Recurrent Ovarian Cancer — Basic Knowledge, Current Management, and Future Directions

Recurrent ovarian cancer is incurable. Chemotherapy is indicated to control disease-related symptoms. The benefit from chemotherapy in these patients depends on the platinum-free interval. Patients with platinum-resistant disease (a relapse of less than six months from the completion of platinum treatment) are managed with non-platinum agents. Patients with platinum semi-sensitive relapse (six to 12 months from the completion of treatment) have a response rate of 30% to second-line platinum treatment. In patients with platinum-sensitive relapse (more than 12 months from the completion of treatment), the response rate to platinum is 60–70%. Limited data is available regarding the benefits of secondary cytoreductive surgery. GOG 213 and the AGO Desktop III studies will define the role of this procedure in patients with recurrent disease. Two studies have shown benefit of bevacizumab in the treatment of patients with platinum-sensitive (Oceans) and refractory disease (Aurelia). Additional studies are needed to establish the optimal duration and timing of treatment. Cediranib has shown activity in patients with recurrent platinum-sensitive ovarian cancer (ICON 6 trial). Numerous novel biological agents are being investigated in relapsed ovarian cancer. This chapter focuses on current management and future directions in patients with relapsed ovarian cancer

Management and Supportive Care of Patients Undergoing Immunotherapy

In many tumor types, where the prognosis was shown to be extremely dismal before, immunotherapy is now a new beacon of hope to many patients. Immunotherapy has been approved for use in a many different cancers including metastatic melanoma, advanced non-small cell lung cancer, metastatic renal cell carcinoma, refractory Hodgkin’s lymphoma, metastatic bladder cancer advanced head and neck cancer, and the list keeps growing each day. It seems to be generally better tolerated in most patients and less toxic compared to what we have seen in different anticancer treatments from before. However, the toxicities here are termed immune-related adverse events. There is almost no prospective data on these toxicities, and guidelines or recommendations are mostly based on symptomatic management from the ongoing clinical trials. Treating oncologists need to be aware of the subtleties in presentation and the huge difference in the way we mange these side effects. Although most adverse events are low-grade and manageable, they have the potential to be life-threatening if not treated promptly. In this chapter, we address the different immune-related adverse events relating to the organ system they can involve, presentation and symptomatology, general recommendations of management, and individual toxicities. Keywords: immunotherapy, PD-1, CTLA-4

Dysregulation of systemic soluble immune checkpoints in early breast cancer is attenuated following administration of neoadjuvant chemotherapy and is associated with recovery of CD27, CD28, CD40, CD80, ICOS and GITR and substantially increased levels of PD-L1, LAG-3 and TIM-3

Neoadjuvant chemotherapy (NAC) may alter the immune landscape of patients with early breast cancer (BC), potentially setting the scene for more effective implementation of checkpoint-targeted immunotherapy. This issue has been investigated in the current study in which alterations in the plasma concentrations of 16 soluble co-stimulatory and co-inhibitory, immune checkpoints were measured sequentially in a cohort of newly diagnosed, early BC patients (n=72), pre-treatment, post-NAC and post-surgery using a Multiplex® bead array platform. Relative to a group of healthy control subjects (n=45), the median pre-treatment levels of five co-stimulatory (CD27, CD40, GITRL, ICOS, GITR) and three co-inhibitory (TIM-3, CTLA-4, PD-L1) soluble checkpoints were significantly lower in the BC patients vs. controls (p<0.021-p<0.0001; and p<0.008-p<0.00001, respectively). Following NAC, the plasma levels of six soluble co-stimulatory checkpoints (CD28, CD40, ICOS, CD27, CD80, GITR), all involved in activation of CD8+ cytotoxic T cells, were significantly increased (p<0.04-p<0.00001), comparable with control values and remained at these levels post-surgery. Of the soluble co-inhibitory checkpoints, three (LAG-3, PD-L1, TIM-3) increased significantly post-NAC, reaching levels significantly greater than those of the control group. PD-1 remained unchanged, while BTLA and CTLA-4 decreased significantly (p<0.03 and p<0.00001, respectively). Normalization of soluble co-stimulatory immune checkpoints is seemingly indicative of reversal of systemic immune dysregulation following administration of NAC in early BC, while recovery of immune homeostasis may explain the increased levels of several negative checkpoint proteins, albeit with the exceptions of CTLA-4 and PD-1. Although a pathological complete response (pCR) was documented in 61% of patients (mostly triple-negative BC), surprisingly, none of the soluble immune checkpoints correlated with the pCR, either pre-treatment or post-NAC. Nevertheless, in the case of the co-stimulatory ICMs, these novel findings are indicative of the immune-restorative potential of NAC in early BC, while in the case of the co-inhibitory ICMs, elevated levels of soluble PD-L1, LAG-3 and TIM-3 post-NAC underscore the augmentative immunotherapeutic promise of targeting these molecules, either individually or in combination, as a strategy, which may contribute to the improved management of early BC

Phase I/II study of first-line irinotecan combined with 5-fluorouracil and folinic acid Mayo Clinic schedule in patients with advanced colorectal cancer

BACKGROUND: This multicentre phase I/II study was designed to determine the maximum tolerated dose of irinotecan when combined with 5-fluorouracil and folinic acid according to the Mayo Clinic schedule and to evaluate the activity of this combination as first-line therapy in patients with advanced colorectal cancer. METHODS: Sixty-three patients received irinotecan (250 or 300 mg/m(2), 30- to 90-minute intravenous infusion on day 1), immediately followed by folinic acid (20 mg/m(2)/day) and 5-fluorouracil (425 mg/m(2), 15-minute bolus infusion) days 1 to 5, every four weeks. RESULTS: Diarrhoea was dose limiting at 300 mg/m(2 )irinotecan in combination with 5-fluorouracil and folinic acid, and this was determined to be the maximum tolerated dose. Grade 3–4 neutropenia was the most frequently reported toxicity. The recommended dose of irinotecan for the phase II part of the study was 250 mg/m(2). The response rate for the evaluable patient population was 36% (13/36), and 44% (16 patients) had stable disease (including 19% of minor response). For the intention-to-treat population, the response rate was 29% (14/49) and 35% (17 patients) stable disease (including 14% of minor response). The median time to progression was 7.0 months and the median survival was 12.0 months. Grade 3–4 non-haematological drug-related toxicities included delayed diarrhoea, stomatitis, fatigue, and nausea/vomiting. There were three deaths due to septic shock that were possibly or probably treatment-related. CONCLUSIONS: This regimen of irinotecan in combination with the Mayo Clinic schedule of bolus 5-fluorouracil/folinic acid every four weeks showed activity as first-line therapy in patients with advanced colorectal cancer. In keeping with other published results of studies using bolus 5-fluorouracil combined with irinotecan, the use of this regimen is limited by a relatively high rate of grade 3–4 neutropenia, and the combination of irinotecan and infusional 5-fluorouracil / folinic acid should remain the regimen of first choice

The emerging problem of bacterial resistance in cancer patients; proceedings of a workshop held by MASCC “Neutropenia, Infection and Myelosuppression” Study Group during the MASCC annual meeting held in Berlin on 27–29 June 2013

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

2023 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting

Nausea and vomiting are still considered to be two of the most troublesome adverse events (AEs) for patients treated with antineoplastic therapy. To optimise the utility of available antiemetic prophylaxis, updated reviews of the relevant literature and evidence-based guideline recommendations are crucial. The European Society for Medical Oncology (ESMO) and the Multinational Association of Supportive Care in Cancer (MASCC) completed the fourth Consensus Conference on Antiemetics for the prevention of nausea and vomiting in patients with cancer in Copenhagen in June 2015. This article is an update of the 2015 guidelines.Meeting and production costs have been covered by MASCC and ESMO from central funds.https://www.esmoopen.comhj2024ImmunologySDG-03:Good heatlh and well-bein

Pitfalls in machine learning‐based assessment of tumor‐infiltrating lymphocytes in breast cancer: a report of the international immuno‐oncology biomarker working group

The clinical significance of the tumor-immune interaction in breast cancer (BC) has been well established, and tumor-infiltrating lymphocytes (TILs) have emerged as a predictive and prognostic biomarker for patients with triple-negative (estrogen receptor, progesterone receptor, and HER2 negative) breast cancer (TNBC) and HER2-positive breast cancer. How computational assessment of TILs can complement manual TIL-assessment in trial- and daily practices is currently debated and still unclear. Recent efforts to use machine learning (ML) for the automated evaluation of TILs show promising results. We review state-of-the-art approaches and identify pitfalls and challenges by studying the root cause of ML discordances in comparison to manual TILs quantification. We categorize our findings into four main topics; (i) technical slide issues, (ii) ML and image analysis aspects, (iii) data challenges, and (iv) validation issues. The main reason for discordant assessments is the inclusion of false-positive areas or cells identified by performance on certain tissue patterns, or design choices in the computational implementation. To aid the adoption of ML in TILs assessment, we provide an in-depth discussion of ML and image analysis including validation issues that need to be considered before reliable computational reporting of TILs can be incorporated into the trial- and routine clinical management of patients with TNBC

The tale of TILs in breast cancer : a report from the International Immuno-Oncology Biomarker Working Group

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed deathligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.The National Health and Medical Research Council of Australia; the Cure; the Royal Australasian College of Physicians; the NIH/NCI ; the National Breast Cancer Foundation of Australia Endowed Chair; the Breast Cancer Research Foundation, New York and the Breast Cancer Research Foundation (BCRF).www.nature.com/npjbcanceram2022Immunolog

Spatial analyses of immune cell infiltration in cancer : current methods and future directions. A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer

Modern histologic imaging platforms coupled with machine learning methods have provided new opportunities to map the spatial distribution of immune cells in the tumor microenvironment. However, there exists no standardized method for describing or analyzing spatial immune cell data, and most reported spatial analyses are rudimentary. In this review, we provide an overview of two approaches for reporting and analyzing spatial data (raster versus vector-based). We then provide a compendium of spatial immune cell metrics that have been reported in the literature, summarizing prognostic associations in the context of a variety of cancers. We conclude by discussing two well-described clinical biomarkers, the breast cancer stromal tumor infiltrating lymphocytes score and the colon cancer Immunoscore, and describe investigative opportunities to improve clinical utility of these spatial biomarkers. © 2023 The Pathological Society of Great Britain and Ireland.http://www.thejournalofpathology.com/hj2024ImmunologySDG-03:Good heatlh and well-bein

Image-based multiplex immune profiling of cancer tissues: translational implications. A report of the International Immuno-oncology Biomarker Working Group on Breast Cancer

Recent advances in the field of immuno-oncology have brought transformative changes in the management of cancer patients. The immune profile of tumours has been found to have key value in predicting disease prognosis and treatment response in various cancers. Multiplex immunohistochemistry and immunofluorescence have emerged as potent tools for the simultaneous detection of multiple protein biomarkers in a single tissue section, thereby expanding opportunities for molecular and immune profiling while preserving tissue samples. By establishing the phenotype of individual tumour cells when distributed within a mixed cell population, the identification of clinically relevant biomarkers with high-throughput multiplex immunophenotyping of tumour samples has great potential to guide appropriate treatment choices. Moreover, the emergence of novel multi-marker imaging approaches can now provide unprecedented insights into the tumour microenvironment, including the potential interplay between various cell types. However, there are significant challenges to widespread integration of these technologies in daily research and clinical practice. This review addresses the challenges and potential solutions within a structured framework of action from a regulatory and clinical trial perspective. New developments within the field of immunophenotyping using multiplexed tissue imaging platforms and associated digital pathology are also described, with a specific focus on translational implications across different subtypes of cancer