Targeted therapies for kidney cancer in urologic practice

Renal cell carcinoma (RCC) is the most lethal of all genitourinary malignancies with nearly half of all patients presenting with locally advanced or metastatic disease. Systemic treatments such as chemo- or immunotherapy have historically been associated with overall response rates of 5-15% with very few durable responses. The basis of newly approved, more effective targeted therapies for metastatic RCC are based on a fundamental knowledge of the molecular mechanisms that give rise to RCC. We review the clinical data for targeted therapies in RCC and discuss the pertinent biology, side effects, and targets important to the practicing clinician.     

Treatment of Advanced and Metastatic Renal Cancer: A Revolution?

ContextA significant proportion of patients with renal cell carcinoma (RCC) will experience recurrence or tumour progression after surgical treatment. Nowadays, several treatment options, including immunotherapy and targeted therapies, are available for management of advanced and metastatic RCC.ObjectiveThis paper aims to give an overview of the current treatment options for patients with advanced and metastatic RCC.Evidence acquisitionThis paper is based on a presentation given at the 6th Meeting of the European Society of Oncological Urology 2009, held in Istanbul, Turkey. Data were retrieved from recent review articles, original articles, and abstracts on the treatment of advanced and metastatic RCC.Evidence synthesisThe potential role of adjuvant vaccines in treatment of patients with advanced RCC after nephrectomy has been suggested. With regard to the newly developed targeted agents for treatment of metastatic clear-cell RCC, sunitinib and bevacizumab plus interferon-α (INF-α) seem promising as first-line therapy for good- and intermediate-risk patients. Temsirolimus appears to be effective as first-line treatment in metastatic RCC (mRCC) patients with poor prognosis. Sorafenib and everolimus should be considered as second-line therapy in mRCC patients. Some targeted therapies have also demonstrated clinical activities in patients with metastatic non–clear-cell RCC. Although grade 1 and grade 2 treatment-related adverse events were common with targeted therapies, most were manageable. The effect of targeted agents in earlier stage disease is currently under investigation. Cytokine therapy was associated with a modest survival benefit in mRCC. A combined analysis, however, suggested that cytoreductive nephrectomy might improve survival in patients with mRCC treated with interferon immunotherapy.ConclusionsMore research on the use of adjuvant vaccines in treating patients with advanced RCC is warranted. Although the management of metastatic disease has undergone a revolution in recent years, a lot of questions still need to be answered.     

Recent advances in molecular targeted therapy for metastatic renal cell carcinoma

Advanced renal cell carcinoma (RCC) is resistant to chemotherapy and radiotherapy. Immunotherapy is relatively effective against RCC. However, the response rate is approximately 15–20%. Therefore, new therapeutic approaches are necessary. Recently, molecular mechanisms responsible for the proliferation of RCC are identified, and molecular targeted therapy is developed. Bevacizumab, sorafenib, sunitinib, axitinib, temsirolimus, everolimus are promising molecular targeted therapeutic agents for metastatic RCC, and will be used widely in clinics in the near future. In addition, combination therapy with molecular targeted therapy and other therapies including immunotherapy may also be developed soon.     

Angiogenesis and angiogenic inhibitors in renal cell carcinoma

In most patients with renal cell carcinoma (RCC) of clear cell subtype, there is inactivation of the von Hippel-Lindau (VHL) tumor-suppressor gene, which leads to a proangiogenic state with overexpression of vascular endothelial growth factor (VEGF). This molecular level knowledge has led to the development of multiple antiangiogenic therapies directed against the VEGF protein or the VEGF receptor. These therapies have significant clinical activity in metastatic RCC. Therefore, a therapeutic strategy based on targeting VEGF in RCC has a sound molecular basis and therapy with VEGF-targeting agents has significant clinical activity. To further improve efficacy, future research should focus on better identification of patients who will most benefit from such therapy. We reviewed the published literature regarding angiogenesis, the VHL gene, VEGF biology, and antiangiogenic therapies in metastatic RCC. This article reviews the role of angiogenesis in RCC and summarizes data regarding antiangiogenic therapy in metastatic RCC.     

Tumor vaccines in renal cell carcinoma

Introduction Although most vaccines target foreign infectious agents, therapeutic cancer vaccines target both well-established and metastatic tumor cells expressing tumor antigens. Active immunotherapy is intended to enhance or activate the immunosurveillance of an individual through a therapeutic vaccine. Renal cell carcinoma (RCC) is one of the most immunoresponsive cancers in humans, which in turn makes it an ideal candidate for immune based therapies. Method Several types of therapeutic vaccines have been tested and applied in the clinical setting and can be divided into cell-based vaccines including direct application of inactivated autologous tumor cells, gene modified tumor cell-based, dendritic cell-based (expressing RCC derived tumor antigens), and non-cell-based vaccines. This review will examine the current status of cell-based vaccine immunotherapy and focuses on non-cell-based vaccine strategies. Conclusion Recent advances in molecular targeting therapy have introduced a battery receptor tyrosine kinase (RTK) and mTOR inhibitors that provide promising treatment options, however, the tolerability of tumor vaccines and the success of clinical effectiveness in selected populations combined with recent advances in cellular therapies warrant the continued exploration of novel methods of tumor vaccine therapies in the clinical setting.     

Renal cell carcinoma 2005: new frontiers in staging, prognostication and targeted molecular therapy

PURPOSE: Renal cell carcinoma (RCC) has traditionally been staged using a purely anatomical staging system. Although current staging systems provide good prognostic information, data published in the last few years has led to significant controversies as to whether further revisions are needed and whether improvements can be made with the introduction of new, more accurate and predictive prognostic factors not currently included in traditional staging systems. This review highlights such controversies and provides an update on current staging modalities, prognostic factors and targeted molecular therapy for RCC. MATERIALS AND METHODS: A comprehensive review of the peer reviewed literature was performed on the topic of current staging modalities, validated prognostic factors, predictive nomograms, molecular markers and targeted molecular therapy for RCC. RESULTS: A staging system for malignant disease such as RCC uses various characteristics of tumors to stratify patients into clinically meaningful categories, which can be used to provide patients with counseling regarding prognosis, select treatment modalities and determine eligibility for clinical trials. The TNM staging system is currently the most extensively used one. However, it has undergone recent systematic revision due to rapidly emerging data from longer patient followup. The identification of various histological and symptomatic factors has led groups at many centers to develop more comprehensive staging systems that integrate these factors and include patients with metastatic and local disease. While integrated staging systems have improved RCC staging, the recent discovery of molecular tumor markers is expected to revolutionize RCC staging in the future and lead to the development of new therapies based on molecular targeting. CONCLUSIONS: Staging systems for RCC serve as a valuable prognostic tool. Several new patient and tumor characteristics have been reported to be important prognostic factors and they have been integrated into current staging systems. In addition, the field of RCC is rapidly undergoing a revolution led by molecular markers and targeted therapies. With this information urologists will be updated with the most current and comprehensive staging strategies, and be provided with a glimpse of the molecular and patient specific staging and treatment paradigms that will in our opinion transform the future management of this malignancy.     

Combined cytoreductive laser therapy and immunotherapy for palliation of metastatic renal cell carcinoma to the head and neck

Interleukin-2 (IL-2) remains the mainstay of treatment for metastatic renal cell carcinoma (RCC), but minimally invasive surgical techniques have provided new options for the combined treatment of RCC. Two patients with metastatic RCC to the head and neck treated by combined laser-induced thermal therapy and IL-2 were described in this case report. Both patients had an extended survival compared to the historical survival of 10 months for metastatic RCC but eventually succumbed to progressive disease. The authors’ initial experience with metastatic RCC suggests that laser thermoablation and immunotherapy in selected patients with metastatic RCC is warranted as a palliative treatment, but a larger study with long-term follow-up is necessary to determine the effectiveness of this approach.     

Renal cell carcinoma: physiology,diagnosis, and therapy

Summary Renal call carcinoma (RCC) is the most common malignancy of the kidney in adults. Heredity appears to play a role within the etiology of RCC. Recent evidence indicates that deletions and translocations involving the short arm of chromosome 3 are important for the oncogenesis and tumor progression of RCC. Overt symptoms accompanying RCC are often associated with advanced local or distant disease. There is an increased number of patients in whom the diagnosis of RCC is made incidentally in cases when the tumor is confined to the kidney. This finding is responsible for the fact that the prognosis is better in this group of patients. Surgical extirpation is the cornerstone of therapy of localized RCC. However, in the presence of metastatic disease, immunotherapy seems to be the most effective adjuvant therapy.     

Should radical nephrectomy be performed in the face of surgically incurable disease?

The role of cytoreductive nephrectomy in the management of metastatic renal cancer remains controversial. Recent trials, like SWOG 8949 have suggested the usefulness of this approach at least in selected patients with good performance status and other favorable indicators. The timing of cytoreductive nephrectomy has also been controversial and remains so to this time.CommentaryAn estimated 30,000 new cases of renal cell carcinoma (RCC) are detected annually in the U.S. In approximately one-third of these cases, metastatic disease is diagnosed at presentation. Multi-modality treatment combines biologic response modifier (BRM) therapy with surgery in an attempt to improve survival with either form of treatment alone. The optimal timing of surgery relative to BRM therapy continues to be debated.Prior to the advent of multi-modality therapy, there were relatively few indications for nephrectomy in patients with metastatic RCC. The incidence of spontaneous regression of metastatic RCC following removal of the primary tumor is only 1–4% and, therefore, nephrectomy on this basis is not justified. There is a palliative role for nephrectomy in selected patients with metastatic RCC who are experiencing severe disability from associated local symptoms; however, some patients in this category can be managed with percutaneous renal angioinfarction. A small subset of patients with a solitary metastasis may benefit from nephrectomy and resection of the metastatic lesion based on reported 5-year survival rates of up to 30–35%.There has been controversy concerning the appropriate timing of adjuvant or cytoreductive nephrectomy in the multi-modality approach to treatment of metastatic RCC. Many protocols have involved preliminary removal of the primary tumor before the administration of BRM therapy. The rationale for this has been to enhance response rates to BRM therapy by reducing tumor volume and, in some cases, to provide immunoreactive cells for treatment. A drawback of this approach was that many patients underwent nephrectomy without subsequently receiving BRM therapy due to postoperative morbidity/mortality or rapid tumor progression. This prompted interest in an alternative approach of delayed adjuvant nephrectomy wherein BRM therapy was administered initially and nephrectomy was subsequently performed only in those patients who demonstrated a response to systemic therapy.The relative merits of initial versus delayed adjuvant nephrectomy in conjunction with BRM therapy for metastatic RCC have recently been clarified through two phase III prospective multicenter clinical trials conducted in Europe (EORTC) and the United States (SWOG). The results of both of these carefully done studies have indicated improved survival with initial nephrectomy followed by BRM therapy. The latter comprised interferon monotherapy in both studies, which opens the studies to criticism, however the essential observation of extended survival with preliminary nephrectomy appears to be valid. On this basis, there is now objective evidence to suggest that initial cytoreductive nephrectomy is the preferred approach in patients with metastatic RCC who are candidates for multi-modality therapy. The most appropriate candidates for such therapy remain patients with good performance status and low-volume (preferably pulmonary) metastatic disease. The ability to perform cytoreductive nephrectomy laparoscopically in some of these patients, with reduced morbidity, is a further development that has strengthened the argument in favor of initial nephrectomy.Andrew C. Novick, M.D.     

Surgical considerations for patients with metastatic renal cell carcinoma

Among patients with renal cell carcinoma (RCC), 25–30% present with metastatic disease at the time of initial diagnosis. Despite the ever-increasing array of treatment options available for these patients, surgery remains one of the cornerstones of therapy. Proper patient selection for cytoreductive surgery is paramount to its effective use in the management of patients with metastatic RCC despite the decrease in reported morbidity rates. We explore the evolving role cytoreductive surgery in metastatic RCC spanning the immunotherapy era to the targeted therapy era. Despite significant advances in the management of patients with metastatic RCC, further evidence on the definitive role of cytoreductive surgery in the targeted therapy era is awaited through large randomized trials.     

Epidemiology,Aetiology, and Pathogenesis of Renal Cell Carcinoma

Significant advances in molecular medicine have made renal cell carcinoma (RCC) the prototype solid organ malignancy for targeted medical cancer treatment. Theseis new options have made it possible to prolong the life of patients with metastatic disease. However, we are far away from thoroughly understanding the molecular processes of RCC development let alone from being able to cure advanced renal cancer. RCC is the most common renal neoplasia and it remains a very aggressive and often fatal disease.There are several known histologic subtypes of this heterogeneous tumor entity with associated distinct molecular alterations and different clinical outcomes [1], [2], [3], [4]. The clear cell renal cell carcinoma (ccRCC) is the most common and apparently most aggressive RCC subtype with the highest rates of local invasion, metastasis and mortality. It constitutes 70–80% of all renal cancers [1], [5]. It is estimated that more than 30% of patients with RCC have metastatic disease at the time of diagnosis and 30% of organ-confined RCCs will develop metastatic disease after local treatment [6]. Thus, RCC remains a very major challenge.     

Prediction of response to combined immunotherapy with interferon-α and low-dose interleukin-2 in metastatic renal cell carcinoma: Expression patterns of potential molecular markers in radical nephrectomy specimens

Objectives:   To evaluate the expression levels of multiple molecular markers in radical nephrectomy specimens from patients with metastatic renal cell carcinoma (RCC) who received combined immunotherapy with interferon-α (IFN-α) and low-dose interleukin-2 (IL-2) and to identify factors predicting susceptibility to this therapy.
Methods:   This study included 40 patients with metastatic clear cell RCC undergoing combined immunotherapy with IFN-α and low-dose IL-2 following radical nephrectomy. Expression levels of 10 markers, including Aurora-A, Bcl-2, clusterin, heat shock protein 27, heat shock protein 90, Ki-67, matrix metalloproteinase-2, matrix metalloproteinase-9, p53 and vascular endothelial growth factor, in RCC specimens were measured using immunohistochemical staining.
Results:   In this series, one, 10, 15 and 16 patients were diagnosed as showing complete response, partial response, stable disease and progressive disease, respectively. Expression levels of Bcl-2 and Ki-67 had significant impacts on the response to this therapy. Furthermore, cancer-specific survival was significantly associated with the expression levels of Ki-67 and Bcl-2 in addition to performance status, presence of metastases at diagnosis, metastatic organ and C-reactive protein on univariate analysis. Only the presence of metastases at diagnosis and Ki-67 expression level appeared to be independent predictors of cancer-specific survival on multivariate analysis.
Conclusions:   It would be useful to consider the expression levels of potential molecular markers, particularly Ki-67, in addition to clinical parameters, such as the presence of metastases at diagnosis, to select metastatic RCC patients likely to benefit from combined immunotherapy.     

Integrating Surgery with Targeted Therapies for Renal Cell Carcinoma: Current Evidence and Ongoing Trials

Context

Surgical intervention is the primary treatment for early-stage renal cell carcinoma (RCC), but alone it has limited benefit in patients with metastatic disease. The advent of targeted agents for RCC has improved the outcome in these patients, and there is increasing interest in exploring the efficacy and safety of these agents in combination with surgery in both early and advanced disease.

Objective

This article reviews approved and emerging targeted therapies for RCC and outlines the rationale and implications for combining these therapies with surgery.

Evidence acquisition

A search of the literature, trial registries, and meeting proceedings was performed, and reports on surgery, receptor tyrosine kinase inhibitors, vascular endothelial growth factor antibodies, mammalian target of rapamycin inhibitors, and cytokine adjuvant therapy relating to RCC were critically reviewed.

Evidence synthesis

Nephrectomy has been shown to improve overall survival in patients with metastatic RCC (mRCC) treated with interferon alpha. Combining targeted therapy with surgery has the potential to improve efficacy and tolerability relative to cytokine therapy and prospective studies are underway. In the localized setting, there is some evidence of tumor downsizing with neoadjuvant targeted therapy. The tolerability and safety of targeted agents used perioperatively must be considered, particularly in the adjuvant setting where chronic therapy is required to prevent recurrence or metastasis. Novel agents with greater specificity and improved safety profiles are under development and have the potential to enhance efficacy and minimize the risk of complications.

Conclusions

For patients with mRCC, randomized controlled trials are ongoing to define the role and sequence of nephrectomy in combination with targeted therapy. Until data are available, nephrectomy remains part of the mRCC treatment algorithm for patients with good performance status and a resectable tumor. Targeted therapy to downsize large primary tumors in nonmetastatic disease is investigational, but the rate of surgically relevant down-staging and tumor shrinkage seen with the current generation of agents is limited. In patients with high-risk nonmetastatic disease, adjuvant therapy must be administered only in the context of the ongoing clinical trials since there are no data showing efficacy in this setting.     

The value of tumor nephrectomy in metastatic renal cell carcinoma

In the case of an organ-confined RCC, tumor nephrectomy is the undisputed therapy of choice even though overall 5-year survival has not surpassed the 60% threshold. Further improvement will most likely have to await the development of more effective systemic treatment strategies. For an exclusively surgical therapy of metastatic RCC, tumor nephrectomy, sometimes in combination with metastasectomy, can be applied. However, more commonly used is a multimodality approach consisting of a cytoreductive operation followed by immunotherapy. Alternatively, one may select immunotherapy first followed by adjuvant nephrectomy in the case of a response, or one may proceed directly to immunotherapy only. Long-term survival does not exceed 5-10%, and patient selection appears to have a higher prognostic impact than any treatment strategy available. Concepts and progress in the field clearly are of increasing value for modern oncologic urologists. The current standard, a multimodality treatment of metastatic RCC, in which an operation becomes necessary at a certain point in time, easily justifies a central role for the urologic surgeon.     

Behandlung des metastasierten Nierenzellkarzinoms. Stellenwert der Immuntherapie gegenüber der Metastasenchirurgie

The prognosis for patients in whom metastatic renal cell carcinoma (RCC) is not treated is unfavorable, with a reported 5-year survival of 0-18%. Before the era of immunotherapy and in the absence of effective nonsurgical therapy, resection of metastases was the accepted way to prolong survival, giving a 5-year survival of 7-69%. Retrospective studies have shown that several clinical factors are associated with a relatively good prognosis. Some patients will benefit from resection of metastases, but most patients with metastatic RCC are not candidates for such aggressive surgery. The use of interleukin-2 has demonstrated that immunotherapy can produce durable remissions. Without randomized trials, it is difficult to know whether survival is longer than that in untreated patients, but there is clear evidence that immunotherapy improves survival and yields long-lasting remissions in selected patients. Many questions remain concerning quality of life and the benefit-to-risk ratio of immunotherapy, but it is the most effective treatment for metastatic RCC.     

Systemic therapy for chromophobe renal cell carcinoma: A systematic review

Background: Chromophobe renal cell carcinoma (chRCC) subtype accounts for almost 5% of total RCC cases. It carries the best prognosis among the rest of RCC types. However, patients with metastatic chRCC disease have worse prognosis than patients with advanced clear cell RCC. Furthermore, available data regarding systemic therapy for chRCC patients are scarce and confusing. Aim: The aim of this systematic review is to search for and critically appraise studies that investigate the results of systemic therapies in patients diagnosed with metastatic chRCC disease. Methods: Search strategy included PUBMED, CENTRAL, clinicaltrials.gov databases, and abstracts of major conferences with a focus on urologic oncology (till March 2019). Studies investigating patients that were treated with systemic therapy for advanced chRCC disease were included. Primary outcomes were progression-free survival and objective response rate. Secondary outcome was overall survival. Screening of available studies was carried out by 2 groups of reviewers, as well as the quality assessment of the included studies. Results: The systematic search yielded 369 studies, of which 15 studies (2 randomized control trials and 13 cohort studies), involving 183 patients, met the eligibility criteria. The 2 randomized control trials that directly compared sunitinib vs. everolimus, suggested an advantage for sunitinib without being statistically significant. Furthermore, sunitinib seems to be superior than sorafenib at least in terms of objective response rate. Regarding mTOR inhibitors, they may have a role in a specific subset of chRCC patients, that needs to be further explored. Finally, as far as immunotherapy is concerned, available data suggest that chRCC seems to be resistant to recent immune check point inhibitors, since just a few tumor responses were observed with the administered immunotherapy regiments. Conclusion: The optimum therapy for metastatic chRCC is still missing, as results from ongoing trials are awaited. More studies, of high quality and adequate sample size, that will be based on the specific biology of chRCC, have to be carried out in order to identify the best treatment.     

Treatment Approaches in Renal Cell Carcinoma: Past,Present, and Future Perspectives

Treatment of localised renal cell carcinoma (RCC) is well established, and surgical resection is curative for most patients. However, for patients with either metastatic disease or whose local disease subsequently metastasises, treatment options have until recently been limited to cytokine therapy or chemotherapy, both of which are ineffective in the majority. As a result, prognosis has been poor for patients with metastatic RCC (mRCC). A better understanding of the pathogenesis of RCC has led to the development and application of therapies targeted at key molecules involved in angiogenesis, which is an integral part of tumour growth and invasion. Research has shown that mutations in the von Hippel-Lindau (VHL) tumour suppressor gene lead to increased expression of vascular endothelial growth factor (VEGF), an angiogenic factor that is frequently over-expressed in clear-cell RCC, and which is believed to contribute to the hypervascularity of RCC. Therefore, novel therapeutics have been developed that target proteins in the VHL–VEGF pathway, with the aim of inhibiting angiogenesis. These agents include sunitinib, sorafenib, temsirolimus, and bevacizumab, all of which improve clinical outcomes compared with immunotherapy or placebo. Although patients with mRCC are now offered a better prognosis, several questions remain: how do we optimise clinical use of these novel agents, how do we identify patients most likely to benefit from targeted therapies, and can combination therapies further improve outcomes? This article reviews the past and present treatment for mRCC and considers the future challenges.     

Basic research in kidney cancer

Context

Advances in basic research will enhance prognosis, diagnosis, and treatment of renal cancer patients.

Objective

To discuss advances in our understanding of the molecular basis of renal cancer, targeted therapies, renal cancer and immunity, and genetic factors and renal cell carcinoma (RCC).

Evidence acquisition

Data on recently published (2005-2011) basic science papers were reviewed.

Evidence synthesis

Advances in basic research have shown that renal cancers can be subdivided based on specific genetic profiles. Now that this molecular basis has been established, it is becoming clear that additional events play a major role in the development of renal cancer. For example, aberrant chromatin remodelling appears to be a main driving force behind tumour progression in clear cell RCC. A large number of potential biomarkers have emerged using various high-throughput platforms, but adequate biomarkers for RCC are still lacking. To bring the potential biomarkers and biomarker profiles to the clinical arena is a major challenge for the field.The introduction of tyrosine kinase inhibitors (TKIs) for therapy has shifted the interest away from immunologic approaches. Nevertheless, a wealth of evidence supports immunotherapy for RCC. Interestingly, studies are now appearing that suggest a combination of TKI and immunotherapy may be beneficial.Thus far, little attention has been paid to patient-specific differences. With high-throughput methods becoming cheaper and with the advances in sequencing possibilities, this situation is expected to change rapidly.

Conclusions

Great strides have been made in the understanding of molecular mechanisms of RCC. This has led this field to the enviable position of having a range of molecularly targeted therapies. Large sequencing efforts are now revealing more and more genes responsible for tumour development and progression, offering new targets for therapy. It is foreseen that through integration of high-throughput platforms, personalised cancer treatment for RCC patients will become possible.     

Molecular targeted therapy for renal cell carcinoma

Renal cell carcinoma (RCC) accounts for approximately 2% of all cancer cases worldwide. Metastatic disease is often present at the time of diagnosis of RCC and its poor response to chemotherapy and radiotherapy causes poor prognosis. Immunotherapy is relatively effective for RCC, but the response rate is approximately 15-20%. Therefore, new therapeutic approaches are necessary for these patients with metastatic RCC. Recently, the mechanisms responsible for the growth of RCC have been clarified, and molecular targeted therapy has been developed. In this paper, we review the new molecular targeted therapeutic agents effective for RCC.     

Overview and management of toxicities associated with systemic therapies for advanced renal cell carcinoma

The advent of novel targeted agents for metastatic renal cell carcinoma (RCC) has offered clinical benefits over traditional immunotherapy (e.g., interleukin-2 and interferon-α) in both efficacy and safety profiles. The major classes of these targeted therapies for metastatic RCC include the tyrosine-kinase inhibitors, monoclonal antibody against vascular endothelial growth factor, and inhibitors of the mammalian target of rapamycin. Most recently, the success of immune checkpoint inhibitors—notably antibodies directed against programmed death-1 and its ligand—has also been demonstrated in RCC. With such progress in therapy, early detection, and subsequent management of treatment-related adverse events allow for patients to remain on active therapy for as long as possible and also enhance the probability of patients tolerating subsequent second line options. However, despite such impressive gains in efficacy with these new agents, therapeutic progress are primarily palliative in nature—hence, the critical importance of minimizing discomfort and potential harm in this patient population cannot be understated.