AbstractThe primary objective of this article is to assist oncologists and advanced practice prescribers to safely and effectively minimize risk when providing opioids for cancer pain relief. The majority of people with cancer are unlikely to misuse or divert opioid medications, yet the prescriber is often unaware of those who are at risk for these behaviors. To provide skillful pain management to each patient in the oncology setting, while limiting harm to the community, all prescribers must consider the potential for risk of misuse, addiction, or diversion. To minimize this risk to the greatest degree possible, it is imperative to include a thorough risk assessment when conducting a comprehensive pain evaluation. This information is then used to triage pain relief interventions based upon the degree of risk, including whether or not to incorporate opioids into the plan of care. Risk mitigation strategies, incorporating universal precautions, are implemented to assess, monitor, and reduce the potential for opioid misuse. Universal precautions include strategies such as the use of urine toxicology, state prescription drug monitoring programs, and agreements. Ongoing monitoring is conducted with the goal being to identify aberrant behaviors early so that they can be addressed and managed appropriately. Referral to addiction specialists may be warranted when substance use disorder precludes safe use of opioids.Implications for Practice.Throughout the trajectory of cancer care, opioid use is often indicated, and, in fact, it may be unethical to limit or prohibit the use of opioids when pain is severe. Oncologists face the significant challenge of providing cancer pain control that is safe and effective, while limiting individual risk for abuse or overdose and keeping the community free of diverted substances. Most oncology providers report inadequate training in chronic pain principles and in managing addiction. Risk assessment and mitigation measures can be incorporated within oncology care to enhance effective pain management while reducing the potential for harm.
A Multicenter Comparison of Complementary and Alternative Medicine (CAM) Discussions in Oncology Care: The Role of Time, Patient‐Centeredness, and Practice Context
AbstractBackground.Little is known about how complementary and alternative medicine (CAM) is discussed in cancer care across varied settings in the U.S.Methods.In two practices affiliated with one academic medical center in southern California (SoCal), and one in the upper Midwest (UM), we audio‐recorded patient‐clinician interactions in medical oncology outpatient practices. We counted the frequency and duration of CAM‐related conversations. We coded recordings using the Roter Interaction Analysis System. We used chi‐square tests for bivariate analysis of categorical variables and generalized linear models for continuous variables to examine associations between dialogue characteristics, practice setting, and population characteristics with the occurrence of CAM discussion in each setting followed by multivariate models adjusting for clinician clustering.Results.Sixty‐one clinicians and 529 patients participated. Sixty‐two of 529 (12%) interactions included CAM discussions, with significantly more observed in the SoCal university practice than in the other settings. Visits that included CAM were on average 6 minutes longer, with CAM content lasting an average of 78 seconds. In bivariate tests of association, conversations containing CAM included more psychosocial statements from both clinicians and patients, higher patient‐centeredness, more positive patient and clinician affect, and greater patient engagement. In a multivariable model including significant bivariate terms, conversations containing CAM were independently associated with higher patient‐centeredness, slightly longer visits, and being at the SoCal university site.Conclusion.The frequency of CAM‐related discussion in oncology varied substantially across sites. Visits that included CAM discussion were longer and more patient centered.Implications for Practice.The Institute of Medicine and the American Society of Clinical Oncology have called for more open discussions of complementary and alternative medicine (CAM). But little is known about the role population characteristics and care contexts may play in the frequency and nature of those discussions. The present data characterizing actual conversations in practice complements a much larger literature based on patient and clinician self‐report about CAM disclosure and use. It was found that CAM discussions in academic oncology visits varied significantly by practice context, that the majority were initiated by the patient, and that they may occur more when visit time exists for lifestyle, self‐care, and psychosocial concerns.
AbstractOpioids are required by a majority of patients with advanced cancer. Oncologists and palliative care clinicians are faced with the challenge of safely prescribing opioids in the current environment of an opioid crisis. Many patients with cancer use opioids unsafely, store them in unsecure locations, and do not dispose of unused opioids, leading to increased availability of these opioids for others to misuse. More than 50% of people who misuse opioids obtain the drugs from a friend or relative with or without their consent. Patient and provider education has been shown to improve safe opioid use, promote secure storage, and also increase disposal of unused opioids safely in drug take‐back programs that are now widely available. This article highlights the importance of patient education and cautious opioid prescribing in patients with cancer.Implications for Practice.The current opioid crisis makes it challenging to effectively manage cancer pain. Providers play a prominent role in minimizing opioid misuse. Cautious prescribing with limits enforced on the quantity of opioids prescribed, close follow‐up, and consistent and frequent provision of opioid education are a must. Evidence points to the impact of patient education in promoting safety around opioid use. Most people who misuse prescription opioids obtain them from family or friends. Storing opioids in the open or not disposing of unused opioids increases the availability of these opioids for misuse by others. The importance of not sharing, always locking up, and disposing of unused and expired opioids must be highlighted as part of the opioid education that must be delivered every time that opioids are prescribed. Information about local drug take‐back programs may also help increase disposal of unused opioids.
Anti‐PD‐1 Immunotherapy‐Induced Flare of a Known Underlying Relapsing Vasculitis Mimicking Recurrent Cancer
AbstractSafe use of immune checkpoint blockade in patients with cancer and autoimmune disorders requires a better understanding of the pathophysiology of immunologic activation. We describe the immune correlates of reactivation of granulomatosis with polyangiitis (GPA)—an antineutrophil cytoplasmic antibody (ANCA)‐associated vasculitis—in a patient with metastatic urothelial carcinoma treated with pembrolizumab. After PD‐1 blockade, an inflammatory pulmonary nodule demonstrated a granulomatous, CD4+ T‐cell infiltrate, correlating with increased CD4+ and CD8+ naïve memory cells in the peripheral blood without changes in other immune checkpoint receptors. Placed within the context of the existing literature on GPA and disease control, our findings suggest a key role for PD‐1 in GPA self‐tolerance and that selective strategies for immunotherapy may be needed in patients with certain autoimmune disorders. We further summarize the current literature regarding reactivation of autoimmune disorders in patients undergoing immune checkpoint blockade, as well as potential immunosuppressive strategies to minimize the risks of further vasculitic reactivation upon rechallenge with anti‐PD‐1 blockade.Key Points. Nonspecific imaging findings in patients with cancer and rheumatological disorders may require biopsy to distinguish underlying pathology.Patients with rheumatologic disorders have increased risk of reactivation with PD‐(L)1 immune checkpoint blockade, requiring assessment of disease status before starting treatment.Further study is needed to evaluate the efficacy of treatment regimens in preventing and controlling disease reactivation.
A Practical Guide for the Follow‐Up of Patients with Advanced Basal Cell Carcinoma During Treatment with Hedgehog Pathway Inhibitors
AbstractThe Hedgehog pathway inhibitors (HPIs), vismodegib and sonidegib, are increasingly employed in the treatment of patients with advanced basal cell carcinoma (BCC). The aim of this review is to create a synthesis of available information in the literature regarding the follow‐up of patients with advanced BCC treated with HPIs and to provide the treating physician with a structured practical guide to standardize clinical practice. Several challenges during treatment are addressed: to optimally evaluate tumor responses, to differentiate between resistance (HPI rechallenge not possible) and recurrence (HPI rechallenge may be possible) in case of BCC regrowth, to readily assess for toxicity and tolerability issues, to provide patients with practical ways and behaviors to effectively cope with adverse events, and to improve patient adherence and quality of life.Implications for Practice.This is a practical guide for clinical practice regarding the monitoring and follow‐up of patients with advanced basal cell carcinoma (BCC) during treatment with the Hedgehog pathway inhibitors (HPIs) vismodegib and sonidegib. This review aims to bridge the gap in knowledge of assessing tumor response for BCC with both an externally visible component and an infiltrating component measurable with imaging. Furthermore, it addresses the follow‐up for adverse events as a challenging multistep process involving practices aiming to readily assess new‐onset symptoms of HPI toxicity, perform total‐body skin examination, and improve patient adherence and quality of life.
AbstractAdvanced adrenocortical carcinoma (ACC) is an aggressive disease with poor prognosis, and the current therapeutic options, such as mitotane or platinum‐based chemotherapy regimens, often offer limited efficacy. Here, we present the first report, to the author's knowledge, of metastatic ACC with positive octreoscan scintigraphy that was successfully treated with octreotide long‐acting release (LAR). A patient with metastatic ACC who showed poor tolerance to mitotane received octreotide LAR because of positive octreoscan scintigraphy. She obtained major partial response to the somatostatin analog. Interestingly, the expression of somatostatin receptor 2 from the previous local recurrence lesion was negative. The next‐generation sequencing‐based circulating tumor DNA analysis in the patient was performed and failed to identify any alterations. These findings suggest that octreotide LAR may be a good option for the treatment of metastatic ACC in selected patients.
Phase II Study of Bendamustine and Ofatumumab in Elderly Patients with Newly Diagnosed Diffuse Large B‐Cell Lymphoma Who Are Poor Candidates for R‐CHOP Chemotherapy
AbstractLessons Learned. The combination of ofatumumab and bendamustine in elderly patients with diffuse large B‐cell lymphoma demonstrated modest efficacy compared with standard of care.The poor response may have been due to patient age and the high rate of treatment discontinuation.Background.This phase II trial evaluated the efficacy of bendamustine and ofatumumab in elderly patients with newly diagnosed diffuse large B‐cell lymphoma (DLBCL) who were not candidates for rituximab cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP).Methods.Patients received IV 90 mg/m2 bendamustine on days 1 and 2 of cycles 1 through 6 and IV 1,000 mg ofatumumab on days 1 and 8 of cycle 1 and on day 1 of cycles 2 through 6. Both drugs were administered at the U.S. Food and Drug Administration‐approved dose for combination therapy. All patients received premedications before each infusion of ofatumumab and hematopoietic growth factors. Treatment was administered in 21‐day cycles, with restaging after cycle 3 and cycle 6. The primary endpoint was complete response rate (CRR).Results.Twelve of 21 enrolled patients completed treatment; median age was 83 years. The most common reasons for treatment discontinuation were disease progression (three patients), intercurrent illness (two patients), and death (one patient due to drug‐related sepsis and bowel necrosis and one patient due to unknown cause). Thrombocytopenia (14%), neutropenia (10%), diarrhea (10%), vomiting (10%), and dehydration (10%) were the most common grade ≥3 treatment‐related adverse events. The overall response rate was 90.5% and the CRR was 33.3%. Median progression‐free survival (PFS) and overall survival (OS) were 8.6 and 12.0 months, respectively.Conclusion.The combination of ofatumumab and bendamustine is feasible in elderly patients with DLBCL.
Conformity to Clinical Practice Guidelines at Initial Management in Adult Soft Tissue and Visceral Tumors since the Implementation of the NetSarc Network in Eastern France
AbstractBackground.Soft tissue sarcomas are rare and heterogenous tumors that are hard to diagnose. The aim of this study was to evaluate local practices and conformity to clinical practice guidelines (CPGs) for their initial diagnostic management.Materials and Methods.Patients were carriers of a soft tissue or visceral tumor, presented at a sarcoma tumor board (STB) between 2010 and 2016. Conformity to CPGs was evaluated using ten criteria designed for this purpose. Associations between different factors and conformity to composite criteria, reflecting the three main diagnostic steps (imaging, biopsy and histological report) were analyzed.Results.A total of 643 patients were included. A preoperative tumor imaging assessment and a biopsy were performed according to CPGs in 80.8% and 36.8% of the cases, respectively. When done, the first surgical resection was R0 in 30.3% of cases, R1 in 28.6%, and R2 in 10.9%. The rest of the operated patients with sarcoma had a second surgical excision (11.4%), an intraoperative fragmentation (4.3%), or margins were unknown (14.4%). Six of the ten quality criteria presented a conformity rate higher than 70%. Two criteria with a conformity rate lower than 20% were the most controversial: presentation at a STB before biopsy and freezing of a tumor fragment. A multivariate analysis revealed that the common predictor of nonconformity to composite criteria was the initial management in a nonexpert center.Conclusion.Initial diagnostic management requires improvement, especially outside of specialized centers.Implications for Practice.This article supports the essential need to refer patients with soft tissue tumors to specialized centers to improve the management of sarcomas beginning at the diagnostic phase. Indeed, the reported data were very similar to those already described at the national level of the NetSarc network and indicate the necessity to keep raising awareness about this simple issue: early referral to reference centers will save lives.
AbstractBackground.Delta‐like protein 3 (DLL3) is a Notch ligand that has an important role in the tumorigenesis of small cell lung cancer (SCLC). Recently, rovalpituzumab tesirine (Rova‐T), a DLL3‐targeted antibody‐drug conjugate, has been developed for treating SCLC. DLL3 is a transcriptional target of the achaete‐scute homolog‐1 (ASCL1) transcription factor, which is involved in pulmonary neuroendocrine cell development. However, the relationship between DLL3 and/or ASCL1 expression and the clinical features of SCLC remains unknown, especially for early‐stage resected SCLC. This study aimed to investigate the expression of DLL3 and ASCL1 in resected SCLC samples using immunohistochemical analysis.Materials and Methods.We collected 95 surgically resected SCLC samples, which were formalin fixed and paraffin embedded. Immunohistochemistry staining was performed to investigate the correlation between the expression of either DLL3 or ASCL1 and clinicopathological features of study patients.Results.Seventy‐seven (83%) of 93 immunohistochemically evaluable samples were positive for DLL3 (expression in ≥1% of tumor cells), and DLL3‐high expression (≥75%) was observed in 44 samples (47%). Sixty‐one (64%) of 95 samples were positive for ASCL1 (expression in ≥5% of tumor cells). A positive correlation was observed between DLL3 and ASCL1 expression. DLL3 and ASCL1 expression were not associated with survival in SCLC patients. DLL3 was more prevalent in patients with advanced clinical disease.Conclusion.DLL3 and ASCL1 were highly expressed in patients with surgically resected SCLC. DLL3 and ASCL1 may be targets for the treatment of SCLC.Implications for Practice.This article examines the relationship between delta‐like protein 3 (DLL3) and achaete‐scute homolog‐1 (ASCL1) protein expression with the clinical features of 95 surgically resected small cell lung cancer (SCLC). DLL3 is attracting attention because rovalpituzumab tesirine (Rova‐T), a DLL3‐targeted antibody‐drug conjugate, was developed recently. DLL3 and ASCL1 were highly expressed in patients with surgically resected SCLC. DLL3 and ASCL1 may be targets for the treatment of early‐stage SCLC, including with Rova‐T.
Prevention, Monitoring, and Management of Cardiac Dysfunction in Patients with Metastatic Breast Cancer
AbstractCardiac monitoring is becoming an important part of breast cancer care. Breast cancer and cardiovascular disease (CVD) share many common risk factors, and it is estimated that by the median age of diagnosis, many patients with breast cancer will have established or subclinical CVD. In addition, a number of treatments for metastatic breast cancer are known to have cardiac effects. As such, there is a clear need to prevent, identify, and effectively manage cardiovascular events in patients with breast cancer. Current clinical practice for patients with metastatic breast cancer involves a comprehensive set of assessments to ensure efficacy and safety of treatment. Adding cardiac monitoring to the assessments already required for patients with breast cancer may improve survival and quality of life. Currently, cardiac monitoring is recommended for several breast cancer treatments, and guidelines related to cardiac monitoring are available. Here, we review the risk of CVD in patients with breast cancer, providing an overview of the cardiac events associated with standard therapies for metastatic breast cancer. We also assess the current clinical recommendations relating to cardiac monitoring, and practical management strategies for oncologists. Cardio‐oncology is a growing medical subspecialty that promotes the need for effective cancer therapy while minimizing cardiac effects. Integrating cardiac monitoring into routine clinical practice may safeguard patients with metastatic breast cancer against adverse cardiac effects.Implications for Practice.This review details the common risk factors associated with cardiovascular disease that are frequently observed in patients with metastatic breast cancer, as well as the adverse cardiac effects of many therapies that are commonly prescribed. The review also provides a rationale for routine and comprehensive cardiovascular assessment of all patients at baseline, and during and after therapy depending on the treatment and presence of risk factors for cardiovascular disease. The medical discipline of cardio‐oncology is increasingly being recognized as an important part of clinical practice to ensure effective cancer therapy while maintaining cardiac health.
AbstractEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR‐TKIs) have become the first choice for patients with sensitive mutations and have significantly improved prognosis. EGFR exon 19 deletions and L858R mutation in exon 21 are the most common sensitive mutations in lung adenocarcinoma. With advances in detection technology, some rare variants of EGFR have been detected, including EGFR kinase domain duplications and EGFR fusions. Only a few reports have revealed the effectiveness of EGFR‐TKIs in patients with these rare variants. In this study, we report a case of EGFR‐RAD51 fusion in lung adenocarcinoma that showed a response to icotinib; these findings provide additional support for the use of EGFR‐TKIs for patients with these atypical variants.Key Points. A young patient with lung adenocarcinoma harboring a rare EGFR‐RAD51 fusion who responded to icotinib with a PFS of longer than 15 months.All reported EGFR‐RAD51 fusions have the same breakpoints and show responses to EGFR‐TKIs including icotinib, except for one patient who responded to chemotherapy.Although EGFR fusion is a rare EGFR variant type, the efficacy of EGFR‐TKIs suggests the necessity for new detection technology, such as NGS, for patients with lung adenocarcinoma.The clinical usage of NGS could maximize the benefits of precision medicine in patients with cancer.The current case provides new evidence for the efficacy of icotinib in patients with the rare EGFR‐RAD51 fusion and EGFR‐activating mutations.
Comprehensive Clinical Trial Data Summation for BRAF‐MEK Inhibition and Checkpoint Immunotherapy in Metastatic Melanoma
AbstractBackground.Immune checkpoint inhibitors, along with BRAF and MEK inhibitors, have dramatically changed the management of and outlook for patients with metastatic melanoma. Analyses of long‐term follow‐up data and subanalyses based on disease characteristics may inform clinical decision making.Methods.Reports of clinical trials in metastatic melanoma published between January 1, 2012, and August 30, 2018, were identified using PubMed (terms: melanoma AND [dabrafenib OR trametinib OR vemurafenib OR cobimetinib OR encorafenib OR ipilimumab OR nivolumab OR pembrolizumab]) and were systematically reviewed. Relevant congress proceedings were also assessed. Efficacy data from key phase III trials were analyzed and trends identified.Results.Substantial improvements in objective response rates, progression‐free survival, and overall survival were documented across 14 identified publications. Subgroup findings supported that patients with lower disease burden derive greater benefit than patients with more advanced disease, limiting the value of disease burden in the clinical decision‐making process. However, these agents consistently conferred benefits despite the presence of poor prognostic features. Several clinically relevant questions remain, including how best to sequence immune checkpoint inhibitors and combination targeted therapy.Conclusion.This research, coupled with ongoing investigations, including those on predictive biomarkers, suggests that the treatment decision‐making process is likely to become more nuanced.Implications for Practice.The management of melanoma has been rapidly advancing with new classes of agents, including immune checkpoint and BRAF inhibitors. With long‐term follow‐up, their impact on response rates and survival outcomes is well documented. Additional findings from subgroup analyses suggest that patients with lower disease burden derive greater benefit, yet both consistently confer benefit in patients with higher disease burden. Currently, there is a paucity of data to guide first‐line treatment selection between immunotherapy and BRAF‐targeted therapy in clinical practice or to estimate their impact when sequenced. Gaining these insights will facilitate a more nuanced management approach.
A Phase I/II Open‐Label Study of Nivolumab in Previously Treated Advanced or Recurrent Nasopharyngeal Carcinoma and Other Solid Tumors
AbstractLessons Learned. Nivolumab treatment at doses of 3 mg/kg once every 2 weeks (Q2W), 240 mg Q2W, and 360 mg once every 3 weeks was well tolerated in the Chinese population, with no new safety signals identified.Comparison of intensive pharmacokinetic profiles of nivolumab at 3 mg/kg Q2W in Chinese versus global populations revealed no ethnic differences of nivolumab treatment.Nivolumab shows promising preliminary antitumor activity in nasopharyngeal carcinoma.Background.This phase I/II study investigated the safety and pharmacokinetics (PK) of nivolumab (anti‐programmed cell death‐1 monoclonal antibody) in Chinese patients with nasopharyngeal carcinoma (NPC) and other solid tumors.Methods.A dose evaluation phase (3 mg/kg once every 2 weeks [Q2W]) was followed by a cohort expansion phase (3 mg/kg Q2W or flat doses of 240 mg Q2W or 360 mg once every 3 weeks).Results.In the dose evaluation phase, 8/8 patients completed one cycle with no dose‐limiting toxicities. At data cutoff, 46/51 patients were evaluable for safety (all cohorts). Treatment‐related adverse events (TRAEs) occurred in 35 (76%) patients and were primarily grade 1–2; one patient (3 mg/kg Q2W) discontinued because of study drug toxicity. Intensive PK profiles at 3 mg/kg, 240 mg, and 360 mg were well characterized at single and multiple doses of nivolumab. An objective response was determined in six (6/46) patients, four (4/32) of whom had NPC tumors.Conclusion.Nivolumab monotherapy at 3 mg/kg and flat doses of 240 mg and 360 mg were well tolerated in this Chinese patient population, with PK profiles at 3 mg/kg being similar to those of global patients. Preliminary efficacy results showed promising antitumor activity of nivolumab in advanced NPC.
Concurrent EGFR‐TKI and Thoracic Radiotherapy as First‐Line Treatment for Stage IV Non‐Small Cell Lung Cancer Harboring EGFR Active Mutations
AbstractLessons Learned. This single‐arm, phase II study shows that concurrent EGFR‐tyrosine kinase inhibitor plus thoracic radiotherapy as the first‐line treatment for stage IV non‐small cell lung cancer harboring EGFR active mutations provides long‐term control for the primary lung lesion, and 1‐year progression‐free survival (PFS) rate and median PFS are numerically higher than those of the erlotinib monotherapy.Serious adverse events are acceptable, although grade >3 radiation pneumonitis occurred in 20% of patients.Background.Studies show effective local control by EGFR‐tyrosine kinase inhibitor (TKI) combined with radiotherapy at metastatic sites in advanced lung cancer harboring EGFR active mutations. Salvage local radiotherapy is associated with prolonged progression‐free survival (PFS) in local disease during EGFR‐TKI treatment. However, no prospective study has been reported on concurrent EGFR‐TKI and radiotherapy for primary lung lesions. This study investigated the efficacy and safety of first‐line EGFR‐TKI combined with thoracic radiotherapy in treating stage IV non‐small cell lung cancer (NSCLC) harboring EGFR active mutations.Methods.We conducted a single‐arm, phase II clinical trial. Each patient received EGFR‐TKI (erlotinib 150 mg or gefitinib 250 mg per day) plus thoracic radiotherapy (54–60 Gy/27–30 F/5.5–6 w) within 2 weeks of beginning EGFR‐TKI therapy until either disease progression or intolerable adverse events (AEs) appeared.Results.From January 2015 to March 2018, 401 patients were screened, and 10 patients (5 male and 5 female) were eligible. These patients had a median age of 55 years (40–75) and median follow‐up of 19.8 months (5.8–34). The 1‐year PFS rate was 57.1%, median PFS was 13 months, and median time to progression of irradiated lesion (iTTP) was 20.5 months. Objective response rate (ORR), was 50% and disease control rate (DCR) was 100%. The most common grade ≥3 AEs were radiation pneumonitis (20%) and rash (10%). One patient died after rejecting treatment for pneumonitis. The others received a full, systematic course of glucocorticoid therapy. Pneumonitis was all well controlled and did not relapse.Conclusion.Concurrent EGFR‐TKI plus thoracic radiotherapy as the first‐line treatment for stage IV NSCLC harboring EGFR active mutations shows a long‐term control of primary lung lesion. The 1‐year PFS rate and median PFS of this combined therapy are numerically higher than those of the erlotinib monotherapy. The risk of serious adverse events is acceptable.
Analysis of DNA Damage Response Gene Alterations and Tumor Mutational Burden Across 17,486 Tubular Gastrointestinal Carcinomas: Implications for Therapy
AbstractBackground.Alterations in the DNA damage response (DDR) pathway confer sensitivity to certain chemotherapies, radiation, and other DNA damage repair targeted therapies. BRCA1/2 are the most well‐studied DDR genes, but recurrent alterations are described in other DDR pathway members across cancers. Deleterious DDR alterations may sensitize tumor cells to poly (ADP‐ribose) polymerase inhibition, but there are also increasing data suggesting that there may also be synergy with immune checkpoint inhibitors. The relevance of DDR defects in gastrointestinal (GI) cancers is understudied. We sought to characterize DDR‐defective GI malignancies and to explore genomic context and tumor mutational burden (TMB) to provide a platform for future rational investigations.Materials and Methods.Tumor samples from 17,486 unique patients with advanced colorectal, gastroesophageal, or small bowel carcinomas were assayed using hybrid‐capture‐based comprehensive genomic profiling including sequencing of 10 predefined DDR genes: ARID1A, ATM, ATR, BRCA1, BRCA2, CDK12, CHEK1, CHEK2, PALB2, and RAD51. TMB (mutations per megabase [mut/Mb]) was calculated from up to 1.14 Mb of sequenced DNA. Clinicopathologic features were extracted and descriptive statistics were used to explore genomic relationships among identified subgroups.Results.DDR alterations were found in 17% of cases: gastric adenocarcinoma 475/1,750 (27%), small bowel adenocarcinoma 148/666 (22%), esophageal adenocarcinoma 467/2,501 (19%), and colorectal cancer 1,824/12,569 (15%). ARID1A (9.2%) and ATM (4.7%) were the most commonly altered DDR genes in this series, followed by BRCA2 (2.3%), BRCA1 (1.1%), CHEK2 (1.0%), ATR (0.8%), CDK12 (0.7%), PALB2 (0.6%), CHEK1 (0.1%) and RAD51 (0.1%). More than one DDR gene alteration was found in 24% of cases. High microsatellite instability (MSI‐H) and high TMB (TMB‐H, ≥20 mut/Mb) were found in 19% and 21% of DDR‐altered cases, respectively. Of DDR‐altered/TMB‐H cases, 87% were also MSI‐H. However, even in the microsatellite stable (MSS)/DDR‐wild‐type (WT) versus MSS/DDR‐altered, TMB‐high was seen more frequently (0.4% vs. 3.3%, P < .00001.) Median TMB was 5.4 mut/Mb in the MSS/DDR‐altered subset versus 3.8 mut/Mb in the MSS/DDR‐WT subset (P ≤ .00001), and ATR alterations were enriched in the MSS/TMB‐high cases.Conclusion.This is the largest study to examine selected DDR defects in tubular GI cancers and confirms that DDR defects are relatively common and that there is an association between the selected DDR defects and a high TMB in more than 20% of cases. Microsatellite stable DDR‐defective tumors with elevated TMB warrant further exploration.Implications for Practice.Deleterious DNA damage response (DDR) alterations may sensitize tumor cells to poly (ADP‐ribose) polymerase inhibition, but also potentially to immune checkpoint inhibitors, owing to accumulation of mutations in DDR‐defective tumors. The relevance of DDR defects in gastrointestinal (GI) cancers is understudied. This article characterizes DDR‐defective GI malignancies and explores genomic context and tumor mutational burden to provide a platform for future rational investigations.
Lymphopenia in Esophageal Squamous Cell Carcinoma: Relationship to Malnutrition, Various Disease Parameters, and Response to Concurrent Chemoradiotherapy
AbstractBackground.Lymphopenia occurs commonly in esophageal squamous cell carcinoma (ESCC) and may influence treatment outcomes. We aimed to examine its association with treatment response and tumor progression in patients with locally advanced ESCC treated with concurrent chemoradiotherapy (CCRT).Materials and Methods.A total of 286 patients with stage II–IVa ESCC treated with CCRT between 2015 and 2017 were analyzed. Total lymphocyte counts were assessed at baseline, weekly, and 4 weeks after CCRT. Pretreatment lymphopenia was defined as total lymphocyte count <1,000 cells per mm3 at diagnosis, and treatment‐related lymphopenia was defined as total lymphocyte count <200 cells per mm3 with 6 weeks after starting CCRT. Univariate and multivariate logistic regression methods were used to analyze factors associated treatment‐related lymphopenia and treatment response.Results.Lymphopenia was observed in 44 patients (15.4%) at initial diagnosis. Pretreatment lymphopenia was significantly associated with greater tumor length, worse T status, body mass index ≤18.5 kg/m2, and weight loss ≥3 kg in the previous 3 months. Six weeks after starting CCRT, 89 patients (31%) developed treatment‐related lymphopenia. Tumor progression and cancer‐related death were more frequently observed in treatment‐related lymphopenia group than those without (76.4% vs. 52.8% and 58.4% vs. 39.6%). A complete response (CR) was achieved in 62 patients (21.7%). In multivariate analysis, treatment‐related lymphopenia was significantly associated with lack of clinical CR, and older age, lower tumor location, greater tumor length, and larger planning target volume were independent predictors of treatment‐related lymphopenia.Conclusion.Treatment‐related lymphopenia during CCRT is an independent predictor for poor treatment response in ESCC.Implications for Practice.A total of 286 patients with locally advanced esophageal squamous cell carcinoma were treated with concurrent chemoradiotherapy (CCRT), and treatment‐related lymphopenia occurred in 31% of patients within 6 weeks from the start of CCRT. Treatment‐related lymphopenia was significantly associated with lack of treatment response, and older age, lower tumor location, greater tumor length, and larger planning target volume were independent predictors of treatment‐related lymphopenia. Lymphocyte count is an inexpensive biomarker that may be easily used by clinicians to identify patients who are most likely to benefit from CCRT.
Adjuvant Zoledronic Acid in High‐Risk Giant Cell Tumor of Bone: A Multicenter Randomized Phase II Trial
AbstractLessons Learned. Adjuvant treatment with zoledronic acid did not decrease the recurrence rate of giant cell tumor of bone (GCTB) in this study. The efficacy could not be determined because of the small sample size.GCTB recurrences, even in the denosumab era, are still an issue; therefore, a randomized study exploring the efficacy of zoledronic acid in the adjuvant setting in GCTB is still valid.Background.Bisphosphonates are assumed to inhibit giant cell tumor of bone (GCTB)‐associated osteoclast activity and have an apoptotic effect on the neoplastic mononuclear cell population. The primary objective of this study was to determine the 2‐year recurrence rate of high‐risk GCTB after adjuvant zoledronic acid versus standard care.Methods.In this multicenter randomized open‐label phase II trial, patients with high‐risk GCTB were included (December 2008 to October 2013). Recruitment was stopped because of low accrual after the introduction of denosumab. In the intervention group, patients received adjuvant zoledronic acid (4 mg) intravenously at 1, 2, 3, 6, 9, and 12 months after surgery.Results.Fourteen patients were included (intervention n = 8, controls n = 6). Median follow‐up was long: 93.5 months (range, 48–111). Overall 2‐year recurrence rate was 38% (3/8) in the intervention versus 17% (1/6) in the control group (p = .58). All recurrences were seen within the first 15 months after surgery.Conclusion.Adjuvant treatment with zoledronic acid did not decrease the recurrence rate of GCTB in this study. The efficacy could not be determined because of the small sample size. Because recurrences, even in the denosumab era, are still an issue, a randomized study exploring the efficacy of zoledronic acid in the adjuvant setting in GCTB is still valid.
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