The ESMO Congress was held in Barcelona from September 27 to October 1, 2019. The conference recognized excellence in translational research and focused on clinically important findings and multidisciplinary topics. Following are highlights of breast cancer advances.

Neoadjuvant treatment for triple-negative breast cancer

In patients with early triple-negative breast cancer (TNBC), neoadjuvant pembrolizumab with chemotherapy followed by adjuvant pembrolizumab led to a higher pathologic complete response (pCR) rate than did neoadjuvant chemotherapy plus placebo.

Lead study author Peter Schmid, of the Centre for Experimental Cancer Medicine, Barts Cancer Institute-Queen Mary University of London, commented, “Now this is important, because large analyses have demonstrated that patients who achieve a pCR have a fantastic outlook and the recurrence risk is very low. Ninety to 95% of patients will not see any recurrence in that situation. However, patients who do not experience a PCR, we find residual tumor at the surgery. Even if we remove that residual tumor, unfortunately they have a relatively high risk of recurrence. Often around 40% to 50% in the first 3 to 5 years.”[2]

In the study, 784 patients with untreated, metastatic TNBC were randomized to receive pembrolizumab (200 mg every 3 weeks) and 390 were randomized to receive placebo. Both arms were treated with neoadjuvant chemotherapy before definitive surgery and adjuvant pembrolizumab.

In total, 602 patients could be assessed after a median follow-up of 15.5 months. In those receiving the pembrolizumab-chemotherapy regimen, the pCR rate was 64.8% compared with that of 51.2% for placebo plus chemotherapy. Of note, pCR was defined as ypT0/Tis ypN0.

A beneficial trend in event-free survival was also observed in those receiving neoadjuvant pembrolizumab arm compared with those in the placebo arm (hazard ratio [HR] 0.63; 95% CI, 0.43-0.93). On subgroup analysis, pCR was increased regardless of PD-L1 status.

The rate of grade 3 or more treatment-related adverse events was 78.0% in those in the pembrolizumab arm compared with that of those in the placebo arm. Moreover, mortality rates were 0.4% vs. 0.3% in these arms, respectively.[1,2,3]

HER2+ Advanced Breast Cancer and PD-L1 inhibitors

In patients with HER2+ advanced breast cancer who progressed following treatment with trastuzumab and a taxane, the programmed death ligand 1 (PD-L1) inhibitor atezolizumab plus trastuzumab emtansine (T-DM1) outperformed placebo plus T-DM1 in terms of overall survival (OS), according to the results of the phase 2 KATE2 trial.

Lead author Leisha Emens, of UPMC Hillman Cancer Center, Pittsburgh, stated, "Currently, there is a large effort to develop effective immunotherapy combinations that can enhance the activity of single agent PD-1 or PDL-1 blockade. HER2-positive breast cancer is unique in that there are a number of HER2-targeted agents that could potentially be combined with immune checkpoint blockade. The main ones include trastuzumab and trastuzumab emtansine, an antibody-drug conjugate. Both of those have, as a backbone, the trastuzumab antibody which in and of itself has immune-modulating activity. The antibody drug conjugate also has a chemotherapeutic agent conjugated directly to the antibody and that could also potentially have immune-modulating activity.”

She continued, “So, the rationale underlying KATE2, which is a phase II randomized trial that explored the clinical activity of adding atezolizumab to TDM1, is that combining these 2 agents maybe additive or even synergistic relative to the clinical activity of the single agents alone."[4]

In the current trial, patients were assigned 2:1 to receive either atezolizumab 1200 mg or placebo, with both cohorts receiving T-DM1 3.6 mg/kg intravenously every 3 weeks. Patients with PD-L1+ subtypes were determined via immune cell (IC) staining and included IC0 versus IC1/2/3 (<1% vs ≥ 1%, respectively).

In the atezolizumab plus T-DM1 arm, the median follow-up was 19.5 months compared with that of 18.2 months in the placebo arm. Although median overall survival was not attained, there were 52 measures of overall survival reported. One-year survival was similar in all patients, per the intention-to-treat population; whereas in PD-L1+ patients, 1-year OS was longer in the atezolizumab plus T-DM1 cohort. Compared with known safety profiles of each individual drug, the combined treatments had similar profiles. Pyrexia, however, was more common in those receiving atezolizumab plus T-DM1.

“Given the small number of OS events, the short follow-up and lack of statistical power, further study is necessary,” concluded the authors.[5]

Results presented from the phase 1/II MEDIOLA trial supported the combination treatment of olaparib and durvalumab in the treatment of patients with breast cancer.

The MEDIOLA trial assessed the efficacy and safety of olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer. In eligible patients, previous treatment with platinum was permitted, but previous treatment with PARP inhibitors or anti-PD1/PDL1 therapy was exclusionary. Treatment consisted of olaparib 300 mg twice-a-day for a 4-week run-in followed by olaparib 300 mg twice-a-day and durvalumab 1.5 g intravenous for 4 weeks. Primary endpoints were safety and disease control rate (DCR) at 12 weeks.[6]

In total, 30 patients were assessed for safety, and 34 patients were assessed for efficacy. Beating the target rate of 75%, the DCR at 12 weeks was 80% and the 28-week DCR was 50%.[7]

In other results, median progression-free survival (mPFS) in all patients was 8.2 months (95% CI, 4.6-11.8), median OS was 20.5 months (95% CI, 16.2-23.9), objective response rate (ORR) was 63.3% (95% CI, 43.9-80.1), and median duration of response (mDoR) was 9.2 months (95% CI, 5.5-20.3). The most common treatment-related adverse events of grade 3 or higher were anemia, neutropenia, and pancreatitis.

More specifically, in patients with hormone receptor (HR)-positive disease, mPFS was 9.9 months. The mPFS was 4.9 months in patients with triple-negative breast cancer.

“The data suggest that pts with fewer prior lines of chemotherapy (0/1) had higher ORR, longer mDoR, mPFS and mOS than those with 2 prior lines,” concluded the authors. “The chemo-free combination was well-tolerated, with safety consistent with the individual agent profiles. Confirmation of these results in early-line patients is warranted.”[6]

Abemaciclib and fulvestrant in breast cancer

In hormone-receptor (HR)-positive HER2-negative patients with advanced breast cancer resistant to endocrine therapy, adding the CD4/6 inhibitor abemaciclib to fulvestrant extended OS compared with fulvestrant and placebo, per the results of the MONARCH 2 trial.

In total, 669 patients were randomly assigned 2:1 to receive abemaciclib plus fulvestrant or placebo and fulvestrant, respectively. Fulvestrant was administered 500 mg twice daily, and abemaciclib was given 150 mg twice a day continuously.

The median OS in the abemaciclib-fulvestrant arm was 46.7 months compared with a median OS of 37.3 months in the placebo-fulvestrant arm (HR, 0.757; 95% CI, 0.606-0.945; P = .0137).

Principal investigator George W. Sledge Jr, of the Stanford University Medical Center concluded, “The addition of abemaciclib to fulvestrant provided a statistically significant OS improvement in patients with HR-positive, HER2-negative breast cancer who had progressed on prior endocrine therapy. “This OS benefit is consistent across subgroups, including patients with poor prognostic factors such as visceral metastasis and primary endocrine therapy resistance. Abemaciclib significantly delayed the receipt of subsequent chemotherapy in a subsequent analysis."[8,9]

 ESMO. Adding Pembrolizumab to Neoadjuvant Chemotherapy Improves Outcome in Early TNBC. 

https://www.esmo.org/Oncology-News/Adding-Pembrolizumab-to-Neoadjuvant-Chemotherapy-Improves-Outcome-in-Early-TNBC

 Schmid P, Cortes Castan J, Bergh J, et al. KEYNOTE-522: Phase III study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo + chemo as neoadjuvant followed by pembro vs placebo as adjuvant therapy for triple-negative breast cancer (TNBC). Ann Oncol. 2019; 30(suppl 5):abstr 233TiP.

 Emens LA, Esteva FJ, Beresford M, et al. Overall survival (OS) in KATE2, a phase II study of programmed death ligand 1 (PD-L1) inhibitor atezolizumab (atezo)+trastuzumab emtansine (T-DM1) vs placebo (pbo)+T-DM1 in previously treated HER2+ advanced breast cancer (BC). Ann Oncol . 2019; 30(suppl 5):abstr 3050.

 Domchek S, Postel-Vinay S, Im S-A, et al. Phase II study of olaparib (O) and durvalumab (D) (MEDIOLA): Updated results in patients (pts) with germline BRCA-mutated (gBRCAm) metastatic breast cancer (MBC). Ann Oncol. 2019; 30(suppl 5):abstr 11910.

 Kaufman PA, Iwata H, Nikolinakos P, et al. Abemaciclib plus fulvestrant in patients (pts) with HR+/HER2- endocrine therapy naÃ¯ve (EN) advanced breast cancer - an exploratory analysis of MONARCH 2. Ann Oncol. 2019; 30(suppl 5):abstr 253P.

 Interview. Cancer Network. Dr. Schmid Discusses the KEYNOTE-522 Trial. 

https://www.cancernetwork.com/esmo/dr-schmid-discusses-keynote-522-trial

 Interview. Dr. Emens Discusses Overall Survival in HER2+ Breast Cancer. 

https://www.cancernetwork.com/esmo/dr-emens-discusses-overall-survival-her2-breast-cance

 Emens LA, Esteva FJ, Beresford M, et al. Overall survival (OS) in KATE2, a phase II study of programmed death ligand 1 (PD-L1) inhibitor atezolizumab (atezo)+trastuzumab emtansine (T-DM1) vs placebo (pbo)+T-DM1 in previously treated HER2+ advanced breast cancer (BC). Ann Oncol. 2019; 30(suppl 5):abstr 3050.

 Interview. OncLive. Olaparib/Durvalumab Combo Shows Promising Long-Term Activity in Germline BRCA+ Breast, Ovarian Cancer. https://www.onclive.com/web-exclusives/olaparibdurvalumab-combo-shows-promising-longterm-activity-in-germline-brca-breast-ovarian-cancer?p=2. Accessed November 5, 2019.

 Interview. OncLive. Abemaciclib/Fulvestrant Improves Survival in HR+ Advanced Breast Cancer. 

https://www.onclive.com/conference-coverage/esmo-2019/abemaciclib-fulvestrant-improves-survival-in-hr-positive-advanced-breast-cancer

Articles

Highlights of breast cancer advances at the ESMO Congress.

Esmo Congress 2019: Focus on Breast Cancer

From September 7-10, 2019, the International Association for the Study of Lung Cancer (IASLC) hosted the 2019 World Conference on Lung Cancer (WCLC) in Barcelona, touted as the biggest gathering of lung cancer researchers and clinicians worldwide. Below are five notable abstracts from the conference.

Concerning Lack of Public Knowledge About Lung Cancer Clinical Trials

A study performed by Lung Cancer Europe (LuCE) to garner insights into clinical trials from a patient perspective found that 50% of Europeans surveyed did not know what cancer clinical trials were and 22% were unaware that cancer clinical trials existed.[1]

“We shared our online survey with lung cancer advocates and patients with lung cancer,” stated lead author AM Baird, on behalf of LuCE in an IASLC press release.[2]

LuCE advocates for the interests of lung cancer patients in Europe and is dedicated to education as well as addressing disparities in detection, diagnosis, and treatment. In this study, researchers interviewed 15 stakeholders in the medical community and surveyed 262 lung cancer patients from 15 European countries.[1]

Only 11% of patients surveyed had participated in a clinical trial, with more than 50% reporting it to be a positive experience. Moreover, 89% found trial information on the Internet, but only 10% reported that they could routinely find the information they required.[1]

“This is critical, as the more information patients obtained, the more willing they were to participate in clinical trials,” wrote the authors in the study abstract. “Overall 80% wanted to find out more about clinical trials, and 75% believed that it would be beneficial for patients to work together with researchers in the clinical trial development process.”[1]

The authors continued, “Key areas identified by this research included difficulties in cross-border access, language barriers, lack of accurate accessible information, lack of awareness by patients and clinicians, and disparities in access across Europe.”[1]

European Lung Cancer Screening Model Bests United States Model

Globally, PLCOm2012 is the best validated and most popular lung cancer risk prediction model; it calls for CT screening in patients with a 6-year lung cancer risk of ≥ 1.5%. Although this model has demonstrated efficacy, it runs counter to recommendations of the United States Preventive Services Task Force (USPSTF) and the Centers for Medicare and Medicaid Services which recommend screening in those with 30 or more pack-years, those who smoked within the past 15 years, and patients age 55 to around 80 years.[3]

“Our analysis of ILST (International Lung Screening Trial) data indicates that classification accuracy of lung cancer screening outcomes supports the PLCOm2012 criteria over the USPSTF criteria,” stated principal investigator, Stephen Lam, MD, University of British Columbia, Vancouver, in an IASLC press release.[4]

The ILST trial is enrolling participants who meet criteria per USPSTF or PLCOm2012. Patients receive two annual screening tests, and patient outcomes are followed for 6 years.[3]

“Many studies indicate that using accurate risk prediction models is superior for selecting individuals for screening, but these findings are based on retrospective analyses. The ILST was implemented to prospectively identify which approach is superior,” wrote the authors.[3]

Overall, 110 of 5013 patients screened had lung cancer, with 99% of cancers discovered per PLCOm2012 criteria compared with 77% per USPSTF criteria. Furthermore, 21.8% of cancers were discovered solely per PLCOm2012 whereas only 0.9% was discovered solely using USPSTF guidelines.[4]

“Our analysis of ILST data indicates that classification accuracy of lung cancer screening outcomes supports the PLCOm2012 criteria over the USPSTF criteria,” concluded Dr Lam.[4]

KEYNOTE-021: Tumor Mutational Burden With or Without Pembrolizumab

According to the results of an exploratory study in first-line treatment for metastatic non-squamous non-small cell lung cancer (NSCLC), tumor mutational burden (TMB) was not related to the efficacy of pembrolizumab plus carboplatin and pemetrexed or carboplatin and pemetrexed alone. TMB was not related to PD-L1 expression.[5]

“KEYNOTE-021 cohort C was the first study to show antitumor activity for pembrolizumab plus platinum-based chemotherapy in previously untreated advanced nonsquamous NSCLC; the combination significantly improved efficacy vs platinum-based chemotherapy alone in cohort G. We explored the relationship between TMB and outcomes in KEYNOTE-021 cohorts C and G,” wrote authors, led by Corey Langer, MD, Abramson Cancer Center, University of Pennsylvania, Philadelphia.[5]

Patients in Cohort C were given pembrolizumab plus carboplatin and pemetrexed. Whereas, patients in cohort G were randomly assigned 1:1 to receive either pembrolizumab plus carboplatin and pemetrexed or the chemotherapy component alone. Langer et al. used whole-exome sequencing of tumors, as well as matched normal DNA, to assess TMB.[6]

Data on TMB were available for 70 patients, with initial patient characteristics similar among both cohorts. As a continuous variable, TMB was not related to progression-free survival, overall response rate (ORR), or overall survival (OS) in either arm of the study. Notably, ORR was high in both the TMB low and high subgroups. In the pembrolizumab with chemotherapy arm, the ORR was 60.8% (95% confidence interval [CI], 38.5-80.3) in the 23 patients with high TMB (TMB <175) and 71.4% (95% CI, 47.8-88.7) in the 21 patients with low TMB (TMB ≥175). No association between TMB and tissue polypeptide-specific antigen was observed (r=0.12, 

“Sample size is a limitation of this study; exploration in larger datasets is required to understand any differential efficacy of pembrolizumab plus chemotherapy vs chemotherapy alone based on TMB status,” concluded the researchers.[5]

Autoantibody Test Followed by CT Decreases Diagnosis of Late-Stage Lung Cancer and May Reduce Mortality

The novel EarlyCDT-Lung Test plus CT imaging in a Scottish cohort of patients at risk for lung cancer led to a decrease in the diagnosis of late-stage lung cancer and could drop mortality secondary to the disease.[7]

The EarlyCDT-Lung Test is a new autoantibody diagnostic test that stratifies patients according to their risk of developing lung cancer. With a specificity of 90%, it catches 41% of lung cancers compared with CT scanning that only identifies 67% of lung cancers, with a specificity of about 49%.[7]

“The study was not powered to detect a difference in mortality, however there was a non-significant trend suggesting fewer deaths in the intervention arm compared to the control (87 vs 108 respectively). Similar results were noted relating to lung cancer-specific mortality (17 vs 24),” said Sullivan, according to an IASLC press release.[7]

In this randomized controlled trial, the team examined whether EarlyCDT-Lung Test followed by x-ray and CT could reduce the frequency of advanced lung cancer or unclassified presentation in 12,208 high-risk patients. Patients who tested positive per the EarlyCDT-Lung Test were offered chest-x ray and then non-contrast thoracic CT. If the CT was within normal limits, follow-up CTs were available to patients for a period of 24 months. Patients with lesions were followed up by the investigators or sent for referrals and clinical treatment.[8]

Overall, 9.8% of patients in the experimental group had positive EarlyCDT results, with 3.4% diagnosed with lung cancer during the 2-year study period. Furthermore, 127 lung cancer cases were identified, with 56 cases the experimental group and 71 cases in the control group.[8]

Mutations Associated with Response to Immunotherapy: MYSTIC Trial

In patients with metastatic NSCLC, investigators assessed the relationship between STK11, KEAP1, and ARID1A mutations and response to immunotherapy.[9,10]

“The STK11 and KEAP1 mutations … influence outcomes and need to be factored into our analysis of TMB and other outcomes of lung cancer,” said presenter Naiyer A. Rizvi, MD, Director of Thoracic Oncology, Division of Hematology/Oncology, Columbia University Medical Center, New York. “STK11 and KEAP1 are sort of bad actors in terms of lung cancer outcomes [as supported by current knowledge].”[11]

The phase III MYSTIC trial compared durvalumab monotherapy or durvalumab/tremelimumab vs chemotherapy as first-line treatment in patients with epidermal growth-factor receptor and anaplastic lymphoma kinase wild-type locally advanced or metastatic NSCLC. During further analysis, a subset of patients with high TMB were identified via plasma assay using a 20 mutation/megabase threshold.

Participants harboring STK11 or KEAP1 mutations had lower median OS in all experimental groups. In those with ARID1A mutations who received durvalumab/tremelimumab, the investigators saw survival benefits.[9,10].

 Baird AM, Villalon D, Aquaron A, et al. Challenges in lung cancer clinical trials: a European perspective. Program and abstracts of the International Association for the Study of Lung Cancer 20th World Conference on Lung Cancer. September 7-10, 2019. Barcelona, Spain. Abstract MA24.01.

 Martin C, Bunn B. International Association for the Study of Lung Cancer. Europeans face significant challenges to participate in lung cancer clinical trials. (press release) Available at: 

https://wclc2019.iaslc.org/wp-content/uploads/2019/09/Challenges-in-Lung-Cancer-Finalbbedits.pdf

 Lam S, Myers R, Ruparel M, et al. Lung cancer screenee selection by USPSTF versus PLCOm2012 criteria – interim ILST findings. Program and abstracts of the International Association for the Study of Lung Cancer 20th World Conference on Lung Cancer. September 7-10, 2019. Barcelona, Spain. Abstract PL02.02

 Langer CJ, Gadgeel S, Borghaei H, et al. KEYNOTE-021: TMB and outcomes for carboplatin and pemetrexed with or without pembrolizumab for nonsquamous NSCLC. Program and abstracts of the International Association for the Study of Lung Cancer 20th World Conference on Lung Cancer. September 7-10, 2019. Barcelona, Spain. Abstract OA04.05.

Rizvi NA, Cho BC, Reinmuth N, et al. Mutations associated with sensitivity or resistance to immunotherapy in mNSCLC: analysis from the MYSTIC trial. Program and abstracts of the International Association for the Study of Lung Cancer 20th World Conference on Lung Cancer. September 7-10, 2019. Barcelona, Spain. Abstract OA04.07

 Lam S, Myers R, Ruparel M, et al. Lung cancer screenee selection by USPSTF versus PLCOm2012 criteria – interim ILST findings. Program and abstracts of the International Association for the Study of Lung Cancer 20th World Conference on Lung Cancer. September 7-10, 2019. Barcelona, Spain. Abstract PL02.02.

 Martin C, Bunn B. International Association for the Study of Lung Cancer. Lung cancer screening model favored in Europe detects more cancers than one preferred in the United States. (press release) Available at: 

https://www.iaslc.org/About-IASLC/News-Detail/lung-cancer-screening-model-favored-in-europe-detects-more-cancers-than-one-preferred-in-the-united-states

 Martin C, Bunn B. International Association for the Study of Lung Cancer. New KEYNOTE 021 data shows no association with tumor mutational burden. (press release) Available at: 

https://www.iaslc.org/About-IASLC/News-Detail/new-keynote-021-data-shows-no-association-with-tumor-mutational-burden

 Martin C, Bunn B. International Association for the Study of Lung Cancer. Scottish study demonstrates that autoantibody test followed by CT imaging may reduce lung cancer mortality. (press release) Available at: 

https://wclc2019.iaslc.org/wp-content/uploads/2019/09/ECLS-Scottish-news-release_SSfs-8-16bbedits.pdf

 Sullivan F, Schembri S. Early Detection of Cancer of the Lung Scotland (ECLS): trial results. Program and abstracts of the International Association for the Study of Lung Cancer 20th World Conference on Lung Cancer. September 7-10, 2019. Barcelona, Spain. Abstract PL02.03.

 Martin C. Mutations associated with sensitivity or resistance to immunotherapy in mNSCLC: analysis from the MYSTIC trial. (press release). International Association for the Study of Lung Cancer. Available at: 

https://www.eurekalert.org/pub_releases/2019-09/iaft-maw090819.php

 Rizvi NA, Cho BC, Reinmuth N, et al. Mutations associated with sensitivity or resistance to immunotherapy in mNSCLC: analysis from the MYSTIC trial. Program and abstracts of the International Association for the Study of Lung Cancer 20th World Conference on Lung Cancer. September 7-10, 2019. Barcelona, Spain. Abstract OA04.07.

 International Association for the Study of Lung Cancer 20th World Conference on Lung Cancer. Press conference. September 8, 2019. 

https://www.youtube.com/watch?time_continue=455&v=KjGfnruciLo

Five notable abstracts from the 2019 World Conference on Lung Cancer (WCLC).

2019 World Conference Of Lung Cancer Round-Up

A rare occurrence, cancer in the esophagus requires an individualized treatment plan.

A 63-year-old man presented with a 3-month history of significant weight loss, dysphagia, and odynophagia. His past medical history was relevant for a radical cystectomy for a stage II muscle-invasive urothelial bladder cancer 10 years ago. He had an hepatic, pulmonary, and lymph-node systemic recurrence 8 years ago, with complete response to 6 cycles of gemcitabine/carboplatin, and has been in continuous surveillance ever since.

His physical examination and laboratory tests were unremarkable. An esophagram revealed distal esophageal stenosis with proximal dilation. A CT scan showed a concentric thickening in the middle and distal esophagus. Positron emission tomography and F-18-fluorodeoxyglucose (18F-FDG) integrated with CT (18F-FDG PET/CT) displayed hypermetabolism in the middle and distal third of the esophagus, with no evidence of other sites of metastatic disease (

An upper gastrointestinal endoscopy was performed and revealed a complex ulcerated stenosis at 35 cm from the upper incisors. Biopsies were taken. The pathology examination revealed metastatic high-grade urothelial carcinoma: CK7-positive, CK20-negative, GATA3-positive, p63-positive, and uroplakin-positive (

). Morphologic appearance and immunohistochemistry were highly similar to that of the primary tumor and the previous systemic recurrence.

What is the primary tumor that most commonly metastasizes to the esophagus?

. Lung cancer is the primary tumor that most often causes secondary infiltration to the esophagus.

Esophageal metastases are a rare phenomenon. According to autopsy registries of any kind of neoplasm, incidence ranges from 0.3% to 6.1% of all metastases, most of them asymptomatic.[1,2] Esophageal involvement may be caused by three principal mechanisms: direct extension, mediastinal lymph node metastases with subsequent esophageal infiltration, and hematogenous dissemination. Direct extension from adjacent organs is by far the most common manifestation (up to 45.2% of cases), followed by infiltration from mediastinal lymphatic metastases (35.5% of cases). True distant hematogenous metastases are the rarest mechanism, accounting for 19.3% of cases.[3] Direct extension from a contiguous organ can be recognized most of the time by the obvious primary tumor. This does not hold true for the other two mechanisms, and therefore most clinical series admix them.[3]

The first case of esophageal metastasis (from the prostate) was published by Gross and Freedman in 1942.[4] After that, a wide array of malignant tumors with metastases to the esophagus were reported, including lung, breast, ovarian, kidney, gastrointestinal, lymphoma, testicular, tongue, bone, liver, uterine, and skin.[2,3] According to the largest retrospective autopsy case series, the most common cause of esophageal metastases is lung cancer, followed by breast and gastric neoplasms (45.5%, 12.5%, and 11.6% of all esophageal metastases, respectively).[2] This study and other case series are summarized in the Table. Thus, option B is correct, but histologic differences need to be addressed. Up to 15% of adenocarcinomas metastasize to the esophagus and the corresponding percentages for small-cell lung cancer and squamous cell carcinoma are 9.8% and 8.1%, respectively.[2]

Urothelial carcinoma is the 10th most common malignant neoplasia worldwide.[5] About 10% to 20% of those patients have the aggressive muscle-invasive disease, which gives them higher risk of lymphatic and systemic dissemination.[6,7] Even with curative treatments like radical cystectomy, up to 16% and 50% will have locoregional and distant recurrences, respectively.[8–10] The most common sites of distant metastases from urothelial carcinoma are nonregional lymph nodes (90%), liver (47%), lung (45%), and bone (32%); other sites might include peritoneum, pleura, kidney, adrenal gland, and intestine.[11] To the best of our knowledge, this is the first case report of esophageal metastasis ever reported.

Esophageal metastases are a diagnostic challenge, because in most cases clinical presentation is indistinguishable from primary esophageal cancers. No difference in the severity or duration of symptoms correlates to primary versus secondary neoplasms.[2] Radiographic studies might be useful to detect primary adjacent tumors, but these are not that useful to discriminate metastasis from primary neoplasms. Esophagrams can display esophageal stenosis with normal mucosa, and CT scans may show concentric thickening of the esophageal wall, with or without an associated extrinsic mass.[2,3]

Upper gastric endoscopy is the most useful test in this setting. A normal epithelium is seen in 68% of esophageal stenosis due to the submucosal nature of most metastases. In any esophageal stenosis with normal mucosa, metastasis must be contemplated as a differential diagnosis, especially in patients with a history of cancer. Endoscopic ultrasound might also help to determine the layer where a tumor comes from and also to achieve histopathologic diagnosis, as many traditional endoscopy biopsies might only show normal epithelium overlying to the tumor.[2,11,12]

Treatment of esophageal metastases depends on several factors, such as origin, symptom severity, and presence of metastases to other organs. In most patients, treatment consists of chemotherapy with or without radiotherapy.[2] Although chemosensitive, most metastatic urothelial carcinomas remain an incurable disease. Without systemic treatment, most patients die of progressive disease within 6 months.[13] The cornerstone of treatment for urothelial cancer is platinum-based chemotherapy, achieving an objective response rate of 50% to 60% and complete responses in 10% to 20% of patients. In most cases, responses are transitory and few patients achieve long-term survival.[8,9,13]

Local control with esophagectomy has provided excellent palliation in several case reports of esophageal metastases, with primary tumors coming from breast, lung, and malignant melanoma.[10,14,15] Metastasectomy in urothelial carcinoma and its impact in survival is controversial.[15,16] Single-site metachronous tumors have achieved prolonged survival in case reports, however, so an aggressive surgical approach must be taken into consideration. Palliation with endoscopic dilation and stents might be an alternative, given that many patients have maintained oral intake with those procedures in recent reports of esophageal metastases.[3,17,18]

Prognosis of esophageal metastases is uncertain, ranging from a few months to several years. A case-by-case detailed analysis must be done in every patient to select the proper treatment and attain quality of life.

• Esophageal metastases are a rare phenomenon, ranging from 0.3% to 6.1% of all metastases.

• The most common cause of esophageal metastases is lung cancer, followed by breast and gastric neoplasms.

• In esophageal stenosis with normal mucosa, metastasis must be considered as a differential diagnosis, especially if the patient has a previous history of cancer.

• There is no standard treatment for esophageal metastases; a case-by-case selection for aggressive treatment must be considered.

The patient was started on chemotherapy with gemcitabine and carboplatin, given the adequate clinical response he had had to this combination previously and the fact that he could sustain adequate oral intake despite his symptoms. Currently, he has received 2 cycles of chemotherapy with adequate tolerance. A control CT scan to ascertain response is pending.

The other authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article. Dr. MarÃ­a Bourlon has served as a speaker and a member of the advisory board for Bristol-Myers Squibb. She has been a speaker, advisor, and/or travel grant recipient for BMS, Janssen, Ipsen, MSD, and Asofarma.

Dietrich B, Siefker-Radtke AO, Srinivas S, Yu EY. Systemic therapy for advanced urothelial carcinoma: current standards and treatment considerations. Am Soc Clin Oncol Educ Book. 2018;38:342-53.

 Shankar PR, Barkmeier D, Hadjiiski L, Cohan RH. A pictorial review of bladder cancer nodal metastases. Transl Androl Urol. 2018;7:804-13.

Hiensch R, Belete H, Rashidfarokhi M, et al. Unusual patterns of thoracic metastasis of urinary bladder carcinoma. J Clin Imaging Sci. 2017;7:23.

 Fan W, Jiang H, Chen H, et al. Esophageal metastasis from endometrial adenocarcinoma: a case report and literature review. Transl Cancer Res. 2018;7:1178-83.

 Patel V, Collazo Lorduy A, Stern A, et al. Survival after metastasectomy for metastatic urothelial carcinoma: a systematic review and meta-analysis. Bladder Cancer. 2017;3:121-32.

Esophageal cancer is the 7th most common cancer worldwide.

When esophageal cancer occurs, it starts in the inner layers of the esophagus and grows outward.

Other cancers metastasizing to the esophagus is a rare occurrence, but symptoms are often similar to those in primary esophageal cancer.

Cancer affecting the esophagus can sometimes narrow the esophagus which may make it difficult to swallow or eat properly.

Other signs and symptoms of esophageal cancer or cancer metastasized to the esophagus include heartburn, unexplained weight loss, hiccups, or a lasting cough.

An esophagectomy, surgery to move all or part of the esophagus, is a common treatment for esophageal cancer.

While recovering from surgery, patients with cancer in the esophageal may not be able to eat by mouth and need a feeding tube to meet their nutritional needs.

Barrett esophagus is a pre-cancerous condition in which the cells at the lower part of the esophagus have been replaced by abnormal cells due to damage by stomach acid from reflux. People with Barret esophagus are at higher risk for esophageal cancer.

There are approximately 17,000 new esophageal cancer diagnoses each year in the USA.

Esophageal cancer is 3-4 times more common in men than women

 Abrams HL, Spiro R, Goldstein N. Metastases in carcinoma: analysis of 1000 autopsied cases. Cancer. 1950;3:74-85.

 Mizobuchi S, Tachimori Y, Kato H, et al. Metastatic esophageal tumors from distant primary lesions: report of three esophagectomies and study of 1835 autopsy cases. Jpn J Clin Oncol. 1997;27:410-4.

 Simchuk EJ, Low DE. Direct esophageal metastasis from a distant primary tumor is a submucosal process: a review of six cases. Dis Esophagus. 2001;14:247-50.

 Gross P, Freedman LJ. Obstructing secondary carcinoma of the esophagus. Arch Pathol Lab Med. 1942;33:361-4.

 International Agency for Research on Cancer. World Health Organization. Asia. Source: Globocan 2018. May 2019: Global Cancer Observatory.

 Dietrich B, Siefker-Radtke AO, Srinivas S, Yu EY. Systemic therapy for advanced urothelial carcinoma: current standards and treatment considerations. Am Soc Clin Oncol Educ Book. 2018;38:342-53.

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 Sternberg CN, de Mulder P, Schornagel JH, et al; EORTC Genito-Urinary Cancer Group. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006;42:50-4.

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What Are the Most Common Esophageal Metastases

ABSTRACT: Burnout is defined as an occupational-related syndrome characterized by physical and emotional exhaustion, cynicism/depersonalization, and low sense of professional accomplishment. Multiple oncology-specific risk factors are associated with an increased susceptibility for the development of burnout. On a daily basis, oncologists are faced with life and death decisions and grieving much more frequently than are physicians in other specialties. Continuous exposure to fatal illnesses with limited success in curing them, exceedingly long work hours with more administrative time demands, limited autonomy over daily responsibilities, endless electronic documentation requirements, and a shifting medical landscape seem to be making oncologists more vulnerable to suffering from burnout. Evidence suggests that burnout can impact quality of care in a variety of ways and have potentially profound personal implications. In this review, the definition, prevalence, causes, and management of oncologist burnout are analyzed. Steps oncologists can take to promote personal well-being and professional satisfaction are also explored.

Oncology is largely viewed as an inherently challenging specialty due to its nature of dealing with daily life and death circumstances. Exposure to long hours of direct patient care for desperately ill patients, counseling their families, endless electronic documentation requirements, continual loss of autonomy over daily responsibilities, and a constantly changing medical environment set the stage for what is called a “burnout syndrome” for most practicing oncologists. Feeling inadequately equipped to deal with the emotional reactions of patients and their families can be a further source of stress among oncologists whose daily work may also force them to face their own mortality, as well as that of their family and friends.

Burnout was first described by psychologist Herbert Freudenberger in the 1970s as a condition that occurs when work coupled with additional life pressures exceeds the ability to cope, resulting in physical and mental distress.[1] In the 1980s came the 22-item Maslach Burnout Inventory (MBI)–Human Services Survey, which became the most widely used and validated assessment tool for self-reported symptoms of burnout.[2] The MBI consists of three distinct components: emotional exhaustion, depersonalization, and personal accomplishment/experience of ineffectiveness. These components, however, are usually part of a continuum that may include overlapping symptoms of cardiovascular, gastrointestinal, musculoskeletal, cognitive, and affective origin. The Copenhagen Burnout Inventory, which was introduced in the early 2000s, gauges burnout at three scales: personal burnout, work-related burnout, and client-related burnout.[3] Finally in May 2019, the World Health Organization added burnout to the 11th revision of the International Classification of Diseases (ICD-11), characterizing it as a syndrome of three dimensions: feelings of energy depletion or exhaustion, increased mental distance from one’s job or feelings of cynicism or negativism about one’s job, and reduced professional efficacy.[4]

Energy depletion or exhaustion is described as a complete lack of energy frequently resulting in a debilitating feeling of dread for what the day ahead will bring. Basic tasks and, sadly, even things that would normally provide joy turn into chores. Trouble sleeping to the point of insomnia, inability to rest and recharge, and difficulty to concentrate and focus eventually lead to panic attacks, chest pain, breathing difficulties, migraines, and stomach pains. Increased mental distance from one’s job and feelings of cynicism or negativism about that job refer to feelings of worthlessness, hopelessness, and an inability to accept consolation or connect to the empathy offered by others, leading to isolation from work, family, friends, and life. Reduced professional efficacy can manifest as going through the motions, making it to the office, and somehow still getting the job done in an almost robotic manner. There is no zest, no pleasure, and therefore, no optimum performance. Ordinary tasks take longer, and things that were once easy now seem overwhelming.

Burnout is not a diagnosis listed in the 

Diagnostic and Statistical Manual of Mental Disorders,

 5th edition, but it is classified by ICD-11 as a phenomenon under problems associated with employment and has been recognized as a diagnosable condition (diagnostic code QD85) resulting from chronic workplace stress about exhaustion, cynicism, and reduced efficacy. Notably, it is highlighted to be an occupational phenomenon rather than a medical condition. [4] An occupational phenomenon is defined as factors influencing health status or contact with health services, which includes reasons individuals look for health services. It is not classified as an illness or health condition.

The hallmark features of burnout are similar to the criteria for endogenous depression; however, ICD-11 specifically excludes mood disorders from the definition of burnout. Although burnout is classified and conceptualized as a workplace-related disorder, this assertion may not be entirely true. Burnout may look similar to depression and other psychiatric disorders, in that it is multifactorial and complex. Symptoms of emotional exhaustion and depersonalization can originate from not only direct workplace stress but also stress at home, such as having difficulties in marriage, having to care for an older parent, or a long commute to work, and more. Many of the factors that contribute to depression also contribute to burnout. Sufficiently long vacations can help differentiate depression from burnout, but burnout relief post vacation has been shown to be short lived. [5] Psychiatrists who support physicians affected by burnout are left to consider the possibility of differential diagnoses or comorbidities because burnout and depression may have overlapping symptoms and clinical features. The stigma of mental illness and its treatment may allow burnout to become a catchall term for emotional distress and thus less stigmatized. Importantly, erroneously labeling a physician’s distress as burnout may prevent or delay appropriate treatment of depression and sometimes a life-threatening mental disorder.

As burnout is poorly defined, one may expect considerable variation in the reported prevalence of burnout to exist due to significant differences in the way it has been defined, diagnosed, and assessed. [6, 7] Depending on the definition chosen, the prevalence of burnout identified can vary significantly. This complexity arises because the classic triad of burnout symptoms can manifest to differing degrees in each individual. Most of the reported data come from survey studies. A national survey among US oncologists found a 45% burnout prevalence, while other studies reported 20% to 70% burnout rate globally. [8–12] A systematic review and meta-analysis of 4,876 participants from 17 studies reported a 32% rate of burnout, which possibly gives the best estimate on oncologist burnout. [13]

Similar to its definition and prevalence, leading causes and risk factors of burnout come from observational, cross-sectional, and survey-type studies. The three most commonly stated causative factors include clinical and nonclinical work burden, electronic medical record (EMR) implementation, and loss of autonomy. Causes and risk factors can be summarized into demographic, workplace, and work/life balance categories. Among demographic factors, younger age, living alone, lack of access to support services, and being an early career oncologist have been found to be related to burnout.[14,15] Workplace-related factors refer to not only increased work hours but also to increased administrative workload and reduced meaningful professional activity such as research and educational time.[16–19] The significant loss of physician independence, excessive time spent on regulatory and clerical work, and stressful professional experiences in delivering bad news to cancer patients have been connected to workplace-related burnout among oncologists.[20–22] Impaired work/life balance occurs when quality time away from work such as vacation time, time for hobbies, and time for family becomes increasingly inadequate.[23,24] Every additional after-hours time at home spent on work-related tasks such as accessing work-related emails and EMRs has been associated with higher rates of burnout.[25]

As oncologists, we deal with life and death and grieving much more frequently than other specialties. With continuous exposure to lethal illnesses and limited success in curing them, oncologists may seem to be particularly vulnerable to stress and burnout. Challenges of staying ahead of the extensive new discoveries in cancer science and trying to assimilate enormous quantities of new research on new drugs and molecular therapies, augmented by demands posed by EMRs and compliance, regulation, and payment issues, oncologists may very quickly reach a breaking point. Despite speculation that oncologists may be at greater risk for burnout than physicians in other disciplines, however, there have been very few well-designed studies examining distress rates among oncologists relative to other specialties. [26] A preliminary analysis from a national study conducted in collaboration with the American Medical Association of 7,000 US physicians did not find evidence to support the supposition that oncologists are at higher risk for burnout (unpublished data). Medical oncologists (n = 87) had a lower rate of burnout than other internal medicine physicians (n = 1,328), with a burnout rate of 37.9% vs 48.8%, respectively (

 = .05). Medical oncologists were also more likely to state they would choose the same specialty if they could redo their career choice compared with other internal medicine physicians, at 81.4% vs 61.9%, respectively (

On the brighter side, practicing oncologists caring for cancer patients have the most rewarding profession. Cancer research is intellectually more than stimulating. Witnessing revolutionary discoveries in molecular biology and seeing them translated into clinical practice, ie, “bench to bedside” happening more frequently than in any other specialty, is extremely gratifying. Being part of cancer science discoveries and having the opportunity to implement these advances into clinical practice by taking part in standard care and/or participating in clinical trials, oncologists have the unique advantage of professional satisfaction more than those in other specialties of medicine. Being part of the efforts leading to improved patient outcomes in prevention, diagnosis, treatment, palliative care, and quality of life of cancer patients provides tremendous opportunity for meaning and purpose in the professional lives of oncologists. They can derive high levels of satisfaction from their professional status and associated collegial respect, as well as from the intellectual stimulation that their role provides. [22]

As oncologists, we evaluate and diagnose complex problems, devise and administer individualized treatment strategies, and provide critical support to patients and their families who face life-threatening illnesses. We can identify values and determine how to align our work activities with the areas we find most meaningful. Our relationships with patients, along with the intellectual stimulation that our specialty provides, establish the foundation for professional meaning for many of us. Every day, we directly and indirectly affect hundreds of people’s lives. Although in most other medical specialties beneficence and altruism overlap, in oncology, we have the advantage and capability of being more altruistic than beneficent in our daily practice. In fact, neurobiologists have found that when engaged in an altruistic act, the pleasure centers of the brain become active. [28]

Given the high prevalence of physician distress and the potential repercussions for quality of care, however, hospitals, practice groups, national societies, and healthcare organizations must have a responsibility and obligation in coming up with solutions to help reduce physician burnout. This will require various individual strategies as well as concerted efforts across national, organizational, and departmental levels for change. Professional bodies such as the American Society of Clinical Oncology, the European Society for Medical Oncology, and the Society of Gynecologic Oncology have already taken important steps to promote cultural change through the introduction of sessions addressing burnout at international congresses and the provision of policy recommendations. We oncologists, just like our cancer patients, are strong, resilient, and capable of handling the very demanding aspects of our profession. Still, what is most needed are concerted efforts to address characteristics in the organizational culture and environment that contribute to distress and burnout. These include nonclinical work burden; EMR burden; compliance, regulation, and payment issues; loss of autonomy; productivity-driven staffing models; inefficient use of physician time; and a focus on short-term profitability objectives. [29]

Oncologist burnout is a multifaceted issue with a negative impact on physicians, patients, and institutions. Globally, a multitude of professional bodies and organizational leaders are giving this important subject much-deserved attention. Reducing oncologist burnout will require various individual strategies as well as a concerted effort across national, organizational, and departmental levels for change.

 ICD-11 for Mortality and Morbidity Statistics, QD85 Burn-out. International Classification of Disease, 11th ed. 2019. Available at: 

https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/129180281

 de Bloom J, Geurts SAE, Taris TW, et al. Effects of vacation from work on health and well-being: lots of fun, quickly gone. Work Stress. 2010;24:196-216.

 Shanafelt TD, Gradishar WJ, Kosty M, et al. Burnout and career satisfaction among US oncologists. J Clin Oncol. 2014;32:678-86.

 Banerjee S, Califano R, Corral J, et al. Professional burnout in European young oncologists: results of the European Society for Medical Oncology (ESMO) Young Oncologists Committee Burnout Survey. Ann Oncol. 2017;28:1590-6.

 Dunn PM, Arnetz BB, Christensen JF, Homer L. Meeting the imperative to improve physician well-being: assessment of an innovative program. J Gen Intern Med. 2007;22:1544-52.

1. Freudenberger HJ. Staff burn-out. J Soc Issues. 1974; 30:159-65.

2. Maslach C, Jackson SE, Leiter MP. Maslach burnout inventory manual. 3rd ed. Palo Alto, CA: Consulting Psychologists Press; 1996.

3. National Academy of Medicine. Validated instruments to assess work-related dimensions of well-being. Available at: 

https://nam.edu/valid-reliable-survey-instruments-measure-burnout-well-work-related-dimensions/

4. ICD-11 for Mortality and Morbidity Statistics, QD85 Burn-out. International Classification of Disease, 11th ed. 2019. Available at: 

5. de Bloom J, Geurts SAE, Taris TW, et al. Effects of vacation from work on health and well-being: lots of fun, quickly gone. Work Stress. 2010;24:196-216.

6. Kristensen TS, Borritz M, Villadsen E, Christensen KB. The Copenhagen Burnout Inventory: a new tool for the assessment of burnout. Work Stress. 2005;19:192-207.

7. Legassie J, Zibrowski EM, Goldszmidt MA. Measuring resident well-being: impostorism and burnout syndrome in residency. J Gen Intern Med. 2008;23:1090-4.

8. Schaufeli WB, Bakker AB, Hoogduin K, Schaap C, Kladler A. On the clinical validity of the Maslach Burnout Inventory and the Burnout Measure. Psychol Health. 2001;16:565-82.

9. Shanafelt TD, Gradishar WJ, Kosty M, et al. Burnout and career satisfaction among US oncologists. J Clin Oncol. 2014;32:678-86.

10. Mampuya WA, Matsuo Y, Nakamura A, Hiraoka M. Evaluation of the prevalence of burnout and psychological morbidity among radiation oncologist members of the Kyoto Radiation Oncology Study Group (KROSG). J Radiat Res. 2017;58:217-24.

11. Leung J, Rioseco P, Munro P. Stress, satisfaction and burnout amongst Australian and New Zealand radiation oncologists. J Med Imaging Radiat Oncol. 2015;59:115-24.

12. Mordant P, Deneuve S, Rivera C, et al; European Society of Surgical Oncology Young Surgeons and Alumni Club (EYSAC). Quality of life of surgical oncology residents and fellows across Europe. J Surg Educ. 2014;71:222-8.

13. Medisauskaite A, Kamau C. Prevalence of oncologists in distress: systematic review and meta-analysis. Psychooncology. 2017;26:1732-40.

14. Shanafelt TD, Raymond M, Horn L, et al. Oncology fellows’ career plans, expectations, and well-being: do fellows know what they are getting into? J Clin Oncol. 2014;32:2991-7.

15. Banerjee S, Califano R, Corral J, et al. Professional burnout in European young oncologists: results of the European Society for Medical Oncology (ESMO) Young Oncologists Committee Burnout Survey. Ann Oncol. 2017;28:1590-6.

16. Allegra CJ, Hall R, Yothers G. Prevalence of burnout in the U.S. oncology community: results of a 2003 survey. J Oncol Pract. 2005;1:140-7.

17. Elit L, Trim K, Mand-Bains IH, et al; Society of Gynecologic Oncology Canada. Job satisfaction, stress, and burnout among Canadian gynecologic oncologists. Gynecol Oncol. 2004;94:134-9 .

18. Wallace JE, Lemaire JB, Ghali WA. Physician wellness: a missing quality indicator. Lancet. 2009;374:1714-21.

19. Sinsky C, Colligan L, Li L, et al. Allocation of physician time in ambulatory practice: a time and motion study in 4 specialties. Ann Intern Med. 2016;165:753-60.

20. Landon BE, Reschovsky J, Blumenthal D. Changes in career satisfaction among primary care and specialist physicians, 1997-2001. JAMA. 2003;289:442-9.

21. Shanafelt TD, Dyrbye LN, West CP. Addressing physician burnout: the way forward. JAMA. 2017;317:901-2.

22. Ramirez AJ, Graham J, Richards MA, et al. Burnout and psychiatric disorder among cancer clinicians. Br J Cancer. 1995;71:1263-9.

23. Banerjee S, Califano R, Corral J, et al. Professional burnout in European young oncologists: results of the European Society for Medical Oncology (ESMO) Young Oncologists Committee Burnout Survey. Ann Oncol. 2017;28:1590-6.

24. Glasberg J, Horiuti L, Novais M, et al. Prevalence of the burnout syndrome among Brazilian medical oncologists. Rev Assoc Med Bras. 2007;53:85-9.

25. Dhande M. Writing out loud: to computers, patients, and burnout, 2016. JAMA Cardiol. 2016;1:639.

26. Ramirez AJ, Graham J, Richards MA, Cull A, Gregory WM. Mental health of hospital consultants: the effects of stress and satisfaction at work. Lancet. 1996;347:724-8.

27. Shanafelt T, Dyrbye L. Oncologist burnout: causes, consequences, and responses. J Clin Oncol. 2012;30:1235-41.

28. Klimecki OM, Leiberg S, Ricard M, Singer T. Differential pattern of functional brain plasticity after compassion and empathy training. Soc Cogn Affect Neurosci. 2014;9:873-9.

29. Dunn PM, Arnetz BB, Christensen JF, Homer L. Meeting the imperative to improve physician well-being: assessment of an innovative program. J Gen Intern Med. 2007;22:1544-52.

Burnout is defined as an occupational-related syndrome characterized by physical and emotional exhaustion, cynicism/depersonalization, and low sense of professional accomplishment.

ONCOLOGY Vol 33 No 11 | Oncology

Esmo Congress 2019: Focus on Breast Cancer

2019 World Conference Of Lung Cancer Round-Up

What Are the Most Common Esophageal Metastases

Burnout in Oncology

A Novel Combination Immunotherapy Approach for Neuroendocrine Tumors

The Role of the Comprehensive Geriatric Assessment in the Evaluation of the Older Cancer Patient

CLL14 Trial: Fixed-Duration Chemotherapy-Free Regimen for Frail Patients with Treatment-Naïve CLL