Bile duct/gallbladder cancer
Bile duct cancer (cholangiocarcinoma) and gallbladder cancer are in most cases adenocarcinomas. Bile duct cancer is located 60% centrally in the liver hilum, 20% in intrahepatic bile ducts, and 20% in extrahepatic bile ducts.
Gall bladder cancer is considered relatively rare. It is usually highly malignant with early metastasis to lymph nodes.
The bile ducts extend from the liver to the duodenum and create a delicate system of branches. The bile ducts are connected to the gallbladder, which is a small hollow organ located beneath the liver.
The bile ducts consist of:
- intrahepatic bile ducts
- bile capillaries
- interlobular bile ducts
- extrahepatic bile ducts
- the liver's common hepatic duct
- cystic duct from the gall bladder
- the common bile duct
In Norway in 2013, there where 193 new cases of gall bladder cancer/cholangiocarcinoma. The incidence of the disease is increasing.
Gall bladder cancer appears to be more common among women.
Both cancer types occur mainly between ages 50–70.
Age-specific incidence of bile duct/gallbladder cancer, 2009–2013.
Source: Cancer Registry of Norway
Incidence of bile duct/gallbladder cancer, 1954–2013.
Source: Cancer Registry of Norway
Etiology of bile duct/gallbladder cancer
In most cases, the cause is unknown.
- 10–20% of patients with primary sclerosing cholangitis (PSC) will develop cholangiocarcinomas.
- Chronic infections usually caused by a gallstone may be a factor triggering gallbladder cancer, and about 0.3–3% of patients with gallstones develop gallbladder cancer.
- A calcified gallbladder (porcelain gallbladder) is more susceptible to gallbladder cancer (1).
Histology of bile duct/gallbladder cancer
The gall bladder is a hollow organ that is covered by a single cell cubical epithelium, which is the origin of the majority of malignant tumors in this organ (adenocarcinoma).
Similar to many other carcinomas, the tumors in these organs often originate from precursor lesions. The nomenclature of precursor lesions has varied, though an international consensus conference has decided on the following terms; Extrahepatic and intrahepatic hilar bile ducts = biliary intraepithelial neoplasia grade I, II and III (BIL-IN I-III). This terminology is not well spread and not consistently used by pathologists. The terminology is used in the biliary ducts, not in the gallbladder. The precursor lesions are flat and not recognizable by radiological techniques. Brush cytology is a useful method to evaluate the precursor lesions in patients with primary sclerosing cholangitis.
In addition to flat intraepithelial precursor lesions there are also polyps. They represent papillary or tubular adenomas that can appear in all parts of extrahepatic ducts, but are predominately seen in the gall bladder. Transition into adenocarcinoma can be seen, but the risk is probably very low. On rare occasions, multicentric papillomatosis in the biliary ducts can be seen. The risk for developing adenocarcinomas is much higher in these instances. Cystadenomas similar to those in pancreas and liver can also appear in the biliary ducts. The risk of carcinoma is present and these lesions should be removed surgically.
Malignant tumors in the gall bladder and biliary ducts are almost exclusively adenocarcinomas. More specifically, they are classified as extrahepatic cholangiocarcinoma when the tumors originate from the extrahepatic ducts close to the hilum. Adenocarinomas originating from the distal part of ductus choledochus/ampulla Vateri can sometimes be difficult to separate from adenocarcinomas arising in the pancreas. The adenocarcinomas originating from extrahepatic biliary ducts are generally immunohistochemically positive for CK7 and negative for CK20.
However, there are variants of adenocarcinoma, including papillary adenocarcinoma (especially in the gall bladder), adenocarcinoma of intestinal type, mucinous adenocarcinoma (adenocarcinomas with > 50% mucin), clear cell adenocarcinoma and signet cell carcinoma (can give a linitis plastica appearance such as in the stomach).
Squamous cell carcinoma can appear, especially in the gall bladder with chronic cholecystitis with squamous cell metaplasia. Small cell carcinoma (poorly differentiated endocrine carcinoma) and undifferentiated carcinoma (in the gall bladder) can in rare cases appear.
Other malignant tumor
- Endocrine tumors
- Mesenchymal tumors
These are very rare tumors in this localization.
Operation specimen handling
Cancer in the gall bladder is sometimes an accidental finding in cholecystectomy specimens from patients with cholecystitis. Cancer in the distal part of ductus choledochus is usually seen in a pancreaticoduodenectomy specimen (Whipple). In a few occasions with proximally located tumor, an exclusive resection of extrahepatic ducts with the gall bladder can be performed. The surgeon should mark the different resection borders using sutures in order for the pathologist to be able to orient the specimen correctly. The specimen must be well fixed in neutral buffered formalin as for all operation specimens.
Reports on operation specimens as for cholecystectomy and resection of extrahepatic biliary ducts should include the following information:
- Tumor localization
- Tumor size (largest diameter)
- Histological type (WHO)
- Infiltration depth
- Resection borders
- Blood vessel invasion
- Perinneural infiltration
- Lymph node metastasis
Metastatic patterns of bile duct/gallbladder cancer
Spreading of bile duct cancer often occurs locally in the wall of the gallbladder (intramurally) and along the nerves (perineural), blood vessels (perivascular), and to lymph nodes. Metastasis may often occur to aorta-caval lymph nodes, the liver, and the upper abdominal cavity.
Spreading of gallbladder cancer can occur to segments 4 and 5 of the liver. Metastasis to local glands and the peritoneum occurs frequently, and metastases are also often detected in the lungs.
Staging of bile duct/gallbladder cancer
The TNM classification is used to determine the stage for bile duct/bladder cancer. The TNM system assesses the tumor (T), lymph nodes (N), and metastasis (M) at the time of diagnosis.
The TNM classification distinguishes between the clinical classification (TNM) and the pathology classification (pTNM).
This classification applies to extrahepatic bile ducts and carcinomas in the main bile ducts.
Primary tumor (T)
- TX Primary tumor cannot be assessed
- T0 No evidence of primary tumor
- Tis Carcinoma in situ
- T1 Tumor confined to the wall of the bile duct
- T2 Tumor invades beyond the wall of the bile duct
- T3 Tumor infiltrates the liver, gallbladder, pancreas or unilateral branches of the portal vein or hepatic artery.
- T4 Tumor infiltrates the main portal vein or one of the branches bilaterally, the common hepatic artery or other adjacent structures such as the colon, stomach, duodenum, or abdominal wall.
Regional lymph nodes (N)
- NX Regional lymph nodes cannot be assessed
- N0 No regional lymph node metastasis
- N1 Regional lymph node metastasis
This classification applies only to carcinomas.
Primary tumor (T)
- TX Primary tumor cannot be assessed
- T0 No evidence of primary tumor
- Tis Carcinoma in situ
- T1 Tumor invades lamina propria or muscle layer
- T1a Tumor invades lamina propria
- T1b Tumor invades muscle layer
- T2 Tumor invades perimuscular connective tissue, no extension beyond serosa or into liver
- T3 Tumor perforates serosa and/or directly invades the liver and/or other adjacent organ or structure such as the stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts.
- T4 Tumor infiltrates the main portal vein or hepatic artery, or invades two or more extrahepatic organs or structures.
Regional lymph nodes (N)
- NX Regional lymph nodes cannot be assessed
- N0 No regional lymph node metastasis
- N1 Regional lymph nodes metastasis
|Common stage divisions for gallbladder cancer
Carcinoma in situ
T1 N0 M0(T1a)
T2 N0 M0 (T1b)
Growth into muscle tissue, but not through serosa
T3 N0 M0
Growth through serosa, invasion of liver < 2 cm, or
T1–T3 N1 M0
Lymph node metastasis to hepatoduodenal ligament
T4 N0–N1 M0
Invasion of liver > 2 cm with or without lymph node metastasis
T1–T4 N2 M0
Lymph node metastasis outside hepatoduodenal ligament or
Symptoms of bile duct/gallbladder cancer
Bile duct cancer usually manifests itself by jaundice, possibly accompanied by change in general health status. Pain is often absent and is first observed in an advanced stage.
Inflammation of the bile ducts (cholangitis) is more uncommon as a debut symptom. Weight loss and other general health symptoms may indicate a more advanced stage.
Symptoms of gallbladder cancer often first develop at an advanced stage.
Symptoms may be pain similar to plain gallstone disease, and change in character:
- discomfort and pain in the upper abdomen and right subcostal area during meals
- pain radiating towards the right shoulder blade
Differential diagnoses of bile duct/gallbladder cancer
Possible differential diagnoses are:
- Benign or malignant pancreatic tumors
- Sclerosing cholangitis
Prognosis of bile duct/gallbladder cancer
The prognostic factors for long-term survival are the disease stage and presence of metastases.
For hilar bile duct carcinomas, five year survival is about 30–40%. Tumor-free margins (R0) as well as lymph node negative tumors have the best prognosis (1).
For stage 2 gallbladder cancer, the long-term survival after an extended cholecystectomy is 80–100%. Long-term survival is reduced to 25–50% if there is lymph node metastasis.
In stages 3 and 4, involvement of lymph nodes increases to 60–70%, and long-term survival after surgery is reduced to 15–25%.
Five-year relative survival for patients with bile duct/gallbladder cancer, in percent, during the diagnosis period 1974–2013.
Source: Cancer Registry of Norway
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References on bile duct/gallbladder cancer
Jarnagin WR, Fong Y, DeMatteo RP, Gonen M, Burke EC, Bodniewicz J et al. Staging, Resectability, and Outcome in 225 Patients With Hilar Cholangiocarcinoma. Ann Surg. 2001 October; 234(4): 507–519
- Ortner ME, Caca K, Berr F et al. Successful Photodynamic Therapy for Nonresectable Cholangiocarcinoma: A Randomized Prospective Study. Gastroenterology. 2003;125(5):1355-1363
- Connor S, Barron E, Redhead D, Ireland H, Madhavan K, Parks R et al. Palliation for suspected unresectable hilar cholangiocarcinoma. EJSO 2007;33(3):341–345
- Ben-David M, Griffith K, Abu-Isa E, Lawrence T, Knol J, Zalupski M et al. External-beam radiotherapy for localized extrahepatic cholangiocarcinoma. Int J Radiat Oncol Bio Phys 2006; 66(3): 772–779
- Khan SA, Thomas HC, Davidson BR, Taylor-Robinson SD. Cholangiocarcinoma. Lancet 2005; 366: 1303–14
- Thongprasert S. The role of chemotherapy in cholangiocarcinoma. Ann Oncol. 2005;16(2): 93–96
- Nordic Gastrointestinal Tumor Adjuvant Therapy Group. Expectancy or primary chemotherapy in patients with advanced asymptomatic colorectal cancer: A randomized trial. J Clin Oncol 1992;10: 904–11
- Rea DJ , Heimbach JK , Rosen CB , Haddock MG , Alberts SR, Kremers WK, Gores GJ, Nagorney DM. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg. 2005 Sep;242(3):451-8.
- Sarwa Darwish Murad, W. Ray Kim, Denise M. Harnois, David D. Douglas, James Burton, Laura M. Kulik, Jean F. Botha, Joshua D. Mezrich, William C. Chapman, Jason J. Schwartz, Johnny C. Hong, Jean C. Emond, Hoonbae Jeon, Charles B. Rosen, Gregory J. Gores, Julie K. Heimbach. Efficacy of Neoadjuvant Chemoradiation, followed by Liver Transplantation, for Perihilar Cholangiocarcinoma at 12 US Centers. Gatroenterology 2012; DOI: 10.1053/j.gastro.2012.04.008
- Cancer in Norway 2013, Cancer Registry of Norway, Institute of Population-based Research. Oslo, Norway
Diagnostics of bile duct/gallbladder cancer
The clinical examinations carried out for the diagnosis of bile duct/bladder cancer focus on jaundice, tumors in the epigastrium, and enlargement of the liver and gallbladder. Work-up using CT, MR, ERCP and EUS has improved the selection of resectable patients.
- EUS (endoscopic ultrasound) is a relatively simple method for assessing local invasion and allows for taking specimens for cytology.
- CT is sensitive for detection of the primary tumor and metastasis. The examination provides good information about the extent of the tumor, especially the tumor's relation to surrounding vessels, and is the standard for diagnostics and stage determination.
- MRCP (magnetic resonance cholangio pancreaticography) is an MRI examination of the bile ducts and the duct system in pancreas. A contrast agent is usually used.
- ERCP (endoscopic retrograde cholangio-pancreatic ductography), possibly with brush cytology, is recommended when the common bile duct is dilated, and the cause is not revealed by ultrasound or CT.
- PTC (percutaneous transhepatic cholangiography) may be appropriate if the level of the tumor in the bile duct is unclear.
- Tumor marker CA19–9 is of limited value, but may cause suspicion of bile duct cancer. Tumor marker CEA and CA 19–9 may be a sign of gallbladder cancer with sensitivity and specificity of 50–70 %. Bilirubin > 75 µmol/l and elevated CA 19–9 is often a sign of a more advanced stage. CA 19–9 values > 400 U/ml are associated with an inoperable illness.
A stricture in the middle of the common bile duct is often a sign of gallbladder cancer. It is not uncommon that gallbladder cancer is first detected by histological examination after a regular cholecystectomy.
In some cases, tumors in the bile ducts or pancreas are difficult to visualize by external ultrasound or CT/MRI. Endoscopic ultrasound-guided fine-needle aspiration (EUS) allows for ultrasound visualization of the area with high resolution and improved possibility for tissue sampling.
- Cancer in the liver/bile ducts
- Cancer in the pancreas
- Tissue sampling of small lesions which are not suitable for a percutaneous examination.
- Survey the relationship of the tumor to adjacent structures, for example blood vessels, focusing on operability.
- Ultrasound duodenoscope with accessories
- Fine needle and equipment for preparing cytological specimens
- If the patient is treated with the anticoagulant warfarin, this must be discontinued 3 days before the examination when tissue sampling is an option.
- The patient must be fasting for 6 hours before the examination.
- The examination is normally performed under light sedation or local anesthesia sprayed in the throat.
- The patient lies on their left side on the examination table.
- A hollow mouth piece is put between the teeth for insertion of the scope.
- The scope is carefully inserted through the mouth down to the stomach and the duodenum.
- The ultrasound probe on the end of the endoscope is placed toward the stomach/intestinal wall. The rest of the examination focuses on the ultrasound images.
- If necessary, a needle can be inserted through the endoscope for aspiration of test material. The specimen is prepared and assessed by a cytologist.
- The patient may eat/drink at the earliest 1 hour after the procedure due to the local anesthesia of the throat.
- The examination is performed on an outpatient basis and the patient may return home after 1–2 hours.
- The result is usually available within a week.
Treatment of bile duct/gallbladder cancer
Surgical treatment of bile duct/gallbladder cancer can provide long-term survival. Twenty-five to thirty percent of patients with bile duct cancer are operable. There is a tendency for more aggressive surgical treatment.
Macroscopic and microscopic classifications of tumor growth are decisive for surgical treatment of gallbladder cancer. Involvement of lymph nodes in the hepatoduodenal ligament often occurs, but is not an absolute contraindication for surgery.
Definite signs of inoperability are:
- involvement of 2nd order of bile ducts
- peritoneal metastasis
- metastasis to aorta-caval lymph nodes
- distant metastasis
Chemotherapy is usually administered in the palliative setting.
Photodynamic treatment (PDT) may have a successful palliative effect for patients with inoperable bile duct cancer and obstructed bile ducts (2).
Palliative treatment in the form of endoscopic or percutaneous transhepatic dilatation or stenting is appropriate for symptoms caused by jaundice or cholangitis.
Surgery/intervention of bile duct/gallbladder cancer
When the hilum is affected, a resection of extrahepatic bile ducts combined with a formal/extended liver resection gives a better result than an isolated resection of bile ducts. Segment one should be removed to ensure that the procedure is radical. It is also possible that a routine resection of the portal vein, especially on the right side, will give a better result.
An isolated resection of bile ducts does not improve long-term survival (> 5 years).
Mortality related to this procedure is relatively high. Higher than normal morbidity is also reported after the surgical procedure. It is therefore recommended that surgical treatment is centralized.
A selected group of patients with bile duct cancer can be offered a liver transplantation accordance with the Mayo Protocol (8,9). This protocol combines preoperative external radiation therapy and brachytherapy together with chemotherapy (5-FU) before the liver transplant. The results show that patients with hilar cholangiocarcinomas without extrahepatic metastases have a similar five year survival as patients with benign liver diseases. A liver transplantation program for this selected group of cholangiocarcinomas started in 2009 in Norway. Patients to be considered must satisfy the following criteria:
- Diagnosis of irresectable hilar cholangiocarcinoma with intraluminal brush cytology, intraluminal biopsy, or carcinoma antigen (CA) 19.9 higher than 100 ng/ml combined with malignant stricture detected radiologically. Percutaneous biopsy is contraindicated.
- Largest diameter of tumor < 30 mm
- No sign of local local recurrence determined by CT or MRI taken within 3 weeks before assessment at transplant meeting.
- No sign of extrahepatic tumor growth assessed with CT or MRI and PET (thorax, abdomen, pelvis) taken within 3 weeks before assessment of transplant meeting. Skeletal scintigraphy should be performed.
- Age 18–65 years
- Good performance status, ECOG 0 or 1
- Satisfactory blood tests Hb > 9 g/dl, neutrophiles > 1.0 trc > 50, creatinine < 1.25 x upper reference value.
- A negative staging laparoscopy entailing retrieval of lymph nodes from the hepatoduodenal ligament for histological examination. This must be completed before start of radiation therapy.
- Completed work-up and approval for liver transplantation.
- No sign of lung metastasis assessed by CT of thorax immediately before the transplantation.
- No sign of extrahepatic tumor growth at peroperative lymph node dissection.
For tumors in stage 1 (T1a), a cholecystectomy is sufficient treatment to cure the disease.
For stage 2 tumors (T1b), long-term survival varies if only a cholecystectomy is performed. The gallbladder wall is often thin and it may be difficult to determine whether there is invasion. It is therefore recommended to perform an extended cholecystectomy for this condition. An extended cholecystectomy includes:
- Liver resection (segment 4b and 5)
- Extrahepatic resection of bile ducts with removal of lymph nodes in the hepatoduodenal ligament
- A hepatico-jejunostomy Roux-Y is installed with confluence from the right and left bile duct
For stage 3, an extended cholecystectomy is also performed. As in stage 2, an extrahepatic resection of bile ducts with removal of lymph nodes is performed in the hepatoduodenal ligament and a hepatico-jejunostomy is prepared.
For stage 4a, the same treatment plan is followed as in stage 3. A formal or extended liver resection is added.
For stage 4b, the disease is too advanced for surgical treatment to prolong survival.
Gallbladder cancer diagnosed at the histological examination
Patients who had their cancer diagnosis at the histological examination of the cholecystectomy specimen, should be assessed for reoperation. The depth of the tumor should be determined microscopically and the treatment must be determined according to this. Before the operation, the patient must be assessed by image diagnostics. If the cystic duct is not free of tumor growth, it is recommended to remove the extrahepatic bile ducts with installation of a hepatico-jejunostomy Roux-Y at the confluence from the bile ducts. At the same time, lymph node removal in the hepatoduodenal ligament should be carried out. There is consensus that if the gallbladder is removed by laparoscopy without a bag, the incision through the abdominal wall must be excised. Otherwise, all of the port sites are excised, however the benefit of this has not been conclusively documented.
A Whipple procedure is performed when there is suspicion of a malignant tumor in the head of the pancreas or adjacent organs such as the duodenum or bile ducts. The operation is also carried out for some cases of chronic pancreatitis.
A Whipple procedure is not performed if there is spreading of cancer to other organs or to peripheral lymph nodes. Invasion of blood vessels (especially the mesenteric artery and greater mesenteric vein) is also a contraindication. In some cases of limited vessel invasion, the operation can still be carried out in combination with vascular surgery.
The head of the pancreas is removed. Since the pancreas shares blood supply and lymphatic drainage with adjacent organs, some of the common bile duct is removed along with the entire duodenum and often the distal stomach . Finally, a reconstruction is performed where the small intestine is anastomosed to the remaining bile ducts, stomach, and remaining pancreas.
Mortality of the procedure is low, but postoperative morbidity is still significant. To reduce postoperative mortality, the patient should be operated at a hospital with a large volume of operations and after critical preoperative assessment of the patients.
- Tumor in the pancreas
- Tumor in the duodenum
- Tumor in distal end of the common bile duct
- Antibiotic prophylaxis
- Thrombosis prophylaxis
- Urinary bladder catheter
- Epidural catheter is installed for postoperative pain relief.
- The patient lies in the supine position.
- The operation is performed under general anesthesia.
A Whipple procedure consists of three steps:
- The procedure is performed via an angled, epigastric transverse incision.
- The abdominal cavity is inspected and palpated thoroughly.
- Inoperability criteria are:
- liver metastasis
- peritoneal metastasis
- invasion of the base of the mesentery
- infiltration of the peritoneal surface
- growth into adjacent organs (not the duodenum)
- Kocherization is completed when the duodenum and head of the pancreas are dissected off the underlying structures.
- The hepatic artery and the base of the gastroduodenal artery are dissected and identified by vessel loops.
- The common bile duct is dissected and the area of division is identified with a vessel loop.
- The superior mesenteric vein is dissected at the lower edge of the pancreas.
- The lesser sac is divided and the omental bursa is opened, and the caudal edge of the pancreas is isolated.
- The portal vein is bluntly dissected behind the pancreas to isolate the portal vein. The dissected pancreas is identified with a vessel loop.
- The gastroduodenal artery is divided at the origin from the hepatic artery.
- The small intestine is divided 8–10 cm distal to the ligament of Treitz using a GIA stapler. This apparatus inserts two double rows of staples and divdes the tissue between them in one operation.
- The stomach is divided at the angulus, also with a GIA. The staple suture is inverted manually with sutures.
- A cholecystectomy is performed.
- The pancreas is divided with a knife between the head and body.
- The loop around the common bile duct is removed and the duct is divided.
- The tissue between the head of the pancreas and the portal vein and superior mesenteric artery is divided by dissection towards the vessels. The specimen is now free to be removed.
- The pancreas is anastomosed end-to-side to the distal small intestine with interrupted sutures.
- The common bile duct is anastomosed end-to-side further down on the small intestine. The anastomosis is performed with running sutures posteriorly and interrupted sutures anteriorly.
- The stomach is anastomosed side-to-side to the small bowel. The anastomosis is created with a GIA or with sutures. The opening from the GIA is closed with running sutures.
- The abdomen is flushed and a drain is placed in the anastomosis area.
- The abdominal wall is closed by two layers of running sutures. The skin is closed with staples.
- The surgical specimen is marked by the surgeon and sent to the pathologist.
- Epidural pain relief is usually given for 3–5 days and helps the mobilization of the patient.
- The patient often has a naso-gastric tube for the first 24 hours.
- The patient may drink as soon as he/she would like to.
Possible serious complications are often due to:
- Failure in one or more anastomoses
- Abscess and/or sepsis
Less serious complications involve delayed gastric emptying. Thus, long-lasting delay of stomach emptying should raise the suspicion of an underlying intraabdominal complication.
After a complication-free postoperative stay, the patient is usually transferred to a local hospital after about 1 week and is discharged after 10–14 days.
When histology report from the surgical specimen is available, treatment with chemotherapy will be considered.
The patient is usually followed up by their primary care physician after treatment is completed.
- Patients having stomach resections may develop vitamin B12 and iron deficiencies. Hemoglobin should be checked every 4 months and a B12 injection is recommended.
- Exocrine insufficiency can occur. This is treated with pancreatic enzymes in tablet form.
- After a pancreatic resection, there is an increased risk for developing diabetes and the patient must be informed about the initial symptoms of diabetes mellitus.
Endoscopic retrograde cholangiopancreatography (ERCP) provides an X-ray image of the bile ducts and pancreatic ductal system by direct injection of contrast into the ductal system.
The technique also provides access to both extended diagnostics and therapeutic procedures for the bile ducts and pancreas.
The procedure can be performed on an outpatient basis and is similar to gastroscopy. If a therapeutic procedure is performed, the patient often stays in the hospital for observation.
For ERCP, a duodenoscope is used which is a special gastroscope with side viewing optic. This makes it significantly more suitable to manipulate the duodenal papilla, however navigation is more difficult. Various customized instruments can be passed through the instrument canal of the endoscope and further on through the papilla.
Cancer in the pancreas or liver/bile ducts:
- Diagnostic technique for ambiguous cases (visualization of ductal system and possible brush sampling or biopsy)
- Preoperative bile/pancreatic duct decompression
- Symptom relieving drainage of bile/pancreatic ductal system in cases of inoperable cancer
- Local removal of early stage cancer in duodenal papilla
A common feature is that all of these indications include therapy. Diagnostic ERCP is applied to a diminishing degree, but may still be used for collecting tissue samples (cytology or biopsy).
- Obtain a diagnosis
- Drain stenotic ductal systems
- Side optic endoscope (duodenoscope) with accessories
Plavix®, Clopidogrel®, Brillique®, Pradaxa®, Xarelto®, Eliquis®, Fragmin® or Marevan® (warfarin) should be stopped to reduce the risk of bleeding during the procedure, if the patients general practitioner doesn´t decides otherwise.
- Plavix®, Clopidogrel® and Brilique® may be taken up to seven days before the procedure.
- Pradaxa®, Xarelto® and Eliquis® may be taken up to 48 hours before the procedure.
- Marevan® (warfarin) may be taken up to 48 hours before the procedure, and the patient must also have an INR control at least an hour before the examination.
- The patient may continue to take Albyl-E® (acetylsalicylic acid).
- Fragmin® injections may be taken until the night before the procedure.
- If the patient has an artificial heart valve, contact the ward in charge of the excamination.
The stomach must be empty before the procedure.
- The patient can´t eat or drink anything in the last six hours before the procedure.
- If the patient is very thirsty he/she may drink 1-2 glasses of water until two hours before the procedure, and then only rinse the mouth without swallowing anything.
If the patient have diabetes and use insulin or other essential medecines that can´t be postponed, the patient can get an appointment early in the day.
The procedure is usually carried out under light sedation with Dormicum®/Pethidin®, however propofol-anesthesia is becoming more common. General anesthesia is only exceptionally use.
- The procedure is performed with the patient on the stomach with the right side slightly raised.
- The endoscope is inserted carefully through the mouth and stomach to the duodenal papilla.
- A thin plastic tube is manipulated into the bile duct or pancreatic duct and contrast fluid is injected to visualize the ductal system, and an X-ray picture is taken simultaneously.
- If necessary, a brush or biopsy forceps is inserted into the duct for sampling.
- If necessary stenotic areas can be expanded with a balloon, plastic tubing, or a stent.
The patient can often return home the same day, unless a procedure is performed which increases the risk for complications. This is determined on an individual basis.
Results from biopsies are usually available after 1 week.
If a stent is inserted, this must usually be removed or changed after 2–3 months by a repeated ERCP procedure.
Most ERCP procedures are carried out without complications. It is common to have a sore throat and light abdominal pain (including gas pain) after the procedure.
Pancreatitis is the most threatening complication and occurs in 4–15% of cases. There are some known risk factors, most significantly previous ERCP pancreatitis and possibly ampullary dysfunction. However, pancreatitis occurs for unknown cause. Fortunately, most cases are mild with only abdominal pain requiring a few extra days in the hospital. However, necrotizing pancreatitis also occurs with significant mortality.
Other, less frequent complications are cholangitis, bleeding, or perforations after endoscopic papillotomy. If any of these are discovered during the examination, they are usually treated conservatively without the need for surgery or other intervention. Delayed bleeding (within 24 hours) also occurs and will often require a repeat endoscopic procedure for treatment.
Generally, only jaundice which causes symptoms is treated. Itching which is not relieved by antihistamines and socially unacceptable jaundice are indications for treatment. Patients with long-lasting jaundice should receive potassium to reduce the risk for bleeding disturbances. This should be administered parentally due to poor intestinal uptake.
Drainage of the bile ducts with a stent using endoscopy is the primary option. Compared to open surgery, this procedure has low acute morbidity, but cholangitis and recurrence of jaundice is more common than after surgical anastomosis. The total morbidity throughout the entire disease period should therefore not be underestimated. Plastic endo-prostheses are usually changed after 3 months due to deposition of bile salts, which can obstruct the stent and cause recurrence of jaundice. An alternative is to install a self-expanding metal stent for patients with a longer survival.
Percutaneous transhepatic drainage
Percutaneous transhepatic drainage combined with external/internal transhepatic drainage is reserved for patients where the endoscopic technique is unsuccessful. PTC treatment is painful for the patient and is often carried out under sedation and analgesia, or possibly under general anesthesia. In addition, there is a risk for both bleeding and sepsis. This technique should therefore be secondary to the ERCP technique.
Surgical enterobiliar anastomosis has a higher treatment mortality and morbidity than an endoscopic tent but usually remains open for the patient`s remaining survival time. A cholecystojejunostomy can be performed if the cystic duct is well expanded and opens sufficiently into the bile duct with a safe distance from the tumor. A choledochal duodenostomy gives successful results if the tumor does not grow too high into the hepatoduodenal ligament. Alternatively, an anastomosis can be made between the common hepatic duct and either the duodenum or a jejunal Roux loop.
Exploration is not recommended if only installing an enterbiliary anastomosis. In these cases, endoscopic or percutaneous drainage should be performed instead. If a non-resectable tumor is found by laparotomy, surgical by-pass is recommended as routine treatment.
Drug therapy of bile duct/gallbladder cancer
According to a randomized phase III study from Japan, adjuvant chemotherapy has little effect and is usually not recommended, unless it is administered in connection with a study.
Cholangiocarcinoma is relatively sensitive to chemotherapy (2, 3). A Nordic study has shown an increase in survival with 5FU compared to BSC (6.5 months versus 2.5 months) (4).
There are a series of phase II studies using newer chemotherapy drugs and combination regimens that have given response rates of 20–40%, and prolonged survival for 5–15 months (2, 3). However, there is no established international standard treatment. Downstaging with conversion to secondary surgery and long-term survival has occurred.
Patients with metastasis and good general health status with acceptable bilirubin values should be assessed for palliative chemotherapy. Appropriate regimens are cisplatin or oxaliplatin-based chemotherapy, combined with capecitabine or gemcitabine.
Radiation therapy of bile duct/gallbladder cancer
If resection margins are not free, it should be assessed whether postoperative chemotherapy in combination with radiation therapy can be given. There are no prospective randomized studies showing increased survival with administration of adjuvant radiation therapy or chemo/radiation therapy for bile duct/gallbladder cancer. Retrospective studies indicate an increase in survival after radiotherapy when the surgical resection margins were not free from cancer.
For locally advanced inoperable cancer, the main problem is local progression of the tumor, not metastasis. Multiple radiation therapy studies and studies using combination regimens of chemotherapy and radiation have shown effectiveness for local control, pain, and biliary decompression. The effect of radiation therapy is probably dependent on a high radiation dose (> 55 Gy).
For locally advanced inoperable cancer, chemotherapy with or without combination with radiation therapy can be administered (1).
Complication treatment of bile duct/gallbladder cancer
Surgery, chemotherapy, and radiation therapy cause side effects to varying degrees.
It may be necessary to provide supportive care in order for the patient to complete and obtain the full effect of planned treatment.
Supportive care can also be provided to reduce side effects and improve the patient's quality of life during and after treatment.
Neurolytic procedures can produce long-term blocking by destroying nerve tissue. This kind of nerve blockage lasts until the nerves regenerate. Pain is not only conducted by the afferent and sensory nerve fibers, but also the sympathetic nerve system. Most neurolysis procedures are directed toward the sympathetic nerve structures.
Today, by means of CT guidance, the neurolytic drug can be injected with high precision with a minimal risk of exposing the surrounding structures to the neurolytic chemicals. CT guidance also provides for a better possibility for optimal placement of the needle in cases where tumor masses have changed the normal anatomical conditions of the retroperitoneal room. The procedure is performed in cooperation with interventional radiologists.
Invasive techniques still play an important role in treating cancer pain in a correct selected group of patients. The quality of the blockages increases when the procedure is guided by imaging and with the help of an interventional radiologist. Neurolytic blockades should never be considered an isolated treatment form, but as part of a broader treatment strategy, where one of the goals is to reduce the need of strong opioids and other analgesic.
Celiac plexus neurolysis is the most common neurolytic blockage for patients with pain associated with cancer. It has been shown that patients with pancreatic cancer can obtain significant pain relief from a single (sympathetic nerve) blockade for the remainder of their life, on condition that distribution to sympathetic nerves are satisfactory.
Access to the celiac plexus is reached by:
- Posterior antecrural or retrocrural access. May be done with C-bow, but preferably CT.
- Endoscopic ultrasound-guided access (via gastroscopy with ultrasound.)
- Open abdominal. Neurolysis can be performed preoperatively (in connection to exploratory laparotomy.)
Pain, often deep, diffuse and localized to the upper abdomen with radiating pain to the back. This treatment is primarily for patients with pancreatic cancer, but also those with malignant tumors in the upper abdomen, suffering from visceral pain, may benefit from this blockage.
Refractory nausea for the same patient group.
Neurolysis of the celiac plexus (sympathetic nerves) may be appropriate for different cancer types in the upper abdomen, but is mostly utilized for pancreatic cancer. Visceral pain is the one that can be alleviated by this blockade. Sensory and sympathetic nerve fibers from all organs in the upper part of the abdominal cavity, including bowel up to and including proximal part of colon, goes through the celiac plexus.
Improved pain control and reduced side effects from opioid pain relievers due to dosage reduction.
- Needles (22 G) and equipment for local anesthesia.
- Contrast medium to confirm correct position before the neurolysis.
- Local skin anesthetic also for testing effect ahead of the neurolysis.
- Alcohol, concentration minimum 50%.
- Intensive care with vital signs (pulse rate, blood pressure, EKG and SaO2).
- Medications for sedation and pain relief.
- Blood tests: INR, thrombocytes and hematological tests, leukocytes, CRP, electrolytes and kidney function.
- Agreement for possible cessation of anticoagulants and antiplatelet agents is made individually.
- Any fasting ahead is agreed individually for each patient. Some sedation is common in addition to local anesthesia. If the patient requires deep sedation/sleep, fasting for 6 hours before the procedure is necessary.
- Prone, supine, or lateral position. Anterior access is primarily used when the patient cannot lie on their abdomen or the lateral decubitus position or when anatomical conditions do not allow posterior access.
The celiac plexus (sympathetic nerve fibers) lies retroperitoneal at the level of the L1 vertebra. The fibers are arranged as a network in front of the aorta and around the celiac trunk.
- With the patient in the prone or lateral position, the needle is inserted at level of the T12 and L1 vertebrae using local anesthesia.
- The direction of the needle is guided by CT. The needle is guided a few cm to the side of the midline on each side of the spine with the tip close to both sides of the aorta.
- After a test dose of local anesthesia, and confirmation of correct position by injection of contrast medium, 75-95% alcohol is injected, 20-30 ml on each side.
- In some cases it may be difficult to achieve good dispersion of the neurolysis because of tumor masses filling up the retroperitoneal space. In such cases the blockade may be inserted retrocrurally, also at level of the T12 and L1, but with less volume. The effect is then substantially as a result of blockade of the splanchnic nerves proximally to the celiac plexus.
Complications can occur but are uncommon.
- Temporary side effects in the form of orthostatic hypotension and diarrhea are relatively common the first 24-48 hours.
- Back pain, usually in the form of soreness for 2-4 days is experienced by some.
- Retroperitoneal bleeding, aortic dissection and paraplegia are very rare, but have been reported.
The majorities of chemotherapy drugs are emetic to varying degrees and may cause nausea and vomiting. Today, there are efficient antiemetic drugs that can significantly reduce the side effects.
Other factors that can aggravate or prolong the presence of nausea and vomiting are: pain, anxiety, electrolyte disturbances, constipation, dyspepsia, and ulcers.
There is a distinction between acute nausea, which occurs within the first 24 hours, and late nausea, which occurs later than 24 hours after the treatment.
Acute nausea can be effectively treated with 5HT3-antagonists (ondansetron, tropisetron, palonosetron), and possibly combined with steroids. Dopamine antagonists (metoklopramid, metopimazine) also have some effect on acute nausea. If this treatment is not effective, it may be improved with aprepitant.
If standard prophylaxis and treatment of nausea is not satisfactory, other nausea regimens should be tried.
- Nausea induced by chemotherapy drugs.
- Prevention and treatment of nausea and vomiting.
|Chemotherapies according to emetic potential
|All cisplatin-containing regimens (CiFu, GemCis, BEP, TIP, VIP, PV, AP, EDP, DHAP, ECX, weekly dose cisplatin, and others)
||BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosfamide, vincristine, prokarbazine, prednisolone)
|Doxorubicin/epirubicine weekly dose
|FEC-60 og FEC-100
(fluorouracil, epirubicin, cyklophosfamide)
| ENAP (etoposide, mitoxsantrone, cytarabine, prednisolone)
|ABVD (doxorubicin, bleomycin, vinblastine, dakarbazine
| FLv (fluorouracil)
| FuMi (fluorouracil, mitomycin)
|CHOP (cyclophosfamide, doxorubicin, vincristine, prednisolone)
|CHOEP (cyclophosfamide, doxorubicin, vincristine, etoposide, prednisolone)
|Methotrexate weekly dose
||ECO/ACO (epirubicin/doxorubicin, cyclophosfamide, vincristine)
||EOX (epirubicin, oxaliplatin, capecitabine)
||EPOCH-F (etoposide, prednisolone, vincristine, cyclofosfamide, doxorubicin, fludarabine)
||EPOCH-F (etoposide, prednisolone, vincristine, cyclophosfamide, doxorubicin, fludarabine)
||FLIRI (fluorouracil, irinotecan)
||FLOX (fluorouracil, oxaliplatin)
||IGEV (ifosfamide, gemcitabine, vinorelbine)
|| IME (ifosfamide, methotreksate, etoposide)
|| Vorphase (cyclophosfamide)
- Lehne G, Melien Ø, Bjordal K, Aas N, Mella O. Kvalme og oppkast ved cytostatikabehandling i: Dahl O, Christoffersen T, Kvaløy S, Baksaas. Cytostatic Medication cancer treatment. 7. edition. Oslo. Department of Pharmacotherapeutics and The Norwegian Cancer Society, 2009, p 119-130.
Nausea regimens are selected according to the emetogenicity of the relevant drugs.
- Inform about the risk for and treatment of nausea.
- In the event of anxiety or conditional nausea, give tranquilizers if necessary.
- Start with an optimal antiemetic regimen starting with the first cycle of chemotherapy in order to counteract the amplification of the nausea that often occurs with a new treatment.
- Start the oral antiemetic regimen 1-2 hours before chemotherapy and approx. 15-30 minutes before an intravenous injection.
- If the patient is already nauseous, the medication should be administered parenterally or rectally.
Mildly emetic chemotherapy
- Metoclopramide 10 mg is given intravenously before treatment with cytostatic agents.
- Metoclopramide 10 mg is given orally uptil 3 times.
Moderately emetic chemotherapy
Ondansetron 8 mg orally 2 x daily. In the event of nausea before treatment, give ondansetron intravenously. If this has little effect, try ondansetron 8 mg x 3 or change to a 5HT3-antagonist, for example, tropisetron 5 mg orally/intravenously or palonosetron 250 µg intravenously.
Highly emetic chemotherapy, or if other treatment does not help
For highly emetic chemotherapy drugs, or if other treatment is not adequate, a 5HT3-antagonist can be given orally or intravenously. It should be combined with dexamethasone 8-16 mg intravenously ½-1 hour before treatment, and further, 8 mg x 2 intravenously or orally on the first day.
In addition, dopamine antagonists may be given, for example, metoclopramide 10 mg x 3.
In some cases, traditional nausea treatment is not sufficient. In this case, the patient can be treated with aprepitant. Aprepitant is used for highly emetic regimens and for patients where the usual antiemetic treatment has failed during moderate emetogenic treatment. Aprepitant is given orally 1 hour before chemotherapy and is combined with dexamethasone and 5HT3-antagonists: 125 mg capsules orally on day 1, then 80 mg orally on days 2-5, depending on the duration of the treatment. Aprepitant can enhance the effect of taxane and etoposide, as well as vinorelbine, and can reduce the effect of warfarin.
The regimen is repeated daily if highly emetic treatment is given over a number of days.
Aprepitant in combination with dexamethasone and 5HT3-antagonists is preferable if there is a high risk of delayed nausea and vomiting. This is offered especially to patients who have previously experienced delayed nausea.
In the event of conditional nausea, diazepam or other tranquilizers may be considered. Diversion or desensitization can be tried in more serious cases.
Ondansetron can have a constipating effect. Use of a laxative for several days should be considered.
Monitoring the patient's nutritional status is an important part of cancer treatment. The goal is to identify malnutrition as early as possible in order to initiate treatment as quickly as possible.
Measures include diet according to symptoms and the nutritional condition. The patient should be offered nutrition-rich food, snacks, nutritional drinks, tube feeding and intravenous nutrition.
Because cancer treatment breaks down both cancer cells and normal cells, the body requires an adequate supply of nourishment to increase growth of new cells.
In cancer patients, the sensation of hunger is not always present to the necessary degree. In these cases, it is important to take actions to improve the nutritional status of the patient. The nutritional condition is easiest followed by monitoring body weight over time.
- Cancer treatment (chemotherapy, radiation, surgery).
- Maintain nutritional status in order for the patient to have the best possible conditions for implementing treatment.
Subjective Global Assessment (SGA)
Subjective Global Assessment (SGA) is a scheme for classifying the patient's nutritional status.
Other tables that are frequently used are Malnutrition Universal Screening Tool (MUST), Mini Nutritional Assessment (MNA) and Nutrition Risk Score (NRS). In principle, these schemes are prepared in the same way as SGA, but they are not validated for patients with cancer.
Weight loss is one of the most important signs of change in nutritional status. A weight loss of more than 15% over the past 6 months or more than 5% over the last month is a significant and serious weight loss. If the weight loss occurs in combination with low BMI (body mass index) (< 20 kg/m2 for adults) and/or a food intake of less than 60% of the calculated requirement over the past 10 days, the patient will be malnourished or be at nutritional risk.
Calculation of nutrition and fluid requirements
Ambulatory patients: 30-35 kcal/kg/day
Bed-ridden patients: 25-30 kcal/kg/day
Elderly above 70 years: Recommended amount is reduced by 10%
Fluid requirement: 30-35 ml/kg/day
Nutritionally enriched diet / enrichment of food and beverages
Nutritional beverages may be used as a meal in itself or between meals. Nutritional drinks can be a more valuable snack than "normal" food, because it is often easier for the patient to drink than to eat. It has been shown that if nutritional drinks are introduced as snacks, it does not affect the energy intake during the main meals.
There are a number of ready-made nutritional drinks on the market. Some of the products are of nutritionally complete. They contain carbohydrates, protein and fat and are supplemented with all the necessary vitamins, minerals and trace minerals and possibly fiber. Some of these products can be used as the sole source of nutrition. The energy content varies from 85-200 kcal/100 ml and some products have a high protein content. Other nutritional drinks are supplement drinks adjusted to individual needs such as allergies, intolerance and special conditions associated with illnesses.
The products are also adapted to age, and the dose is determined individually by a clinical dietician/doctor.
Many patients prefer homemade nutritional drinks based on full fat milk, cream, ice cream, fruit and possibly flavor supplements. These are free of additives and have a fresher taste. The energy and protein content is close to the commercial products and at the same time they are more sensibly priced.
Tube feeding is preferable to total parenteral nutrition (TPN) when the digestive system is working. Nutrition supply to the intestine is more physiological. It protects against bacterial growth, maintains the intestine's mucous membrane structure and function, and promotes motility. Tube feeding involves less risk of metabolic complications.
Tube feeding is used in the event of
insufficient food intake (less than 60% of energy requirements) over the past 5-7 days despite oral intake
weight loss >2 % over the past week, >5 % over the past month or >10% over the past 6 months
danger of weight loss due to planned treatment
low albumin values (under 35 g/l, lower limit for normal area)
stenosis with feeding obstacles in pharynx/gullet
Tube feeding must not be used for the following conditions.
Paralysis or ileus of the alimentary tract
Short bowel syndrome
Serious acute pancreatitis
Obstruction of the intestine
Serious fluid problems
Tube feeding solutions
The tube feeding solution must be nutritionally complete because they shall be used as the sole source of nourishment. The most frequently used are standard (1 kcal/ml), fiber-containing (1 kcal/ml) or energy-rich (1.5 kcal/ml). There are also tube feeding solutions which are adapted to patients with digestion and absorption problems, patients with diabetes or lactose allergy, and intensive care patients.
Tube feeding solutions, which are adapted to cancer patients are energy-rich (1.5 kcal/ml). They contain extra omega-3 fatty acids, rich in MCT acid and enriched with extra vitamins and minerals. Recommended dosage is 500 ml/day.
Parenteral nutrition should only be used if food by mouth or tube feeding cannot be maintained. Parenteral nutrition can also be used as a supplement to tube feeding or ordinary food.
Precautions must be taken for kidney failure, heart failure, lung failure, large fluid and electrolyte loss, diabetes mellitus and liver failure.
The patient is classified as well-nourished, somewhat malnourished or seriously malnourished on the basis of information about weight development, food intake, symptoms and physical functioning. This classification has been shown to correlate well with more objective measurements of nutritional status and morbidity, mortality and quality of life.
Actions include individual adjustment of diet according to symptoms and nutritional status.
The end of the tube is often inserted into the stomach. In the event of poor gastric function, total gastrectomy or pancreatic resection, the feeding tube should be inserted in the duodenum or jejunum. The position of the feeding tube is vital for the choice of feeding-tube solution and mode of administration.
The most common solution is to insert the tube nasogastrically, but it can also be done through the abdominal wall (PEG).
It is preferable to use intravenous or parenteral nutrition as a supplement to oral/tube feeding instead of only TPN (total parenteral nutrition).
Central veins must be used for TPN with high osmolality.
Peripheral veins can be used for short-term parenteral nutrition. In this case, a large vein on the forearm is used and a small needle. Nutrition is then given as more diluted solutions.
ImplementationAll patients are weighed regularly (1–2 times each week). This is a prerequisite to being able to register changes in the nutritional status.
Varied and healthy food contributes to the growth of new cells and enhances the immune system.
- Fruit, berries and vegetables are rich in vitamins, minerals, antioxidants and fiber, which contribute to enhances the immune system and contributes to keeping the digestive system working.
- Fish, shellfish, poultry, meat, eggs, cheese, milk, beans and nuts are rich in proteins, which are the building blocks of new cells.
- Bread, rice, pasta, porridge and breakfast cereals supplement the diet with proteins, carbohydrates, fiber, vitamins and minerals.
- Oil, margarine, butter, mayonnaise products, nuts, cream, heavy cream, desserts etc. are fat and energy rich products, which are important to maintain the energy intake at a satisfactory level.
- Cancer patients also have a requirement for plenty of fluid, especially during treatment, to discharge waste.
Often, the patients must have an individually adjusted diet. In the event of lack of appetite, it is generally more important that you eat (enough food) than what you eat (the right food). It is beneficial to have small portions and for the food to be as abundant in energy as possible. These patients will often have a need for 6–8 small meals everyday to obtain their energy requirements.
Enrichment of food and drink is done in order to increase the energy content of the food product without increasing the volume. Full-fat products such as full-fat milk, cream, butter, heavy cream, mayonnaise, sugar, honey, eggs and cheese etc. are primarily used. Enrichment powders from pharmacies may also be used. Some powders are nutritionally complete, i.e. they contain everything the body requires in terms of energy and nutrients, while others only contain pure energy (carbohydrates, fat and/or protein).
Tube feeding is given continuously with a low drop rate or by interval/bolus administration (individually adapted meals with high drop rate).
When the patient's energy and fluid requirements are fulfilled, it will be decided whether the patient will be given bolus or continuous supply at night, in order to increase mobilization during the day. However, this requires that the patient does not have diarrhea, nausea or other complaints associated with the supply of nutrition.
For a running feeding tube:
- Every 4-8 hours, it should be aspirated in order to monitor the gastric emptying. This applies especially to immobile and weak patients.
- Weekly or more often, the nutrition program/fluid balance, evaluation, edema control, blood tests (albumin, K, Mg, P, blood glucose) should be monitored weekly or more often.
- Every 4-6 weeks, the tube should be changed. Alternate the uses of nostrils avoid irritation in the nose through prolonged feeding.
Experience shows that the use of infusion pumps causes fewer side effects and ensures correct volume and rate.
Initiation of tube feeding with bolus supply is only recommended
- if the patient been taking any food until the last 24 hours
- if the patient is taking some food and requires tube feeding for additional nourishment
It is recommended to use pumps for bolus supply for the first 1–2 days.
If the patient cannot tolerate bolus supply (vomiting, abdominal discomfort, nausea, diarrhea), reverting to continuous supply should be considered.
Tube feeding should always be administered continuously to very malnourished patients or if the tube end is located distally to the pylorus.
If the patient has a satisfactory nourishment status, begin with 100% of the requirement. If the patient is seriously malnourished, start with 80 % of the requirement and increase slowly to 100% over the course of three days.
The patient must be monitored closely in relation to
- electrolytes (potassium, phosphate and magnesium).
- infusion rate.
- twenty-four hour urine sample and fluid balance should be calculated daily.
- glucose in the blood and urine, and electrolyte in the blood should be examined daily at the start.
- liver tests, kidney function tests and triglycerides should be taken examined at least once every week.
For TPN treatment longer than 1 month, vitamins and trace elements should be examined.
The patient's nutrition status should be monitored at follow-up visits after the end of treatment.
Febrile neutropenia occurs in compromised immune systems due to a low number of leukocytes, especially granulocytes. Patients with a declining number of granulocytes after chemotherapy, can during bacterial sepsis, quickly develop extensive neutropenia and become critically ill. Febrile neutropenia can be a life-threatening condition.
A patient with neutropenia and simultaneous fever or clinical suspicion of systemic infection should be treated as quickly as possible with broad spectrum antibiotics including gram-negative and gram-positive coverage as soon as the required microbiological samples are taken.
The clinical situation is most critical in patients who have not yet started antibiotic treatment. When broad-spectrum antibiotic treatment is started, monitoring the fever may be permitted.
Fever is often the only symptom. Some have septicemia without fever. One should therefore also be aware of other symptoms such as lethargia, diarrhea, or visible sign of infection. The local clinical symptoms and signs (redness, pain, temperature increase, swelling (boil), and reduced organ function) are most often very much reduced or completely absent during neutropenia.
- A patient with neutropenia and simultaneously fever or clinical suspicion of systemic infection
- Avoid septicemia.
- The patient is able follow the planned scheme of treatment.
Fever is defined as:
- a single (rectal) temperature ≥ 38.5 °C or
- temperature ≥ 38 °C for more than 2 hours or
- temperature ≥ 38 °C measured three times during 24 hours
There is a known increase of infections when neutrophil < 1.0 x 109/l. The infection risk increases with degree and duration of neutropenia. The neutropenia is considered severe when granulocytes are ≤ 0.5 x 109/l.
The following diagnostic tests should be performed:
- Adequate microbiologic tests: blood culture x 2-3, throat/nasopharynx, urine, catheter opening any surgical incisions. All blood cultures should be taken simultaneously to avoid losing valuable time.
- Blood culture and other microbiological samples should be taken before antibiotic treatment is started
- Blood tests with differential count of leukocytes, thrombocytes, Hb, CRP, SR, creatinine
- X-ray of chest
Before initiation of chemotherapy, the patient should be extensively informed, both verbally and in writing, of febrile neutropenia and its consequences.
A patient who can develop febrile neutropenia should obtain a written statement of the condition to present to other treatment providers.
Use of an isolated or private room
Patients with neutrophil granulocytes ≤ 0.3 x 109/l should have a private room if possible. Guidelines for protective isolation should be followed. Thorough washing of hands is especially important.
- Treatment is started as soon as possible. Treatment may be postponed a maximum of 30 minutes to complete microbiological testing.
- Start septicemia treatment for fever if neutropenia is expected, regardless of granulocyte value.
- Benzylpenicillin sodium 5 mg IE x 4 tobramycin or gentamicin 5-10 mg/kg x1
- Tazocin® 4 g x 3
- Cefotaxime® 1 g x 4 if aminoglycoside should be avoided
- Ceftazidim® 1 g x 4 with suspicion of pseudomonas infection
- Meronem ® 0.5 g x 4 usually 2nd or 3rd choice
When using aminoglycoside, the first dose should be high. Keep in mind the following:
- kidney function
- fat index
Otherwise, the dose should be decided from concentration of aminoglycoside determined after the second day and thereafter monitored 2x per week.
Serum concentration of tobramycin and gentamycin
For single dose in 24 hours
- Trough concentration (0-test = 24 hour test) < 0.5 mg/l
- Top concentration (30 minute after infusion is completed) > 12 mg/l
For multiple doses in 24 hours
- Trough concentration < 2 mg/l, top concentration (30 minutes after the infusion is completed) preferably > 8-10 mg/l
- Avoid aminoglycoside :
- If kidney function is reduced. Avoid aminoglycoside if cisplatin is used. If cisplatin has been previously used, many patients will have subclinically reduced kidney function. If necessary, use aminoglycoside for a short period and monitor kidney function closely.
- If carboplatin is used, determine glomerulus filtration rate (GFR) for each new treatment. Penicillin/aminoglycoside can be used if GFR is stable (has not declined more than 15% if initial value is in the normal range)
- With sarcoma: Protocols with very high doses methotrexate and ifosfamid (> 5 g/m2) should be used in sarcoma treatment. It is not abnormal for these patients to have an increase in creatinine.
- with massive ascites
- with suspicion of or documented myeloma kidney (myelomatosis)
- If aminoglycoside has been used in the past two weeks
- Suspicion of staphylococcus aureus as a cause of infection (relatively rare)
- Give penicillinase-stable penicillin, cloxacillin, or dicloxacillin, possibly clindamycin instead of ordinary penicillin. Yellow staphylococci are also killed by cefotaxime and by merop
- Gram-positive cocci in multiple blood cultures and if the patient has clinical signs of infection
- Use vancomycin 500 mg x 4 until resistance determination is available
- Poor patient condition and suspicion of gram-negative septicaemia
- Use “double gram-negative” with for example ceftazidim or tobramycin
- Other preparations with good effects against most gram-negative bacteria are meropenem and ciprofloxacin
- Suspicion of anaerobic infection
- Use an anaerobic drug: Metronidazol 500 mg x 3, clindamycin 600 mg x 4, piperacillin/tazobactam 2g x 4 or meronem 500 mg x 4. This especially applies if there is suspicion of anaerobic infection under the diaphragm such as gallbladder, intestines, perforation, abscess.
- penicillin is often adequate for anaerobic infections above the diaphragm.
With continuing clinical signs of infection, adjust the antibiotic treatment according to resistance determination in blood culture. Maintain gram-negative coverage.
Systemic fungal treatment
By persistent fever after multiple days with broad spectrum antibiotic treatment, one should consider empirical treatment of possible candida-sepsis, for example with fluconazole 600 mg the first 24 hours, and thereafter 400 mg x 1.
If candida is documented without adequate response to fluconazole, a fungicide drug should be used, for example amphotericin B.
If suspected infection with Aspergillus apply voriconazole, amphotericin B or caspofungin.
Observe for symptoms of a new infection.
Transfusions of blood components are often necessary for the patient to complete the planned cancer treatment.
Blood transfusions are appropriate for low hemoglobin (Hb) and thrombocyte transfusions for low thrombocytes (trc) which also poses a risk for serious bleeding.
- Hemoglobin 13.4–17 g/dl
- Platelets 145–348 109/l
Assessment for a blood transfusion based on:
- symptoms/sign/function level
- underlying disease (heart/lung, serious infection)
- expected development of anemia (marrow function, current bleeding)
- acute blood loss > 15% of total blood volume
- Hb < 8.0 g/dl and symptom causing chronic anemia
- Hb < 8.0 g/dl and reduced bone marrow production without sign of regeneration
- Hb < 8.0 g/dl in perioperative period
- Hb < 7.0 g/dl in patients without symptoms of other disease
- Hb < 10.0 and receiving radiation therapy
The patient is assessed for thrombocyte transfusion based on:
- clinical status (bleeding, bleeding tendency, or fever/infection)
- ongoing bleeding and thrombocytopenia < 50x19/l
- degree of thrombocytopenia and cause of thrombocytopenia (reduced production or increased consumption)
Prophylactic platelet transfusion
- For values < 10x109/l secondary to previous chemotherapy
- Before invasive procedures
- For spinal puncture and installation of central vein catheter, thrombocytes should be 30x109/l and
- Puncture biopsies (liver/kidney/tumor) > 40x109/l
- For major surgeries, thrombocytes should be > 50x109/l. After surgery, thrombocytes should be monitored and transfusion repeated, if necessary.
Remember clinical evaluations: possible bleeding, other risk factors for bleeding, diagnosis, treatment, prognosis.
- Complete the planned treatment
- Ensure hemostasis
- Ensure adequate oxygen transport to peripheral tissue.
- Maintain intravascular fluid volume for adequate circulations of vital organs
For a blood transfusion for anemia, SAGMAN erythrocytes are used. One unit is obtained from 450 ml blood. Most of the plasma is removed and replaced with 100 ml SAGMAN solution (Saltwater-Adenine-Glucose-Mannitol). Hematocrit is about 0.60%.
One unit contains 240-300 x 109
platelets and is prepared from blood donors with type O and A. In acute situations, the receiver's blood group is of minor importance.
Two kinds of platelet products are available:
- Apheresis platelets produced from thrombophereses from one donor
- Buffcoat platelets produced from buffy coat from 4 donors
All cellular blood products should be leukocyte filtered. Leukocyte filtration is done to remove antigen-presenting and virus-bearing cells. 99.99% of leukocytes in the unit are removed.
Blood and thrombocytes are irradiated to a minimum of 25 Gy in the blood bank to eliminate T-lymphocytes.
This is done for:
- Bone marrow transplant or stem cell transplant (1 month before or 3 months after HMAS until 1 year after allogeneic stem cell transplant)
- For use of HLA-compatible platelet concentrations
- For all transfusions from relatives
- For use of fresh blood
- For use of fludarabine
Before the first blood transfusion, the following blood tests are performed:
Every three days, and as needed, pre-transfusion tests are taken.
Erythrocyte concentration—Rh(D) negative products can usually be given to everyone while Rh(D) positive can only be given to Rh(D) positive receivers.
Thrombocyte concentration—Rh(D) negative girls and women in fertile ages who obtain Rh(D) positive thrombocyte products should be given a prophylaxis for Rh immunization. Boys/men and women who are over the fertile age may obtain thrombocytes regardless of Rh(D) type.
Blood components should never be given together with other medications.
- Premedication if the patient has reacted to previous transfusions.
- Secure venous access
- The blood product is checked to ensure the correct unit is given to the correct patient.
- Use blood set with filter
- Give SAGMAN over 1 hour and thrombocytes 20-30 minutes per unit.
- Rinse the set with NaCl 9 mg/ml at the end of the infusion
- Store the blood product bag for one day before discarding
The patient should be observed during the transfusion with emphasis on reactions. Most serious transfusion reactions occur within the first 20 minutes.
Symptoms of transfusion reaction:
- feeling of heat in the face
- breathing difficulty
- fall in blood pressure
Suspect/manifest blood transfusion reaction:
- Stop transfusion immediately
- Start treatment if necessary (intravenous fluid, adrenalin, steroids, oxygen, respirator)
- Check blood bag and compatibility form. The residue should be sent to the blood bank.
Hemoglobin and thrombocytes are checked.
If poor effect of platelet transfusion, platelet value should be checked after approximately one hour. The value should have increased by approximately 30x109
/l or more after a standard dose.
If the increase is drastically less, the cause may be:
- Abnormally high consumption. This is an indication for more frequent transfusions.
- Antigens against HLA or platelet-specific antigens. The patient must be examined in cooperation with the blood bank to find compatible donors.
Bone marrow stimulation with G-CSF (Neupogen®, Granocyte®) is only recommended for febrile neutropenia which does not respond to antibiotic treatment, severe neutropenia (granulocytes < 0.5 x 109 /L for more than 1 week), and in cases where it is necessary to administer curative treatment with sufficient dosage intensity.
- To maintain dosage intensity for curative treatment; when a reduction in dosage will significantly reduce the chance of cure.
- As prophylaxis for treatments associated with a high risk for febrile neutropenia (> 40 %)
- Febrile neutropenia that does not respond quickly to antibiotic treatment
- Long-lasting neutropenia
- Maintain treatment intensity
The patient should be adequately informed about the treatment.
- The dosage of Neupogen® is 5 µg/kg daily. The treatment is initiated, at the earliest, 48 hours after the treatment is completed. The treatment continues for 10 days.
- The dosage of Neulasta® is 6 mg subcutaneously administered 24 hours after chemotherapy is completed. The neutrophil cells are counted on day 15.
- The subsequent course is started on day 21, if the neutrophil count is 0.5 or higher, and the patient has not had febrile neutropenia.
- It is important not to postpone the treatment if the neutrophil count is 0.5 or higher. The neutrophil count will compulsory decline after ending Neupogen® stimulation. Low values at the start of treatment should not be alarming if the values during hospitalization have been high enough to avoid febrile neutropenia.
- Stimulation late in the cycle should only be performed for long-lasting, severe neutropenia. At least 48 hours should pass after completed stimulation treatment before the next chemotherapy course is started. In these cases, it is always important to check that the doses are correct and to recalculate GFR etc. Continuation of chemotherapy will either require a drastic dosage reduction or secondary prophylaxis with G-CSF.
It is of utmost importance that the patient is informed of the risk of infections associated with a low neutrophil count.
Patients at risk for developing very low values, must be informed to take their temperature if they feel unwell or febrile. In case of a temperature above 38 °C they should contact their doctor immediately.
Intravenous extravasation occurs when there is an accidental leak of intravenous cytotoxic fluid (chemotherapy drug) from the vein to surrounding tissue.
If chemotherapy is given in a peripheral vein, a large vein should be used, which is preferably in the underarm. Before the infusion begins, the vein should be checked for leaks by injecting NaCl 9 mg/ml or glucose 50 mg/ml. Backflow should also be checked. The patient must be informed that pain or burning in the area is not normal and they must inform the doctor.
Cytotoxic chemotherapy drugs should always be given through a central vein catheter to reduce the risk of intravenous extravasation.
Risk factors for intravenous extravasation:
- Small veins (infants and children)
- Brittle veins (elderly patients)
- Reduced physical health (cancer patients)
- Sclerosizing veins
- Rolling veins
- Poor circulation (if the needle is placed in an arm with edema)
- Obstructed vena cava (raised venous pressure may cause leakage)
- Conditions such as diabetes and radiation damage
Chemotherapeutic drugs are separated into three groups according to the degree of toxicity:
- Tissue irritant
Cytotoxic drugs can cause blisters or ulcerations leading to skin necrosis if extravasation occurs. If intravenous extravasation is left untreated, it can lead to permanent tissue damage, necrosis, scar formation around ligaments, nerves and joints, infections, abscesses, contractures, and in the worst case, amputation.
- Intravenous extravasation of cytotoxic drugs.
- Limit damage of tissue from intravenous extravasation.
Non-cytotoxic drugs or non-irritants
Non-cytotoxic/non-irritant drugs normally do not cause skin necrosis.
Drugs that are tissue irritants can cause pain in and around the injection site and along the vein. They can also cause inflammation. Some tissue irritating drugs cause ulceration if a large amount leak extravasally.
Cytotoxic drugs are categorized into subgroups according to the mode of damage. This categorization is important for the choice of treatment.
DNA binders absorb locally into the cells, bind to DNA, and cause cell death. After cell death, the drug molecule can be liberated from the dead cell and start killing healthy cells. This group is divided into these subgroups:
- Alkylating drugs
For doxorubicin and mitomycin, progrediating tissue damage has been reported over weeks, and in some cases, months after intravenous extravasal injection.
This group of medications can lead to cell death through other mechanisms than DNA binding drugs. This group is divided into:
|Chemotherapy cytotoxicity (1)
Irritant, can cause flaking or inflammation
|Non-cytotoxic or non-irritant
* = Anthracycline
** = Alkylating agents
*** = Vinca alkaloids
**** = Taxanes
*****= Methylene blue is not a chemotherapy drug, but is used for ifosfamide-induced encephalopathy, and is therefore included on the list.
All chemotherapy drugs can damage tissue in high concentrations.
- Allwood M, Stanley A WP. The Cytotoxics Handbook. Ed. 4th ed. 2002. 2001
- Ekstravasation Guidelines Implementeringsværktøj [Online] 2007 [hentet 10. mars 2009]; Tilgjengelig fra URL: http://www.cancerworld.org/CancerWorld/getStaticModFile.aspx?id=2726
Identification of an extravasal injection
- A burning, stinging pain or other acute change of the puncture site.
- Local redness or inflammation of the skin around the puncture site.
- The infusion rate slows/stops.
- Swelling of the puncture site.
Extravasation has probably also occurred if blood cannot be aspirated, resistance is felt on the plunger when a syringe is used, and/or there is no current if the drug is infused.
Flow chart for treatment of intravenous extravasation of cytotoxic drugs:
- Stop the infusion immediately.
- Allow the needle to remain and aspirate with as much water as possible. Avoid applying direct pressure on the area of extravasation.
- The volume, type, and time of extravasation should be recorded.
- A doctor/plastic surgeon should be called for to examine the patient.
- The damaged area and skin manifestations should be marked/photographed.
- The affected area should be kept elevated.
- The remaining chemotherapy should not be discarded.
- The patient should be informed about what is happening and what must be done.
- The needle is removed while aspirating.
- Pain medication is administered if necessary.
Based on which medication has leaked extravasally, the doctor or plastic surgeon will decide whether conservative treatment or primary surgery is necessary.
Conservative treatment consists of two different treatment strategies to limit the damage by extravasation: localize/neutralize and spread/dilute (2).
Localize and neutralize:
- Place an ice pack on the area for 15-20 minutes, at least 4 times daily for multiple days. A coldpack is used to limit spreading of the drug. Studies have indicated that there is reduced cellular uptake of drugs at lower temperatures (2).
- The drug that has leaked extravasally is neutralized by a specific drug if the instructions are followed.
- The affected area of the body should be kept elevated.
Spread and dilute (applies to vincristine, vinorelbine, vindesine, and vinblastine):
- Warm compresses are placed on the area for 15–20 minutes, at least 4 times daily, for multiple days.
- To dilute the drug that has leaked extravasally, many subcutaneous injections are given with hyaluronidase diluted with sterile water.
If the patient has lasting pain or blisters, surgical treatment should be considered by excising the area with direct sutures, skin transplant, or flap reconstruction.
Another type of reconstruction may be necessary at a later time.
Dexrazoxan is an EDTA analong used to treat extravasation of anthracycline (doxorubicin, daunorubicin, epirubicin, idarubicin). The mechanism of action is not fully understood, but it is believed that it may work through two mechanisms. By chelating iron, the formation of the iron-doxorubicin complex and iron-mediated hydroxy radicals are hindered, which cause oxidative damage to cell membranes and proteins. Another possible mechanism is inhibition of topoisomerase II (3).
Treatment lasts for 3 days. In all cases of extravasation of anthracycline, this treatment should be assessed by an oncologist and surgeon/plastic surgeon.
- The first infusion should start as soon as possible and within 6 hours after extravasation.
- On the following two days, the infusions should occur at the same time as the previous infusion (+/- 3 hours).
- If possible, the infusion should be placed in a vein where there is no extravasation.
- An ice pack or cooling element used on the area must be removed at least 15 minutes before the infusion starts to ensure sufficient blood circulation.
A package costs about NOK 100,000.-. If the expiration date runs out, the drug is replaced by the pharmaceutical company free of cost.
DMSO (70–90% solution) quenches free radicals and prevents formation of sores. The solution can be used after extravasation of cytotoxic drugs (anthracycline, mitomycin C, doxorubicin, idarubicin, epirubicin andactinomycin D) together with cooling of the area when other treatment methods cannot be used (5, 6). DMSO cannot be used in combination with dexrazoxan (3, 4).
- An area twice as big as the affixed area is treated with the solution every 8 hours for one week.(6)
Hyaluronidase is an enzyme that breaks down hyaluronic acid found in connective tissue. This leads to permeability and increased diffusion of the drug that is leaking extravasally, and is used only to spread the drug out into the tissue (spread and dilute).
- Hyaluronidase is administered subcutaneously or intradermally in 5-10 locations on the border of the area where the drug has leaked extravasally (7).
The washing out technique can be used with chemotherapy drugs when tissue damage is likely. When used with anthracycline, it is important that this is performed before the chemotherapy drug goes intracellularly.
In most cases, this is a very successful method if it is performed within 6 hours after the extravasation.
- The patient receives regional anesthesia.
- Multiple small incisions must be made to ensure sifficient access to the damaged subcutaneous tissue.
- With an infiltration needle, which is usually used for liposuction, isotonic NaCl is flushed through the tissue and drains through the incisions.
- The infiltrated fluid is then carefully removed by suction through a small needle used for liposuction.
- The procedure is repeated until 300-500 ml fluid is used.
- Ekstravasation Guidelines Implementeringsværktøj [Online] 2007 [hentet 10. mars 2009]; Tilgjengelig fra URL: http://www.cancerworld.org/CancerWorld/getStaticModFile.aspx?id=2726
- Hasinoff BB. Dexrazoxane use in the prevention of anthracycline extravasation injury. Future Oncol 2008; 2006: 1–15.
- Statens legemiddelverk. Preparatomtale. 2008
- Langstein HN, Duman H, Seeling D, Butler CF, Evens GR. Retrospective study of the management of chemotherapeutic extravasation injury. Ann Plastic Surg 2002; 49: 369–74.
- Bertelli G, Gozza A, Forno GB, Vidili MG, Silvestro S, Venturini M et al. Topical dimethylsulfoxide for the prevention of soft tissue injury after extravasation of vesicant cytotoxic drugs: A prospective clinical study. J Clin Oncol 1995; 13: 2851–5.
- Clinical Pharmacology© 2008 database. Hyaluronidase. 2008.
For conservative treatment
The damaged tissue should be observed for multiple weeks (with mitomycin at least 13 weeks) since necrosis can occur after months.
For emergency surgical treatment
Patients treated by a plastic surgeon should receive follow-up care by the surgeon until the wound has healed.
In patients treated with surgery, radiation and/or chemotherapy, the treatment efficacy may be affected by smoking. Smoking has an impact on both metabolism and pharmacokinetics.
Smoking may inhibit wound healing after surgery and increase the probability of surgical site infections. Because smokers generally have more mucus in the airways and are less able to remove it, they also may have a increased risk of serious lung complications during anesthesia. However, it is disputed whether or not it is beneficial to quit smoking directly prior to surgery and this should be considered in each case individually. (28,30-33). Smokers are more prone to stagnation of bronchial secretion than non-smokers and rapid postoperative extubation is important.
Patients who continue smoking during radiation therapy have a lower risk of complete respons, development of secondary cancer, increased toxicity and several other side effects compared to non-smokers and smokers that quit before treatment. Continued smoking during radiation therapy is also associated with oral mucositis, impaired ability to taste, dry mouth, reduced voice quality, weight loss, cachexia, fatigue, pneumonia, bone-and soft tissue necrosis.
Tobacco may have an effect the metabolism and the mechanisms of chemotherapy and in this way may make the treatment less effective. Smokers undergoing chemotherapy may also experience a weakened immune system, increased rates of infection, exacerbation of common side effects, weight loss, cachexia, fatigue and cardiac or pulmonary toxicity. Some findings suggest that it may also apply to monoclonal antibodies.
Cancer patients who quit smoking before chemo- and radiation therapy get a total symptom burden equal to that of non-smokers, but those who continue to smoke state a higher symptom burden. Targeted measures in smoking cessation may increase quality of life and lead to less treatment interruptions.
A lot of patients wonder if there is any point to quit smoking after receiving a cancer diagnosis. tudies show that continued smoking is associated with increased treatment-related toxicity, increased risk of second primary cancers, reduced quality of life, reduced treatment effect and reduced survival in patients with cancer. This applies to both cancer diagnoses where smoking is a known causal factor, as with lung- and head and neck cancers and in cases where smoking has no known correlation with the diagnosis. Studies conducted on smoking and cancer diagnoses such as breast cancer, prostate cancer, colorectal cancer, esophageal cancer, cervical and ovarian cancer as well as leukemia and lymphoma cancers show that to continuation of smoking after a proven cancer diagnosis is associated with increased risk of mortality.
Studies support that quitting smoking improves cancer, and emphasizing the potential importance of targeted smoking cessation in cancerpatients during and after treatment. The link between tobacco and impact on cancer and cancer treatment is a complex matter.
Regarding the significance of the various components much is still unkown. When it comes to tobacco use in cancer treatment research is primarily done on the link between cigarette smoking and efficacy of cancer treatment. Nevertheless, it cannot be excluded that using other smokeless tobacco products such as snuff and chewing tobacco, may also impact the cancer treatment. According to international guidelines all tobacco use should be stopped during cancer treatment.
|Benefits of smoking cessation and risks of continued smoking in patients with cancer
|Quitting smoking results in the following benefits:
||Continued smoking results in a risk of :
- improved treatment results.
- less side effects
- fewer infections
- improved respiration and circulation
- increased survival
- reduced efficacy of treatment.
- postoperative complications and longer recovery.
- cardiovascular and respiratory complications.
- recurrence of cancer, and secondary cancer.
- shortened life expectancy.
Weaning of nicotine in connection to cancer treatment.
Healthcare providers should convey evidence-based information to patients about how smoking affects cancer treatment, the risk of side effects and prognosis and also provide guidance and relevant treatment for smoking cessation.
Patients require clear, formalized and fact-based guidance and continuous follow-up. Many patients want encouragement for smoking cessation early in the disease. Being hospitalized is a good opportunity because patients have access to support and help to reduce nicotine withdrawal symptoms and discomfort.
A patient recently diagnosed with cancer is often motivated to quit smoking and also receptive to conversations about how to do this. Motivation or willingness to quit often changes during the treatment, and use of tobacco and motivation should therefore be discussed at every consultation.
Clarifying the patient´s smoking habit is important. The time of day the patient lights their first cigarette says something about the degree of addiction. Making the patient aware of the situations in which he or she smokes most; at work, at home or in social settings, can help break unwanted patterns of behavior.
The best and most direct approach to motivate the patient is telling that tobacco use will decrease the effectiveness of treatment and the most important thing the patient can do himself is to stop using tobacco.
- Speak directly to the patient about how tobacco use may decrease the effectiveness of treatment.
- Discuss smoking cessation with the patient at each visit.
- Clarify any misunderstandings about the risks of tobacco use. Point out the importance of quitting.
Sometimes there may be misunderstandings about what kind of health risk smoking during and after cancer treatment may entail.
Advice to those who are not ready for smoking cessation
|The smokers statement
||The response of health care professionals
|The damage from smoking is already done.
|Some damage is done, but continued smoking will still damage your health and reduce the effects of treatment. Quitting smoking is more important now than ever.
|This response tells the patient that it is not too late to quit smoking, and the effect of treatment will be positive.
|I have reduced smoking.
|That is great, and now you need to focus on quitting completely. What do you think keeps you from quitting altogether?
|This response tells the patient the importance of quitting completely, as the benefits of quitting at baseline are documented.
|This is not a good time to quit smoking.
|The benefits of quitting are greatest now, before treatment begins. What is needed to make you feel ready to quit smoking?
|This response make the patient aware of the fact that quitting smoking optimizes the cancer treatment.
Health professionals must assist the patient identifying realistic expectations and goals for smoking cessation. For some, it may feel easier to scale down the number of cigarettes than to quit completely. The patient should know that every puff affects their health, and that the total health benefits can only be achieved through smoking cessation. For patients unable to stop completely, a gradual reduction may be a step in the right direction.
The probability of success for smoking cessation significantly increases for those who receive professional help in combination with nicotine replacement therapy (NRT) or non-nicotine based products. For the best possible effect of NRT the patient needs professional guidance to find the right product and dosage. For some patients combining two products or receiving a higher dosage than recommended will give the best effect. Sometimes the product must be replaced during the treatment.
Treatment with nicotine replacement therapy
Topical products are patches (Nicorette®, Nicotinell®), chewing gum (Nicorette®, Nicotinell®), lozenges (Nicorette®, Nicotinell®), inhalator (Nicorette®) or a combination of these. These products contain nicotine and therefore reduce the withdrawal symptoms experienced after smoking cessation.
- Patch: Nicorette® 5 mg,10 mg and 15 mg/16 hours up to 6 months or Nicotinell® 7 mg,14 mg og 21 mg/24 hours up to 3 months.
- Chewing gum: Nicorette®/Nicotinell® 2 mg and 4 mg, 8-12 pcs/day up to 12 months.
- Lozenges: Nicorette® 2 mg and 4 mg, typically 8-12 pcs/day, maximum respectively 15 pcs/day up to 9 months or Nicotinell® 1 mg and 2 mg, typically 8-12 pcs/day, maximum is respectively
25 and 15 pcs/day up to 12 months.
- Inhalator: Nicorette® 10 mg/dosage container, 4-12 pcs/day up to 6 months.
Combination therapy means combining patches with chewing gum, lozenges or an inhalator.
- Nicorette® patch15 mg/16h and Nicorette chewing gum 2 mg. 5-6 chewing gums daily. Maximum 24 pcs/day
- Nicorette® patch 15 mg/16h and Nicorette® inhalator 10 mg: 4-5 dosage-container daily. Maximum 8 pcs/day
Nicotine replacement therapy increases the chance of smoking cessation by 50 to 70% after six months. Two products used in combination increase the chance of smoking cessation compared to the use of only one product.
- Headache, dizziness, nausea, flatulence and hiccup.
- Irritation in the mouth and esophagus using chewing gum/ lozenges/inhalator
- Skin irritations while using patches.
- Precaution in acute cardiovascular disease, peripheral arterial disease, cerebrovascular disease, hyperthyroidism, diabetes mellitus, kidney- and liver failure and peptic ulcers.
- Should not be used during pregnancy, unless the potential benefit outweighs the potential risk.
- The products should not be used during breastfeeding.
Treatment with non-nicotine medications
Bupropion (Zyban®) is a selective reuptake inhibitor of dopamine and norepinephrine. The mechanism behind why the ability to refrain from smoking increases by using bupropin is unknown. A should be set for smoking cessation for the second week of treatment.
Bupropion increases the chance of smoking cessation after 6 months by nearly 70%.
- Dry mouth, nausea, insomnia, hypersensitivity reactions and seizures (convulsions)
- Contraindicated in people with disease that can cause convulsions, people with substance abuse or other circumstances lowering the seizure threshold.
- Depression, which in rare cases includes suicidal thoughts and – behavior including suicide attempt.
- Safety and efficacy have not been established for people under 18 years.
- Should not be used during pregnancy.
Varenicline (Champix®) is a partial agonist by a subtype of nicotinic receptors. It has both agonistic activity with lower intrinsic efficacy than nicotine and antagonistic activity in the presence of nicotine.
A date for smoking cessation should be set. Treatment should start 1-2 weeks, or up to 35 days, before that date. The starting dose is 0,5 mg one time daily on days 1-3, then 0,5 mg two times daily on days 4-7, then 1 mg two times daily on day 8 and until the end of treatment. The treatment should last for 12 weeks.
- Nausea, sleep disturbances, headache, constipation, flatulence and vomiting
- Links have been reported between the use of varenicline and an increased risk of cardiovascular events, suicidal thoughts, depression and aggressive and erratic behavior
- Safety and efficacy have not been established for people under 18 years of age
- Should not be used during pregnancy
If the patient experiences a relapse, it is important to inform them that this is completely normal, and encourage them to continue. If the most common measures do not work,
consideration should be given both to increase the NRP and to provide closer follow-up by health care providers.
Guidance in smoking cessation is described in the literature as brief and clear advice and then further follow-up with a telephone helpline offering treatment for addiction and behavior change/issues. It is not necessary for the patient to have decided to quit smoking in order to be referred to a quitline. If the patient agrees to receive a call from quitline, he or she will be followed up by a supervisor. Supervisors are bound by confidentiality, are up-to-date professionally and offer free follow-up counseling calls for up to a year.
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- Cahill K, Stead LF, Lancaster T, Polonio IB. Nicotine receptor partial agonists for smoking cessation. Sao Paulo Med J. 2012;130(5):346-7
Follow-up care after treatment of bile duct/gallbladder cancer
Patients who have completed treatment intended to cure primary bile duct cancer should be followed-up every 3 months for the first year, thereafter every 6 months. The frequency and duration of follow-up is individual and based on the treatment modality. In patients having a non-curative treatment, the frequency should be according to the needs of the patient.
Follow-up of the patient should take place at the treatment center. After one year, if geographical conditions require, the follow-up can be performed at the patient's local hospital. Tests performed at follow-up:
- CT scan of liver (3 phase), possibly MRI
- Ultrasound of the liver, possibly with contrast
- MRCP, possibly ERCP
- CT scan of thorax
- Blood tests (liver tests and cancer markers, among others). Cancer markers (CEA, CA 19-9, AFP) may provide postoperative prognostic information in patients who had raised levels before treatment.
Transplant patients are included in Oslo University Hospital's separate follow-up arrangement after the transplant.
There are many reasons why cancer patients feel fatigued. In many patients, the causes are synergistic. Cancer patients are often very sick during treatment periods and may experience extreme fatigue during intensive chemotherapy. It is also very important to be aware that fatigue is a symptom of many other medical conditions, both physical and psychological, which also affects cancer patients. Some known causes of fatigue associated with cancer and cancer treatment are:
- Cancer itself
- An operation
- Current or recently concluded chemotherapy
- Current or recently finished radiation therapy
- Severe anemia
- Other symptoms such as pain and nausea
- Fever or infection
- Too little fluid or food intake
- Reduced lung function
- Changes in sleep
- Worries, anxiety, stress, or depression
For some of these conditions, such as infections, there is medical treatment available. Fatigue that occurs after an operation or during chemotherapy and radiation therapy will, for most, gradually disappear when strength is regained. If a patient was feeling healthy after treatment and all of the sudden experiences fatigue, they should contact their doctor. If a patient feels fatigue and at the same time feels stressed, worried, or down, they may be reluctant to speak to their doctor or health personnel about it. It is still recommended to talk about these problems. Talking about it may be therapeutic, and provides room for discussing measures with a qualified person with experience with patients that have the same problems. For cured patients experiencing chronic fatigue, it may be difficult to pinpoint a specific cause. Many of these patients experience improvement by changing their lifestyle to a lower tempo than before the diagnosis.
Everyone knows what it feels like to be tired, fatigued, or lethargic when sick. This feeling is the most common side effect of cancer and cancer treatment. A symptom is a condition or state that something is not right in the body. Other frequent symptoms associated with cancer and cancer treatment are reduced appetite and nausea. Most patients who experience fatigue associated with cancer say that the feeling does not improve with rest, and many describe a lack of energy or exhaustion.
If fatigue arises during chemotherapy or radiation therapy, most patients experience that it will gradually go away when treatment is over and their strength is regained. This type of fatigue is considered acute. Improvement may take time depending on the intensity of treatment. Some patients experience that fatigue lasts for months, or even years. This is considered chronic fatigue. The ability to carry out daily activities, a lack of humor, health-related worries, a reduced capacity to carry out work functions, or less energy for family, can also accompany chronic fatigue. Most patients will find it difficult to be told by their doctor that they are considered healthy, while their friends and family expect them to be normal again, despite having a lack of energy and ability to perform activities they want to.
For many, feeling fatigued is often accompanied by having difficulty concentrating, poor memory, and an increased need for sleep. Most patients will need more sleep than before they became sick. For many, sleep is not restful, and it may take time to "get going" in the morning. Many also experience that they quickly become drained of strength if they exert themselves, and that it takes a long time before regaining strength after exertion. Exertion in this context can mean both physically and mentally such as working on a task that requires concentration.
Fatigue can occur in all phases of cancer illness. Some patients feel it before the diagnosis, and almost all patients experience fatigue during radiation therapy or chemotherapy. A minority of patients experience long term fatigue after cancer treatment is over and the disease is cured. Patients who cannot be cured will almost always feel tired, worn-out, and exhausted. The degree of fatigue in these patients varies depending on the cancer type, spreading, and other symptoms of the disease.
The patient should be given necessary information on both causes of fatigue and measures he/she can take.
General measures that can reduce feeling tired and fatigued
Following suggestions are meant as general advice that may not necessarily apply to everyone in all situations. This advice is based on results from studies, experiences from cancer patients, and recommendations from experts. Each patient should assess what works for them. It is recommended to express concerns and seek advice for what measures you can take and what you should avoid.
- Try to live as "normal" as possible.
- Try to plan your day to include time to rest.
- Take many small breaks during the day instead of a few long ones.
- Rest after strenuous activity.
- Plan your daily activities and do those that are most important for you.
- Set realistic goals for yourself and try to be happy with those you accomplish.
- Try to recognize activities that make you especially tired/fatigued and limit them, or spread them out over longer intervals.
- Try to accept that you do not have the energy to do the things you could previously.
- Assess what is important for you to do yourself and what you can allow others to do.
- Assume you will be tired after something strenuous even if you experience the activity as positive.
Physical activity and exercise
Exercise and physical activity that is appropriate for you will reduce the feeling of fatigue. Regular exercise is the most effective measure against chronic fatigue in cancer patients. Nevertheless, both too much and too little exercise can worsen fatigue, therefore, it is important to find a level (frequency and intensity) that suits you. You should never exercise so intensely that you must stop a session or exercise period because you are exhausted. Remember that daily form varies for everyone and adjust your exercise routine accordingly. Make long-term goals (months) and gradually increase activity, and carefully for a period.
- Activities such as walking, biking, swimming, dance, and aerobics are recommended.
- Light exercise periods at regular intervals are better than intense, sporadic periods.
- Always start with a slow tempo and increase gradually before finishing with a slow tempo again.
- Always sit down and rest after exercise but try not to lay down and sleep.
- Physical therapists and sport pedagogs can provide advice on exercises that are right for you. The principles are the same for all exercise, but it should be adjusted for your energy level.
Many cancer patients with chronic fatigue have sleep pattern disturbances. It is important to maintain a normal rhythm even if you feel like sleeping during the day.
- Try to wake up at the same time every day and keep a regular bedtime.
- Avoid too much activity right before bedtime.
- Try not to sleep during the day because this will disturb your biological rhythm.
- But, a short afternoon nap may be energizing!
- Rest during the day by relaxing in a good chair, but try not to fall asleep.
- Speak to your doctor about lasting sleep disturbances.
Having a reduced appetite or intake of food can also result in a lack of strength and energy. We recommend eating healthy food regularly, and to follow the national guidelines on nutrition. Special diets or supplements do not improve fatigue unless there is a deficiency.
Some patients do not have the strength to continue working, or they must reduce their hours because of chronic fatigue. Consulting with a social worker may be beneficial for guidance regarding your work situation, your welfare rights, and financial situation.
Some adjustments that you and your employer can make:
- Discuss the possibility for more simple or easier tasks, especially if you have a physically demanding profession.
- Assess the possibility of reducing your hours.
- Remember to take regular breaks also at work, if possible.
- Assess the possibility of flexi-time to work during the hours you have energy, as well as the possibility of working from home.
Care for children
Caring for children or adolescents may be very difficult when you are fatigued or lack energy and strength. There are, however, some measures you can take:
- Explain to your children that you are tired and are not able to do as much as you used to.
- Discuss what the children can help you with and allow them to take part in household chores.
- Try to establish permanent household chores for all family members.
- Try to do activities that suit you that do not require too much energy, and can be performed without too much exertion.
- Ask and accept help from others for driving to and from activities, school, etc. if this relieves you.
In Norway, there is currently no specific drug therapy for chronic fatigue associated with cancer. If the fatigue is due to specific conditions, this is of course treated with medication, if possible. Sometimes, such treatments improve the fatigue, but other times they do not. Examples of treatment that often reduce fatigue are treatment for infections and depression.
Treatment with medications that stimulate production of red blood cells is not recommended for cancer patients due the the danger of serious side effects.
Information about fatigue
Healthcare workers in cancer care will often have knowledge about fatigue and cancer. Most general care physicians have general experience with fatigue but meet relatively few cancer patients. There is a lot of information available on the internet of varying quality. Below is a list of web adresses and some literature. Be aware that you may find opposing advice because knowledge on treatment especially, is limited.
- Armes J., m.fl. (2004). Fatigue in cancer. Oxford University Press.
- Berger A.M., m.fl. (2009). NCCN Clinical Practice Guidelines in Oncology. Cancer-Related Fatigue. www.nccn.org
- Patarca-Montero R. (2004). Handbook of cancer-related fatigue. Haworth Medical Press