a surveillance regimen was developed and a clinical team organised for ongoing management so that genetic testing could be offered to both adults and minor children. Surveillance recommendations addressed cancer risks associated with FAMMM, and other cancers exhibited by this family with a large contiguous gene deletion.
ABSTRACT
BACKGROUND: Platinum-based neoadjuvant chemotherapy has been shown to improve survival outcomes in muscle-invasive bladder cancer patients. We performed a systematic review and meta-analysis to provide updated results of previous findings. We also summarized published data to compare clinical outcomes of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) versus gemcitabine and cisplatin/carboplatin (GC) in the neoadjuvant setting. METHODS: A meta-analysis of 15 randomized clinical trials was performed to compare neoadjuvant chemotherapy plus local treatment with the same local treatment alone. Because no randomized trials have investigated MVAC versus GC in the neoadjuvant setting, a meta-analysis of 13 retrospective studies was performed to compare MVAC with GC. RESULTS: A total of 3,285 patients were included in 15 randomized clinical trials. There was a significant overall survival (OS) benefit associated with cisplatin-based neoadjuvant chemotherapy (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.79-0.96). A total of 1,766 patients were included in 13 retrospective studies. There was no significant difference in pathological complete response between MVAC and GC. However, GC was associated with a significantly reduced overall survival (HR, 1.26; 95% CI, 1.01-1.57). After excluding carboplatin data, GC still seemed to be inferior to MVAC in OS (HR, 1.31; 95% CI, 0.99-1.74), but the difference was no longer statistically significant. CONCLUSION: These results support the use of cisplatin-based combination neoadjuvant chemotherapy in muscle-invasive bladder cancer. Although GC and MVAC had similar treatment response rates, the different survival outcome observed in this study requires further investigation. IMPLICATIONS FOR PRACTICE: Platinum-based neoadjuvant chemotherapy (NCT) has been shown to improve survival outcomes in muscle-invasive bladder cancer (MIBC) patients, but the optimal neoadjuvant regimen has not been established. Methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) and gemcitabine and cisplatin/carboplatin (GC) are two of the most commonly used chemotherapy regimens in modern oncology. In this two-step meta-analysis, an updated and more precise estimate of the survival benefit of cisplatin-based NCT in MIBC is provided. This study also demonstrated that MVAC might have superior overall survival compared with GC (with or without carboplatin data) in the neoadjuvant setting. The findings suggest that NCT should be standard care in MIBC, and MVAC could be the preferred neoadjuvant regimen.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Urinary Bladder Neoplasms/drug therapy , Chemotherapy, Adjuvant , Cisplatin/administration & dosage , Humans , Neoadjuvant Therapy , Neoplasm Invasiveness , Urinary Bladder Neoplasms/mortality , Urinary Bladder Neoplasms/pathologySubject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Leukemia, Myeloid, Acute/drug therapy , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Decitabine/administration & dosage , Decitabine/adverse effects , Female , Humans , Male , Middle AgedABSTRACT
A teenage girl presented with multiple warty skin lesions and had a diagnosis of epidermodysplasia verruciformis made several years later. Later in life she presented with an extensive SCC in situ in her gluteal crease that was surgically resected with wide margins. Despite this treatment, the lesion recurred with extension onto her lower back. Biopsies at the time confirmed SCC in situ of the perianal tissue and invasive SCC above her gluteal cleft.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Squamous Cell/drug therapy , Epidermodysplasia Verruciformis/complications , Skin Neoplasms/drug therapy , Adolescent , Antibodies, Monoclonal, Humanized/administration & dosage , Biopsy , Capecitabine , Carcinoma in Situ/drug therapy , Carcinoma in Situ/pathology , Carcinoma in Situ/virology , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/virology , Cetuximab , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Epidermodysplasia Verruciformis/pathology , Female , Fluorouracil/administration & dosage , Fluorouracil/analogs & derivatives , Humans , Neoplasm Invasiveness , Palliative Care/methods , Perineum/pathology , Skin Neoplasms/pathology , Skin Neoplasms/virologyABSTRACT
Renal cell carcinoma (RCC) is not a single entity, rather it is a term defining a group of histologically distinct tumors arising in the renal parenchyma. Each histologic subtype is clinically and genetically unique. It is our understanding of the genetic basis for these cancers that has led to the variety of targeted systemic therapies now available in RCC. This review will cover the basic tumor biology behind each histology, as well as the associated therapeutic targets identified thus far. Mechanisms and associated side effects of the currently available drugs will be examined. Completed clinical trials will be discussed, leading into the rationale behind currently active trials, and future directions for drug development.
Subject(s)
Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/genetics , Kidney Neoplasms/drug therapy , Kidney Neoplasms/genetics , Clinical Trials as Topic , Humans , Molecular Targeted TherapyABSTRACT
In order to effectively treat melanoma, targeted inhibition of key m-echanistic events regulating melanoma development such as cell proliferation, survival, angiogenesis and invasion or metastasis needs to be accomplished. The Mitogen Activated Protein Kinase (MAPK) pathway has been identified as a key player in melanoma development making this cascade an important therapeutic target. However, identification of the ideal pathway member to therapeutically target for maximal clinical benefit remains a challenge. In normal cells, the MAPK pathway relays extracellular signals from the cell membrane to the nucleus via a cascade of phosphorylation events, which promote cancer development. Dysregulation of the MAPK pathway occurs frequently in many human cancers including melanoma. Mutations in the B-RAF and RAS genes, genetic or epigenetic modifications are the key aberrations observed in this signaling cascade. Constitutive activation of this pathway causes oncogenic transformation of cells by promoting cell proliferation, invasion, metastasis, migration, survival and angiogenesis. This review provides an overview of (a) key members of MAPK signaling regulating melanoma development; (b) key proteins which can serve as biomarkers to assess disease progression; (c) the clinical efficacy of various pharmacological agents targeting MAPK pathway; (d) current clinical trials evaluating downstream targets of the MAPK pathway; (e) issues associated with pharmacological agents such as drug resistance, induction of cancers; and finally (e) various strategies overcoming drug resistance.
Subject(s)
Melanoma/drug therapy , Skin Neoplasms/drug therapy , Clinical Trials as Topic , Drug Delivery Systems , Drug Resistance, Neoplasm , Humans , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/physiologyABSTRACT
BACKGROUND: Patients with bladder cancer (BC) who are cisplatin ineligible or have unresectable disease have limited treatment options. Previously, we showed targeting programmed death-ligand 1 (PD-L1) with durvalumab (durva) and radiation therapy (RT) combination was safe in BC. We now report results from a phase II study evaluating the toxicity and efficacy of durva and RT in localized BC. METHODS: This is a single-arm, multi-institutional phase II study; N=26. Enrolled patients had pure or mixed urothelial BC (T2-4 N0-2 M0) with unresectable tumors and were unfit for surgery or cisplatin ineligible. Patients received durva concurrently with RT ×7 weeks, followed by adjuvant durva × 1 year. PRIMARY ENDPOINTS: (A) progression-free survival (PFS) at 1 year and (B) disease control rate (DCR) post adjuvant durva. Key secondary endpoints: (A) complete response (CR) post durvaRT (8 weeks), (B) overall survival (OS), (C) PFS and (D) toxicity. Correlative studies included evaluation of baseline tumor and blood (baseline, post durvaRT) for biomarkers. RESULTS: Median follow-up was 27 months. Evaluable patients: 24/26 post durvaRT, 22/26 for DCR post adjuvant durva, all patients for PFS and OS. Post adjuvant durva, DCR was seen in 72.7%, CR of 54.5%. 1-year PFS was 71.5%, median PFS was 21.8 months. 1-year OS was 83.8%, median OS was 30.8 months. CR at 8 weeks post durvaRT was 62.5%. Node positive (N+) patients had similar median PFS and OS. DurvaRT was well tolerated. Grade ≥3 treatment-related adverse events: anemia, high lipase/amylase, immune-nephritis, transaminitis, dyspnea (grade 4-COPD/immune), fatigue, rash, diarrhea and scleritis. No difference in outcome was observed with PD-L1 status of baseline tumor. Patients with CR/PR or SD had an increase in naïve CD4 T cells, a decrease in PD-1+CD4 T cells at baseline and an increase in cytokine-producing CD8 T cells, including interferon gamma (IFNγ) producing cells, in the peripheral blood. CONCLUSION: Durva with RT followed by adjuvant durva was safe with promising efficacy in localized BC patients with comorbidities, including N+ patients. Larger randomized studies, like S1806 and EA8185, are needed to evaluate the efficacy of combining immunotherapy and RT in BC. TRIAL REGISTRATION NUMBER: NCT02891161.
Subject(s)
Antibodies, Monoclonal , B7-H1 Antigen , Urinary Bladder Neoplasms , Humans , Antibodies, Monoclonal/therapeutic use , Cisplatin , Urinary Bladder Neoplasms/drug therapyABSTRACT
BACKGROUND: Cancer diagnosis can adversely affect mental well-being and overall clinical outcome. We evaluated the efficacy of a group-led creative writing workshop (CWW) on mood in patients with cancer prospectively. METHODS: We conducted a single-institution phase II study. Sixty adult patients with cancer (any type or stage) were randomised 2:1 to CWW (4×CWW sessions, bimonthly over 8 weeks) versus active control (AC) (independent writing at home with the help of a book, four sessions, bimonthly over 8 weeks). The total study duration was 6 months with a follow-up of up to 3 months. PRIMARY OBJECTIVE: changes in overall mood, depression and anxiety symptoms before and after intervention in both arms. Emotional Thermometer Scale (ETS) was used to assess changes in patients' mood. Additionally, the Patient Health Questionnaire (PHQ)-9 and General Anxiety Disorder Scale (GAD)-7 were used to evaluate depression and anxiety symptoms. RESULTS: Of 50 evaluable patients (CWW 34, AC 17), 26 patients in the CWW arm attended at least one class and 19 attended at least four classes. Patients in CWW had significant immediate improvement in the overall ETS (post vs preclass scores; p<0.0001, 95% CI -4.31 to -2.47). Four of the five subscale ETS scores were significantly lower for the CWW arm: distress (p=0.0346, 95% CI -2.6 to -0.1), anxiety (p=0.0366, 95% CI -4.1 to -0.2), depression (p=0.0441, 95% CI -3.9 to -0.1) and anger (p=0.0494, 95% CI -3.3 to 0). No significant differences were seen in the AC arm. No significant differences were observed in the PHQ-9 or the GAD-7 scores. CONCLUSION: CWW had a positive effect on mood based on ETS scores, suggesting a potential therapeutic benefit among patients with cancer.
Subject(s)
Cognitive Behavioral Therapy , Neoplasms , Adult , Affect , Anxiety/therapy , Depression/therapy , Humans , Neoplasms/complications , Neoplasms/therapy , Treatment Outcome , WritingABSTRACT
BACKGROUND: Patients with metastatic urothelial carcinoma (mUC) have poor prognosis, so further development of novel combinations for these patients is needed. OBJECTIVE: To assess the safety and efficacy of eribulin mesylate (eribulin) with avelumab in mUC. DESIGN, SETTING, AND PARTICIPANTS: This was an open-label, phase 1b study in which patients with mUC who were cisplatin-ineligible and treatment-naïve or platinum-resistant were treated with eribulin and avelumab. A 3 + 3 design was used. The study was prematurely terminated because the free study drug became unavailable, but we performed extended follow-up for patients enrolled in the study. INTERVENTION: Patients received eribulin 1.1 mg/m2 plus avelumab 10 mg/kg on days 1 and 15 in every 28-d cycle in cohort 0, or eribulin 1.4 mg/m2 plus avelumab 10 mg/kg on days 1 and 15 in every 28-d cycle in cohort +1. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary objectives were to determine the maximum tolerated dose (MTD) of eribulin with avelumab and assess the objective response rate. A key secondary endpoint was to assess efficacy by evaluating the disease control rate. Exploratory endpoints included PD-1 expression on T cells in peripheral blood and in tumor cells, and tumor DNA sequencing. RESULTS AND LIMITATIONS: A total of six patients were enrolled in the MTD group (n = 3 in cohort 0 and n = 3 in cohort +1). No dose-limiting toxicity (DLT) was observed in cohort 0, whereas two DLT events were observed in cohort +1. Two patients in cohort 0 had a partial response that was durable, with one patient having a durable response for 7.8 mo. Disease control was observed in 4/6 patients (66.7%). Owing to the early termination, MTD could not be determined. CONCLUSIONS: While early termination of this trial precludes any definitive conclusions, the combination of eribulin and avelumab shows promise in mUC. We observed that treatment was better tolerated and efficacious at lower doses of eribulin. Further research is warranted for this combination in mUC. PATIENT SUMMARY: We evaluated different doses of eribulin (a chemotherapy drug) in combination with a fixed dose of avelumab (an antibody used to treat several different cancers) in a small group of patients with metastatic cancer of the urinary tract. The lower dose of eribulin was easier to tolerate and the combination had an anti-cancer effect. This trial is registered at ClinicalTrials.gov as NCT03502681.
Subject(s)
Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Transitional Cell/drug therapy , Furans , Humans , Ketones , Urinary Bladder Neoplasms/drug therapyABSTRACT
Tyrosine kinase is a key enzyme activity utilized in many intracellular messaging pathways. Understanding the role of particular tyrosine kinases in malignancies has allowed for the design of tyrosine kinase inhibitors (TKIs), which can target these enzymes and interfere with downstream signaling. TKIs have proven to be successful in the treatment of chronic myeloid leukemia, renal cell carcinoma and gastrointestinal stromal tumor, and other malignancies. Scattered reports have suggested that these agents appear to affect blood glucose (BG). We retrospectively studied the BG concentrations in diabetic (17) and nondiabetic (61) patients treated with dasatinib (8), imatinib (39), sorafenib (23), and sunitinib (30) in our clinical practice. Mean declines of BG were dasatinib (53 mg/dL), imatinib (9 mg/dL), sorafenib (12 mg/dL), and sunitinib (14 mg/dL). All these declines in BG were statistically significant. Of note, 47% (8/17) of the patients with diabetes were able to discontinue their medications, including insulin in some patients. Only one diabetic patient developed symptomatic hypoglycemia while on sunitinib. The mechanism for the hypoglycemic effect of these drugs is unclear, but of the four agents tested, c-kit and PDGFRß are the common target kinases. Clinicians should keep the potential hypoglycemic effects of these agents in mind; modification of hypoglycemic agents may be required in diabetic patients. These results also suggest that inhibition of a tyrosine kinase, be it c-kit, PDGFRß or some other undefined target, may improve diabetes mellitus BG control and it deserves further study as a potential novel therapeutic option.
Subject(s)
Antineoplastic Agents/therapeutic use , Benzenesulfonates/therapeutic use , Blood Glucose/drug effects , Diabetes Mellitus/drug therapy , Hypoglycemic Agents/therapeutic use , Indoles/therapeutic use , Neoplasms/drug therapy , Piperazines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyridines/therapeutic use , Pyrimidines/therapeutic use , Pyrroles/therapeutic use , Thiazoles/therapeutic use , Aged , Antineoplastic Agents/adverse effects , Benzamides , Benzenesulfonates/adverse effects , Dasatinib , Diabetes Mellitus/blood , Female , Humans , Hypoglycemia/blood , Hypoglycemia/chemically induced , Hypoglycemic Agents/adverse effects , Imatinib Mesylate , Indoles/adverse effects , Linear Models , Male , Middle Aged , Neoplasms/enzymology , Niacinamide/analogs & derivatives , Pennsylvania , Phenylurea Compounds , Piperazines/adverse effects , Protein Kinase Inhibitors/adverse effects , Protein-Tyrosine Kinases/metabolism , Pyridines/adverse effects , Pyrimidines/adverse effects , Pyrroles/adverse effects , Retrospective Studies , Risk Assessment , Risk Factors , Sorafenib , Sunitinib , Thiazoles/adverse effects , Time Factors , Treatment OutcomeABSTRACT
OBJECTIVE: No standard therapeutic option exists for men with prostate cancer who have failed local therapy, have no gross metastatic disease, and whose only manifestation of disease is a rising prostate-specific antigen (PSA) level. Soy products are able to affect PSA kinetics in some men with prostate cancer, and this effect has been attributed to the decreased expression of the androgen receptor and other mechanisms. METHODS: We treated 10 men with rising PSA levels after radical prostatectomy and salvage radiotherapy with commercially available soy products. Scans revealed no gross metastatic disease. Three men also had been receiving androgen-deprivation therapy (ADT) and had rising PSA levels that were consistent with castration-resistant (CR) disease. We reported the results of this modality on PSA levels, PSA kinetics, and the duration of PSA response. RESULTS: Responses occurred in 4 of 7 (57%) patients with ADT-naïve disease and 1 of 3 (33%) patients with CR disease. The median duration of treatment response was 24 months. The overall clinical benefit, therefore, was noted in 5 of 10 (50%) patients. Therapy was well tolerated. CONCLUSIONS: Our findings are fairly congruent with what has been described in the literature on the use of this modality in prostate cancer. We used commercially available soy products. We also show that soy can provide benefit in CR prostate cancer. Our clinical experience suggests that soy supplementation using commercially available soy products can have durable beneficial effects on PSA levels and PSA kinetics in some men with prostate cancer.
Subject(s)
Prostate-Specific Antigen/metabolism , Prostatic Neoplasms/diet therapy , Salvage Therapy , Soy Foods , Aged , Aged, 80 and over , Androgen Antagonists/therapeutic use , Antineoplastic Agents, Hormonal/therapeutic use , Humans , Male , Middle Aged , Prostatectomy , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/therapy , Retrospective Studies , Soy Milk , Treatment OutcomeABSTRACT
Background: We hypothesized that the addition of receptor tyrosine kinase inhibitors (RTKis, e.g., lapatinib, erlotinib, cetuximab, bevacizumab, panitumumab) to radiotherapy-based treatment for solid tumors does not increase overall survival but may increase toxicity. Methods: Population, Intervention, Control, Outcome, Study Design; Preferred Reporting Items for Systematic Reviews and Meta-Analyses; and Meta-analysis of Observational Studies in Epidemiology methods were used to identify prospective randomized studies including patients with solid tumor cancers treated with radiotherapy with or without RTKis. Extracted variables included use of radiotherapy vs chemoradiotherapy, RTKi type (antibody vs small molecule), outcomes, and toxicities. The primary endpoint was overall survival; the secondary endpoint was grade 3+ toxicity. Random-effects meta-analyses were performed for each outcome measure. All statistical tests were 2-sided. Results: A total of 405 studies met the initial search criteria, of which 13 prospective randomized trials of radiotherapy with or without RTKi met the inclusion criteria, encompassing 5678 patients. The trials included cancers of the head and neck (6 trials, 3295 patients), esophagus (3 trials, 762 patients), lung (2 trials, 550 patients), and brain (2 trials, 1542 patients). Three studies evaluated a small molecule and radiotherapy in 949 patients, and 10 studies evaluated antibodies and radiotherapy in 4729 patients. The addition of RTKis to radiotherapy-based treatment did not improve overall survival (hazard ratio = 1.02, 95% confidence interval = 0.90 to 1.15, P = .76) but increased grade 3+ toxicity (relative risk = 1.18, 95% confidence interval = 1.06 to 1.33, P = .009). Conclusions: The addition of RTKis to radiotherapy does not improve survival and worsens toxicity.
Subject(s)
Neoplasms/drug therapy , Neoplasms/radiotherapy , Protein Kinase Inhibitors/therapeutic use , Bevacizumab/adverse effects , Bevacizumab/therapeutic use , Brain Neoplasms/drug therapy , Brain Neoplasms/mortality , Brain Neoplasms/radiotherapy , Cetuximab/adverse effects , Cetuximab/therapeutic use , Chemoradiotherapy/adverse effects , Chemoradiotherapy/methods , Chemoradiotherapy/mortality , Combined Modality Therapy/methods , Erlotinib Hydrochloride/adverse effects , Erlotinib Hydrochloride/therapeutic use , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/mortality , Esophageal Neoplasms/radiotherapy , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/mortality , Head and Neck Neoplasms/radiotherapy , Humans , Lapatinib/adverse effects , Lapatinib/therapeutic use , Lung Neoplasms/drug therapy , Lung Neoplasms/mortality , Lung Neoplasms/radiotherapy , Neoplasms/mortality , Outcome Assessment, Health Care , Panitumumab/adverse effects , Panitumumab/therapeutic use , Protein Kinase Inhibitors/adverse effects , Randomized Controlled Trials as TopicABSTRACT
Importance: Currently, there are limited published data regarding resource use and spending on cancer care in the US. Objective: To characterize the most frequent medical services provided and the associated spending for privately insured patients with cancer in the US. Design, Setting, and Participants: This cohort study used data from the MarketScan database for the calendar year 2018 from a sample of 27.1 million privately insured individuals, including patients with a diagnosis of the 15 most prevalent cancers, predominantly from large insurers and self-insured employers. Overall societal health care spending was estimated for each cancer type by multiplying the mean total spending per patient (estimated from MarketScan) by the number of privately insured patients living with that cancer in 2018, as reported by the National Cancer Institute's Surveillance, Epidemiology, and End Results program. Analyses were performed from February 1, 2018, to July 8, 2021. Exposures: Evaluation and management as prescribed by treating care team. Main Outcomes and Measures: Current Procedural Terminology and Healthcare Common Procedure Coding System codes based on cancer diagnosis code. Results: The estimated cost of cancer care in 2018 for 402â¯115 patients with the 15 most prevalent cancer types was approximately $156.2 billion for privately insured adults younger than 65 years in the US. There were a total of 38.4 million documented procedure codes for 15 cancers in the MarketScan database, totaling $10.8 billion. Patients with breast cancer contributed the greatest total number of services (10.9 million [28.4%]), followed by those with colorectal cancer (3.9 million [10.2%]) and prostate cancer (3.6 million [9.4%]). Pathology and laboratory tests contributed the highest number of services performed (11.7 million [30.5%]), followed by medical services (6.3 million [16.4%]) and medical supplies and nonphysician services (6.1 million [15.9%]). The costliest cancers were those of the breast ($3.4 billion [31.5%]), followed by lung ($1.1 billion [10.2%]) and colorectum ($1.1 billion [10.2%]). Medical supplies and nonphysician services contributed the highest total spent ($4.0 billion [37.0%]), followed by radiology ($2.1 billion [19.4%]) and surgery ($1.8 billion [16.7%]). Conclusions and Relevance: This analysis suggests that patients with breast, colorectal, and prostate cancers had the greatest number of services performed, particularly for pathology and laboratory tests, whereas patients with breast, lung, lymphoma, and colorectal cancer incurred the greatest costs, particularly for medical supplies and nonphysician services. The cost of cancer care in 2018 for the 15 most prevalent cancer types was estimated to be approximately $156.2 billion for privately insured adults younger than 65 years in the US.
Subject(s)
For-Profit Insurance Plans/standards , Health Care Costs/statistics & numerical data , Neoplasms/economics , Patient Acceptance of Health Care/statistics & numerical data , Adult , Cohort Studies , Female , For-Profit Insurance Plans/statistics & numerical data , Humans , Male , Middle Aged , Neoplasms/epidemiology , United States/epidemiologyABSTRACT
Cancer of Unknown Primary (CUP) occurs in 3-5% of patients when standard histological diagnostic tests are unable to determine the origin of metastatic cancer. Typically, a CUP diagnosis is treated empirically and has very poor outcomes, with median overall survival less than one year. Gene expression profiling alone has been used to identify the tissue of origin but struggles with low neoplastic percentage in metastatic sites which is where identification is often most needed. MI GPSai, a Genomic Prevalence Score, uses DNA sequencing and whole transcriptome data coupled with machine learning to aid in the diagnosis of cancer. The algorithm trained on genomic data from 34,352 cases and genomic and transcriptomic data from 23,137 cases and was validated on 19,555 cases. MI GPSai predicted the tumor type in the labeled data set with an accuracy of over 94% on 93% of cases while deliberating amongst 21 possible categories of cancer. When also considering the second highest prediction, the accuracy increases to 97%. Additionally, MI GPSai rendered a prediction for 71.7% of CUP cases. Pathologist evaluation of discrepancies between submitted diagnosis and MI GPSai predictions resulted in change of diagnosis in 41.3% of the time. MI GPSai provides clinically meaningful information in a large proportion of CUP cases and inclusion of MI GPSai in clinical routine could improve diagnostic fidelity. Moreover, all genomic markers essential for therapy selection are assessed in this assay, maximizing the clinical utility for patients within a single test.