Popper, Helmut H.; Gruber-Mösenbacher, Ulrike; Pall, Georg; Müllauer, Leonhard; Hochmair, Maximilian; Krenbek, Dagmar; Brcic, Luka; Schmitz, Katja; Lamprecht, Bernd; Eckmayr, Josef; Hilbe, Wolfgang; Hutarew, Georg; Errhalt, Peter; Kolb, Rainer; Pirker, Robert; Setinek, Ulrike; Webersinke, Gerald; Absenger, Gudrun; Hernler, Tamara; Rauter, Markus; Wasicky, Richard
SummaryThe knowledge on molecular alterations in lung cancer have increased during the last decade considerably. Almost every year new genes were detected being targetable, and drugs have been developed and provided for those patients being diagnosed with such a lung cancer. Therefore, it was necessary to update previous recommendations to facilitate a uniform handling for the diagnosis and molecular tests of lung cancer specimen all over Austria. Originally mutation of the epidermal growth factor receptor (EGFR) was the only actionable molecular alteration, now there are more than 10 driver mutations known, and more are detected, and clinical studies are performed. In addition, the technique to test for these mutations have improved, next generation sequencing has opened the option to test several genes in one test. Immuno-oncology has entered the field, and besides the checkpoint death receptor and ligand molecules PD-1/PD-L1 more molecules have been detected and are also tested in clinical studies.To provide equal opportunities to our patients the tests have to be implemented in all pathological institutes involved in lung cancer management. Because pathologists as part of the tumor board have to explain the diagnosis and the molecular alterations and suggest possible treatment options, the tests should be performed in-house, which will provide the optimal quality control.
Greinix, Hildegard T.; Attarbaschi, Andishe; Girschikofsky, Michael; Greil, Richard; Holter, Wolfgang; Neumeister, Peter; Peters, Christina; Petzer, Andreas; Rudzki, Jakob; Schlenke, Peter; Schmitt, Clemens A.; Schwinger, Wolfgang; Wolf, Dominik; Worel, Nina; Jaeger, Ulrich
SummaryChimeric antigen receptor T cells (CAR-T cells) are a novel form of cellular immunotherapy for patients with hematologic and oncologic malignancies. Known side effects of these approved cellular immunotherapies are cytokine release syndrome, immune-cell associated neurotoxicity syndrome, cytopenias, infections and long-lasting B cell aplasia. Safe administration of CAR-T cell therapy requires thorough patient selection and patient care in qualified CAR-T cell centers.
SummaryDiffuse large B‑cell lymphoma (DLBCL) comprises 30–40% of non-Hodgkin’s lymphoma. Clinical factors such as a high International Prognostic Index (IPI) or molecular factors as cell of origin (COO) have an influence on the clinical outcome after conventional immunochemotherapy. Patients with resistant or relapsed (r/r) DLBCL have a poor prognosis with a median overall survival of 6,3 months and low complete response rates (CR 7%) to salvage chemoimmunotherapy. Currently, therapy with autologous chimeric antigen receptor T‑cells (CAR T‑cells) provide encouraging complete responses (CR) of up to 50%. However, high costs for approved products and elaborate logistics have to be encountered.
SummaryChimeric antigen receptor (CAR) T cells are genetically engineered cells containing fusion proteins combining an extracellular epitope-specific binding domain, a transmembrane and signaling domains of the T cell receptor. The CD19-CAR T cell product tisagenlecleucel has been approved by the US Food and Drug Administration and the European Medicines Agency for therapy of children and young adults under 25 years with relapsed/refractory B‑cell acute lymphoblastic leukemia (ALL) due to a high overall response rate of 81% at 3 months after therapy. The rates of event-free and overall survival were 50 and 76% at 12 months. Despite the high initial response rate with CD19-CAR‑T cells in B‑ALL, relapses occur in a significant fraction of patients. Current strategies to improve CAR‑T cell efficacy focus on improved persistence of CAR‑T cells in vivo, use of multispecific CARs to overcome immune escape and new CAR designs. The approved CAR‑T cell products are from autologous T cells generated on a custom-made basis with an inherent risk of production failure. For large scale clinical applications, universal CAR‑T cells serving as “off-the-shelf” agents would be of advantage. During recent years CAR‑T cells have been frequently used for bridging to allogeneic hematopoietic stem cell transplantation (HSCT) in patients with relapsed/refractory B‑ALL since we currently are not able to distinguish those CAR‑T cell induced CRs that will persist without further therapy from those that are likely to be short-lived. CAR‑T cells are clearly of benefit for treatment following relapse after allogeneic HSCT. Future improvements in CAR‑T cell constructs may allow longer term remissions without additional HSCT.
SummaryStarting with the approval of bortezomib, a proteasome-inhibiting drug, tremendous progress has been achieved in the treatment of multiple myeloma (MM) patients during the last 15 years. Due to a plethora of novel drugs such as second generation proteasome inhibitors, immunomodulating agents and monoclonal antibodies the 5‑year survival of MM patients has been extended from 33% at the turn of the millennium to approximately 60% in younger patients (<65–70 years) who were eligible for consolidation with high-dose chemotherapy and autologous stem cell transplantation. Unfortunately, virtually all patients suffer from relapse and ultimately succumb to the disease, indicating the need for additional treatment strategies. Currently there are two promising immunologic approaches. First, bispecific antibodies called BITE (bispecific T-cell enhancer), which act as fusion proteins with two single-chain variable fragments, target antigens on malignant cells and bind the CD3 receptor and thereby recruit T‑cells to the target cells. The second strategy is chimeric antigen receptor (CAR) engineered T‑cell therapy that attacks myeloma cells by recognizing specific targets such as CD138, BCMA (B-cell maturation antigen), light-chains, SLAM-F7 (signaling lymphocytic activation molecule family member 7) or the pan B‑cell antigen CD19.Several early phase clinical trials show encouraging results in patients who have relapsed after modern treatment including proteasome inhibitors, immunomodulating drugs and monoclonal antibodies. Here, we briefly summarize current clinical knowledge about CAR‑T cell treatment in multiple myeloma, including clinical data presented at the 61st American Society of Hematology annual meeting held in December 2019 in Orlando.
SummaryThe treatment options for newly diagnosed and relapsed/refractory acute myeloid leukemia (AML) have substantially improved over the last 5 years. However, even though novel targeted agents (e.g. venetoclax, IDH1/2 and novel FLT-3 inhibitors; cytosolic isocitrate dehydrogenase 1/2 and fms-like tyrosine kinase 3 inhibitor) and improved chemotherapeutics (e.g. CPX-351; liposomale Daunorubicin/Cytarabine) are entering clinics, physicians are still confronted with high relapse and treatment failure rates. Thus, novel new strategies are required to improve AML therapy. Application of genetically engineered T cells (i.e. chimeric antigen receptor T cells, CAR-T cells) has proven to be highly effective in B cell-derived neoplasia and early data suggest also a high potential in the treatment of AML. This short review highlights the current approaches but also limitations of CAR-T cell therapy in AML precluding their current routine clinical use. Among a plethora of problems to be overcome, a critical issue will be to find relatively selective actionable targets in AML.
SummaryIn both Hodgkin’s Lymphoma and aggressive Non-Hodgkin’s-Lymphoma, complete remissions and long term survival can be achieved in a high number of patients, especially in those young and fit for intensive chemotherapy. The purpose of this review is to summarize the evidence and recommended follow-up procedures following curative therapy for these entities. After completion of treatment, a tight follow-up schedule is recommended, with history and physical examination being the mainstay of follow-up. There is no convincing evidence of the value of routine imaging for follow-up of lymphoma.After several years, the risk of recurrence decreases drastically, and the focus shifts to the detection and management of late treatment effects. One of the most significant late toxicities of lymphoma treatment is cardiac toxicity, both due to mediastinal/chest radiotherapy and cardiotoxic chemotherapy. Patients have to be watched closely, and other cardiac risk factors should be managed aggressively. While there is no randomized trial proving benefit, serial echocardiograms seem a reasonable approach to approach this high-risk population.Secondary neoplasms after treatment are another focus of follow-up. Chemotherapy and radiotherapy have strong potential to lead to both leukemia and secondary lymphoma, as well as solid tumors such as lung cancer and gastrointestinal tumors. Radiation therapy greatly increases the risk for breast cancer. Young (<40 years) women receiving radiotherapy should, in follow-up after treatment, be screened for breast cancer. Other than this, there is currently no sufficient rationale for any deviation from the cancer screening recommendations for the general population.
SummaryA large number of medical societies have issued recommendations for follow-up after primary treatment for early breast cancer, which mostly differ only in the details. The central statement in all of these guidelines has been based on two studies that were published in 1994 and came under criticism due to methodological flaws and the lack of modern diagnostic tools. This statement contains the merely symptom-induced search for distant metastasis and the rejection of routine imaging procedures and biomarker analyses in the follow-up process. Prospective, randomized and optimally designed trials are necessary to re-evaluate this dogma in view of the diagnostic and treatment progress since that time. The prognosis of mono- and oligometastatic disease diagnosed in this connection could lead to long-term survival. Presently, the existing guidelines should be followed accurately. The objectives of follow-up include early detection of local–regional recurrences and contralateral breast cancer, the management of treatment side effects and toxicities, motivation of patients to comply, psychosocial rehabilitation and lifestyle counseling with regard to the improvement of breast cancer prognosis. In conclusion, breast cancer survivors require comprehensive follow-up management based on evidence, whenever possible.
SummaryColorectal cancer is the third most common and the third most lethal cancer disease in the western world. As most patients undergo treatment with curative intent at initial diagnosis, postoperative surveillance protocols have been established with the primary aim to detect possible disease recurrence in an early resectable stage. Various international guidelines recommend an intensive surveillance protocol over a 5-year time period. These guidelines are based on the reported significant benefit regarding overall patient survival, and on the observation that 90% of recurrences occur within the first 5 years following resection. Surveillance protocols include regular clinical examinations, measurement of the carcinoembryonic antigen, computed tomography scans and regular endoscopies. While there is plenty of evidence regarding the scheduling of endoscopies, the frequency of carcinoembryonic antigen measurements and computed tomography scans has been ever since under debate. The benefit of intensive compared to low frequency surveillance protocols regarding disease-specific survival has never been shown. Moreover, recent meta-analyses and randomized controlled trials challenge current guidelines. Intensive carcinoembryonic antigen assessment and computed tomography scan follow-up protocols seem to fail in generating better overall and disease-specific survival in colorectal cancer patients compared to less intensive surveillance strategies. This change over the last few decades parallels the treatment evolution of colorectal cancer from a primarily surgical to a multidisciplinary task. Instead of advocating a reduction of the follow-up intensity, these findings should stimulate the colorectal oncology field to move from a one-fits-all to a patient-centered surveillance.
SummaryPurposeStructured follow-up is an integral part of efficient care in non-small cell lung cancer (NSCLC). However, since randomized prospective clinical trials giving clear indications for an optimal follow-up algorithm are still missing, it is necessary to seek currently available evidence to determine which follow-up strategy is advisable. For this purpose, a review of the current literature has been undertaken.ResultsThere is controversy in the literature about intensity, duration and modalities of follow-up in NSCLC. While some propose a higher intensity routine follow-up during the first 4 years after treatment, followed by yearly visits up to 5 years after treatment, others prefer a high-intensity follow-up for only the first 2 years, and yearly visits thereafter life-long. Most papers insist on measuring efficiency of routine follow-up upon its impact on overall survival. Routine chest CT should be integral part of the follow-up, while PET or PET/CT only in selected situations. The 2017 European Society for Medical Oncology guidelines formulate a consensus between all these positions by recommending visits every 6 months for the first 2 years, followed by life-long yearly surveillance, while for selected high-risk patients more frequent visits should be offered.ConclusionCurrent evidence from the literature supports a more intense routine follow-up in NSCLC during the first 2 years after treatment, followed by less frequent regular visits life-long.
SummaryIn 2012 approximately 410,000 patients were diagnosed with lung cancer and about 353,000 lung cancer deaths were registered in the European Union. Although lung cancer is still the leading cause of cancer-related death worldwide, advances in detection and treatment have increased the likelihood of long-term survival. In patients receiving definitive curative treatment for lung cancer guidelines suggest follow-up of patients using clinical and radiological examinations over a certain period of time. However, standards differ and there are no generally accepted follow-up recommendations. Aim of this short review is to summarize the currently available knowledge and guidelines regarding surveillance of patients receiving definitive lung cancer treatment.
SummaryThe optimal surveillance strategy in renal cell carcinoma after curative resection or ablation is a field of ongoing research. This review discusses the evidence behind routine follow up, duration of follow up, imaging modality and intervals as well as surveillance after local ablative therapy. The recommendations and differences of major guidelines are outlined as well. A risk based approach is advocated taking into account both tumor and patient specific characteristics.
SummaryIt is undeniably a great challenge to adequately weigh the benefits and harms of tumor-specific therapy near the end of life and to find the right time for changing the objective of therapy to palliative care alone. In a curative situation, the “survival” benefit of the treatment outweighs its potential harm due to side effects. However, things are different when the possibility of cure is ruled out. Important prerequisites to avoid overly zealous care are adequate communication about the therapeutic options and consensus between the doctor and the patient with regard to the (realistic) therapeutic goal, a realistic estimated prognosis and early integration of palliative care.
SummaryEnd of life is an issue that affects every human being sooner or later. Several aspects at the end of life should not be neglected to achieve good symptom control. Basic knowledge and skills on symptom control and palliative care are important to support patients in this threatening phase of their life. Palliative care should not be provided only at the end of life. The concept of early integration of palliative care is increasingly coming into focus. Nevertheless, at the end of life there are some important facts and issues that should be taken into account. This short article provides a list of ten important facts at the end of life that are important for the authors. Prognostication, early integration, benzodiazepines, death rattle, palliative sedation, standard therapy for refractory dyspnea, opioids in renal failure, psylocibin, denial and reduction of drugs at the end of life will be discussed in detail.
SummaryDelirium is a frequent neurocognitive complication in cancer patients, particularly in advanced stage and terminal disease. It is associated with increased morbidity and mortality and is a critical source of stress for patients and caregivers. For healthcare staff, delirium poses significant challenges in diagnosis and treatment as well as assessment of other symptoms due to its fluctuating nature, communication impediments, and possible agitation in hyperactive subtypes. Pathophysiological mechanisms underlying delirium are complex, but the approach to adequate symptom management consists of nonpharmacological strategies as well as the use of antipsychotic agents. However, when nonreversible and refractory delirium occurs, palliative sedation is an invaluable treatment option and may be offered after careful consideration. This short review attempts to cover important aspects of clinical features of delirium, diagnostic and treatment strategies as well as the role of palliative sedation in refractory situations in delirious cancer patients at the end of life.
SummaryThe ancient Latin quote Dum spiro, spero from Cicero means While I breathe, I hope. This article outlines five clinically relevant principles for pulmonary palliative care to treat chronic breathlessness in advanced lung diseases: (1) be aware of the finality of life, (2) palliative care does not mean “doing nothing”, (3) consider interdisciplinary and multidisciplinary therapeutic concepts, (4) conduct future talks and (5) use opioids for refractory breathlessness and think of treatable causes of respiratory distress.
Schlintl, Verena; Schlick, Konstantin; Russ, Gudrun; Gampenrieder, Simon Peter; Monzo Fuentes, Claudia; Kos, Tea; Renneberg, Felix; Rettenbacher, Lukas; Gradl, Johann; Sotlar, Karl; Hoffmann, Alexander; Greil, Richard
SummaryWith fewer than 100 cases described in the English literature so far, Langerhans cell sarcoma represents an orphan malignant disease deriving from histiocytic cells. Clinical course is extremely aggressive and associated with poor survival rates, especially in disseminated condition. Herein, we describe the case of a young patient with fulminant development of metastatic Langerhans cell sarcoma, who achieved persistent remission after polychemotherapy and subsequent high-dose chemotherapy with autologous stem cell transplantation.
SummaryCutaneous squamous cell carcinoma (cSCC) accounts for approximately 20% of all skin cancers. Its rising incidence represents a major public health concern. The majority of cSCC are curable by surgical resection. Although less than 5% of cSCC patients develop metastases or local recurrence after complete excision, advanced cSCC is difficult to treat. Until recently, no standard therapeutic regimen for advanced cSCC exists. Traditional therapies include chemotherapy and EGFR-targeted therapy, but their clinical benefit remains modest and has been demonstrated mostly in retrospective studies. On the contrary, PD-1 inhibitors dramatically improve outcomes in many immunocompetent cSCC patients, resulting in the approval of cemiplimab as the first FDA-approved systemic drug for patients with locally advanced or metastatic cSCC who are not candidates for curative surgery or radiation. In the coming years combination therapies are an emerging treatment strategy that could improve efficacy of PD-1 inhibitors in advanced cSCC. Moreover, several prospective controlled trials have been designed to explore the potential role of PD-1 inhibitors in the adjuvant and neodjuvant setting. Given the paucity of data, the management of immunocompromised cSCC patients requires a heightened awareness in this new era of cancer therapeutics.
SummaryEpidemiology of polycythemia vera (PV) is derived from cohort studies in Western populations. PV studies in the Latin population are limited and have described a lower prevalence of JAK2 mutation. A retrospective cohort of 90 Mexican patients from a single center with PV according to the 2016 World Health Organization diagnostic criteria was studied to establish clinical presentation in Mexicans and evaluate risk factors for mortality and vascular events. At diagnosis, the median age was 59 years; half were females, 90.7% harbored the JAK2 V617F mutation, and 7.1% had an exon 12 mutation. Arterial and venous thromboses were observed in 13.3 and 27.8% of patients, respectively. Seventy-one patients received hydroxyurea and one interferon alpha-2a, of which 51.5% achieved a complete response and 25.0% a partial response. The incidence rate for postdiagnosis arterial thrombosis was 2.68 cases per 100 person–years, for venous thrombosis 2.84, for major hemorrhage 2.57, for progression to myelofibrosis 1.14, and for leukemic transformation 0.44. The mortality rate was 3.54 cases per 100 person–years, and median of survival was 150 months. In multivariable analysis, survival was adversely affected by leukocytosis ≥12 × 109/L (p = 0.013); thrombocytosis ≥450 × 109/L was a risk factor for arterial thrombosis (p = 0.023), and anticoagulation at diagnosis for major hemorrhage (p = 0.049). In conclusion, epidemiology of PV in Mexican population is similar to that reported in Western studies, but with more venous thrombosis at diagnosis and a higher incidence of vascular complications postdiagnosis.
SummaryTongue cancer is one of the most aggressive oral cavity malignancies. It is more common in Southeast Asia. Epidemiology in Africa and Arab countries is not well studied. Herein the authors searched the hospital-based registry for tongue cancer patients whether surgically treated or not. The authors retrieved 156 cases eligible for the study. The tumour mainly affected older individuals with a male to female ratio of 1.04:1. Most of the patients received surgical treatment mainly partial or hemiglossectomy with either elective or therapeutic neck dissection. Overall survival was affected by age and recurrence, while disease-free survival was affected by age, grade, T stage, lymph node status, type of surgery and adjuvant therapy. In conclusion, population based registries are needed to further quantify the risk of disease in Africa and the Middle East. In addition, high treatment failure after classic treatment of tongue cancer warrants further research in identifying underlying aetiology and implementing neoadjuvant and adjuvant therapy in the treatment tools.
Peluso, Gaia; Masone, Stefania; Campanile, Silvia; Criscitiello, Carmen; Dodaro, Concetta; Calogero, Armando; Incollingo, Paola; Minieri, Gianluca; Menkulazi, Marsela; Scotti, Alessandro; Tammaro, Vincenzo; Jamshidi, Ali Akbar; Pelosio, Luigi; Caggiano, Marcello; Carlomagno, Nicola; Santangelo, Michele L.
SummaryBackgroundWe evaluated the frequency of incidental papillary thyroid microcarcinomas (mPTC) in thyroidectomies performed for benign diseases, to better characterize this nosologic entity and to assess the best treatment.MethodsBetween 2009 and 2017, a total of 1777 patients underwent surgery for benign thyroid disease. Patients with preoperative undetermined or positive for malignancy cytology were excluded, as well as incidental thyroid cancer larger than 1 cm.ResultsTotal thyroidectomy was performed in 1649 patients (92.7%) and hemithyroidectomy in 128 (7.2%). Papillary thyroid cancer, sized between 2–10 mm, was found in 89 patients (5%), which were all by definition microcarcinomas (mPTC). In 11 patients mPTCs were multifocal and in 7 bilateral. Just 6 patients received hemithyroidectomy and later underwent radical surgery without complications. No tumor-related morbidity or mortality was observed. The χ2 test showed a statistically significant association between mPTC and non-toxic multinodular goiter.DiscussionIn the literature, the rates of incidental mPTC vary, due to various factors such as histopathological examination and sampling numbers. Regarding surgical treatment, some authors support a “conservative” approach for the positive prognosis, but considering that it can be associated with mortality, lymph node recurrence and metastasis, its treatment is still controversial.ConclusionsOur experience confirms that total thyroidectomy in multinodular goiter is a safe procedure, which ensures endocrine control and oncologic complete tumor resection, in case of mPTC. In uninodular goiter, we recommend hemithyroidectomy; if mPTC is discovered, we suggest radical surgery especially in patients older than 50 years and with familial disposition for thyroid cancer and peripheral tumors larger than 5 mm and aggressive variants.