ABSTRACT: Significant improvements in the management of patients with endstage renal disease (ESRD) who are on chronic renal replacement therapy (CRRT), has led to an increased prevalence of this population among older Americans. Since cancer is also common in the elderly, oncologists are likely to be faced with patients who suffer from both cancer and ESRD. There is a paucity of information regarding issues surrounding the optimal management of such patients, especially those needing chemotherapy. This review surveys the relevant problems oncologists may encounter in such patients and summarizes the available literature on chemotherapeutic management of common cancers. The reader is strongly urged to consult the original references for details of chemotherapy administration prior to use in an individual patient.
Significant improvement in the management of end-stage renal disease (ESRD) has led to increased survival for patients receiving chronic renal replacement therapy (CRRT)-hemodialysis or continuous ambulatory peritoneal dialysis (CAPD)-over the past 2 decades. In the United States from 1980 to 2001, the overall mortality for patients with ESRD declined by 10% from roughly 275 to 250 deaths per 1,000 patientyears at risk. Since 1985, the mortality rate for patients on dialysis for less than 2 years declined by 23%, from roughly 290 to 220 deaths per 1,000 patient-years at risk. Much of this improvement can be attributed to advances in the dialysis vascular access, improvements in artificial dialyzers, availability of recombinant erythropoietic agents to treat anemia, and improvement in general supportive care.
From 1994 to 2001, however, the mortality of patients who had been on dialysis for more than 5 years increased by 12%, from 259 to 291 deaths per 1,000 patient-years at risk. This suggests an increased need to address medical issues that arise later in the clinical course of patients with ESRD. While the majority of deaths in patients on CRRT are due to cardiovascular disease and infection, cancer is not infrequently observed in this population. Approximately 6% of patients currently initiating hemodialysis in the United States have cancer as a comorbidity. Furthermore, several reports have linked chronic renal insufficiency with an increased incidence of cancer.[2-10]
About 300,000 patients were on hemodialysis in the United States in 2001. By the year 2030, an estimated 2,240,000 people in the United States are expected to have ESRD and half these patients will be 65 years of age or older. The life expectancy for patients on CRRT aged 50, 60, and 70 years is approximately 5, 4, and 3 years, respectively. These life expectancies are only one-third to one-sixth that of the general US population, but they represent a significant period of potentially good quality life during which the treatment of cancer with chemotherapy may be appropriate.
Although the population of patients requiring CRRT is increasing and ESRD is associated with an increased risk of cancer, there is a paucity of available information on the optimal management of ESRD patients with cancer. Because of uncertainty, general treatment goals may vary widely with clinician and patient preferences. This is even more relevant given that subspecialists such as nephrologists and oncologists increasingly serve as their patient's primary care providers. Challenges facing nephrologists caring for patients with ESRD may include delays in cancer diagnosis, unclear utility of cancer screening, and dilemmas in diagnostic imaging.[12,13] Furthermore, in patients with advanced or refractory cancer, both nephrologists and oncologists may be called upon to help negotiate ethically complex palliative care issues including the withholding of dialysis treatment.[14-17]
This article will address the supportive, palliative, diagnostic, and prognostic dilemmas facing clinicians caring for cancer patients with ESRD. We review here the current reports available in the literature and provide an overview of chemotherapy use in ESRD. One recent review focused principally on the pharmacokinetic details for selected single agents. Our review is broader in scope and oriented to guiding the practicing oncologist in clinical decision-making. The use of various chemotherapeutic agents for patients with lesser degrees of renal insufficiency and acute renal dysfunction has been extensively reviewed elsewhere, and the reader is referred to these available sources.[19-21] Table 1 provides a summary of chemotherapeutic agents requiring dose modification or monitoring in renal insufficiency.
The Comorbidity of Cancer and ESRD
The relationship between chronic renal failure and malignancy is complex. The increased incidence of cancer in ESRD patients may be explained through multiple mechanisms, which are detailed in Table 2 and two pertinent review articles.[22,23] Several of these pathways are speculative and warrant further study.
As noted previously, elderly ESRD patients on CRRT can have several years of good-quality life. Oncologists should appreciate this when formulating a cancer-directed treatment plan for their patients with ESRD. Performance status can occasionally be difficult to assess in patients on dialysis because of time spent on dialysis and transient complications of CRRT. Given the paucity of information on quality of life in cancer patients with ESRD, decisions to initiate cancer treatment, especially with chemotherapy, are problematic.
Oncologists also can expect to face palliative care and ethical dilemmas among cancer patients with ESRD. Dialysis represents a proximate lifesustaining measure, and withdrawal of such support could hasten death far in advance of an incurable malignancy. Formulating a plan for hospice care could additionally include a discussion regarding the option of withdrawal of dialysis support. When considering cessation of dialysis, patients should have a full evaluation (including a psychiatric assessment) and counseling. A discussion of withdrawing CRRT or withholding initiation of CRRT involving patients or their proxies should be documented, and appropriate orders should be written.
A recent multicenter prospective cohort study of acute hemodialysis in hospitalized patients demonstrated that a diagnosis of cancer was more commonly associated with withholding (ie, not starting) hemodialysis than it was with withdrawing from ongoing hemodialysis. This was particularly true among older patients, and patients viewed as having a poor overall prognosis. This study also demonstrated infrequent recording of decisions in the medical chart, with only 18% of decisions to withhold hemodialysis and 4% of decisions to withdraw hemodialysis documented.[ 15] Optimizing palliative care for this complex patient population and their families can prove to be a challenge that greatly benefits from a multidisciplinary approach.[14,16]
Diagnostic and Prognostic Issues
Several confounding factors associated with ESRD can affect the diagnosis and evaluation of a malignancy. These include the following: (1) delayed symptomatic presentation, (2) unclear utility of tumor markers in ESRD, (3) imaging dilemmas, and (4) lack of prognostic information.
• ESRD and Cancer Presentation—There are several clinical scenarios in which the common clinical symptoms of malignancy may be missed in the setting of ESRD. For example, hypercalcemia may be associated with malignancy or the secondary hyperparathyroidism of ESRD. An elevated serum phosphate level, however, may favor a renal etiology over malignancy. Oliguria and anuria may mask the symptoms of urinary retention secondary to obstructive uropathy from certain pelvic cancers such as prostate cancer. Other symptoms, such as pruritis related to hyperphosphatemia or anemia from renal disease, may also mask similar initial presentations of malignancy.
• ESRD and Tumor Markers—Serum cancer antigen 125 (CA-125) can serve as a useful tumor marker but can be increased by intraperitoneal volume such as ascites, even when nonmalignant. Indeed, CA-125 concentration in the dialysate of peritoneal dialysis patients is a marker of mesothelial mass and can help determine optimal dwell times for continuous ambulatory peritoneal dialysis.[ 28] Although prostate-specific antigen (PSA) in 63 men on hemodialysis was found to be lower than that of a comparison group of 729 healthy male subjects, the prevalence of abnormally elevated levels of total PSA was similar. In another study of 41 Japanese patients (a population with a low incidence of prostate cancer) on hemodialysis, 4 patients required further diagnostic evaluation based on a cut-off point of 4 ng/mL for PSA, resulting in a biopsy diagnosis of prostate cancer in 2 patients (5%). Although PSA is not dialyzed, fluctuations and increases in PSA levels may still occur secondary to hemoconcentration or alteration in binding proteins following dialysis.
• ESRD and Imaging—Imaging studies requiring contrast are frequently ordered for cancer diagnosis, staging, or monitoring. In ESRD patients, controversy surrounds the issue of whether and when to perform dialysis (hemodialysis or CAPD) around the time of intravenous contrast administration. Because of a lack of consensus among radiologists, guidelines were developed by the Contrast Media Safety Committee of the European Society of Urogenital Radiology (ESUR).
It is important to distinguish the issues of contrast administration in patients with renal insufficiency from those of patients with ESRD and al- ready on CRRT. In the presence of renal insufficiency, water-soluble iodinated contrast agents that are predominantly cleared by the kidney can have a longer half-life and increased toxicity-in particular, additional renal toxicity. Recommendations for patients with renal insufficiency who are not receiving dialysis include judicious use of iodinated contrast media with prehydration, use of low or iso-osmolar contrast media, discontinuation of nephrotoxic drugs for at least 24 hours before contrast administration, and possible use of N-acetylcysteine or sodium bicarbonate(Drug information on sodium bicarbonate).
Prophylactic hemodialysis prior to contrast administration has not demonstrated any benefit and could be harmful. However, intravenous contrast administration for computed tomography scans is not usually contraindicated in patients already on CRRT, as preservation of residual renal function is of minimal value. While it is recommended that excessive volume load with intravenous contrast be avoided, the subsequent timing of dialysis is unimportant and additional dialysis treatments are not recommended.
The use of gadolinium-based contrast agents has also been studied in renal failure because of their predominant renal clearance, and the frequent performance of magnetic resonance imaging examinations in patients with ESRD. No adverse events were reported in a prospective, randomized, double-blind, placebo-controlled study of patients with chronic renal insufficiency (not requiring CRRT) using gadolinium at a concentration of 0.2 mmol/kg vs saline. However, in patients with renal insufficiency, doses greater than 0.3 mmol/kg should be avoided.
The safety of gadolinium administration in ESRD patients undergoing dialysis has also been established. CAPD is very slow to clear gadolinium, with nearly one-third of administered gadolinium remaining after 20 days. However, no adverse events have been observed with the use of 0.1 to 0.3 mmol/kg of gadoliniumbased contrast media. With hemodialysis, gadolinium-based contrast concentrations decline to 97% of initial levels after three dialysis sessions over 6 days. Despite this, no adverse effects were seen in a case series report of 70 hemodialysis patients, even when dialysis was delayed for up to 3 days following contrast administration in 6 of the patients.
As with iodinated contrast media, the ESUR does not recommend any specific timing for performance of hemodialysis following gadolinium administration. However, in selected situations, interpretation of gadolinium- enhanced images can be misleading in CRRT patients. For example, in two hemodialysis patients, retention of gadolinium was associated with its excretion into the cerebrospinal fluid, resulting in artifactual subarachnoid enhancement.
• ESRD Impact on Cancer Prognosis—The validity of conventional prognostic factors and outcome data for specific cancers in ESRD patients on CRRT is uncertain because of the absence of clinical trials in this population. Therefore, treatment recommendations are subject to clinical judgment and extrapolation from cancer clinical trials in patients with adequate renal function. We suggest that the prognosis from ESRD and the specific cancer condition should be judged independent of the other condition, and that known, powerful, and consistent prognostic factors are assumed to be generalizable to ESRD patients.