Abstract
Introduction
Pancreatic cancer is often diagnosed at late stages, where disease is either locally advanced unresectable or metastatic. Despite advances, long-term survival is relatively non-existent.
Discussion
This review article discusses clinical factors commonly encountered in practice that should be incorporated into the decision-making process to optimize patient outcomes, including performance status, nutrition and cachexia, pain, psychological distress, medical comorbidities, advanced age, and treatment selection.
Conclusion
Identification and optimization of these clinical factors could make a meaningful impact on the patient’s quality of life.
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Introduction
Despite being the 12th most common malignancy in the USA, pancreatic cancer (PCa) is the third leading cause of cancer death and is projected to be the second by 2030 [1, 2]. This is in part due to the fact that a majority of PCa is diagnosed at a late stage, when symptoms develop prompting further workup [3]. Despite advances in medical knowledge and drug development, the only cure for PCa relies upon surgical resection. Unfortunately, only 15–20% of patients are surgical candidates at presentation and thus the majority of patients have locally advanced unresectable or metastatic disease. Prognosis for patients with metastatic disease is extremely poor if left untreated (median survival of 3–6 months) [4]. The effectiveness of chemotherapy in the metastatic setting has historically been modest at best. Recently, multi-agent cytotoxic chemotherapy has showed incremental improvements in survival (Table 1). Despite these improvements, the long-term survival with this disease is relatively non-existent, with 5-year survival of 8.2% [5]. Given that treatment for metastatic disease is palliative in nature, physicians must balance the goals of extending life with that of optimizing the patient’s quality of life.
The era of personalized medicine in oncology has arrived with treatment selection aimed at vulnerabilities within the cancer’s biology. However, here, we will consider clinical factors commonly encountered in clinical practice that must be equally incorporated into this decision-making process to optimize patient outcomes. Thus, a comprehensive assessment of the patient and the cancer should be taken into consideration when developing a potential treatment plan. In this paper, we discuss various patient factors which should be identified and corrected, when possible, to increase success in optimizing therapy goals.
Methods
This systematic literature review adhered to the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two databases (MedLine from 1946 and Embase from 1949) were searched to October 2017. The search terms included “pancreatic cancer” AND (“performance status” OR “nutrition” OR “cachexia” OR “pain” OR “depression”), and a total of 2693 studies were found on MedLine and Embase, with 84 additional records identified through manual search of references. Two thousand and seven hundred fifty-one articles were reviewed after duplicates were removed. After assessing articles for eligibility based on aim and scope of the manuscript as well as article subject matter, 99 studies were included in this review.
Performance Status
One of the most important prognostic variables for patients with stage IV disease is their performance status (PS). The two major scales used in clinical practice include the Eastern Cooperative Oncology Group (ECOG) and Karnofsky scales. The ECOG score is based on a scale of 0–5 (Table 2), where a score of 0 indicates that the patient has no physical limitations, and a score of 4 indicates that the patient is completely disabled and is bed-bound [6]. The Karnofsky PS scale measures similar functional capacity, but is based on a scale of 0–100, with a higher score indicating better performance status (Table 2) [7]. For both scales, values between the two extremes represent progressive decline in the ability to perform activities of daily living, provide independent self-care and reduced physical activity.
Patients with advanced PCa and satisfactory PS have superior outcomes as compared to those with poor PS. That statement is intuitive in that patients with adequate functional status and overall conditioning are able to receive and tolerate therapies known to confer survival [8,9,10]. Further, the performance status is indicative of the patient’s nutritional status (discussed below) which is of utmost importance in the management of pancreatic cancer patients. Additionally, access to clinical trials with additional potential treatment benefits are available only to those with adequate PS. Thus, a good PS is a surrogate for physiologic reserve and allows access to standard and novel therapies.
When reviewing currently approved palliative treatments for patients with advanced PCa, it is important to recognize the role of PS in the studies that led to regimens becoming the standard of care. Based on the published study eligibility, only patients with good performance status (ECOG 0 or 1) were eligible to receive FOLFIRINOX [8] or gemcitabine and nanoparticle-bound paclitaxel (defined as a Karnofsky of 70 or higher) [11]. However, for patients with less robust PS, other FDA-approved palliative treatments include gemcitabine alone (Karnofsky of 50 or higher) [12], gemcitabine and erlotinib (ECOG of 0–2) [13], and gemcitabine and capecitabine (ECOG 0–2) [14]. Unfortunately, these latter therapies offer a marginal survival benefit at best.
Thus, prior to a discussion of treatment options, oncologists must take into account the patient’s ECOG and/or Karnofsky PS. However, the use of either of these scales alone is not sufficient to truly make individualized treatment decisions. Other clinical factors that need to be considered when assessing a patient is their age, concurrent medical conditions, cognitive function, psychological condition, nutritional status, pain level, medications (including polypharmacy), and social support system. Some of these factors can certainly contribute to a patient’s PS. Upon addressing these clinical factors, the PS could improve significantly.
Nutrition and Cachexia
An assessment of the patient’s body mass index (BMI) and nutritional status should be addressed as part of initial treatment planning. Loss of appetite is one of the most common symptoms in patients with incurable cancer [15] and is particularly noteworthy in advanced PCa. Patients with weight loss prior to chemotherapy have been found to have decreased median survival [16, 17] along with a possible decrease in chemotherapy response rates [16]. Patients with advanced PCa commonly have impairment of their digestive tract function. The proximity of the pancreas to the duodenum and celiac nerve plexus can result in gastroparesis and/or gastric outlet obstruction. Additionally, many patients develop exocrine pancreatic insufficiency. Collectively, this can lead to the classic picture of anorexia and cachexia seen with PCa [18, 19].
Mechanical obstruction in the form of duodenal compression occurs in 15–20% of patients with PCa [20], resulting in nausea, vomiting, early satiety, and weight loss. Potential therapies include surgical bypass (i.e., a gastrojejunostomy) or a duodenal stent. While stent placement has been shown to have superior initial relief of symptoms, gastrojejunostomy offers better long-term symptom control [21]. An assessment of disease burden, life expectancy, PS, and patient symptoms should guide which approach is preferable for the patient.
Even in patients without direct tumor invasion, pancreatic cancer has been associated with high rates of gastroparesis [22]. The etiology is thought to be multifactorial, including involvement of celiac nerve plexus, and less often paraneoplastic production of antibodies and neurotransmitters [23]. This is manifested as anorexia, early satiety, nausea, or vomiting, and can be diagnosed via gastric emptying scintigraphy. The treatment approach includes a combination of dietary modification (small, low-fat meals), antiemetics, and prokinetic medications (i.e., metoclopramide and erythromycin). In patients with refractory gastroparesis, decompression with a gastrostomy tube has been shown to provide symptom relief [24]. Another option includes a combined gastrostomy/jejunostomy (GJ) tube in which the jejunostomy can allow for post-pyloric feeding, and the gastrostomy can be used to manage nausea by acting as a valve to relieve gastric distension.
Patients with PCa often experience loss of pancreatic parenchyma and/or obstruction of the pancreatic duct resulting in pancreatic enzyme insufficiency, manifested by postprandial bloating, flatulence, steatorrhea, and subsequent weight loss. This is common in patients with advanced PCa, and although its impact on weight loss is unclear [25], enzyme replacement therapy can improve symptoms and nutritional status in this population [26]. However, pancreatic enzyme replacement therapy is significantly underprescribed compared to the incidence of patients with metastatic PCa [27], as well as low rates of nutritional interventions as a whole [28]. There are multiple FDA-approved pancreatic enzyme replacement therapies available, all formulations of pancrelipase, differing based on their relative concentrations of amylase, lipase, and protease units [29], including Creon, Zenpep, Pancreaze, Ultresa, Pertzye, and Viokace. These are all enteric-coated with the exception of Viokace, which is used in conjunction with a PPI to prevent immediate degradation. Dosing is based on lipase units with respect to body weight per meal [30]. It is also important for the patient to properly time the administration of the enzymes with food intake, as they are active between 30 min and 2 h after ingestion [31].
Many patients with PCa experience cachexia, characterized by excessive weight loss and marked muscle mass decrease. This can occur even in the absence of the aforementioned mechanical and digestive abnormalities, and can affect both PS as well as hospitalizations of the patient [32]. The exact mechanism driving the catabolic process resulting in loss of skeletal muscle (referred to as sarcopenia) is unknown, but multiple potential mechanisms have been proposed. The most likely explanation involves cytokines increasing the basal metabolic rate and inducing anorexia. These include tumor necrosis factor-alpha (TNF-alpha), ciliary neurotrophic factor (CNF), interleukin-1 beta, interleukin-6, and interleukin-8 [18, 31]. These cytokines cause increased satiety via a combination of downregulation of ghrelin release [33] and decrease in neuropeptide Y expression and activity [34, 35]. It has been shown that patients with pancreatic [36], prostate [37], and non-small cell lung cancer [38] who have developed cachexia have increased plasma concentrations of these aforementioned cytokines. Other etiologies include lipolysis with lipid mobilizing factor [39], the activation of the ATP-ubiquitin-proteasome pathway [40, 41], and/or increase in proteolysis-inducing factor [42].
A potential avenue for improving patient outcomes in PCa involves reversing or halting cachexia [43]. Appetite stimulating agents such as corticosteroids [44, 45] or progesterone analogs (i.e., megestrol) [46] have been shown to stimulate appetite and increase weight gain. This, in turn, can potentially improve the patient’s PS. However, these benefits are typically transient and can be associated with fluid retention, hypercoagulability, and insomnia. Nutritional interventions including omega-3 fatty acids, L-carnitine, amino acids, vitamins, and other minerals have not shown consistent significant data and require further research [47,48,49], although the effect of a ketogenic diet on metabolic reprogramming is a potential avenue for diminishing cachexia [50]. A more promising area is that of targeted therapy for the systemic inflammation responsible for cachexia. Initial efforts to impact the cachexia cascade by targeting the inflammatory JAK-STAT pathway have not proven clinically effective [51]. However, several agents and pathways are being actively explored in clinical trials, such as eicosapentaenoic acid [52], insulin [53], and anamorelin [54] with the hope to soon demonstrate a meaningful impact on this important aspect of supportive oncology.
Pain
Pain is often the symptom prompting patients to seek medical attention with newly diagnosed PCa [55]. The pain is most commonly a result of celiac neural plexopathy caused by the tumor mass or infiltrating tumor cells. Patients with moderate or severe cancer-related pain are often started on opioids [56,57,58]. For patients with PCa and concomitant gastroparesis (discussed above), opioids can further decrease gut motility. In such cases, a transdermal delivery (i.e., fentanyl patch) may help; however, this is less efficacious in the cachectic PCa patient without sufficient adipose tissue for proper absorption.
Although opioids are the mainstay for treatment of pain related to PCa, alternate analgesic strategies are indicated in this patient population. Based on the proximity of the celiac plexus to the primary pancreatic cancer, targeting this nerve network with local interventions can be accomplished in a variety of manners [59]. These include inhibition of synaptic pathways with a local anesthetic (celiac plexus block), chemical destruction of the ganglia (celiac plexus neurolysis), or soft tissue regression with radiotherapy. Benefit can be immediate with the first two options and can be performed endoscopically or percutaneously. However, without complete destruction, nerve regeneration occurs, and sensation usually returns within 6 months [60]. Celiac plexus neurolysis has been shown to provide superior analgesic relief [61] with fewer side effects compared to opioid therapy [62]. Patients also report a better quality of life and have less opioid consumption with early celiac plexus neurolysis, although transient diarrhea and post-procedural pain are noted in some patients [63], and overall survival is not affected [64].
Palliative radiotherapy to the pancreas is non-invasive and associated with improved pain control [65], and for patients with good PS, chemotherapy can help relieve pain as well [66]. Pain relief is not as rapid as with celiac plexus neurolysis or block, but it has been shown to improve pain, reduce need for analgesics, and improve obstructive symptoms [67, 68].
Psychological Distress
Along with the patient’s medical comorbidities, patients with a new diagnosis of cancer are prone to the development of psychological distress, most frequently manifesting as depression [69]. This is critical to address and treat, as it has the potential to severely affect the patient’s performance status and quality of life. Depression in cancer patients is more commonly seen in younger patients but can also be seen in the older patient population [70, 71]. It should also be noted that depression is seen more in patients with PCa compared with other malignancies [72, 73]. A hypothesis for this increased incidence of depression with this malignancy is potentially due to increased levels of interleukin-6 [74]. Patients with PCa and higher levels of interleukin-6 were shown to have increased severity of depressive symptoms [75]. The kynurenine pathway (involved with degradation of tryptophan to NAD+) is also thought to play a role, with PCa patients with a lower kynurenic acid:tryptophan ratio having worse depressive symptoms on the Beck Depression Inventory (BDI) scale [76]. Depression has been linked to a functional decline in elderly patients with malignancy, and it has been suggested that the prevention of depression could prevent functional decline in this patient population [77]. Depression is also closely linked to a patient’s social support system [78]. A social support system, which can include family, close friends, church/volunteer/other social groups, is important for patients with PCa and has been shown to be associated with improved outcomes [79]. Therefore, it is also of upmost importance prior to the initiation of potential cancer treatments to assess the patient’s psychological status and social support.
The use of antidepressant medications in this patient population should be made on an individual basis with respect to their medical comorbidities and potential side effects [80]. An adequate trial of SSRI therapy is a reasonable consideration for most patients struggling with depressive symptoms, particularly as part of a comprehensive approach to palliation. Non-pharmacologic interventions including psychotherapy have been shown to have a benefit in treating depression in patients with incurable malignancies [81]. Cognitive-behavioral therapy (both with group and individual treatment) has been shown to reduce psychological distress and improves coping [82, 83]. Lastly, participation in support groups (regardless of style) helps patients and family members alike with psychosocial stressors by sharing experiences with others in similar circumstances.
In addition to the obvious benefits in quality of life that can be improved by alleviating psychological distress, there are safety issues to address before considering treatment. Given the importance of timely self-reporting of cancer and treatment-associated side effects [84], the psychological reserve of all patients should be assessed to determine if they can keep appointments, take supportive medications (antiemetics or analgesics), and whether they have the ability and capacity to report symptoms. Of equal importance is determining if they have assistance with transportation, taking medications, procuring and preparing food, managing independent activities of daily living, and end of life transitions including spirituality support. This assessment is particularly true of all patients being considered for clinical trial enrollment.
Advanced Age
While we rarely take age alone into consideration in treatment selection for patients, the median age for those diagnosed with PCa is approximately 70 years old, and two-thirds of new cases are in patients aged 65 and older [5]. In the extremely elderly, careful consideration must be given to the absolute increase in survival with treatment relative to toxicity. Some argue this is true in PCa more so than other cancers, given its poor prognosis and short median survival after diagnosis [4, 85]. In an elderly patient with numerous other medical conditions, treatment of an advanced malignancy may not result in clinical benefit [86].
It is known that medical comorbidities increase with age, and accordingly, many patients with PCa take multiple medications that may contribute to polypharmacy. It has been shown that a higher number of medical comorbidities are associated with increased morbidity in patients with breast [87], colorectal [88], and non-small cell lung cancer [89]. Patients with multiple medical comorbidities who take multiple medications may also experience overlapping side effects with their chronic medications and chemotherapy as well as potential drug-drug interactions. Examples include the interaction of antacids or blood thinners with capecitabine [90] or antiepileptics with multiple chemotherapy regimens [91]. Comorbidities may also have associated organ complications (i.e., diabetic neuropathy or hypertensive chronic renal insufficiency) that impact antineoplastic treatment options. Considerations of dose adjustments, less intensive or alternative therapies may be necessary. It is important to note that age alone should never be considered in making treatment recommendations. Rather, it is advanced age that predisposes patients with PCa to concurrent medical comorbidities that may negatively impact treatment and contribute to worse survival.
After the consideration of the aforementioned issues and discussion with the patient, the decision may be made to pursue supportive care with or without treatment of the cancer. Clinicians and patients alike should be comfortable discussing a purely palliative approach, recognizing it does not represent an “abandonment” of life prolonging treatment or that they are “giving up.” In fact, data supports an improved quality of life, length of life, and overall satisfaction with decisions when palliative care is included with or without traditional cancer therapies [92]. In PCa specifically, a longer mean survival with hospice support compared to no hospice care has been demonstrated [93].
Treatment Selection
The choice of anti-cancer treatment should only be undertaken after all of the above clinical factors have been addressed and optimized. Additional considerations in selecting treatment relates to understanding the biology of the cancer and the potential therapeutic targets. This latter topic is beyond the scope of this review. However, in the absence of a specific molecular target, patients with a good performance status and newly diagnosed unresectable or metastatic PCa should be considered for treatment with either FOLFIRINOX (5-FU, leucovorin, irinotecan, and oxaliplatin) [8] or gemcitabine and nanoparticle-bound (nab) paclitaxel [11]. Many of the clinical factors discussed above will dictate the choice of regimen, particularly PS. For those with a less robust PS or reasons to avoid platinum, taxanes, or campothecans, consideration can be given to gemcitabine and erlotinib [13] or gemcitabine alone [12]. Each of these options is FDA-approved and based on Level 1 evidence of benefit [94] (Table 1). Second-line treatment after disease progression is influenced by which first-line regimen was given. Typically, an alternate set of agents to promote non-cross resistance is recommended. Importantly, close attention to the patient’s PS and other clinical factors discussed in the previous sections is critical prior to second-line therapy. The recent approval of nanoliposomal irinotecan with 5-FU helped establish that a survival advantage can be seen in select patients treated in the second-line setting [95].
Despite decades of attempts to improve PCa patient outcomes, there have been only marginal improvements [96]. Thus, more effective systemic therapies and strong consideration to clinical trial enrollment for any patient with PCa is required. The next generation of clinical trials in metastatic PCa will take into consideration biology of the cancer (particularly DNA damage repair gene mutations), the host immune system and the associated stromal microenvironment. These targeted approaches will move the field forward and offer hope against this devastating disease. Refinement in the selection of rare subsets of patients with molecular profiling will hold a critical key to bringing truly impactful therapies to the precise patient. The hope of precision medicine for a select group of patients is highlighted by the recent breakthrough of programmed-death ligand 1 (PD-1) antibodies (e.g., pembrolizumab) for any tumor with DNA mismatch repair deficiency (dMMR) or is microsatellite instability high (MSI-H) [97,98,99]. Unfortunately, this represents a small percentage (approximately 2–3%) of patients with metastatic PCa, but it is a clear of example of progress.
Conclusion
In patients with metastatic PCa, it is prudent to consider multiple clinical factors in addition to PS, such as age, medical comorbidities, nutritional status, pain, and other aspects of their health when considering potential treatment options. Identification and optimization of these clinical factors could make a meaningful impact on the patient’s quality of life. Further, addressing these factors could also permit for therapies, both standard and investigational, that could potentially prolong survival with this disease. Clinical trial enrollment should be considered for all eligible patients given the critical need for more effective therapies and palliative interventions. Ultimately, the decision of whether to pursue treatment should be based on a comprehensive assessment of the whole patient, not just the cancer.
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Skelton, W.P., Parekh, H., Starr, J. et al. Clinical Factors as a Component of the Personalized Treatment Approach to Advanced Pancreatic Cancer: a Systematic Literature Review. J Gastrointest Canc 49, 1–8 (2018). https://doi.org/10.1007/s12029-017-0021-z
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DOI: https://doi.org/10.1007/s12029-017-0021-z