Business as unusual: medical oncology services adapt and deliver during COVID-19.

BACKGROUND: The COVID-19 pandemic has challenged cancer care globally, introducing resource limitations and competing risks into clinical practice. AIMS: To describe the COVID-19 impact on medical oncology care provision in an Australian setting. METHODS: Calvary Mater Newcastle and Newcastle Private Hospital medical oncology data from 1 February to 31 April 2019 versus 2020 were retrospectively analysed. RESULTS: Three hundred and sixty-four inpatient admissions occurred in 2020, 21% less than in 2019. Total inpatient days decreased by 22% (2842 vs 2203). April was most impacted (36% and 44% fewer admissions and inpatient days respectively). Mean length of stay remained unchanged (6.4 vs 6.2 days, P = 0.7). In all, 5072 outpatient consultations were conducted, including 417 new-patient consultations (4% and 6% increase on 2019 respectively). Telephone consultations (0 vs 1380) replaced one-quarter of face-to-face consultations (4859 vs 3623, -25%), with minimal telehealth use (6 vs 69). Day Treatment Centre encounters remained stable (3751 vs 3444, -8%). The proportion of new patients planned for palliative treatment decreased (35% vs 28%, P = 0.04), observation increased (16% vs 23%, P = 0.04) and curative intent treatment was unchanged (both 41%). Recruiting clinical trials decreased by one-third (45 vs 30), two trials were activated (vs 5 in 2019) and 45% fewer patients consented to trial participation (62 vs 34). CONCLUSION: Our medical oncology teams adapted rapidly to COVID-19 with significant changes to care provision, including fewer hospital admissions, a notable transition to telephone-based outpatient clinics and reduced clinical trial activity. The continuum of care was largely defended despite pandemic considerations and growing service volumes.

Heart Failure in Breast Cancer Survivors: Focus on Early Detection and Novel Biomarkers.

PURPOSE OF REVIEW: Breast cancer survival rate has greatly improved in the last two decades due to the emergence of next-generation anti-cancer agents. However, cardiotoxicity remains a significant adverse effect arising from traditional and emerging chemotherapies as well as targeted therapies for breast cancer patients. In this review, we will discuss cardiotoxicities of both traditional and emerging therapies for breast cancer. We will discuss current practices to detect cardiotoxicity of these therapies with the focus on new and emerging biomarkers. We will then focus on 'omics approaches, especially the use of epigenetics to discover novel biomarkers and therapeutics to mitigate cardiotoxicity. RECENT FINDINGS: Significant cardiotoxicities of conventional chemotherapies remain and new and unpredictable new forms of cardiac and/or vascular toxicity emerge with the surge in novel and targeted therapies. Yet, there is no clear guidance on detection of cardiotoxicity, except for significant left ventricular systolic dysfunction, and even then, there is no uniform definition of what constitutes cardiotoxicity. The gold standard for detection of cardiotoxicity involves a serial echocardiography in conjunction with blood-based biomarkers to detect early subclinical cardiac dysfunction. However, the ability of these tests to detect early disease remains limited and not all forms of toxicity are detectable with these modalities. There is an unprecedented need to discover novel biomarkers that are sensitive and specific for early detection of subclinical cardiotoxicity. In that space, novel echocardiographic techniques, such as strain, are becoming more common-place and new biomarkers, discovered by epigenetic approaches, seem to become promising alternatives or adjuncts to conventional non-specific cardiac biomarkers.

Durability of response to immune checkpoint inhibitors in metastatic Merkel cell carcinoma after treatment cessation.

BACKGROUND: Metastatic Merkel cell carcinoma (mMCC) is highly responsive to immune checkpoint inhibitors (ICIs); however, durability of response after treatment cessation and response to retreatment in the setting of progression is unknown. METHODS: Patients (pts) having mMCC from 10 centres who discontinued ICI treatment for a reason other than progression were studied. RESULTS: Forty patients were included. Median time on treatment was 13.5 months (range 1-35). Thirty-one patients (77.5%) stopped treatment electively while 9 patients (22.5%) stopped due to treatment-related toxicity. After median of 12.3 months from discontinuation, 14 pts (35%) have progressed (PD). Disease progression rate following ICI discontinuation was 26% (8 of 31) in patients who discontinued in complete response (CR), 57% (4 of 7) in patients in partial response and 100% (2 of 2) in those with stable disease. Median progression-free survival (PFS) after treatment cessation was 21 months (95% confidence interval [CI], 18- not reached [NR]), with a third of patients progressing during their first year off treatment. PFS was longer for patients who discontinued ICI electively (median PFS 29 months; 95% CI, 21-NR) compared to those who stopped due to toxicity (median PFS 11 months; 95% CI, 10-NR). ICI was restarted in 8 of 14 pts (57%) with PD, with response rate of 75% (4 CR, 2 partial response, 1 stable disease, 1 PD). CONCLUSION: ICI responses in mMCC do not appear durable off treatment, including in patients who achieve a CR, though response to retreatment is promising. Extended duration of treatment needs to be investigated to optimise long-term outcomes.

Successful immune checkpoint inhibitor rechallenge after immune-related pericarditis: Clinical case series.

Pericardial diseases secondary to immune checkpoint inhibitors (ICI) are rare. Here, we describe two cases of immune-related pericarditis caused by ICI for treatment of advanced NSCLC. Select patients can be successfully rechallenged with ICI after immune-related pericardial disease.

Strongyloides-An uncommon cause of eosinophilia whilst on durvalumab.

BACKGROUND: In malignancy, eosinophils have been shown to play an important role in the tumour micro-environment. Increasingly, development of eosinophilia with immune checkpoint inhibitor (ICI) use is thought to be predictive of prognosis and development of immune-related adverse events. However, there are many other causes for developing eosinophilia which can contribute to the difficulties in diagnosis and management. CASE: Here, we present a case of Strongyloides parasitic infection as an uncommon differential for eosinophilia in a patient with lung cancer receiving a PDL-1 ICI, durvalumab, in Australia. CONCLUSION: This case highlights the complexities exploring the multiple potential causes of eosinophilia and the subsequent management, to allow safe continuation of ICI.

A retrospective analysis of nadir-neutropenia directed pegylated granulocyte-colony stimulating factor on febrile neutropenia rates in (neo)adjuvant breast cancer chemotherapy regimens.

BACKGROUND: Pegfilgrastim, a pegylated granulocyte colony-stimulating-factor (GCSF), reduces chemotherapy morbidity and mortality in early stage breast cancer. The optimal approach to individual patient selection for GCSF is unknown, in particular whether secondary GCSF should be given after asymptomatic neutropenia, or only after febrile neutropenia (FN). AIMS: To determine if preplanned nadir blood counts and subsequent nadir-neutropenia directed GCSF was effective to reduce rates of FN associated with (neo)adjuvant breast cancer chemotherapy. We also aimed to describe (neo)adjuvant chemotherapy and GCSF prescribing practices at our institution. METHODS: This was a retrospective electronic medical record review. The rate of FN with secondary GCSF after cycle 1 nadir-neutropenia <1.0 × 109 cells/L was compared with the rate of FN in patients who did not have cycle 1 nadir blood counts or secondary GCSF, and analyzed according to patient and treatment data. RESULTS: Between 11/4/2011 and 22/4/2018, 584 patients received (neo)adjuvant chemotherapy. Over all rates of FN were 17%, compared with 9% in patients who received primary GCSF. Rates of FN were highest in docetaxel/carboplatin/trastuzumab (TCH, 27%) and docetaxel/cyclophosphamide (TC, 27%). There were 268 patients (46%) who received primary GCSF and 238 patients (41%) who received secondary GCSF. Rates of FN did not differ between patients who received nadir-neutropenia directed secondary GCSF (6/125, 5%, 95% CI 1.1-8.6), and those who did not have nadir blood counts or secondary GCSF (0/49, 0%, 95% CI not calculable) (P = .1186). GCSF use was associated with lower rates of non-FN hospital admissions. Patients ≥65 years were more likely to have FN and non-FN admissions. Two of three treatment related deaths occurred due to FN. CONCLUSIONS: In this population, nadir-neutropenia directed secondary GCSF was not associated with reduced rates of FN. Observed rates of FN >20% in TC and TCH in routine clinical practice should guide primary GCSF use in accordance with international guidelines.

Factors Associated with Adverse Cardiovascular Events in Cancer Patients Treated with Bevacizumab.

Background: Bevacizumab, a vascular endothelial growth factor (VEGF) monoclonal antibody commonly used for the treatment of various cancers, is often associated with adverse cardiovascular effects such as hypertension, cardiac and cerebral ischemia, thrombosis, and bleeding events. Factors associated with increased risks of adverse cardiovascular effects with bevacizumab have not been intensively studied. In this study, we determined factors associated with hospital admissions due to cardiovascular complications in patients who received bevacizumab for cancer treatment. Methods and Results: We retrospectively collected data for all patients treated with bevacizumab between the 1st January 2016 and the 31st December 2017 at the Hunter New England Local Health District. Patients' characteristics and their medical history were obtained from hospital electronic medical records. Outcome data were sourced from the Institutional Cardiac and Stroke Outcomes Unit database. A total of n = 230 patients (mean age 65, males n = 124 (53.9%)) were treated with bevacizumab during the study period. N = 28 patients were admitted to hospital for a major cardiovascular-related event. Higher total treatment dose (p < 0.05), concomitant hypertension (p = 0.005), diabetes (p = 0.04), atrial fibrillation (p = 0.03), and lack of use of statin therapy (p = 0.03) were key contributors to hospital admission. Conclusions: Results of our study highlight the fact that patients with concomitant baseline cardiovascular disease/risk factors are at an increased risk of cardiovascular hospitalization related to bevacizumab treatment. Careful baseline cardiovascular assessment may be an essential step to minimize cardiovascular complications.

Retrospective Evaluation of the Use of Pembrolizumab in Malignant Mesothelioma in a Real-World Australian Population.

INTRODUCTION: We investigated the efficacy and toxicity of pembrolizumab in patients with mesothelioma from a real-world Australian population. We aimed to determine clinical factors and predictive biomarkers that could help select patients who are likely to benefit from pembrolizumab. METHOD: Patients with mesothelioma who were treated with pembrolizumab as part of the Insurance and Care New South Wales compensation scheme were included. Clinical information was collected retrospectively. Tumor biomarkers such as programmed death-ligand 1 (PD-L1), BAP1, and CD3-positive (CD3+) tumor-infiltrating lymphocytes (TILs) were examined using archival formalin-fixed paraffin-embedded tumor samples. RESULTS: A total of 98 patients were included with a median age of 70 years (range, 46-91 y); 92% were men; 76% had epithelioid subtype; 21% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0. Pembrolizumab was used as second-line or subsequent-line treatment in 94 patients and as first-line treatment in four patients. The overall response rate was 18%, and the disease control rate was 56%. The median progression-free survival (PFS) was 4.8 months (95% confidence interval: 3.6-6.2), and the median overall survival (OS) was 9.5 months (95% confidence interval: 6.6-13.7). Immune-related adverse events occurred in 27% of patients, of which nine (9%) were of grade 3 or higher. In the multivariable analysis, factors independently associated with longer PFS included baseline ECOG status of 0 (median PFS: 12 mo versus 4 mo, p < 0.01) and PD-L1 tumor proportion score of greater than or equal to 1% (median PFS: 6 mo versus 4 mo, p < 0.01). Baseline platelet count of less than or equal to 400 × 109/liter was independently associated with longer PFS and OS (median PFS: 6 mo versus 2 mo, p = 0.05; median OS: 10 mo versus 4 mo, p = 0.01), whereas lack of pretreatment dexamethasone was independently associated with OS but not PFS (median OS: 10 mo versus 3 mo, p = 0.01). The odds of response were higher for patients with baseline ECOG status of 0 (p = 0.02) and with greater than or equal to 5% CD3+ TILs in the tumor (p < 0.01). PD-L1 expression, BAP1 loss, and CD3+ TILs in the stroma were not significantly associated with the overall response rate. CONCLUSIONS: Immunotherapy is a reasonable treatment option for patients with mesothelioma. Our results are comparable to other clinical trials investigating pembrolizumab in mesothelioma in terms of response. Good performance status assessment remains the most robust predictor for patient outcomes. CD3+ TILs in the tumor may help select patients that are likely to respond to pembrolizumab, whereas factors such as PD-L1 expression, baseline platelet count, and lack of pretreatment dexamethasone may help predict survival outcomes from pembrolizumab treatment.

Hypercalcaemia due to Sarcoidosis during Treatment with Avelumab for Metastatic Merkel Cell Carcinoma.

Merkel cell carcinoma is a rare but aggressive skin cancer. Response to chemotherapy is not durable but avelumab, an anti-PD-L1 inhibitor, showed promising ongoing response in a phase II trial. Checkpoint inhibitors including avelumab are known to cause overactivation of the immune system, leading to immune-related adverse events (irAE). We describe the first reported case of hypercalcaemia secondary to reactivation of sarcoidosis in a patient with metastatic Merkel cell carcinoma on avelumab. Hypercalcaemia was managed with corticosteroids to full resolution and avelumab therapy was safely continued.

Prognostic biomarkers in stage IV non-small cell lung cancer (NSCLC): neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), platelet to lymphocyte ratio (PLR) and advanced lung cancer inflammation index (ALI).

BACKGROUND: Currently, there is no single validated biomarker which can prognosticate survival in patients with stage IV non-small cell lung cancer (NSCLC). This study examines the prognostic significance of four biomarkers: neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), platelet to lymphocyte ratio (PLR) and advanced lung cancer inflammation index (ALI) in patients with stage IV NSCLC. METHODS: This study aimed to establish the relationship between NLR, LMR, PLR, ALI and overall survival (OS) at baseline and post first cycle of treatment using Cox univariate PH models. We also studied these biomarkers in the elderly (age ≥70 years). Clinical data was sourced from Calvary Mater Newcastle between 2010 and 2015. RESULTS: Baseline NLR, PLR, LMR and ALI showed strong association with OS. Five unit increase in NLR and PLR was associated with an 11% and 0.5% increase in the hazard of death respectively while 1 unit increase in ALI resulted in 4% increase in hazard of death. Five unit increase in LMR was associated with a 50% reduction in hazard of death. Post-treatment NLR and low ALI correlated with shorter OS but no statistically significant relationship could be demonstrated for PLR nor LMR. Similar prognostic trends were noted for elderly. CONCLUSIONS: High NLR, high PLR, low LMR and low ALI at baseline are significantly associated with poor OS. High NLR and low ALI are significantly associated with poor OS post treatment. Findings are similar regardless of age.

Patterns of care for stage III non-small cell lung cancer in Australia.

Stage III non-small cell lung cancer (NSCLC) makes up a third of all NSCLC cases and is potentially curable. Despite this 5-year survival rates remain between 15% and 20% with chemoradiation treatment alone given with curative intent. With the recent exciting breakthroughs in immunotherapy use (durvalumab) for stage III NSCLC, further improvements in patient survival can be expected. Most patients with stage III NSCLC present initially to their general practitioner (GP). The recommended time from GP referral to first specialist appointment is less than 14 days with treatment initiated within 42 days. Our review found that there is a shortfall in meeting these recommendations, however a number of initiatives have been established in Australia to improve timely and accurate diagnosis and treatment patterns. The lung cancer multidisciplinary team (MDT) is critical to consistency of evidence-based diagnosis and treatment and can improve patient survival. We aimed to review current patterns of care and clinical practice recommendations for stage III NSCLC across Australia and identify opportunities to improve practice in referral, diagnosis and treatment pathways.

Breast cancer in men: should aromatase inhibitors become first-line hormonal treatment?

Breast cancer is an uncommon malignancy in men; therefore, the approach to treatment is mostly modeled on that used in females. First-line use of aromatase inhibitors (AIs) is now standard practice in hormone-sensitive metastatic breast cancer in postmenopausal females. However, tamoxifen continues to be regarded as first-line treatment in hormone-sensitive male breast cancer. This article reviews the role of second and third generation AIs as first- or second-line hormonal treatment in male patients with metastatic breast cancer. It also explores the potential use of AIs in combination with gonadotropin-releasing hormone analogs or trastuzumab suggesting that in the future this may prove a useful alternative to tamoxifen.

Advances in the adjuvant treatment of colorectal cancer.

BACKGROUND: There have been numerous advances in the adjuvant therapy of colon cancer in the last two decades. METHODS: This review outlines the historical perspectives of adjuvant treatment as well as current and emerging standards of care. RESULTS: Although previous regimens included a variety of equivalent schedules of 5-fluorouracil and folinic acid, integration of newer drugs such as oxaliplatin are offering significant improvements in disease-free survival. The use of targeted agents such as bevacuzimab creates the potential to further increase cure rates in the adjuvant setting. The current low rate of referral of eligible patients for chemotherapy in Australia is also discussed. CONCLUSION: Adjuvant therapy for colon cancer is making major strides as we attempt to cure more patients.

Metastatic Eccrine Porocarcinoma: A Rare Case of Successful Treatment.

The successful treatment of the rare malignancy eccrine porocarcinoma (EP) is extremely challenging, often not rewarding and when associated with metastatic disease, therapy results are disappointing. We present a unique case of treatment response of metastatic EP, with a significant disease-free interval. The patient has remained in clinical and radiological remission for 36 months since diagnosis of metastatic disease.

Reporting time-to-event endpoints and response rates in 4 decades of randomized controlled trials in advanced colorectal cancer.

BACKGROUND: Reporting of randomized controlled clinical trials (RCTs) often is suboptimal. Cancer drug trials are complicated further by multiple survival and response endpoints. The authors of this report determined the frequency of reporting of time-to-event endpoints and tumor response outcomes in advanced colorectal cancer and examined the relation between the year of publication and the reported effectiveness of 5-fluorouracil or equivalent agents. METHODS: A literature search identified 144 RCTs that involved 35,853 patients. The patient characteristics, trial designs, and methods for endpoint reporting were extracted. The clinical effectiveness of 5-fluorouracil or equivalent agents was analyzed in 3 time periods (pre-1990, 1990s, and 2000s) in 28,636 patients. RESULTS: One hundred twenty-nine trials (90%) reported overall survival (OS) and response rates; whereas time to progression (44%), duration of response (43%), progression-free survival (22%), and time to treatment failure (12%) were reported less frequently. Except for stable and progressive disease, the frequency of reporting of endpoints did not improve over the period studied. The median OS for patients who received 5-fluorouracil or equivalent agents increased significantly (from 9.4 months before 1990 to 13.5 months after 2000). During the same period, the rate of stable disease increased (38.2%, 40.5%, and 45.1% for pre-1990, 1990s, and 2000s, respectively; P = .004); whereas the rate of progressive disease decreased significantly (39.2%, 33.3%, and 27.8%, respectively; P = .002). CONCLUSIONS: Its likely that the increasing availability of alternative treatments and better supportive care improved OS, whereas the rates of stable and progressive disease altered because of changes in follow-up schedules. Other intermediate endpoints (duration of response and time to progression) remained largely constant over the time course of the current study, making them superior benchmarks for comparison with future studies.