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BACKGROUND AND AIMS: Dysphagia is a debilitating symptom in patients with inoperable esophageal cancer that contributes to poor quality of life and worsening nutritional status. The 2 most commonly used palliative modalities for dysphagia are radiation therapy and esophageal stent placement. However, radiation therapy is limited by adverse events (AEs) and total dose, and stent placement has a high rate of AEs, including reflux, migration, and chest pain. A relatively new modality of liquid nitrogen endoscopic spray cryotherapy has been described as salvage when other options have been exhausted and when patients are no longer receiving systemic therapy. We evaluated the safety and efficacy of cryotherapy as the primary modality for relieving dysphagia in inoperable esophageal cancer including patients receiving systemic cancer therapy. METHODS: This is a retrospective, multicenter, consecutive case series of 49 inoperable esophageal cancer patients undergoing palliative endoscopic cryotherapy at 4 specialized cancer centers from May 2014 to May 2016. The primary outcomes were change in dysphagia scores between pre- and postcryotherapy and AEs. Dysphagia was measured using a 5-point Likert scale: 0, no dysphagia; 1, dysphagia to solids; 2, dysphagia to semisolids; 3, dysphagia to liquids; 4, dysphagia to saliva. RESULTS: Thirty-nine men and 10 women with a mean age of 58 years underwent a total of 120 cryotherapy treatments. The mean dysphagia score improved significantly from 2.4 precryotherapy to 1.7 postcryotherapy (improvement of .7 points; P < .001). Minor AEs were seen in 6 of 120 (5.0%) cryotherapy treatments (1 intraprocedural and 5 postprocedural). In addition, 1 patient developed a severe intraprocedural AE of dilation-related perforation, whereas another patient developed a benign stricture requiring dilation. CONCLUSIONS: This preliminary retrospective study suggests that liquid nitrogen spray cryotherapy may be safe and effective for dysphagia palliation in inoperable esophageal cancer. Large prospective studies are needed to confirm these findings and identify patient and procedure characteristics associated with the greatest benefit.
Subject(s)
Adenocarcinoma/surgery , Carcinoma, Squamous Cell/surgery , Cryosurgery , Deglutition Disorders/surgery , Esophageal Neoplasms/surgery , Adenocarcinoma/complications , Adult , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/complications , Deglutition Disorders/etiology , Esophageal Neoplasms/complications , Esophagoscopy , Female , Gases , Humans , Male , Middle Aged , Nitrogen , Palliative Care , Retrospective StudiesABSTRACT
BACKGROUND: Pembrolizumab (P) is an anti-PD-1 antibody that blocks the interaction between programmed cell death protein 1 (PD-1) on T-cells and PD-L1 and PD-L2 on tumour cells. A phase Ib trial of P plus chemotherapy was undertaken to evaluate the safety and efficacy. METHODS: Patients with advanced, metastatic solid tumours were enrolled onto one of six treatment arms. Pembrolizumab was given: with gemcitabine (G), G+docetaxel (D), G+nab-paclitaxel (NP), G+vinorelbine (V) or irinotecan (I) until progression or toxicity, or with liposomal doxorubicin (LD) for up to 15 cycles, progression or toxicity. Safety monitoring and response assessments were conducted. RESULTS: Forty-nine patients were enrolled and treated. The most common adverse events were transaminitis, cytopenias, rash, diarrhoea, fatigue, nausea and vomiting. Arm 2 was closed due to poor accrual. The recommended phase II dose (RP2D) was determined for Arms 1, 3a, 4, 5 and 6. There were eight partial responses across multiple tumour types. CONCLUSIONS: Standard dose P can be safely combined with G, G+NP, G+V, I and LD. Efficacy was observed in multiple tumour types and evaluation to determine if response and duration of response are more robust than what would be expected for chemotherapy or immunotherapy alone requires further validation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms/drug therapy , Adenocarcinoma/drug therapy , Adult , Aged , Albumins/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , Breast Neoplasms/drug therapy , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Carcinoma, Non-Small-Cell Lung/drug therapy , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Diarrhea/chemically induced , Docetaxel , Doxorubicin/administration & dosage , Doxorubicin/analogs & derivatives , Drug Eruptions/etiology , Fatigue/chemically induced , Female , Humans , Irinotecan , Lung Neoplasms/drug therapy , Male , Middle Aged , Nausea/chemically induced , Ovarian Neoplasms/drug therapy , Paclitaxel/administration & dosage , Pancreatic Neoplasms/drug therapy , Polyethylene Glycols/administration & dosage , Sarcoma/drug therapy , Small Cell Lung Carcinoma/drug therapy , Taxoids/administration & dosage , Treatment Outcome , Vinblastine/administration & dosage , Vinblastine/analogs & derivatives , Vinorelbine , Vomiting/chemically induced , GemcitabineABSTRACT
The majority of cancer-associated mortalities are due to distant metastases, and systemic therapy alone is generally not curative. Patients with oligometastases are amenable to involved site radiotherapy with the possibility of long-term disease-free survival; however, prognostic factors remain poorly defined. The present retrospective, single institution study consisted of consecutive adult patients with oligometastases from solid tumor malignancy referred to a single high volume radiation oncologist between January 2014 and December 2021. Oligometastases were defined as ≤5 extracranial or intracranial metastatic lesions where all sites of active disease are treatable, including patients requiring treatment of the primary tumor and/or regional lymph nodes. The study population consisted of 130 patients with 207 treated distant metastases. Radical radiotherapy was administered to all areas of known residual disease and included stereotactic radiotherapy (median dose, 27 Gy in 3 fractions) or intensity modulated radiotherapy (median dose, 50 Gy in 15 fractions). At a median follow-up of 28.8 months, the median overall survival was 37.9 months with a 4-year overall survival of 41.1%. The median progression-free survival was 12.3 months and the 4-year progression-free survival was 22.6%. On multivariate an1alysis, the strongest predictors of overall survival were age, ECOG performance status, primary prostate, breast or kidney tumor and pre-radiation serum albumin (P≤0.01 for all). Overall, the present study demonstrated that long-term overall survival was possible after radical treatment for oligometastases and identified potential prognostic factors.
ABSTRACT
Introduction: Despite recent advances in drug development, durable complete remissions with systemic therapy alone for metastatic cancers remain infrequent. With the development of advanced radiation technologies capable of selectively sparing normal tissues, patients with oligometastases are often amenable to comprehensive involved site radiotherapy with curative intent. This study reports the long-term outcomes and patterns of failure for patients treated with total metastatic ablation often in combination with systemic therapy. Materials and methods: Consecutive adult patients with oligometastases from solid tumor malignancy treated by a single high volume radiation oncologist between 2014 and 2021 were retrospectively analyzed. Oligometastases were defined as 5 or fewer metastatic lesions where all sites of active disease are amenable to local treatment. Comprehensive involved site radiotherapy consisted of stereotactic radiotherapy to a median dose of 27 Gy in 3 fractions and intensity modulated radiation therapy to a median dose of 50 Gy in 15 fractions. This study analyzed overall survival, progression-free survival, patterns of failure and toxicity. Results: A total of 130 patients with 209 treated distant metastases were treated with a median follow-up of 36 months. The 4-year overall survival, progression-free survival, local control and distant control was 41%, 23%, 86% and 29%. Patterns of failure include 23% alive and free of disease (NED), 52% distant failure only, 9% NED but death from comorbid illness, 7% both local and distant failure, 4% NED but lost to follow-up, 4% referred to hospice before restaging, 1% local only failure, 1% alive with second primary cancer. Late grade 3+ toxicities occurred in 4% of patients, most commonly radionecrosis. Conclusion: Involved site radiotherapy to all areas of known disease can safely achieve durable complete remissions in patients with oligometastases treated in the real world setting. Distant failures account for the majority of treatment failures and isolated local failures are exceedingly uncommon. Oligometastases represents a promising setting to investigate novel therapeutics targeting minimal residual disease.
ABSTRACT
While the benefits of early palliative care for patients with metastatic cancer are well established, cancer survivorship remains inadequately integrated into the care of patients with distant metastases. Moreover, the optimal model of care delivery is poorly defined. A prognostic model previously developed and validated at Good Samaritan University Hospital identified four groups of patients with metastatic solid tumor malignancy having very favorable, favorable, standard or unfavorable prognoses with median survival of 31, 14, 4 and 1 month, respectively. This framework holds promise for the personalized delivery of supportive, palliative and survivorship care services in the context of radiation therapy. We review the published literature providing the rationale for a novel multidisciplinary care model where the radiation oncology Clinical Nurse Specialist identifies and coordinates interventions to address unmet physical and emotional issues faced by survivors with metastatic cancer with the goal of improving quality of life and overall survival.
Subject(s)
Neoplasms, Second Primary , Neoplasms , Humans , Survivorship , Quality of Life , Neoplasms/radiotherapy , Palliative CareABSTRACT
BACKGROUND: Patients with metastatic cancer referred to radiation oncology have diverse prognoses and there is significant interest in personalizing treatment. We hypothesized that patients selected for higher biologically equivalent doses have improved overall survival. METHODS: The study population consists of 355 consecutive adult patients with distant metastases treated by a single radiation oncologist from 2014 to 2018. The validated NEAT model was used to prospectively stratify patients into four distinct cohorts. Radiation dose intensity was standardized using the equivalent dose in 2 Gy fractions (EQD2) model with an α/ß of 10. Radiation dose intensity on survival was assessed via Cox regression models and propensity score match pairing with Kaplan-Meier analysis. RESULTS: The median survival was 9.3 months and the median follow-up for surviving patients was 18.3 months. The NEAT model cohorts indicated median survivals of 29.5, 11.8, 4.9, and 1.8 months. Patients receiving an EQD2 of ≥40 Gy had a median survival of 16.0 months versus 3.8 months for patients receiving an EQD2 of <40 Gy (p < 0.001). On multivariable analysis, performance status, primary tumor site, radiation dose intensity, albumin, liver metastases, and number of active tumors were all independent predictors of survival (p < 0.05 for all). Propensity score matching was performed for performance status, albumin, number of active tumors, primary tumor site, and liver metastasis, finding higher EQD2 to remain significantly associated with improved survival within the matched cohort (p = 0.004). CONCLUSION: Higher radiation dose intensity was used in patients with better prognosis and was associated with improved survival for patients with metastatic disease.
Subject(s)
Neoplasms/radiotherapy , Radiotherapy Dosage/standards , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Neoplasm Metastasis , Neoplasms/mortality , Survival Analysis , Young AdultABSTRACT
PURPOSE: Angiosarcoma is a rare aggressive endothelial cell cancer with high mortality. Isolated reports suggest immune checkpoint inhibition efficacy in angiosarcoma, but no prospective studies have been published. We report results for angiosarcoma treated with ipilimumab and nivolumab as a cohort of an ongoing rare cancer study. METHODS: This is a prospective, open-label, multicenter phase II clinical trial of ipilimumab (1 mg/kg intravenously every 6 weeks) plus nivolumab (240 mg intravenously every 2 weeks) for metastatic or unresectable angiosarcoma. Primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints include progression-free (PFS) and overall survival, and toxicity. A two-stage design was used. RESULTS: Overall, there were 16 evaluable patients. Median age was 68 years (range, 25-81); median number of prior lines of therapy, 2. Nine patients had cutaneous and seven non-cutaneous primary tumors. ORR was 25% (4/16). Sixty per cent of patients (3/5) with primary cutaneous scalp or face tumors attained a confirmed response. Six-month PFS was 38%. Altogether, 75% of patients experienced an adverse event (AE) (at least possibly related to drug) (25% grade 3-4 AE); 68.8%, an immune-related AE (irAE) (2 (12.5%), grade 3 or 4 irAEs (alanine aminotransferase/aspartate aminotransferase increase and diarrhea)). There were no grade 5 toxicities. One of seven patients in whom tumor mutation burden (TMB) was assessed showed a high TMB (24 mutations/mb); that patient achieved a partial response (PR). Two of three patients with PDL1 immunohistochemistry assessed had high PDL1 expression; one achieved a PR. CONCLUSION: The combination of ipilimumab and nivolumab demonstrated an ORR of 25% in angiosarcoma, with three of five patients with cutaneous tumors of the scalp or face responding. Ipilimumab and nivolumab warrant further investigation in angiosarcoma. TRIAL REGISTRATION NUMBER: NCT02834013.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , CTLA-4 Antigen/antagonists & inhibitors , Hemangiosarcoma/drug therapy , Rare Diseases/drug therapy , Adult , Aged , Aged, 80 and over , Female , Hemangiosarcoma/pathology , Humans , Immune Checkpoint Inhibitors/administration & dosage , Ipilimumab/administration & dosage , Male , Middle Aged , Neoplasm Metastasis , Nivolumab/administration & dosage , Prospective Studies , Rare Diseases/pathologyABSTRACT
PURPOSE: The Targeted Agent and Profiling Utilization Registry (TAPUR) Study is a phase II pragmatic basket trial evaluating antitumor activity of commercially available targeted agents in patients with advanced cancer with genomic alterations known to be drug targets. Results in a cohort of patients with non-small-cell lung cancer (NSCLC) with CDKN2A alterations treated with palbociclib are reported. METHODS: Eligible patients were ≥ 18 years old with advanced NSCLC, no remaining standard treatment options, measurable disease, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function. Patients with NSCLC with CDKN2A alterations and no Rb mutations received palbociclib 125 mg orally once daily for 21 days, followed by 7 days off. Simon's two-stage design was used with a primary study end point of objective response or stable disease (SD) of at least 16 weeks in duration. Secondary end points are progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Twenty-nine patients were enrolled from January 2017 to June 2018; two patients were not evaluable for response but were included in safety analyses. One patient with partial response and six patients with SD were observed, for a disease control rate of 31% (90% CI, 19% to 40%). Median PFS was 8.1 weeks (95% CI, 7.1 to 16.0 weeks), and median OS was 21.6 weeks (95% CI, 14.1 to 41.1 weeks). Eleven patients had at least 1 grade 3 or 4 adverse event (AE) or serious AE (SAE) possibly related to palbociclib (most common, cytopenias). Other AEs or SAEs possibly related to the treatment included anorexia, fatigue, febrile neutropenia, hypophosphatemia, sepsis, and vomiting. CONCLUSION: Palbociclib monotherapy demonstrated evidence of modest antitumor activity in heavily pretreated patients with NSCLC with CDKN2A alterations. Additional investigation is necessary to confirm efficacy and utility of palbociclib in this population.
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BACKGROUND: Small cell lung cancer (SCLC) that has progressed after first-line therapy is an aggressive disease with few effective therapeutic strategies. In this prospective study, we employed next-generation sequencing (NGS) to identify therapeutically actionable alterations to guide treatment for advanced SCLC patients. METHODS: Twelve patients with SCLC were enrolled after failing platinum-based chemotherapy. Following informed consent, genome-wide exome and RNA-sequencing was performed in a CLIA-certified, CAP-accredited environment. Actionable targets were identified and therapeutic recommendations made from a pharmacopeia of FDA-approved drugs. Clinical response to genomically-guided treatment was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. RESULTS: The study completed its accrual goal of 12 evaluable patients. The minimum tumor content for successful NGS was 20%, with a median turnaround time from sample collection to genomics-based treatment recommendation of 27 days. At least two clinically actionable targets were identified in each patient, and six patients (50%) received treatment identified by NGS. Two had partial responses by RECIST 1.1 on a clinical trial involving a PD-1 inhibitor + irinotecan (indicated by MLH1 alteration). The remaining patients had clinical deterioration before NGS recommended therapy could be initiated. CONCLUSIONS: Comprehensive genomic profiling using NGS identified clinically-actionable alterations in SCLC patients who progressed on initial therapy. Recommended PD-1 therapy generated partial responses in two patients. Earlier access to NGS guided therapy, along with improved understanding of those SCLC patients likely to respond to immune-based therapies, should help to extend survival in these cases with poor outcomes.
Subject(s)
Neoplasm Proteins/biosynthesis , Sequence Analysis, RNA/methods , Small Cell Lung Carcinoma/drug therapy , Transcriptome/genetics , Adult , Aged , Biopsy , Exome/genetics , Female , Gene Expression Regulation, Neoplastic/drug effects , Genome, Human , Humans , Male , Middle Aged , Neoplasm Proteins/genetics , Pilot Projects , Platinum/administration & dosage , Sequence Alignment , Small Cell Lung Carcinoma/genetics , Small Cell Lung Carcinoma/pathology , Treatment OutcomeABSTRACT
Purpose: Chromosomal instability is a fundamental property of cancer, which can be quantified by next-generation sequencing (NGS) from plasma/serum-derived cell-free DNA (cfDNA). We hypothesized that cfDNA could be used as a real-time surrogate for imaging analysis of disease status as a function of response to immunotherapy and as a more reliable tool than tumor biomarkers.Experimental Design: Plasma cfDNA sequences from 56 patients with diverse advanced cancers were prospectively collected and analyzed in a single-blind study for copy number variations, expressed as a quantitative chromosomal number instability (CNI) score versus 126 noncancer controls in a training set of 23 and a blinded validation set of 33. Tumor biomarker concentrations and a surrogate marker for T regulatory cells (Tregs) were comparatively analyzed.Results: Elevated CNI scores were observed in 51 of 56 patients prior to therapy. The blinded validation cohort provided an overall prediction accuracy of 83% (25/30) and a positive predictive value of CNI score for progression of 92% (11/12). The combination of CNI score before cycle (Cy) 2 and 3 yielded a correct prediction for progression in all 13 patients. The CNI score also correctly identified cases of pseudo-tumor progression from hyperprogression. Before Cy2 and Cy3, there was no significant correlation for protein tumor markers, total cfDNA, or surrogate Tregs.Conclusions: Chromosomal instability quantification in plasma cfDNA can serve as an early indicator of response to immunotherapy. The method has the potential to reduce health care costs and disease burden for cancer patients following further validation. Clin Cancer Res; 23(17); 5074-81. ©2017 AACR.
Subject(s)
Biomarkers, Tumor/blood , Circulating Tumor DNA/blood , Immunotherapy , Neoplasms/blood , Adult , Aged , Biomarkers, Tumor/immunology , Chromosomal Instability/immunology , DNA Copy Number Variations/genetics , Disease Progression , Female , High-Throughput Nucleotide Sequencing , Humans , Male , Middle Aged , Mutation , Neoplasms/drug therapy , Neoplasms/immunology , Neoplasms/pathology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/pathologyABSTRACT
BACKGROUND: It is widely acknowledged that there is value in examining cancers for genomic aberrations via next-generation sequencing (NGS). How commercially available NGS platforms compare with each other, and the clinical utility of the reported actionable results, are not well known. During the course of the current study, the Foundation One (F1) test generated data on a combination of somatic mutations, insertion and deletion polymorphisms, chromosomal abnormalities, and deoxyribonucleic acid (DNA) copy number changes at ~250× coverage, while the Paradigm Cancer Diagnostic (PCDx) test generated the same type of data at >5,000× coverage, plus provided messenger RNA (mRNA) expression levels. We sought to compare and evaluate paired formalin-fixed paraffin-embedded tumor tissue using these two platforms. METHODS: Samples from patients with advanced solid tumors were submitted to both the F1 and PCDx vendors for NGS analysis. Turnaround time (TAT) was calculated. Biomarkers were considered clinically actionable if they had a published association with treatment response in humans and were assigned to the following categories: commercially available drug (CA), clinical trial drug (CT), or neither option (hereafter referred to as "None"). RESULTS: The demographics of the 21 unique patient tumor samples included ten men and eleven women, with a median age of 56 years. Due to insufficient archival tissue from the same collection period, in one case, we used samples from different collections. PCDx reported first results faster than F1 in 20 cases. When received at both vendors on the same day, PCDx reported first results for 14 of 15 cases, with a median TAT of 9 days earlier than F1 (P<0.0001). Categorization of CA compared to CT and none significantly favored PCDx (P=0.012). CONCLUSION: In the current analysis, commercially available NGS platforms provided clinically relevant actionable targets (CA or CT) in 47%-67% of diverse cancer types. In the samples analyzed, PCDx significantly outperformed F1 in TAT, and had statistically significant higher clinically relevant actionable targets categorized as CA.
ABSTRACT
The purpose of this article is to review the role of maintenance therapy in the treatment of advanced non-small cell lung cancer (NSCLC). A brief overview about induction chemotherapy and its primary function in NSCLC is provided to address the basis of maintenance therapies foundation. The development of how maintenance therapy is utilized in this population is discussed and current guidelines for maintenance therapy are reviewed. Benefits and potential pitfalls of maintenance therapy are addressed, allowing a comprehensive review of the achieved clinical benefit that maintenance therapy may or may not have on NSCLC patient population. A review of current literature was conducted and a table is provided comparing the results of various maintenance therapy clinical trials. The table includes geographical location of each study, the number of patients enrolled, progression free survival and overall survival statistics, post-treatment regimens and if molecular testing was conducted. The role of molecular testing in relation to therapeutic treatment options for advanced NSCLC patients is discussed. A treatment algorithm clearly depicts first line and second line treatment for management of NSCLC and includes molecular testing, maintenance therapy and the role clinical trials have in treatment of NSCLC. This treatment algorithm has been specifically tailored and developed to assist clinicians in the management of advanced NSCLC.