9. Palliative Tumor-directed and Supportive Therapy of Pancreatic Cancer – Pancreatic Cancer
There are now cross-sectional guidelines from the German Guideline Program in Oncology on supportive and palliative therapy, which were not yet available at the time of the last update of this chapter. Generally valid recommendations are therefore taken from these guidelines. Independent recommendations can still be found on certain topics that are not (sufficiently) considered in the corresponding cross-sectional guidelines due to the specific requirements of pancreatic cancer.
9.1 Palliative Care and Supportive Therapy
All patients with pancreatic cancer shall have access to information about palliative care (e.g. by displaying flyers) regardless of the stage of the disease.
EC: Adopted from S3 Guideline Palliative Medicine (5.1.)
- Consensus
- Strong consensus
All patients shall be offered palliative care following the diagnosis of incurable pancreatic cancer, irrespective of whether tumor-specific therapy is carried out.
- Recommendation grade
- D: Expertenmeinung oder inkonsistente bzw. nicht schlüssige Studien jedes Evidenzgrades
- Level of evidence
- 1
Adopted from S3 Guideline Palliative Medicine (5.2.)
Patients shall be offered a needs assessment by an SPC team (specialized palliative care team) following the diagnosis of incurable pancreatic cancer.
Patients with incurable pancreatic cancer and a highly complex situation shall receive specialized palliative care.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 3
Adopted from S3 Guideline Palliative Medicine (5.9.)
Background
The recommendations on access to information, the provision of palliative care and the integration of specialized palliative care are taken from the extended S3 guideline on palliative care for patients with incurable cancer (long version 2.2 – September 2020 AWMF register number: 128/001OL). There was only a specification made for patients with pancreatic cancer.
Due to the high overall mortality of pancreatic cancer, the high recurrence rate after surgical resection and the frequent initial diagnosis at a non-curable stage of the disease, the recommendations should be adopted without restriction, especially for patients with pancreatic cancer. This also applies to the other recommendations of the S3 guideline Palliative Medicine. Even if they are not explicitly mentioned here, reference should be made to them (https://www.awmf.org/leitlinien/detail/ll/128-001OL.html).
The complexity of the patient's situation can best be determined from the recorded needs, problems and burdens of patients and relatives, the functional status of the patient and the phase of the disease (stable / unstable / deteriorating / terminal).
9.2 Recording of Symptoms, Patient Reported Outcomes, Quality of Life
Supportive therapy shall be used in all phases of the diagnosis and treatment of patients with pancreatic cancer.
- Consensus
- Strong consensus
All patients with pancreatic cancer shall be screened for typical distressing symptoms. Symptom screening shall be carried out as early as possible at appropriate intervals if clinically indicated or repeatedly during the course of the disease if a patient's disease status changes (e.g. recurrence or progression of the disease).
- Consensus
- Strong consensus
Validated and standardized screening instruments shall be used to record the symptoms.
- Consensus
- Consent
All patients shall be screened for psychosocial stress. A psycho-oncological screening shall be carried out as early as possible at appropriate intervals if clinically indicated or repeatedly during the course of the disease if a patient's disease status changes (e.g. recurrence or progression of the disease).
EC: Adopted from S3 Guideline Psycho-oncology (7.2)
- Consensus
- Strong consensus
Validated and standardized screening instruments shall be used to record psychosocial stress.
The Distress Thermometer or the HADS-D, for example, are recommended as screening instruments.
In addition, individual psychosocial support needs shall be assessed.
EC: Adopted from S3 Guideline Psycho-oncology (7.3)
- Consensus
- Strong consensus
Pain history and pain-related clinical examination shall be part of every clinical presentation.
EC: Adopted from S3 Guideline Palliative Medicine (9.1)
- Consensus
- Strong consensus
Supportive therapy is part of good oncological care in general and the care of patients with pancreatic cancer in particular. The German Guideline Program in Oncology in cooperation with the AWMF, DKG, and DKH has taken this into account with the cross-sectional guidelines on supportive therapy, psycho-oncology, and palliative medicine. Within cancer, pancreatic carcinoma is a disease with a particularly unfavorable prognosis and a particularly symptomatic course. For this reason, the recording of symptoms, stress, and the so-called „patient-reported-outcomes“ (quality of life) and their treatment is particularly important. Suitable instruments for screening symptoms and distress include the Minimal Documentation System (MIDOS 2) [749], Edmonton Symptom Assessment System (ESAS/revised version ESAS-r) [749], [750], Integrated Palliative Care Outcome Scale (IPOS) [751], Distress Thermometer with problem list [https://doi.org/10.1024/1661-4747.54.3.213]. In addition to the EORTC-QLQ-C30, the EORTC-QLQ-PAN26, which was developed specifically for patients with pancreatic cancer, can be used to assess quality of life. The use of instruments to record the „patient-reported-outcomes“ improves the quality of life of patients, but specific data for patients with pancreatic cancer are lacking [752]. Restrictions in quality of life are associated with a lower survival time [753].
Pain is one of the main symptoms of patients with pancreatic cancer. A pain history is therefore an important part of every clinical presentation. If pain is present, this is followed by a clinical examination, supplemented by further diagnostics if necessary (recommendation 9.10). For further information on pain assessment and treatment, please refer to S3 guideline Palliative Medicine Chapter 9. A nerve block may be an option in the treatment of pain caused by local or regional spread of pancreatic cancer.
9.3 Nutrition
Patients with pancreatic cancer should undergo regular screening for malnutrition (e.g. Nutritional Risk Screening (NRS) or Malnutrition Universal Screening Tool (MUST)).
Background
Unintented weight loss in patients with pancreatic cancer is common (up to 85% of patients at diagnosis) and is associated with low treatment tolerance, reduced quality of life, and higher all-cause mortality. Reasons for this are anorexia, malabsorption and/or cachexia [756]. Screening for malnutrition (evaluation of food intake, weight progression, and BMI) should be carried out at diagnosis and repeated regularly depending on the clinical situation [754].
In the event of nutritional problems, an individual nutritional assessment and appropriate advice shall be carried out. This should be carried out by a qualified nutritionist.
Background
Patients with abnormal findings in the nutritional screening should receive a specific nutritional assessment so that treatable causes of malnutrition can be identified and remedied [758]. The contents include the objective and quantitative assessment of nutrition-relevant symptoms and food intake, determination of body composition, medication, laboratory values (including determination of inflammation), as well as the patient's general condition [754], [757]. The prospective, randomized EFFORT study also showed a positive effect on the functionality and outcome of an individualized nutritional intervention during an inpatient stay in the subgroup of patients with solid gastrointestinal tumors [759]. This was also confirmed for the group of gastrointestinal tumors in another population-matched cohort study with 11,906 oncological patients [760].
Nutritional counseling should be provided by qualified nutritionists. In the studies described, nutritional counseling is provided by “registered dietitians“. The term „dietitian“ is not protected in Germany. In Germany, qualified nutritionists are the professional groups of dieticians and nutritionists with appropriate proof/certification.
A high-calorie, protein-rich food selection (energy 25-30 kcal/kg/day; protein 1.2 -1.5 g/kg bw/day) with a high energy density should be the center of attention. However, enteral or parenteral nutrition should not be routinely used [757]. In patients with non-resectable pancreatic cancer, the use of fish oil shows no benefit in counteracting weight loss [128], [757]
There is currently no approved pharmacological substance for the treatment of cachexia. A short-term trial of steroids to increase appetite in patients with severe cachexia may be considered after careful consideration of the benefits and risks [757].
If spontaneous food intake remains inadequate despite nutritional advice, supplementary or total enteral nutrition or parenteral nutrition may be considered. The aim is to maintain or improve the patient's nutritional status and quality of life while carefully weighing up the benefits and risks.
Background
If oral nutritional intake remains insufficient despite intensive nutritional counseling (and the use of oral nutritional supplements, e.g. liquid nutrition), supplementary or total enteral nutrition or parenteral nutrition can be considered [754]. Nutritional therapy in patients with tumor diseases and malnutrition or risk of malnutrition has shown an improvement in energy intake, body weight, and quality of life in studies with the right patient selection [754]. Ethical concerns apply to use during the last weeks and days in patients with advanced tumor disease [754]. Parenteral nutrition can be tried in selected patient groups (e.g. patients with intestinal obstruction), but should be discontinued at the end of life [757].
Patients with exocrine pancreatic insufficiency due to pancreatic carcinoma shall receive pancreatic enzyme therapy.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 2
Guideline Adaptation: NICE 2018
- Consensus
- Strong consensus
- References
- [761]
Background
In patients with pancreatic cancer, the preoperative incidence of pancreatic insufficiency is between 46-93% and postoperatively between 38% - 93% [762]. The main symptomatology of exocrine pancreatic insufficiency is characterized by steatorrhea (fat content of the stool is more than 7 g/day with a fat content of 100 g fat in the diet [756], [762]). The consequences are abdominal pain, flatulence, loss of weight and muscle mass, deficiency of fat-soluble vitamins [762]. Severe pancreatic insufficiency (fecal elastase concentration <20 ug/g) is an independent factor with regard to poorer prognosis. Pancreatic enzyme therapy is associated with an improved prognosis in patients with pancreatic resection due to carcinoma [763].
The results of randomized studies on the effect of enzyme substitution in non-resectable pancreatic carcinoma on nutritional status are inconclusive [764], [765], [766]. However, a summary of the available studies shows a reduction in symptoms and a trend towards better quality of life, so a trial of enzyme replacement should be undertaken [767].
The amount of pancreatic enzymes taken must be individually tailored to the patient and the meal (50,000-75,000 units of lipase per meal and 25,000-50,000 units per snack) [762]. Ideally, the pancreatic enzymes should be taken during the meal in order to achieve optimal mixing of the chyme.
Patients with pancreatic cancer shall receive an individualized nutritional intervention before and after oncological pancreatic resection.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 5
Guideline Adaptation: ESPEN 2021
- Consensus
- Strong consensus
- References
- [754]
Background
Patients with pancreatic cancer often show reduced nutritional status and weight loss at the time of diagnosis [768]. A pre- or postoperative nutritional intervention adapted to the clinical situation and embedded in an Enhanced Recovery after Sugery (ERAS) program –, in particular the use of oral and enteral immunonutrition (arginine, omega-3 fats, nucleotides) [769] - should be part of the treatment concept [754], [128]. Nutritional components of the ERAS program also include avoiding periods of fasting, preoperative fluid and carbohydrate loading and early oral nutrition postoperatively.
If perioperative nutritional intake is insufficient, the enteral route should be preferred [128].
9.4 Cholestasis and Tumor-induced Stenosis of the Upper GI Tract
9.4.1 Stents
Metal stents are considered the treatment of choice, plastic stents shall be used if the survival time is estimated at < 3 months.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 1a
- Consensus
- Consent
- References
- [770]
Background
One meta-analysis is based on 21 studies comparing surgical procedures with stenting techniques and metal stents with plastic stents. The study included 1,454 patients. Compared to surgery, stenting techniques offer a lower complication rate, but also a higher recurrence rate with regard to obstruction. The surgical group tended to have a higher 30-day mortality rate. There was no difference in terms of technical and therapeutic success. Metal stents have a lower reocclusion rate than plastic stents, no difference was found with regard to technical success, primary therapeutic success, complications and 30-day mortality. Overall, metal stents are rated as the treatment of first choice [770].
Background
Two studies deal with polyurethane-coated stents [771], [772]. In a single-arm study with 30 patients, the results for polyurethane-coated stents correspond to the results known from the literature with non-coated metal stents [771], so that there is no advantage for coated stents. A second study with 112 patients compared polyurethane-coated with self-expanding metal stents and described a significantly higher open rate of the coated stents in distal bile duct stenoses, as the coating prevents tumor ingrowth into the stent. However, there were no significant differences in survival between the two groups and there was an increased rate of cholecystitis and pancreatitis in the group that received coated stents [772].
Percutaneous transhepatic cholangiodrainage, PTCD, is useful in the palliative treatment of pancreatic cancer when endoscopic therapy is not possible (e.g. in the case of tumor-related duodenal stenosis). PTCD is also indicated if endoscopic therapy is unsuccessful.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 3
- Consensus
- Consent
- References
- [773]
Background
The literature on PTCD is „historical“ [773]. More recent studies comparing the percutaneous application of metal stents with endoscopic access using the same stent design do not exist.
9.4.2 Biliodigestive Anastomosis
Surgical intervention with the sole aim of creating a biliodigestive anastomosis certainly remains the exception. However, if irresectability is detected during a curative surgical procedure, the creation of a biliodigestive anastomosis is indicated if cholestasis is present and a longer survival time is expected. A distinction must be made between patients with peritoneal seeding or liver metastases.
- Consensus
- Consent
If a biliodigestive anastomosis is performed in the palliative situation, choledochojejunostomy should be preferred over other bypass procedures.
9.4.3 Recurrent Cholangitis after Biliodigestive Anastomosis
Before any therapeutic intervention, a mechanical obstruction must be ruled out in any case. If there is a mechanical obstruction, proceed accordingly. An attempt at long-term administration of antibiotics can then be made.
- Consensus
- Consent
Background
There is no specific literature on this topic available.
9.4.4 Stenosis of the Upper GI Tract
For the treatment of nausea and vomiting in patients with pancreatic cancer and incomplete malignant intestinal obstruction (MIO), prokinetics such as metoclopramide should be used for antiemesis.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 4
Adopted from the S3 Guideline Palliative Medicine (14.37)
- Consensus
- Strong consensus
For the treatment of nausea and vomiting in patients with pancreatic cancer and complete malignant intestinal obstruction (MIO), prokinetics such as metoclopramide should not be used for antiemesis.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 4
Adopted from the S3 Guideline Palliative Medicine (14.38)
- Consensus
- Strong consensus
In patients with incurable cancer and with a tumor-related obstruction in the gastric outlet and duodenum, endoscopic stenting can be performed to relieve symptoms.
EC: Adopted from S3 Guideline Palliative Medicine (14.31)
- Consensus
- Strong consensus
EC: Adopted from S3 Guideline Palliative Medicine (14.34)
- Consensus
- Strong consensus
EC: Adopted from S3 Guideline Palliative Medicine (14.35)
- Consensus
- Strong consensus
EC: Adopted from S3 Guideline Palliative Medicine (14.35)
- Consensus
- Strong consensus
Background
Adopted from S3 guideline Palliative Medicine:
The recommendations on endoscopic procedures for MIO are based on the expert opinion of the guideline group.
Although the clinical picture can be dramatically impressive, interventional treatment of MIO is not an emergency procedure and should be discussed in detail with the patient and their relatives. Endoscopic therapy and stent placement allows the intestinal passage to be restored with minimal invasive effort and a high technical success rate [777], [778], [779], [780], [781], [782], [783].
The advantage of endoscopic therapy and stent implantation lies in the low invasiveness and the associated lower risk of morbidity. In addition, this procedure leads to a faster resumption of oral feeding and shorter hospital stays [784], [785].
Before placing a stent in the upper GI tract, distal passage stops should be largely excluded, as otherwise there is a risk of aggravation of the symptom burden.
Patients who persistently vomit have an increased risk of aspiration. In addition, vomiting, especially if it occurs several times a day, is very distressing for many patients. The distension caused by the amount of fluid also prevents the stomach from emptying [786]. Temporary decompression using a nasogastric tube can help to improve the symptoms of nausea and vomiting, as well as abdominal pain, by emptying gastric and small intestinal secretions. However, the tube is not tolerated well or at all by many patients, especially if it is left in place for a longer period of time (> 2-3 days).
Studies on the placement of a drainage PEG are retrospective [787], [Rath, KS et al. 2013], [789], [790], [791], [792], [793], [794] – with one exception [793]. Patients with a high MIO in the stomach or duodenum and insatiable vomiting in particular can benefit from a drainage PEG [786]. Early placement of the drainage PEG appears to be advantageous in order to achieve faster symptom relief [792], [795]. After placement of a drainage PEG, patients can usually consume fluids and possibly also small amounts of food. However, it must be carefully ensured that the tube does not become blocked. The drainage PEG is usually inserted endoscopically. Ascites should be drained beforehand [796]. Contraindications are infragastric tumor masses or perigastric peritoneal carcinomatosis.
9.5 Primary Anticoagulation
Prophylactic anticoagulation to prevent venous thromboembolic events in outpatients with advanced pancreatic cancer undergoing chemotherapy
In outpatients with advanced pancreatic cancer who are undergoing chemotherapy, prophylactic anticoagulation with a low-molecular-weight heparin can be carried out after weighing up the risk/benefit with regard to the risk of bleeding.
- Consensus
- Strong consensus
Background
A large number of studies have shown that pancreatic adenocarcinoma is associated with an increased risk of thromboembolic events [797].
Therapeutic anticoagulation and secondary prophylaxis of patients with pancreatic cancer and an acute venous thromboembolic event should be based on the recommendations of the S2k guideline „Diagnosis and treatment of venous thrombosis and pulmonary embolism“.
Prophylactic anticoagulation to prevent venous thromboembolic events in hospitalized patients with pancreatic cancer should be based on the recommendations of the S3 guideline „Prophylaxis of venous thromboembolism“. This applies to both internal medicine and surgical patients and includes postoperative and post-inpatient anticoagulation after pancreatic cancer resection.
The question of prophylactic anticoagulation to prevent (symptomatic) venous thromboembolic events in outpatients with advanced pancreatic cancer undergoing chemotherapy is currently assessed differently by various guidelines [Sohal, Davendra P. S. et al. 2016], [798]. The primary data basis are 2 prospective, randomized clinical trials that investigated the value of prophylactic anticoagulation with a low-molecular-weight heparin (LMWH) in addition to standard gemcitabine-based chemotherapy in patients with advanced pancreatic cancer [799], [800].
In the FRAGEM study, the addition of dalteparin (for 12 weeks in parallel with chemotherapy with gemcitabine) reduced the primary study endpoint incidence of „all-type VTE“ (vascular thromboembolism) in the first 100 days after randomization from 23% to 3.4% (risk ratio (RR) 0.145, 95% CI 0.035-0.612, p=0.002) [799]. Fatal VTE were only reported in the control arm in the first 100 days after randomization (8.3% vs. 0%, p=0.057). The rate of non-major bleeding complications was higher in the LMWH arm (9% vs. 3%), but the rate of major bleeding complications (defined according to the International Society on Thrombosis and Haemostasis) was identical (3.4% vs. 3.2%). However, overall survival, time to tumor progression and objective imaging response rate were not significantly different between the two arms.
The CONKO-004 study investigated primary prophylaxis with enoxaparin administered in parallel with gemcitabine-based chemotherapy for advanced pancreatic cancer. Enoxaparin was administered in a weight-adjusted, semi-therapeutic dose for the first 3 months, then at a fixed dose of 40 mg per day until progression. The primary study endpoint, a symptomatic venous thromboembolic event within the first 3 months, occurred in 15 of 152 patients in the observation group and in 2 of 160 patients in the enoxaparin group (HR 0.12, 95% CI 0.03-0.52, p=0.001) [714]. „Major bleeding events“ occurred in 5 of 152 patients in the control arm and in 7 of 160 patients in the enoxaparin arm (HR 1.4, 95% CI 0.35-3.72, p=1.0). In this study, too, concomitant LMWH therapy had no influence on the oncological treatment outcome (measured by progression-free and overall survival).
In a critical appraisal of these data, it should be noted that some authors recommend outpatient LMWH prophylaxis for patients with advanced pancreatic cancer undergoing chemotherapy and low bleeding risk based on the above findings [801], [802], [803]. This approach is also supported by data from one meta-analysis from 2016 [804]: Here, a „number needed to treat” of 11 patients was calculated to prevent 1 symptomatic venous thromboembolic event; the pooled „risk ratio“ for a „major bleeding event“ was 1.25 (95% CI 0.48-3.3, p=0.65).
The most important counterargument for LMWH prophylaxis in outpatient chemotherapy for pancreatic cancer is based on the fact that no study to date has been able to show a survival benefit or an improvement in oncological outcome parameters (such as response rate or PFS) [805].
It is important to emphasize that these data were collected in pancreatic cancer patients with advanced tumors undergoing chemotherapy and LMWH was used here as primary prophylaxis. The knowledge gained from these studies should therefore not be transferred to other clinical scenarios, such as the adjuvant therapy situation.
9.6 Rehabilitation and Follow-up Care
9.6.1 Rehabilitation after a Curative Resection of Pancreatic Cancer
Post-operative follow-up treatment should be offered to the patient. This should be coordinated with the family environment.
- Consensus
- Strong consensus
Background
No evaluable literature is available on the value of follow-up treatment after pancreatic cancer resection with curative intent.
In everyday clinical practice, care should be taken to ensure that every pancreatic cancer patient is offered social counseling after surgical tumor therapy to discuss rehabilitation options.
The extent to which „prehabilitation“ prior to surgery for pancreatic cancer (surgical & functional) improves outcome parameters is the subject of ongoing studies [806].
9.6.2 Follow-up Program after Curative Resection
A structured follow-up program cannot be recommended for pancreatic cancer regardless of stage.
- Consensus
- Consent
Structured aftercare should be offered to the patient.
- Consensus
- Strong consensus
Background
There is still no scientific evidence that a structured follow-up program in the sense of performing regular imaging staging examinations or serum tumor marker measurements leads to an improvement in overall survival in pancreatic cancer.
A large number of other guidelines currently recommend symptom-oriented follow-up of patients, initially at 3 to 6-month intervals. Therapy-related symptoms such as possible exocrine or endocrine pancreatic insufficiency, nutritional status, as well as psychosocial status should be paid attention to. This requires a medical history and physical examination [807], [808], [805]. Such regular medical follow-up should be offered to every patient after resection of pancreatic cancer.
There is evidence, mainly from population-based studies, that the use of imaging radiology procedures can lead to an earlier diagnosis of recurrence than if it occurs symptomatically; however, the extent to which the earlier diagnosis of recurrence can also improve the patient's prognosis is still unclear. Hypothesis-generating, mostly retrospective surveys exist on this question, but so far no data from prospective randomized studies [809], [810], [811].
Postoperative tumor marker measurements can contribute to prognosis assessment; however, it has not been scientifically proven that this can achieve a survival advantage [812].
Regular medical follow-up can take place with the surgeon, the internist, or the attending general practitioner [813].
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