Submitted - October 18, 2022 | Revised December 4, 2022 Accepted - December 7, 2022 | | ePublished - December 31, 2022
https://doi.org/10.52733/KCJ22n2-r1

ABSTRACT

Prior to the development of new cancer technologies, metastatic Renal Cell Carcinoma (mRCC) had a poor prognosis. Fortunately, advances in treatment are allowing a growing population of patients to live with advanced or mRCC. While quality of life has been an area of investigation in this population as treatments advance, relatively little is known about the specific survivorship needs experienced by these patients in the modern treatment era. Using the five survivorship domains defined by the National Cancer Institute, this narrative review explores the literature addressing the survivorship needs of patients living with mRCC. Significant physical, mental, emotional, social and financial effects of mRCC are herein discussed. By comparing literature from the pre-combination treatment period to the modern era, this narrative review of the published literature highlights the significant gaps in our survivorship knowledge for this unique and expanding population. Specifically, this review identifies gaps in understanding of symptom burden, psychological impact, financial effects, and the particular impact of immunecheckpoint inhibitor based combination therapies. Here, we highlight these areas for further research with the hope of finding strategies to alleviate the effects of mRCC and improve the quality of life of patients living with metastatic disease.

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INTRODUCTION

Kidney cancer is one of the top 10 most common malignancies affecting the United States population, with an estimated 81,800 new cases and 14,890 deaths in 20231. Of these, >80% are renal cell carcinomas (RCC), which arise from the renal cortex. Most new cases are localized or regional at diagnosis and therefore surgically curable. However, for the 15% of cases that are advanced or metastatic, prognosis was historically poor1. Fortunately, recent advances in therapeutic approaches have resulted in an increasing population of metastatic RCC (mRCC) patients with durable responses. Indeed, the 5-year relative survival rate for distant-stage RCC was 13.1% in 2004 and, while data are still maturing, is expected to be 22.9% in 20202. Given this increased survivorship observed among mRCC, a shift in the focus of care is warranted, from merely living as long as possible with disease, to living as well as possible with ongoing disease control. While quality of life has been a focus of study in this patient population3, the specific survivorship needs of individuals living with mRCC remain unexplored.

The National Cancer Institute (NCI) defines survivorship as a “focus on the health and wellbeing of a person with cancer from the time of diagnosis until the end of life,” addressing the key domains of “physical, mental, emotional, social, and financial effects4.” While these domains are salient to any cancer patient, the successes of the shifting treatment landscape for mRCC over the past 30 years have underlined their importance in this population. Early non-chemotherapy approaches to treating mRCC included cytokinebased immunotherapy drugs like interferon-α (IFN-α) and interleukin-2 (IL-2), though high toxicity profiles limited use and long-term survival was infrequent5. The introduction of the tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib in 2006 and 2007 shifted the treatment paradigm and mRCC patients began to live longer with their disease. Most recently, combining immune checkpoint inhibitors (ICIs) with or without these targeted agents has further improved outcomes for mRCC patients, achieving median overall survival rates of more than 4 years6. Several clinical trials have resulted in FDA approvals of therapies in combination, including Checkmate 2147, KEYNOTE 4268, JAVELIN Renal 1019, CLEAR10, and Checkmate 9ER6, marking a new era of combination therapy. Subsequently, a sizable proportion of patients with advanced RCC derive durable benefits from the combination of ICIs and targeted therapies, achieving longer periods of progressionfree survival or remission than previously possible. Yet we still know little about the symptom trajectory and survivorship needs of this growing patient population.

In line with calls from the NCI to better understand the survivorship needs of all patients living with advanced or metastatic cancer11, this narrative review of the published literature examines what is known about the needs of mRCC patients using the framework set out by the NCI definition above. Given how varied the literature addressing this population is, we incorporated the NCI framework for its simplicity and widespread recognition. Specifically, we will examine the literature addressing the physical, mental, emotional, social, and financial effects of cancer in this specific cohort. We compare and contrast the literature in the pre-combination treatment period (before 2018) to the modern era (after 2018) in order to identify gaps in survivorship knowledge. Our primary aim in doing so is to generate interest in further research directed at improving the quality of life for the growing population of patients living with mRCC on contemporary therapies.

SURVIVORSHIP PHYSICAL EFFECTS Symptom Burden prior to Combination Therapy Much of our early understanding of the symptom burden of mRCC in the pre-combination therapy era comes from clinical trials. For this reason, when Harding and colleagues attempted to index symptom burden in RCC patients, they started by reviewing clinical trials that included a quality-oflife assessment or detailed toxicity evaluation12. Borrowing from the various instruments used in these studies, the authors developed a pilot RCC symptom index, which they applied in semi-structured interviews to RCC patients and their caregivers. Among the mRCC patients (n=17) they interviewed, whose treatment exposures were predominantly single agent targeted therapies, the five most common moderate to severe symptoms were fatigue, weakness, worry, shortness of breath, and irritability12. While the resulting symptom index was largely replaced by the shorter but similar Functional Assessment of Cancer Therapy – Kidney Symptom Index (FKSI)13, this early work summarized symptom burden in metastatic patients in the targeted therapy era. Similarly, Graham and colleagues used the Edmonton Symptom Assessment System (ESAS) to evaluate whether baseline symptom scores were predictive of survival in patients with mRCC on first-line sunitinib. They found a small but significant trend towards worse overall survival if baseline scores were high, but perhaps more telling for survivorship purposes were the baseline scores themselves. At baseline, patients in this cohort demonstrated high rates of moderate to severe anxiety (38%), appetite disturbance (46%), drowsiness (32%), fatigue (44%), pain (41%), and poor overall well-being (36%)14. While few interventions at this time were directed at improving symptoms while on treatment, Milbury and colleagues randomized an expressive writing intervention for patients of all stages of RCC (including 40 metastatic patients) and found that writing about thoughts and feelings (expressive writing) was associated with lower overall symptom scores compared to writing about neutral topics15.

Cella et al. investigated fatigue in metastatic patients treated with sunitinib. They showed that fatigue was most severe at time of treatment initiation and did not worsen over time16. The FAMOUS study from Goebell and colleagues delved deeper into the differences between physician-assessed and patient-reported fatigue in mRCC. Among patients being treated with sunitinib, bevacizumab, interferon alpha, temsirolimus, or everolimus, the degree of fatigue was more severe when reported by the patient and increased with progressive treatment lines, contributing to lower quality of life in the realms of emotional, functional and physical well-being17. To counteract cancerrelated fatigue in mRCC, Tsimafeyeu and colleagues evaluated the role of testosterone for patients on firstline pazopanib or sunitinib. Male patients with a normal PSA and low testosterone level were randomized to receive testosterone with their targeted therapy or targeted therapy alone. The study demonstrated significant improvement in Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT – Fatigue) for the patients on testosterone without significant additional toxicities18.

Sexual health was uniquely described in mRCC patients by Marcon and colleagues. In a longitudinal evaluation of erectile dysfunction among men with advanced RCC on firstline targeted therapy, these investigators demonstrated that erectile dysfunction worsened and correlated with worse subjective patient sexual satisfaction 12 weeks into therapy compared to baseline19. While this study did not account for other psychosocial confounders, it provides an initial signal that sexual health should be considered among the survivorship needs of patients with mRCC.

Symptom Burden in the Combination Therapy Era Few studies have specifically described the symptom burden of mRCC patients surviving on combination therapy. Hall and colleagues surveyed physicians and patients with mRCC to collect real-world data about symptoms. Of the 227 patients being treated off clinical trials, the majority were on TKI monotherapy (50.2%), but nearly half were being treated with modern regimens (19.4% on ICI monotherapy, 19.4% on ICI combination therapy, and the remainder on other therapies). On average, patients reported 4.2 symptoms at initial diagnosis and 3.4 symptoms at the time of the study, with loss of appetite, fatigue, and nausea occurring most commonly20. Kastrati and colleagues similarly surveyed patients with mRCC to determine the burden of side-effects of treatment. Again, the majority (66%) were on TKI monotherapy, but a substantial minority were on ICI monotherapy (19.6%) or combination therapy (14.4%). Side effects were more frequent among those taking a TKI (98.4% vs. 68.4%) with significantly more diarrhea, taste alteration, appetite loss, mucositis, and weight loss. Fatigue was noted both in patients on TKIs (62.5%) and ICIs (42.1%)21.

Unfortunately, little additional information in the published literature describes the symptom burden of real-world mRCC patients in the combination therapy era. To glean more, we look to randomized clinical trials of novel pharmaceuticals which, in addition to gathering information on traditional endpoints, have increasingly included Patient Reported Outcome Measures (PROMs) that describe the impact of modern therapies on Health-Related Quality of Life (HRQoL). Both general and disease-specific tools have been developed and validated to evaluate a combination of symptoms, function, psychological health, and overall wellbeing for those with mRCC, offering promising approaches to understanding the patient experience. These tools and the result of their application to patients on different therapies have been expertly reviewed in the TKI era22,23 as well as in the combination therapy era24, however they fall short of being able to identify survivorship needs in patients. PROMs serve well in their primary role, which is to compare the acceptability of different therapy approaches in the eyes of the patient, yet with scales that aggregate symptoms and experiences into a single score, it is challenging to isolate independent treatment-related or diseaserelated phenomena experienced by patients as they continue to survive with their disease.

To illustrate this, we have compiled the published results from HRQoL data collected alongside recent clinical trials for mRCC (Table 1 & 2). HRQoL results from Checkmate 21425,26, KEYNOTE 42627, JAVELIN Renal 10124, CLEAR28, and Checkmate 9ER29 are summarized and, while the results often indicate improved or unchanged HRQoL for the experimental arm compared to the control, it is nearly impossible to dissect these scales to identify intervenable symptom concerns for patients. A unique exception comes from application of the European Organization for the Research and Treatment of Cancer 30-item Quality of Life Questionnaire (EORTC QLQ-C30) in both the CLEAR and Keynote 426 studies. The phase III CLEAR study evaluated the efficacy of lenvatinib with pembrolizumab and lenvatinib with everolimus against standard of care sunitinib for advanced RCC, finding an overall survival benefit of the first combination, but not the second10. Keynote 426 randomized patients to pembrolizumab with axitinib or sunitinib and showed a benefit in progression-free survival and response rate8. The EORTC QLQ-30, which includes symptom-specific subscales, was used for quality of life evaluation for both studies30. The CLEAR trial demonstrated that patients on lenvatinib and pembrolizumab had worsening in symptom subscales at 46 weeks compared to baseline for fatigue, nausea and vomiting, pain, appetite loss, and diarrhea28. While Keynote 426 only presented data for the nausea and vomiting and diarrhea symptom subscales, we saw that those patients on combination axitinib and pembrolizumab at 30 weeks had worsening of their nausea/vomiting and diarrhea. Of the patients on the combination therapy arm, fewer than 10% had improvement in these symptoms, 25% had worsening of their nausea and vomiting, and 50% had worsening diarrhea27.

Cardiotoxicity

The cardiac effects of small molecule agents targeting vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) have been a focus of study since clinical trials in mRCC identified hypertension and decreased ejection fraction as potential adverse effects of use31– 33. Investigators from Stanford University described the incidence of cardiotoxicity among 159 patients on such targeted therapies, noting that 73% developed some form of cardiac toxicity. While the majority were diagnosed with new or worsening hypertension, 16% experienced decreased ejection fraction and 31% developed overt heart failure34. In Taiwan, the incidence rate of major adverse cardiovascular events (MACE) was 6.65 per 100 personyears for individuals on targeted therapies, compared to 3.36 per 100 person-years on cytokine therapy (IL-2 or IFN). In this cohort, presence of a baseline cardiac comorbidity was an independent risk factor for developing MACE35. A review by Franczyk and colleagues summarized the published cardiovascular side effects of sorafenib, sunitinib, and pazopanib, implicating the drugs in development of hypertension, left ventricular function decline, cardiac ischemia or infarction, and heart failure36. Even newer TKIs, such as cabozantinib, have been connected to cardiac dysfunction37. A prospective multicenter trial of 22 mRCC patients on cabozantinib demonstrated a risk of developing left ventricular systolic dysfunction 6 months after treatment initiation38. There has been limited study of the cardiac effects of combination therapies (dual ICI or TKI/ ICI) outside of clinical trials. A prospective study that compared mRCC patients receiving TKI with or without ICI (n=28) to patients with localized RCC (n=29) and healthy controls (n=20) found that patients with mRCC and localized RCC had a significantly lower mean ejection fraction at baseline compared to controls, but did not otherwise find significant changes in echocardiographic findings, clinical incidence of heart failure, or cardiac blood biomarkers in the 6 months of follow up39. It is also known, from the immunotherapy related adverse events (IRAE) literature and from case reports in mRCC40,41, that myocarditis and ventricular arrhythmias can happen on combination therapy, however their overall incidence is rare.

SURVIVORSHIP MENTAL EFFECTS

While there is little known about the cognitive effects of combination therapy in mRCC, data suggests that patients on earlier RCC treatment modalities demonstrated negative impacts on cognition. An early review of cognitive effects of high-dose IL-2 therapy described “cognitive fatigue” as a combination of lethargy, confusion, inability to focus, sleep insufficiency, decreased memory and limited attention span. Prevalence of such mental changes was estimated to be 80% among patients receiving IL-2 treatment for mRCC42. Mental deterioration was noted in a much smaller proportion (13%) of patients treated with IFN-α for mRCC43. In the TKI era, Miller and colleagues demonstrated that mRCC was a risk factor for developing mild cognitive impairment or dementia (MCI/D). Among 2533 patients with mRCC in the SEER database from 2007-2015, having mRCC was associated with a larger than 8-fold greater hazard of developing MCI/D. In contrast, age was a much weaker predictor, with a hazard ratio of 1.05 per 1-year increase in age44. In a prospective study of patients starting antiangiogenic therapy as first- or second-line therapy for mRCC, Joly and colleagues demonstrated cognitive decline in 31% of patients, and increased fatigue in all patients except one. While a relationship between cognitive complaints and fatigue was noted, there was no statistical association between objective cognitive decline and fatigue45. These studies suggest that cognition can be compromised in the mRCC survivorship period, though whether these are disease- or treatment-mediated, and whether cognition is impacted by combination therapies, remains unclear.

SURVIVORSHIP EMOTIONAL EFFECTS

The psycho-emotional impact of mRCC, while far from wellunderstood, has garnered attention in the pre-combination therapy era. Scientific inquiries have reported widely varied prevalence estimates for psychological distress among patients with mRCC, with estimates as high as 77% and as low as 20.7%46,47. Major contributors to distress are described as pain, fatigue, and financial comorbidities, and evidence suggests that younger, unmarried, female populations with non-clear cell histology may be at higher risk47,48. However, it is clear that work in this area is limited, as a recent systematic review identified only three publications discussing distress in metastatic RCC populations49.

There is some evidence that patient outlook can influence the development of psychological symptoms. Milbury and colleagues reported that mRCC patients with high treatment optimism, even if unrealistic, experienced a less severe decline in quality of life than those with low optimism over the course of a clinical trial50. Prinsloo et al. linked mental outlook directly to health by reporting an association between positive affect and biologic markers in mRCC patients51. Bergerot and colleagues extended this understanding of patient attitudes by examining points of frustration for patients with mRCC. They conducted a survey among 450 patients with RCC and found that 71.5% reported frustration, with common sources identified as fear of recurrence and distrust of the cancer care system52.

Depressive symptoms have also been examined in mRCC patients in the pre-combination therapy era, with 23% of 217 mRCC patients screening positive for depression symptoms on the Centers for Epidemiologic Studies – Depression (CES-D) questionnaire in a study from Cohen and colleagues. The presence of depression was notably found to be associated with decreased survival and linked to dysregulation of cortisol and biological markers of inflammation53. Despite a relatively low prevalence, depression has been shown to have devastating impacts in this population. According to a Surveillance, Epidemiology, and End Results (SEER) analysis of genitourinary cancer patients from 1988-2010, there were an estimated 26 suicides per 100,000 personyears in the RCC population overall and 90 per 100,000 person-years in those with metastatic disease. Compared to suicide rates in the general US population, those with kidney cancer experience more than two-times as many suicides in the 0 to 5 years after diagnosis54. A second SEER analysis of cause of death in patients diagnosed with RCC from 2005-2015 showed that a majority of metastatic patients still die from their disease (84.65%), however metastatic patients had a more than three-fold higher risk of death from suicide than patients with less advanced stages of RCC55. These studies suggest that mental health continues to be inadequately addressed in mRCC patients. Far fewer psychological investigations have been conducted in the combination therapy era. Investigators have explored changes in perception of cure among patients on ICI therapy for genitourinary malignancies, including mRCC. For this population, ICI can be very effective, however not all will not experience cure. Bergerot and colleagues showed that accurate perceptions of cure improved over time, suggesting improvement in patient provider communication, and that accurate expectations were associated with lower rates of anxiety. Inaccurate expectations were associated with more severe side effects and worse selfreported performance status56. How the uncertainty of a durable response with combination therapy impacts emotional states in patients with mRCC continues to be largely unexplored.

SURVIVORSHIP FINANCIAL EFFECTS ON PATIENTS AND SOCIETY

Most research addressing social aspects of mRCC survivorship is centered on the financial impact of living with advanced disease. In the pre-combination therapy era, a Danish registry study compared the economic impact of early immunotherapy approaches (IL- 2 and IFN-α) to targeted therapy. The investigators found that health care costs per patient were not significantly different in the immunotherapy period (2002- 2005) compared to the targeted therapy period (2006-2009), but the distribution of costs differed. In the targeted therapy era, inpatient costs were lower, but outpatient, radiology and drug costs were higher57.

A string of cost effectiveness analyses in the pre-combination therapy era primarily used clinical trial data to compare the economic value of various treatment options. Sorafenib was not found to be cost effective compared to supportive care in second-line treatment58. In England, cabozantinib was found to be less expensive and more effective than nivolumab in the secondline59 and neither the combination of bevacizumab, interferon and sunitinib nor interferon alone were found to be cost-effective60. A Swedish study applied similar concepts to real-world data and found that targeted therapy for mRCC patients was cost effective compared to prior treatment modalities, with increased efficiency over time61.

A major concern in the combination therapy era is financial toxicity to the patient, given the high price of ICI and TKI combination therapy and their potentially indefinite use in patients with durable responses. Estimates in Europe suggest that costs are increasing among RCC survivors as a whole62. In the United States, a Kidney Cancer Research Alliance (KCCure) mediated survey assessed financial burden in the combination therapy era and found that financial hardship was low (15%) among respondents, though the sample was predominantly white (91%), most had an advanced degree (52.9%), and few (17%) had an annual household income <$50,00063. Initial estimates from Choueiri and colleagues suggested that combination nivolumab and ipilimumab was associated with an incremental cost of $91,000 and a gain of 1.3 quality adjusted life years (QALYs) compared to sunitinib. They showed that this was more cost effective than the combination of pembrolizumab with axitinib, which had an incremental cost of $333,000 for a gain of 0.5 QALY64. Unfortunately, additional information about the costs of care in the combination era are lacking.

CONCLUSIONS

As patients with mRCC continue to see increased survival, it becomes essential to refocus our approach to care with a survivorship lens. Applying said lens to the mRCC literature reveals that most patients have a significant physical symptom burden, with fatigue, loss of appetite, and gastrointestinal upset being most common. We also see significant mental health and cognitive impacts. Finally, financial effects seem to contribute to distress among patients as they continue to survive with advanced disease for longer periods of time. While this review effectively summarizes the literature addressing survivorship for mRCC patients, there are limitations. First, we pursued a narrative instead of a systematic review, which permits the possible exclusion of relevant publications from our account. However, given the new lens offered by this review, a systematic search was considered too broad to be feasible. Further, due the nature of the review, we do not comment on the quality of the data included. This narrative review reveals that there are still many unknowns about the nature of the physical, mental, emotional, social, and financial impact of mRCC, especially in the era of combination therapy. Given the growing population of patients living with advanced disease, it becomes imperative to develop a better understanding of these issues, and how we can alleviate them, with future study.

AUTHORS DISCLOSURES:

NVB declares no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. MSS declares no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. AD declares no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. AJP declares no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

FUNDING

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

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