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David I. Quinn, Kenneth J. Norris Jr Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Ave Suite 7408 Los Angeles CA 90033, USA. e-mail: email@example.com
Recent advances in the systemic therapy of RCC have delivered three new drugs for treating this disease. Despite this, patients with RCC have many symptomatic issues that need to be managed to maximize their quality of life (QoL). These include anorexia–cachexia syndrome, hypercalcaemia, pain, venous thromboembolism (VTE) and site-specific symptoms. As newer targeted therapies make RCC a more chronic disease, symptomatic management challenges related to chronic side-effects are becoming more common.
GENERALIZED SYMPTOMS WITH A PARANEOPLASTIC BASIS: ANOREXIA, CACHEXIA, LETHARGY, ANAEMIA AND HYPERCALCAEMIA
Cachexia, often intertwined with anorexia and lethargy in what some clinicians call ‘anorexia–cachexia syndrome’, is a common problem for patients with RCC. Other features can include symptoms such as fever, night sweats and dysgeusia (altered taste and foul-smelling breath). RCC models suggest that cancer cachexia occurs through several mechanisms, including elucidation of prostaglandins, parathyroid-related peptide (PTHrp), interleukin (IL)-6, and IL-1, and TNF, as well as poorly understood nutrient diversion [1–3]. With the notable exception of increased serum IL-6, studies in human subjects with RCC have not definitely shown the definitive involvement of these factors with anorexia–cachexia syndrome . In addition to potentially mediating symptoms in patients with RCC, these factors have also been associated with resistance to therapy, including cytokine therapy . Small molecules or antibodies for each of these factors are currently under development in clinical trials for kidney cancer . However, at present, specific targeted therapy for cachexia is not available. Several drugs with more general metabolic effects are available and potentially useful. Progestins were long thought to have antitumour activity in kidney cancer but have since been shown to lack significant effects on progression or overall survival. The commonly used progestins, medroxyprogesterone acetate and megestrol acetate, have shown benefit in decreasing loss of lean body mass and improving appetite in patients with advanced human immune virus infection [7,8]. In RCC, and many other cancers, progestins improve appetite and reduce or reverse cancer cachexia in some patients. Some patients benefit from a subsequent dose-escalation. Recent meta-analyses of studies using megestrol acetate in cancer showed an improvement in appetite and body weight [9,10]. The optimum dose of megestrol acetate varies among patients, but a starting dose of 160 mg/day is well tolerated and increases or stabilizes weight over the subsequent 2 weeks [11,12]. Corticosteroids are used in managing cachexia in a proportion of patients, as well as being useful for treating anorexia, lethargy, spinal cord compression and pain from bone and liver metastases, in part through decreasing the amount of oedema present in and around tumour deposits. When studied in a formal phase III setting, dexamethasone 0.75 mg/day was equivalent in improving or maintaining weight gain and appetite to megestrol acetate 800 mg/day in patients with cancer-related anorexia–cachexia syndrome . However, the two medications result in different side-effect profiles, which generally favour megestrol acetate except for the increased incidence of deep vein thrombosis (5% for megestrol vs 1% for dexamethasone) .
Anaemia is a classic presenting symptom of RCC . On occasion, RCC can also produce polycythaemia through erythropoietin production, which might be mediated through certain point mutations in the von Hippel-Lindau gene and loss of the feedback-loop effect in the erythropoietin pathway [15–18]. Anaemia can occur for various reasons in RCC and it is important to clinically evaluate the patient for signs of haematuria or alternative sites of bleeding, as well as potential iron, vitamin B12 or folate deficiency, before assuming they have paraneoplastic anaemia of malignancy. Similarly, not all lethargy is due to anaemia. A clinical evaluation for the contribution of side-effects from therapy, renal impairment and/or infection is important. The underlying cause of anaemia in patients with malignancy is complex, but in those with RCC it might relate to tumour production of IL-6 , once again suggesting it might be fruitful to target this and other similar molecules as part of the supportive therapy of patients with RCC. Anaemia of malignancy responds to erythropoietin in appropriately selected patients with an increase of 1–2 g/dL in haemoglobin over 6–12 weeks. Patients with a need for more rapid increase in haemoglobin need to consider red-cell transfusion.
Hypercalcaemia can produce symptoms of confusion, constipation, somnolence and dehydration. Paraneoplastic production of PTHrp is the major underlying mechanism for hypercalcaemia in RCC, although some hypercalcaemic patients might have underlying osteolytic or prostaglandin-mediated increases in serum calcium [20–22]. The precise mechanisms by which PTHrp overproduction occurs in RCC are being elucidated, but patients with hypercalcaemia most likely have a distinct molecular signature that might include K-ras overexpression, among other molecular aberrations . The incidence of hypercalcaemia in patients with RCC increases with stage . The required treatment involves adequate hydration, either orally or i.v., and institution of therapy with i.v. bisphosphonates such as pamidronate or zoledronate. Adding cortociosteroids or routine diuretics to treatment regimens incorporating hydration and i.v. bisphosphonates has not been established, although some patients will require diuresis if they develop clinical volume overload. Oral agents such etodronate and aledronate are less potent, and are associated with symptomatic dyspepsia and reflux symptoms, potentially resulting in diminished compliance. Alternative agents such s.c. calcitonin and mithramycin are limited by difficulties in administration and side-effects, e.g. several daily s.c. injections for calcitonin and prolonged myelosuppression from mithramycin.
The management of cancer-related pain is of paramount importance in patients with RCC ; 90% of patients with advanced disease have at least daily pain . The WHO scale for weak, moderate and strong pain, and the corresponding use of simple analgesics, weak and strong opioids, respectively, are summarized in Fig. 1[27,28–34]. The use of this scale is standard practice in patients with somatic pain patterns in RCC that often involve bone, hepatic and s.c. metastases or neural-impingement syndromes. Various scales are available to quantify pain and measure therapeutic effect. The most common of these is an 11-point scale (from 0 to 10, where 0 is no pain and 10 is severe pain) . Sequential reporting by a patient using this or other validated scales allows comparison with previous reports of pain state in that patient, but does not permit comparison with other patients. Pain reporting is now recognized as being so important that it is referred to as ‘the fourth vital sign; after pulse rate, blood pressure and temperature. Generally, the recording of the pain scale should be routinely reviewed on inpatient rounds and at outpatient consultations.
Some patients can control their pain with ‘as needed’ simple or compound analgesics, but as the pain reaches a moderate level patients will have an increase in medication requirement, with frequent pain in the nocturnal hours between doses, and then during the day, with deterioration in QoL (Fig. 2) [26,36,37]. This situation suggests that providing a relatively constant level of opioid analgesic in the blood is optimal, by contrast with fluctuating levels seen with ‘as needed’ dosing in response to the development of pain. This proactive use of longer-acting opioids results in better pain control and has less potential to produce habituation, even in an acute or peri-operative setting. Generally, longer-acting opioid therapy is achieved through regular dosing of oral extended-release formulations of morphine or oxycodone, or transdermal therapy with fentanyl or similar short-acting opioid, that is consistently released into the blood from a topical cutaneous patch [25,38–40]. The therapeutic principal proposes that the level of opioid achieved in the patients’ blood should exceed the level of pain during most times of the day. If pain occurs or reaches a threshold as a ‘breakthrough’, needing further intervention, then a ‘breakthrough dose’ of a short-acting agent should be administered [41–43]. If patients have breakthrough pain more than three times per day after the longer-acting medication has reached steady state, then consideration should be given to increasing the dose of longer-acting opioid. Pain with autonomic dysfunction or associated with nerve involvement or vascular occlusion is usually classified as visceral or neuropathic pain, which might not respond optimally to opioid therapy [44–47]. In these situations adjunctive therapy with other agents such as anticonvulsants or antidepressants might provide symptomatic benefit [48,49].
Managing the side-effects of opioid medications is extremely important. Most common side-effects, e.g. sedation, mental clouding and nausea, improve over several days after introducing or increasing the dose of medication. Importantly, constipation does not improve with time on opioids or after an increase in dosage, and needs to be treated proactively with stool softeners, such as docusate, to agents inducing peristalsis, e.g. senna or magnesium aperients. Some patients are truly intolerant of opioids and in this situation the use of tramadol, a µ-opioid receptor agonist with a good side-effect spectrum, might be useful [50,51]. Unfortunately, tramadol has a ‘ceiling effect’ with no improvement in analgesia at higher dosage.
While opioids form the basis for the treatment of most RCC-related pain, significant benefit can be gained by adding therapies to opioids in selected cases. For example, adding NSAIDs, acetaminophen (paracetamol), antidepressants or gabapentin can reduce the opioid dose requirements for patients with pain unresponsive to standard analgesics, while the use of acupuncture or acupressure techniques can improve pain and other symptoms in 25–50% of patients [49,52,53]. Similarly, in selected cases, patients might benefit from topical therapy in the form of local anaesthetic patches  or specific nerve block .
VTE is a common complication of cancer. On occasions, the signs and symptoms can be subtle or not specific, with incidental detection on re-staging scans . In the case of RCC, a diagnosis of VTE can precede diagnosis of the cancer by several months . Recent studies showed that patients treated with low molecular weight heparin rather than warfarin have a lower incidence of recurrent blood clots, with a survival advantage in some subgroups . The issues pertaining to cancer-related VTE have been extensively reviewed [58,59]. Continuing to treat patients who are in the agonal phase of RCC, using anticoagulant therapy, is a difficult topic, where the clinician and patient need to weigh the contribution of therapy to symptom management.
SITE-SPECIFIC MANAGEMENT CHALLENGES AND STRATEGIES
BONE METASTASES AND BONE PAIN
The involvement of bone and bone marrow might be subclinical in a significant proportion of patients with no other evidence of metastatic disease. On this basis, therapies directed at this milieu can show benefit earlier in the disease process than currently appreciated [60,61]. Patients with bone metastases, particularly in the context of metastases to multiple osseous sites, have a poorer prognosis than patients that do not [62–64]. Bone metastases from RCC are classically lytic with a higher risk of fracture than with metastases from other cancers. They tend to have an alarming tendency to be variably detected by conventional bone and fluoro-deoxyglucose positron emission scans [65,66]. In addition, the exophytic growth of a soft-tissue mass into surrounding soft tissue is quite common. Sarcomatoid renal cancer has a propensity to produce more frequent osseous metastases, including lesions with variable sclerosis, as well as rib metastases with a soft-tissue component across several ribs in a ‘rack of lamb’ pattern [67,68]. Patients with good performance status, as measured by Eastern Cooperative Group system, of ‘zero’ rarely have bone metastases at presentation, while those with higher performance status scores often have bone pain and a solitary metastasis . The presence of bone metastases at presentation is strongly associated with poorer performance status . Serum total alkaline phosphatase and other serum markers of bone turnover are poor predictors of the presence of bone metastases .
SURGERY AND RADIATION THERAPY (RT) FOR BONE METASTASES
There are now several lines of evidence that suggest that traditional internal-rod fixation and standard external beam RT has a limited duration of efficacy in bone metastases from RCC, despite producing good acute palliation . For patients with solitary metastases or in selected patients with a dominant lytic metastasis, our practice has developed and we attempt total excision with an endoprosthesis to maximize local control and function [71,72]. Based on practice initially piloted in patients with sarcoma, control of the lesion can be augmented by several interventions, including embolization or cryoablation , but there are few studies as yet that have analysed this systematically. Results at other centres suggest that even excision of chest-wall metastases can have palliative and local disease control benefits in RCC .
Spinal metastases and cord compression require special attention. Previous experience suggests that patients with solitary spinal metastasis could fare well after primary surgery directed at decompression and excision, where permissible . Subsequently, a randomized phase III study in patients with a favourable performance status and clinical or radiological evidence of spinal cord compression from various primary neoplasms showed that surgical cord decompression before RT produces a better functional (walking) outcome, with reduced pain, than RT alone . In patients with a poor performance status or who have multiple metastases, external beam RT remains the standard of care. For patients with vertebral body metastases, the use of various techniques might improve control of disease or provide significant palliation, and contribute to the maintenance of function, including focused high-dose RT (γ-knife, cyberknife, or proton-beam radiation), embolization and percutaneous vertebroplasty [77,78].
BISPHOSPHONATES AND SYSTEMIC THERAPY
A proportion of patients with bone metastases respond to cytokine therapy, i.e. high-dose IL-2, as well as newer targeted therapies such as sorafenib, sunitinib, and temsirolimus. The response has been favourable, with a reduction in pain, shrinkage of soft-tissue components and improvements in the bone scan. However, the optimum choice of anticancer therapy for patients with bone metastases from RCC has not been defined. Bisphosphonates, principally in the form of zoledronic acid (ZA), inhibit osteoclast activity and reduce cancer cell adhesion to bone matrix. In a study comparing ZA at a dose of 4 mg i.v. every 4 weeks, vs placebo, in patients with RCC, ZA reduced the incidence of skeletal-related events (defined as pathological fracture, spinal cord compression, RT, or surgery to bone) by 61%[79,80]. This led to the approval of ZA for treating bone metastases from various solid-tumour cancers by the USA Food and Drug Administration [81,82]. Importantly, ZA has not shown a direct clinical effect on tumour cells, and therefore should be considered an adjunctive therapy to agents specifically directed at the cancer itself. In addition, ZA therapy does not tend to produce a measurable, radiological, or clinical response that suggests successful therapy, and therefore tends to be prophylactic. With the longer survival of patients with RCC on tyrosine kinase inhibitor (TKI) therapy, issues of toxicity are important. The development of osteonecrosis of the jaw bones is now an uncommon but well described complication of longer term ZA therapy . An additional concern is the effect of combined ZA and TKIs in inducing low serum phosphate levels [84,85].
The therapy of brain metastases has changed in recent years. All patients with brain metastases are not equal with respect to prognosis. In considering therapeutic options for these patients, characteristics in two compartments on either side of the parenthetical blood-brain barrier (BBB) require assessment. In assessing the intracranial compartment, patients with left-sided, temporal lobe, or multiple symptomatic brain metastases, as well as those with brain metastases detected soon after first diagnosis, have a poorer prognosis [86–88]. In assessing the extracranial compartment, standard prognostic factors, as incorporated into the Motzer criteria, including multiple visceral sites of metastases, predict functional longevity and mortality [86,89]. Solitary or oligo-metastatic disease in a patient with good performance status is normally aggressively treated with surgical excision and adjunctive focused high-energy RT. Patients who have had a complete response to high-dose IL-2 therapy subsequently presenting with a solitary brain metastasis have very good long-term outcome after aggressive therapy for their CNS metastasis . The approach to patients with multiple (more than three) brain metastases is to use whole-brain RT given as 10 fractions of 3 Gy. Patients who progress after whole-brain RT might benefit from subsequent focal high-dose RT, provided they had an a progression-free interval of >3 months after whole-brain RT .
Reduced cerebral tumour volume in patients treated with sorafenib or sunitinib, even those who are deemed radiation-resistant, has been described at several centres. Recent hypothesis-generating data from the TARGETs trial, where patients were given sorafenib or placebo for metastatic RCC, suggests that sorafenib might delay or even prevent the onset of symptomatic brain metastases. These observations suggest that sorafenib and sunitinib cross the BBB to a degree sufficient to produce a tumour response in some patients with brain metastases, and that these drugs might contribute to disease control in both extracranial and intracranial compartments. The appropriate context and feasibility of combination RT and/or surgery with newer targeted agents in patients with CNS metastases has not been established.
The major therapeutic principle in managing brain metastases in patients with RCC is that cancer control on both sides of the BBB is essential. Adverse prognostic factors within either compartment should give rise to therapeutic caution because of the very real possibility of response in only one compartment with progression in the other, leading to the early death of the patient and wasted treatment, with accrual of side-effects contributing to a poorer overall QoL. On a positive note, this area is ripe for investigative strategies and should bear more interesting data in the not too distant future.
Patients with RCC have two types of problems from pulmonary metastases. They might have airway obstruction, often coupled with bleeding. Alternatively or concurrently, patients might have dyspnoea related to parenchymal metastatic volume and secondary ventilation/perfusion mismatch. In some patients, these might constitute agonal events, but control of these symptoms can result in a meaningful QoL for a significant proportion of patients.
For patients with obstruction with or without bleeding, intraluminal bronchial laser therapy with or without stenting can produce rapid relief, provided there are only a few lesions and that they are proximally located. Selected patients might benefit from alternative methods via bronchoscopy that might limit bleeding, e.g. RT via brachytherapy, diathermy, radiofrequency ablation or cryotherapy . Patients need to be selected well, given the potential for acute fistula formation to mediastinal vessels and other structures. High-dose, low-fraction external beam RT might also have a role in patients with proximal obstruction or bleeding.
Individuals with large-volume parenchymal disease that is resistant to systemic therapy are a major management challenge, particularly as many will have their lungs as the only or predominant site of disease. In this context, local measures of control can help to stabilize their disease and/or their symptoms. Recent data suggest that inhalational IL-2 can produce significant shrinkage of lung lesions in some patients, and stability for more, with relief of dyspnoea [93–95]. The median time to progression in one phase II trial was 8.7 months . There can be a mild to moderate reduction of the vital capacity and forced expiratory volume, with minor effects on relative forced expiratory volume, peak expiratory flow, airway resistance, and PaO2 in individual patients. There appear to be limited systemic side-effects associated with this therapy, although some patients complain of lethargy . Serial broncho-alveolar lavage data show that therapy induces lymphocyte activation. Whether inhaled therapy adds to systemic therapy is unclear , but this route of therapy remains a palliative option for patients with lung metastases [97,98].
This group of patients is also troubled by terminal dyspnoea, the management of which is optimal with systemic opioids, best administered orally or transdermally. The effect is dissimilar to patients with pulmonary oedema treated with opioid medication. An escalation of dose will result in the patients’ sensation of dyspnoea being minimized until pulmonary failure from hypercapnia and/or hypoxia supervenes as the patient becomes comatose. On occasion, adding a bronchodilator such as albuterol or salmeterol can help, if bronchospasm is detected on lung auscultation. In addition, the use of anticholinergic therapy such as hyosine can help to dry excess bronchial secretions. Finally, nebulized opioids or inhaled nitrous oxide can be useful in managing dyspnoea where the patient might have acute fluctuation in symptoms or be unable to take oral medication [99,100].
A common question in the management of patients with advanced cancer relates to the value of immunisation against influenza and Streptococcus. Clearly, patients with advanced malignancy fall into the high-risk group for these infections, and given the developing chronic nature of the condition of many patients with RCC, this issue has become more important. There are several areas where the evidence-base helps on this question. Patients with metastatic cancer who are not on cytotoxic chemotherapy have about the same seroconversion rates to specific influenza and streptococcal antigens as the general population . In addition, immunisation reduces the incidence of influenza and pneumonia diagnoses, with a trend to improved survival . Patients receiving cytotoxic chemotherapy have significantly lower rates of seroconversion , although this appears to vary, based on the cancer diagnosis and chemotherapy given [103,104]. In patients receiving chemotherapy, the optimum time for immunisation appears to be before starting therapy, or ≥ 30 days after it . The applicability of this information to contemporary practice in RCC is questionable, as most patients will be treated long-term with a multi-targeted TKI or mTOR inhibitor, rather than cytotoxic chemotherapy. TKIs reduce circulating T regulatory cells and probably have other effects on the immune system, but do not appear to reduce the seroconversion of patients exposed to antigens. In contradistinction, patients on mTOR inhibitors, many of which are related to drugs used for immunosuppression in the transplant setting, might have distinct inhibition of T cell function and not be as responsive to vaccine . Currently it seems reasonable and safe practice to immunise appropriate patients on TKI therapy, while further study is needed to evaluate the value and effect of this in patients on mTOR inhibitors.
The therapy for RCC has developed significantly in recent years. Despite this, there is a need to control a variety of key symptoms to optimize the QoL of these patients. Newer technologies and drugs targeted specifically at molecules that mediate adverse effects of cancer will provide a series of future opportunities to improve patients’ well being, even in the absence of a cure.