Clinical Pancreatology for Practising Gastroenterologists and Surgeons - part 9 doc

all will suffer significant pain at some stage before they succumb to the disease (Table 51.1). Pain occurs in at least 85% of patients with advanced disease (Table 51.1) and is related to shortened survival, especially if opioids are being administered (Table 51.2). For some patients with the disease, the pain is so severe that all waking hours are devoted to its control, leading to a very poor quality of life. Empirically it is obvious that patients with pancreatic cancer are one of the cancer groups with the most severe pain problems. Origin of the pain in pancreatic cancer Pancreatic cancer pain can be subdivided into somatic, visceral, and neuropathic in origin. Somatic pain occurs as a result of the activation of nociceptors in cutaneous and deep tissues. Somatic pain is typically con- stant and well localized and is frequently described as aching, throbbing, or gnawing. Both bone metastasis and mucosal injury produce somatic pain. Visceral pain originates from injury to sympathetically innervated organs. Mechanisms of visceral pain include necrosis, ischemia of visceral muscles, serosal or mucosal irrita- tion by analgesic substances, or abnormal distension or contraction of smooth muscle walls within a hollow viscus. The pain is characterized as either dull, deep, and aching or paroxysmal and colicky. Neuropathic pain refers to pain syndromes that occur as a result of nerve injury. Neuropathic pain can occur following surgery or radiation therapy. In addition, certain chemotherapeutic agents (e.g., taxanes, vincristine, vinblastine, cisplatin) can produce neuropathic pain. The pain is characterized by burning, tingling, and numbing sensations. From an anatomic point of view, pancreatic cancer pain may result from intrapancreatic and peripancreatic inflammatory processes, an obstructed main pancreatic duct, as well as perineural invasion of the tumor. It is possible that recurrent ischemia of the parenchyma and intrapancreatic causes such as acute pseudocysts and extrapancreatic causes such as common bile duct or duodenal stenosis cause pain. The relative contribution of inflammation, obstruction, neuritis, and scarring to the pathogenesis of pain is still unclear and may vary from patient to patient. Obstruction of the pancreatic duct system was for a PART III 426 Table 51.1 Sixty-six consecutive patients operated on for pancreatic cancer with pancreatectomy in Lund, Sweden, 1995–98. Pain first symptom 37% Pain at diagnosis 58% Not requiring medicine 37% Requiring nonopioids 16% Requiring opioids 5% Pain requiring analgesics at recurrence 88% Pain requiring analgesics 1 month before death 98% Table 51.2 Prospective registration of pain at diagnosis in 160 consecutive, nonradically operated patients with pancreatic cancer in Scandinavia, 1995–98. Visual analog Patients on morphine Median survival Median survival scale Percent (percent of total) (days) on morphine (days) 0 27 6 280 222 1 14 3 263 171 2 14 2 223 178 32 — 238 — 4 8 2 167 113 5 15 7 138 111 6 10 5 101 62 75 — 97 — 85 — 63 — 9 —— — — 10 —— — — long time seen as the major factor in the pathogenesis of chronic pancreatitis and has also been proposed as a cause of pain in pancreatic cancer. However, the relationship between morphologic changes, ductal pres- sures, and pain has repeatedly been shown to be very variable, and other factors must be implicated. An increased intracystic pressure may be assumed when a pseudocyst communicates with a stenotic duct. On the other hand, the same anatomic abnormalities sometimes relate to a painless course. Although data indicate that increased intraductal or parenchymal pressure is associated with pain in pancreatic cancer, the pathomechanism by which increased pressure causes pain is not clear. A more recent pain concept in pancreatic cancer regards direct alterations of pancreatic nerves as one of the major pathophysiologic events in pain generation. It has been reported that phenotypic modification of primary sensory neurons may play a role in the pro- duction of persistent pain. Autodigestion with tissue necrosis and both pancreatic and peripancreatic inflammation in the earlier stages change the focal release and uptake of mediators in peptidergic nerves and could be an important cause of pain. Pancreatic nerves are preferentially retained while exocrine pancreatic parenchyma atrophies and degenerates and is replaced by fibrosis. Moreover, in pancreatic cancer, compared with normal pancreas, the number and diameter of pancreatic nerves are significantly increased and analysis of neuroplasticity markers provides evidence that the nerves actively grow. This leads to differential expression of neuropeptides, such as substance P and vasoactive intestinal peptide (VIP), in the chronically irritated pancreas. In addition, electron microscopic examination has revealed that the perineurium of theses nerves is partially destroyed, indicating loss of the barrier between nerve fibers and bioactive material in the perineural space. Bockman et al. have put forward a concept they call “pancreatitis-associated neuritis,” which implies a comparative increase in the number of sensory nerves in inflammatory pancreatic tissue together with round cell infiltration and a strik- ing disintegration of the perineurium. The loss of function of the perineural barrier may allow an influx of inflammatory mediators or active pancreatic enzymes that could act directly on the nerve cells. It can be speculated that these two mechanisms, increased pancreatic tissue pressure and neuritis, could work together. High tissue fluid pressure would then facilitate influx of pain mediators into the nerves and result in more long- standing pain. There is also evidence that pancreatic ischemia may occur in an experimental model of chronic pancreatitis, and possibly pancreatic cancer, leading to decreased pancreatic blood flow, ischemia, and local depression of parenchymal pH. During ischemia xanthine oxidase becomes activated, which leads to the generation of toxic oxygen metabolites that may contribute to pain in chronic pancreatitis. However, the xanthine oxidase inhibitor allopurinol did not reduce pain in a randomized, two-period, crossover clinical trial. Characteristics of pancreatic cancer pain The characteristic pattern of pain in pancreatic cancer is that of a dull ache in the mid-epigastrium that radi- ates to the back, especially if the body and tail of the pancreas are involved. Pain is usually accentuated at night and may be spasmodic. This symptom is not something usually associated with a visceral solid carcinoma. The pain is typically more severe in the supine position and improves when the patient leans forward. The pain progresses over time and never leaves the patient totally, usually not even with treatment. Com- pared with the pain of chronic pancreatitis, which may have the same distribution, there is less fluctuation in intensity from day to day and there is less influence of eating and drinking. When the cause of the pain is explained to the patient, there is also another obvious difference between patients with pancreatic cancer and those with chronic pancreatitis. The first group is usually very reluctant to take analgesics for the pain, whereas the second group usually needs no persuasion to take drugs but rather has a tendency to use excessively strong analgesics from the start. This is very rarely a problem with pancreatic cancer patients. Sometimes, patients with pancreatic cancer initially describe the pain as a tiredness in the back, making it impossible to work and relax. Later on, they find it difficult to sit and stand without having severe fatigue of the mid-back, which is then impossible to differentiate from pain. At this stage the patients are often restless and seem to continuously move in their search for a position that relieves the fatigue and pain. In later stages, patients tend to lie on the bed and to move as little as possible, which further CHAPTER 51 427 decreases their muscle strength, making movements more difficult. An algorithm for pain management in pancreatic cancer There are several algorithms for the management of pain in pancreatic cancer, most of them with unique positive aspects. However, and unfortunately, most of them focus only on pharmacologic treatment. The most important part of the WHO “analgesic ladder,” and the reason for its success, is probably the efficient use of oral opioids for moderate to severe pain, while making it clear that this treatment is very effective and that dependence problems are negligible. However, this does not mean that alternative analgesics should not be used. For example, acetaminophen (paracetamol) is a potent and cheap analgesic with very few adverse effects and has a central effect like morphine but without the latter’s drug-abuse problems. An algorithm is presented here in which pharmacologic treatment is but one part of the management of pain in pancreatic cancer. It can be used in association with literature more concerned with the details of drugs and how to use them optimally (Fig. 51.1). Is the diagnosis of pancreatic cancer correct? When a patient with pancreatic pain for the first time needs treatment, it is obligatory to critically review the evidence for the diagnosis: does this patient really have pancreatic cancer? In the past, patients have all too often been given the diagnosis of pancreatic cancer when follow-up has shown that the true disease has been, for example chronic pancreatitis. This may be a grave misdiagnosis, as the cancer patient can be expected to have increasing pain and there is little purpose in limiting analgesic use unless the patient is pain-free, whereas patients with chronic pancreatitis may respond better to alternative therapies. Also, patients with other types of cancer might benefit from other types of treatment. An example of this is endocrine pancreatic cancer, for which there is an arse- nal of treatment options, analgesics being only one but probably not the first choice. There are also lymphomas and sarcomas and other rare tumors of the pancreas where good alternative treatment options are available. Once again, if the pancreatic cancer can be resected, this is almost always the best choice. Is the pain due to the cancer or to concomitant diseases? It should be emphasized that not all the symptoms in patients with pancreatic cancer are due to the cancer. Especially common are gallstone disease and peptic ulcers in the stomach and duodenum. Ileus and subileus due to causes other than pancreatic cancer (or peri- toneal carcinomatosis) are found occasionally. If in these cases the pain is treated strictly according to the WHO cancer analgesic ladder, there is a severe risk that the patient will be harmed, and indeed may not be well treated regarding the pain. If possible it is always better to treat the cause of the pain rather than the symptom of pain itself. PART III 428 Is the diagnosis of pancreatic cancer correct? Is the pain due to the cancer? Is the pain due to concomitant diseases? Are other symptoms of the cancer well treated? How severe is the pain? How does the pain influence the patient? What does the patient want? Step I: acetaminophen Step II: combined analgesics Step III: morphine Interventional therapy Figure 51.1 Algorithm for management of pancreatic cancer pain. Are other symptoms of the cancer well treated? There are many symptoms of pancreatic cancer that influence the experience of pain. For example, tired patients have more pain; depressed patients cannot participate in treatments as well as they should; patients with great weight loss experience more pain; ascites, constipation, and pneumonia may generate pain themselves. Moreover, some pharmacologic agents may produce discomfort or pain, for example opioid-induced constipation and nonsteroidal antiinflammatory drug (NSAID)-induced peptic ulcer. Therefore, it is important to understand that the pain must be treated as part of a symptom complex rather than the symptom. Patients themselves frequently re- mark on this: “Doctor, if I could only sleep better/have less nausea/did not have this swollen abdomen, I could stand the pain better.” Thus nutrition support and therapy for insomnia and the like may also be important in pain management. How severe is the pain? Unfortunately, it is a common experience that the language of patients and the language of those who care for them may differ in ways that lead to troublesome misunderstandings. Patients not only use words that overrate the pain but also use words that make care- givers think there is less pain than that actually experienced. The solution to the problem of the description of pain intensity attempts to avoid the use of words like “severe” and “terrible” and instead applies a standardized scale. The standard measurement of pain intensity today is the 10-cm visual analog scale (VAS). The 0–10 numeric rating scale (NRS) is also often used, but it should be understood from a scientific point of view that there are some small but consistent differences between a VAS and an NRS. All the commonly used scales are considered to be reliable and have been shown to give rather similar results as regards construct validity. However, one special problem in pancreatic cancer is that patients, and healthcare providers including doctors, find it difficult to understand VAS and NRS when discussing a variable pain over time. It must also be understood that any given change in NRS or VAS score has no intrinsic meaning. On the other hand, there is almost always good agreement between pain scores derived from VAS and similar scales and those derived from categoric pain relief scales and graphic rating scales. Elderly individuals with chronic pain find scoring on the VAS more difficult than younger patients. Also, sim- ple interest in the measurement of pain may influence the outcome of the patient’s pain score. A discrepancy between physician perception and patient report of pain intensity has been shown to be a predictor of inadequate pain management. How does the pain influence the patient and what does the patient want? The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.” The important part in this context is “emotional experience,” which means that even though pain intensity might be standardized, not all patients demand the same treatment for the same pain intensity. There are patients who are so afraid of a potentially increasing pain that they want analgesics “in case it gets worse,” whereas others do not want any analgesic drugs until it is “really needed.” The solution to this problem may be to watch their behavior: if patients are unable to do what they want due to the pain, then care- givers should act; conversely, if patients continue with their normal way of life despite the pain, it might be wise to wait until they ask for help. If patients have a desire to work or do something else that is important to them, they probably have greater overall ability and greater capacity to cope with the pain. On the other hand, if nothing is important, it is likely that the patient will suffer more pain. The analgesic ladder Step 1 (Fig. 51.2) Nutritional support is one of the most important parts of the first step in pain management. Weight loss typically correlates with inability to tolerate pain and increases the depression and fatigue that make the pain unbearable. Nutritional support must be individual- ized. For some patients it may be enough to provide the food they like, while others need liquid food, some need a better social environment in which to eat, and yet others require special liquid formula diets. Often the addition of pancreatic enzymes improves the absorp- tion of ingested food and it should at least be tried. CHAPTER 51 429 Patients must understand that the enzymes should be taken with meals, and the effect should be evaluated after 10–14 days. If there are questionable effects, the enzymes should be withdrawn and the effects evaluated once more. It is also important to become acquainted with the way patients react and their expectations. Is the patient afraid and how are relations with the relatives? Did the relationship with the relatives change after the illness was detected? These and similar questions can help in the care of the patient. Social support is often worth much more than any drug, and if there is a long disease process it may also be important to investigate the supporter’s network: how long can they stand the extraor- dinary pressure? Can they be supported mentally and physically? It is also important to make patients understand that care-givers know how to treat cancer pain. If they are assured that pain relief can be provided, then it is easier for them to tolerate pain at the borderline of what needs to be treated. It is important that everybody involved in nursing the patient should know what measures have been taken, and this should include the patient and the relatives. This means that all decisions concerning care must be documented. When pharmacologic measures are required, acetaminophen 1 g four times daily is the drug of choice. There is overwhelming scientific evidence that this drug should be the basis of all pain treatment in pancreatic cancer and that it should be given regularly and not on demand. Step 2 (Fig. 51.3) If acetaminophen is not enough to eliminate the pain, it may be combined with NSAIDs. This combination frequently has a combined effect that is significantly better than either drug given alone. The doses used may be the same as those usually given to patients with joint pain for example. It is possible that the antiinflammatory effect is just as important as the analgesic effect, and there are indications that patients with high levels of cytokines and C-reactive protein suffer less anorexia, which may also potentiate the analgesic effect. There are also indications that this can be further potentiated by w-fatty acids, which are without adverse effects. Acetylsalicylic acid and dextropropoxyphene are just as good as acetaminophen from an analgesic point of view, but in clinical practice have been shown to have substantial adverse effects (bleeding tendency and liver toxicity, respectively) and should therefore not be used routinely. If further potentiation is needed, codeine and other nonopioid analgesic drugs can be used, but always in combination with acetaminophen. Codeine may be considered an opioid drug but can be included in this concept. If these measures are insufficient, other drugs should be considered. Neuroleptics may be used to potentiate the other drugs, although some patients become drowsy, with little pain relief, and may experience dys- phoria. If there is some degree of anxiety, benzodiazepines are a better choice. The modern selective serotonin reuptake inhibitors (SSRIs) can also be used successfully in some patients, but never on a routine PART III 430 Figure 51.2 The analgesic ladder: step 1. Figure 51.3 The analgesic ladder: step 2. NSAID, nonsteroidal antiinflammatory drug; SSRIs, selective serotonin reuptake inhibitors. Is the diagnosis correct? Can the cancer be removed? Treat concomitant diseases: gallstones, peptic ulcer, ileus, etc. Concomitant cancer symptoms: nausea, emesis, obstipation, weight loss, depression, etc. Nutritional support including vitamins, trace elements, energy, and water Pancreatic enzymes Become acquainted with the language of the patient, the reactions, and the expectations. Is the patient afraid? Investigate social support network and supporter’s network Make the patient understand that we know how to treat cancer pain Document the decisions of pain treatment (make sure that all involved agree, including patient and relatives) Acetaminophen 1 g four times daily (not on demand) Acetaminophen + NSAID (not acetylsalicylic acid and dextropropoxyphene) NSAIDs +w-fatty acids? Codeine Other nonopioid analgesic drugs Grade of anxiety: benzodiazepines, SSRIs Make sure the patient sleeps well basis: some sadness is a natural and realistic reaction to the disease, and only if there are signs of medically de- fined depression should SSRIs be recommended. It is important to make sure the patient sleeps well. However, many of these patients have too little to do during the daytime and will therefore not be tired at night, especially if they also sleep during the day. There- fore activation during the day may be the best way to treat insomnia at night. A short nap at noon is not a problem, but the patient must then be active during the afternoon. Only when all these measures have been tried should sleeping pills be used. Step 3 (Fig. 51.4) As a “pure” analgesic drug there is nothing better than morphine or its derivatives. However, whether hydro- morphone, fentanyl, oxycodone, or some other drug should be given instead of morphine mostly depends on the experience of the doctor. There is little indication that any one of these drugs is significantly better than another. Therefore it is a good rule of thumb to use few opioids but to be well acquainted with the one usually used. The half-life of morphine is 2–4 hours, while its clinically relevant pain-relieving effects usually last 3–5 hours. In renal failure, the metabolites can accumulate in the body, and thus patients with reduced kidney function must be observed more closely after receiving repeated doses of morphine. There is wide individual variation in plasma opioid concentrations, but no sim- ple correlation between opioid and metabolite concentrations and pain relief has been found, although there is a report of a tendency toward greater stable phase morphine concentrations in cancer patients with optimal pain control. Besides the peroral route, which is the route of choice ordinarily, there are several other ways to administer opioids: sublingual, subcutaneous, intravenous, epidural/intrathecal, transdermal, and rectal, but not intramuscular as this can be painful, particularly for debilitated patients with wasted muscles. All the different routes have their special advantages and disadvantages. If morphine is used, it is wise to start with 10 mg on demand, i.e., when the patient asks for it (tablets if patient not vomiting, otherwise rectal administration). This course of action not only allows patients to become pain-free but also helps to reassure them that the use of morphine can always lead to freedom from pain: it is just a question of dosage. When a steady dosage of morphine has been achieved, it will be easier for the patient to use long-acting formulas twice daily. This means that the patient receives the same amount of morphine but on a fixed schedule and not on demand. If needed (i.e., for “breakthrough” pain), ordinary morphine tablets (10 mg) are used as a complement. If this supplement is used regularly, the dosage of the long- acting drug is increased. However, it should be emphasized to the patient that long-acting drugs do not reach a steady state until after 5 days, and sometimes not until after 10 days. Thus the dosage should not be changed more often than once a week; usually it is changed once a month. Transcutaneously delivered drugs are more expensive but have some advantages for patients who are ex- periencing a stable level of pain. Firstly, the patient does not have to think about medication more than once every third day and does not need to worry about missed doses. From the doctor’s point of view one can expect total compliance. On the negative side, there are some patients who experience less effect with the transcutaneous route, probably because of individual skin properties and blood circulation. Also, the dosage can be changed only in rather large steps and it is impracti- cal to change the dosage more than once every 6 or 9 days. Sedation and nausea occur particularly when starting the drug, although this is usually temporary but may recur with dose increases. Nausea can be avoided CHAPTER 51 431 Figure 51.4 The analgesic ladder: step 3. Morphine 10 mg as often as patient needed (tablets if patient not vomiting) When steady state: long-acting twice daily Transcutaneously delivered drugs more expensive but good for patients with stable level of pain Go to step 4 if excessive adverse effects, such as: Rapidly increasing demand Inability to cooperate with pain treatment Akathisia Decreasing effect (tachyphylaxis) Severe obstipation Drowsiness to apathy, inability to resume activities of daily life by using a centrally acting antiemetic prophylactically. Sedation is usually unavoidable but short-lived (48–72 hours) among patients starting off on low doses. There is no clinically relevant ceiling in analgesia: doses of oral morphine may be varied 1000-fold or more in order to achieve the same end point of pain relief. A change of opioid may be tried if pain relief with one opioid is inadequate or unacceptable adverse effects occur, especially when pain management requires increasing dose escalation. It cannot be overempha- sized that pain is multifactorial and that successful treatment depends on comprehensive evaluation. For the suffering patient it is important that the pain be treated quickly when needed, which indicates the use of an opioid with a rather short half-life. Once stable, sus- tained-release formulations reduce dose frequency to once or twice daily. Breakthrough pain is controlled with extra doses of the unmodified drug (calculated as one-sixth of the total 24-hour opioid dose require- ment). Drugs with a very short half-life (e.g., pethidine) are unsuitable because of the need for more frequent repeat dosing, which is inconvenient and may cause build-up of toxic metabolites. Drugs with inherently long half-lives (e.g., methadone) may be difficult to titrate safely in unstable pain. Many patients with pancreatic cancer are elderly and have concurrent medical conditions, both of which may influence the pharmacokinetics of opioids. Renal impairment is most important as it affects clearance of many opioids. There is a recommendation that conventional dose intervals should be increased by about 50% at moderately reduced renal clearance. Concurrent drug therapy can also alter opioid pharmacokinetics. Generally, at least 90% of pancreatic cancer patients with pain will be effectively treated by steps 1–3. How- ever, if opioids have excessive adverse effects, step 4 may be tried. Such adverse effects may include not only rapidly increasing demand for drug and inability to cooperate with pain treatment, but also akathisia and tachyphylaxis (decreasing effect). One of the most troublesome adverse effects for many patients is obstipation. This is due to the direct effects of opioids on gut motility, but also to low intake of food and water and an overly sedentary lifestyle. Because this is so common, all patients given opioids on a regular basis should receive prophylaxis against obstipation, such as lactulose once daily. Some patients experience drowsiness approaching apathy and feel unable to resume activities of daily life and so on. When it is obvious that the patient feels that life is of very limited value, alternatives should be considered. There is no evidence that the use of high-dose opiates in the palliative chronic setting leads to a dan- gerous level of respiratory depression, not even among patients with respiratory impairment. Step 4 (Fig. 51.5) For some patients subcutaneous or intravenous infusion pumps administering morphine and fentanyl have good effects. An advantage is that patients can to some degree increase the dosage on demand, usually with an upper limit to prevent a suddenly confused patient self- administering an overdose. Often the patient can include the procedure in their daily lives, but for some it is not acceptable to be dependent on mechanical devices. Old people especially dislike it, as they have difficulties learning how to handle the devices. Epidural block with morphine and bupivacaine provides the required pain relief but there is an increased risk of adverse effects, such as intraspinal infections, pneumonia, urinary infections, and gastrointestinal disturbances. Also, the patient needs qualified medical attention on a 24-hour basis. The nerves in the pancreas comprise sympathetic, parasympathetic, sensory, and motor fibers. The sensory fibers mediating pain are conducted toward the central nervous system, without synapsing, via the celiac plexus and the splanchinc nerves to the thoracic spinal cord. From a theoretic point of view, the pain can be inhibited by cutting the nerve fibers anywhere along this path. Celiac plexus block is a neurolytic block of the celiac plexus. For a long time, a block using 50% alcohol was PART III 432 Figure 51.5 The analgesic ladder: step 4. Subcutaneous/intravenous infusion pump (morphine/ fentanyl) Attack the celiac plexus Resection or block at laparostomy Block at angiography Block at ultrasonography, computed tomography, endoscopic ultrasound, or fluoroscopy Thoracoscopic splanchnicectomy Epidural block (morphine/bupivacaine) Transcutaneous nerve stimulation Chordotomy the most common and best-described therapy for the specific back pain in patients with pancreatic carcinoma, a good result being expected in the majority of cases. It can be performed intraoperatively or by a percutaneous approach, from the back or from the abdomen. The percutaneous route can be guided by the bony landmarks, by fluoroscopy, by angiography, or by ultrasonography, computed tomography, or magnetic resonance imaging. The choice between the different methods cannot be determined from the results of randomized studies, probably due to large differences in skill of the performers of different approaches but also to the different traditions underlying those skills. How- ever, randomized trials show a clear advantage for patients treated with celiac plexus block during surgery compared with untreated patients. One problem is that tumor masses may displace the celiac plexus, and when using the classical method guided by bony landmarks the success rate varies from 33 to 94%. The limited use of the technique is due to its short duration (usually a mean of about 3 months in successful cases), its dependence on individual skill, and the effectiveness of the pharmacologic alternatives. Thoracoscopic splanchnicectomy has been used since the mid-1990s. It is a safe and easy procedure that undoubtedly helps some patients with severe pain. However, the method’s place in the algorithm of pain management in pancreatic cancer is still not settled due to lack of appropriate data on effectiveness, which in turn may be due to attempts to treat not only patients with localized painful disease but also those with pain emanating from ingrowth into the abdominal wall, sensory pain afferents from which do not travel through the splanchnic nerves. Whether drainage of a pretumoral dilatated pancreatic duct provides pain relief in pancreatic cancer is not documented. There are also single reports of transcutaneous nerve stimulation, intrapleural block, and chordotomy. These types of procedures should only be used in specialist centers with both sufficient experience and the ability to evaluate each method. Evaluation of treatment options Patients with established pancreatic cancer do not pre- sent uniformly with regard to stage of the disease (early or late), extrapancreatic secondary symptomatology, or morphologic features. This also influences the pattern of pain and the outcome of attempts to manage not only the symptoms but the patient as a whole. The major goal of new treatment modalities must be improvement of the patient’s quality of life, which has many dimensions. To compare the efficacy of different treatments, it is necessary to have a baseline inventory of the patient’s general health status. However, even in the most recent literature there is no consensus on a standard method for assessing pain relief and improved quality of life. In the absence of such a standard method, it is recommended that the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-30 is used. This questionnaire consists of a core of 30 generally ap- plicable items and includes scales on physical functioning; role of functioning; cognitive, emotional, and social functioning; pain; fatigue; and nausea and vomiting. This may be used together with its pancreas- specific part, PAN26, which includes scales on pancreatic pain, digestive function, bowel habit, body image, satisfaction with care, and sexuality. Summary and options for the future The principal prerequisite for treating pain optimally in patients with pancreatic cancer is good personal con- tact with the patient on a regular basis, so that doctor and patient can try to agree to cooperate. This may be hard if the patient is frightened of the disease. However, if the patient has confidence in the doctor’s management, he or she will be able to withstand more pain without escalating analgesic use, and the treatment can be seen from a long-term and holistic perspective. Therefore, continuity of the patient–doctor relationship is of the utmost importance in these patients. An established relationship between the patient and the doctor, whether surgeon, oncologist, general practi- tioner, or gastroenterologist, helps evaluation of each attempt to optimize treatment. Pharmacologic treatment of pain is of the utmost importance in patients with pancreatic cancer, but it is not the only option and it should be seen as one option that is strengthened by others. Recommended reading Aaronson NK, Ahmedzai S, Bergman B et al. The European CHAPTER 51 433 Organisation for Research and Treatment of Cancer QLQ- C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85: 365–376. Andrén-Sandberg Å. Pain relief in pancreatic disease (editorial). Br J Surg 1997;84:1041–1042. Bockman DE, Büchler M, Malfertheiner P, Beger H. Analysis of nerves in chronic pancreatitis. Gastroenterology 1988; 94:1459–1469. Fitzsimmons D, Johnson CD, George S et al. Development of a disease specific quality of life (QoL) questionnaire module to supplement the EORTC core cancer QoL questionnaire, the QLQ-C30 in patients with pancreatic cancer. Eur J Cancer 1999;35:939–941. Grahm AL, Andrén-Sandberg Å. Prospective evaluation of pain in exocrine pancreatic cancer. Digestion 1997;58: 572–579. Ihse I, Zoucas E, Gyllstedt E, Lillo-Gil R, Andrén-Sandberg Å. Bilateral thoracoscopic splanchnicectomy: effects on pancreatic pain and function. Ann Surg 1999;230:785–791. Ischia S, Ischia A, Polati E, Finco G. Three posterior percutaneous celiac plexus block techniques. A prospective, ran- domised study in 61 patients with pancreatic cancer pain. Anesthesiology 1992;76:534–540. PART III 434 Introduction Pancreatic cancer is still a devastating disease that is presently the fourth or fifth leading cause of cancer- related death in Western countries, with a poor prognosis even after tumor resection. Approximately 150 000 people worldwide and 40 000 people in Europe die each year of pancreatic cancer, making it one of the five leading causes of death associated with cancer and one of the most aggressive human tumors. An overall 5- year survival of less than 1% is frequently reported and little progress has been achieved in the last decades. It is still a challenging task to diagnose pancreatic cancer in early tumor stages, the chance of cure being higher the lower the disease stage. However, the overall resectability rate of pancreatic cancer is only 10–15%, although rates ranging from 0.4 to 33% are reported. On the other hand, rapid tumor progression and poor respon- siveness to chemotherapy, radiotherapy, immunother- apy, and antihormonal treatment contribute to the poor prognosis. These facts together result in low tumor resectability rates after diagnosis, early tumor recurrence after resection, and poor overall survival rates. The survival rates are not at all satisfactory and reach a median of only 10–18 months. In the last decade surgical outcomes have improved, mostly because of better perioperative treatment. Begg et al. and Birkmeyer et al. demonstrate that operation-related morbidity and mortality has significantly decreased in centers with high patient load. This critical aspect of the value of centralization on the outcome of pancreatic surgery in high-volume institutions has been demonstrated in several studies. The current mortality rate following pancreatic resection is below 5% in specialized surgical centers and thereby significantly lower than in units with a low frequency of pancreatic surgery. Pan- creatic anastomosis was long considered to be the critical step and represented the main cause of morbidity and death in pancreatic surgery. To reduce morbidity, the concept of secretory inhibition of the pancreas by octreotide was investigated in large, randomized, placebo-controlled, multicenter trials and by meta- analysis, which demonstrated the effectiveness of octreotide with regard to postoperative complications and costs. These nonsurgical improvements combined with better surgical quality and postoperative care in high-volume centers have improved postoperative patient outcome. These parameters are also contri- buting to the improvement of postoperative quality of life. Unfortunately, they have not yet improved the curability rate of patients suffering from pancreatic cancer. What procedures are presently available for resectable pancreatic cancer? Classical Kausch–Whipple procedure Pancreaticoduodenectomy, as described by Allen O. Whipple in 1935, is still the standard operation for pancreatic head carcinoma, as well as for ampullary and distal bile duct cancer. In the years preceding 1935, most surgeons avoided pancreatic resection and fa- vored the use of gastroenterostomy to reconstruct food passage in patients with pancreatic malignancies because of fear of resection-related postoperative complications (e.g., anastomotic leakage). Although Walter Kausch had already reported the first successful 435 52 What is the optimal surgical treatment for resectable pancreatic cancer? Beat M. Künzli, Helmut Friess, and Markus W. Büchler [...]... of (a) 40–45 Gy EBRT plus follow-on bolus 5-FU for 4 months; (b) 50–57 Gy EBRT plus hepatic radiation plus continuous-infusion 5-FU/folinic acid for 4 months; or (c) no adjuvant treatment Group (a) had a significantly better median survival (21 months) and 2-year survival (44%) when compared with the control group (13.5 months and 4 49 198 5 198 7 199 6 199 7 199 8 199 9 199 9 2000 2000 2000 2000 2001 2003... 17 5-FU + FA + Cis 5-FU 5-FU + Cis + IFN-a 26 5.5 15 .9 5-FU + FA 5-FU 5-FU 13 21 17.5 13.5 20 18 20 11 5-FU 5-FU 5-FU + FA 5-FU 5-FU 5-FU Chemotherapy Median survival (months) 78 52 71 48 56 67 50 1 year 39 54 84 38 44 22 30 35 46 42 15 2 years Actuarial survival (%) Cis, cisplatin; EBRT, external bean radiotherapy; FA, folinic acid; 5-FU, 5- uorouracil; IFN-a, interferon-a; MMC, mitomycin C * Randomized... 199 4 199 4 199 6 199 7 199 8 199 9 2000 2000 2001 2001 Ishikawa et al Coia et al Staley et al Spitz et al Hoffman et al White et al Wanebo et al Snady et al Mehta et al Breslin et al Both Resectable Resectable Resectable Unresectable Unresectable Unresectable Resectable Unresectable Resectable EBRT + 5-FU/MMC EBRT + IORT + 5-FU EBRT + 5-FU EBRT + 5-FU/MMC EBRT + 5-FU/MMC/Cis EBRT + 5-FU/Cis EBRT + 5-FU/Cis/Strep... shows a 23% benefit in favor of no chemoradiotherapy, although the 95 % CIs for this estimation cross unity (HR 1.23, CI 0 .98 –1.54) One nonrandomized study of particular interest is by Mehta and colleagues from Stanford who treated 52 patients between 199 4 and 199 9 The tumor bed and regional nodes were irradiated with a dose of 45 Gy in 1.8-Gy fractions followed by a boost to the tumor bed in the 35% of... pancreaticoduodenectomy for right-sided cancer The survival of the entire group was 63% at 1 year and 17% at 5 years, with a median survival of 17 months For right-sided lesions the 1-year and 5-year survival rates were 64% and 17% respectively compared with 50% and 15% for left-sided lesions Why left-sided tumors have a worse prognosis in this study, even though the included left-sided pancreatic carcinomas... From November 199 3 to May 199 9, in 331 consecutive operations for patients undergoing pancreatic head resections (133 pylorus-preserving Whipple and 83 classical Kausch–Whipple procedures), the pancreatic fistula rate was 0% for the classical Kausch–Whipple and 3% in the pylorus-preserving Whipple These data clearly demonstrate that a pancreatojejunostomy performed by experienced hands and in a center... not been Table 53.2 Adjuvant regional chemotherapy for pancreatic ductal adenocarcinoma Actuarial survival (%) Number of cases Regimen Median survival (months) Series Year Ishikawa et al 199 4 97 67 27 — HAI + HPVI Gansauge et al.* 199 6 18 CAI 17.8 Link et al.* 199 7 29 20 (18 PDAC) — CAI 9. 3 21 Beger et al.* 199 9 ? 24 — CAI 10.5 23 Ozaki et al 2000 27† 19 IORT + HPVI or HAI IORT + HPVI or HAI 31.1 36... lymph-node metastases 446 5 years 31 28 447 14 34 199 7 199 7 199 7 199 8 199 9 2000 2000 2000 2001 2002 2004 Di Carlo et al Dobelbower et al Farrell et al Hishinuma et al Klinkenbijl et al (EORTC)* Mehta et al Lee et al Kokubo et al Alfieri et al Allen et al Neoptolemos et al.* 26 42 (with gemcitabine) 40 n = 26 45–55 49 45–54 (PVI 5-FU) Not specified (bolus 5-FU) n = 21 25 n=8 n = 13 EBRT + IORT n = 24 40... resection Am J Surg 199 2;163:125–131 Lin PW, Lin YJ Prospective randomized comparison between pylorus-preserving and standard pancreaticoduodenectomy Br J Surg 199 9;86:603 Neoptolemos JP, Russell RCG, Bramhall S, Theis B Low mortality following resection for pancreatic and periampullary tumours in 1026 patients: UK survey of specialist pancreatic units UK Pancreatic Cancer Group Br J Surg 199 7;84:1370–1376... adjuvant phase III study #9 7-0 4 recruited over 500 patients to receive a 3-week course of chemotherapy, then chemoradiotherapy, and then a final 3-month course of chemotherapy Patients were randomized to one of two adjuvant pre-chemoradiotherapy chemotherapy regimens (continuous-infusion 5-FU 250 mg/m2 daily for 3 weeks vs gemcitabine 1000 mg/ m2 daily once weekly for 3 weeks) and parallel postchemoradiotherapy . QLQ-C30 in patients with pancreatic cancer. Eur J Cancer 199 9;35 :93 9 94 1. Grahm AL, Andrén-Sandberg Å. Prospective evaluation of pain in exocrine pancreatic cancer. Digestion 199 7;58: 572–5 79. Ihse. Research and Treatment of Cancer QLQ- C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 199 3;85: 365–376. Andrén-Sandberg Å. Pain relief in pancreatic. Zoucas E, Gyllstedt E, Lillo-Gil R, Andrén-Sandberg Å. Bilateral thoracoscopic splanchnicectomy: effects on pancreatic pain and function. Ann Surg 199 9;230:785– 791 . Ischia S, Ischia A, Polati

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