oncolex logo
Utskriftsdato (24.3.2017)

Neuroendocrine tumors

Neuroendocrine tumors develop from cells neuroendocrine stem cells. Previously, this tumor type was referred to as "carcinoid" meaning "cancer-like". This expression is now rarely used, and then primarily for neuroendocrine tumors in the small intestines or first part of the colon. 

Hormone-producing cells are found in almost all of the body's organs, therefore these tumors can occur in most organs.

The prognosis depends on the degree of histological differentiation (see Grading). Patients with highly differentiated tumors and metastatic disease can live for years, whereas patients with non-resectable poorly differentiated disease will die within months, even with aggressive therapy.

The most common high differentiated neuroendocrine tumors originate from the small intestines (25%), lungs (20%), colon (8%), pancreas (7%), rectum (6%), stomach (5%), and veriform appendix (5%). Neuroendocrine tumors also occur in the thymus, adrenal glands, testicles, ovaries, breasts, thyroid gland, and in rare cases other organs (1).

The poorly differentiated tumors originates mainly from the lungs and the gastrointestinal tract.

The tumors are separated into:

  • well differentiated neuroendocrine tumor
  • poorly differentiated neuroendocrine carcinoma

A large number of  patients with highly differentiated tumors live with the disease for many years without symptoms. There are, however, great differences in the degree of malignancy in tumors of the same organ, with the same grading, from patient to patient. While some tumors are benign with barely visible growth from year to year, others grow quickly and respond poorly to treatment.

Incidence

In 2013 it was registered 1214 neuroendocrine tumors in Norway, 612 new cases were diagnosed in men and 602 in women.

Etiology of neuroendocrine tumors

Besides a few, very rare hereditary cases, the cause is unknown. As for most other tumor types, it is assumed that a combination of genetic dispositions and exogenous factors play a role.

In multiple endocrine neoplasia (MEN), von Hippel-Lindau disease and Neurfibromatosis type l, one finds mutations in sigle genes that causes a variety of neuroendocrine tumors in various organs of the same patient (3).

  • In MEN (mutation in the MEN gene), the organs which are most often involved are the pancreas, parathyroid gland, pituitary gland, and adrenal glands.
  • In von Hippel-Lindau disease (mutation in VHL gene), the pancreas and adrenal glands are involved, among others
  • For neurofibromatosis type I, neuroendocrine tumors are found in the pancreas and duodenum. 

Histology of neuroendocrine tumors

Endocrine tumors appear in all parts of the gastrointestinal tract. In the last edition of the WHO classification of tumors, this group was designated neuroendocrine tumors of the GI tract. The diagnosis is based on immunhistochemical positivity for one or several of the following markers: chromogranin, synaptophysin, neuron specific enolase (NSE) or CD56 (N-CAM).

Esophagus

Endocrine tumors rarely appear in the esophagus. These comprise only 0,1% of esophagus cancers. There are two types of endocrine tumors in the oesophagus:

  • Well differentiated endocrine carcinoma appears in the lower third of the oesophagus. Histologically, they grow as solid tumor cell islands in the deeper part of the esophagus wall.
  • Small cell carcinoma is almost identical to small cell carcinoma of the lung. The tumor consists of closely lying cells with sparse cytoplasm and hyperchromatic nuclei. This tumor appears in lower half of the oesophagus and can be difficult to separate from small cell carcinoma of the lung growing through the esophagus wall.

Gastric

Endocrine tumors of the gastric sac are not uncommon. Most tumors in the gastric sac are small and related to other clinical manifestations such as pernicious anemia or hypergastrinemia. They can be divided into the following groups:

Photomicrograph demonstrating the gastric mucosa with ECL hyperplasia. Click to enlarge. Immunhistochemical chromogranin staining of the tumor in the left image with positive brownish granula. Click to enlarge.

1. Well differentiated endocrine neoplasms

  • Enterochrommafin Cell Like – ECL endocrine neoplasms
  • Enterochrommafin Cell – EC, serotonin-produsing endocrine neoplasms
  • Gastrin-produsing G-cell endocrine neoplasms

2. Poorly differentiated endocrine carcinoma

  • Small cell carcinoma
  • Large cell endocrine carcinoma

3. Tumor-like lesions

  • Hyperplasias
  • Dysplasias

The most common endocrine neoplasia in the gastric mucosa is ECL neoplasia. They comprise 9 out of 10 endocrine neoplasms in the GI tract. In ECL neoplasms, three types are recognized depending on relation to autoimmue gastritis/pernicious anemia (type I), hypergastrinemia (type II) or abscence from autoimmune gastritis or hypergastrinemia, or sporadic ECL neoplasia.  The typical  type I and II tumors are relatively small tumors (< 15 mm) and they are localized within mucosa or submucosa. They show trebelcular tumor cell groups with monotonous cells and are positive for chromogranin. The sporadic (type III) tumors are generally larger than type I/II and demonstrate a more aggressive growth pattern with deeper invasion in the wall and more polymorphic cells and more frequent mitotic figures. They also often demonstrate vascular invasion.

Serotonin-producing endocrine neoplasms (EC cells) are mostly associated with the terminology carcinoid. EC neoplasms are frequent in the small intestine, but are rare in the gastric mucosa.

Gastrin-producing tumors are usually found incidently during endoscopy or gastrectomy. They are generally small growing in the mucosa or submuca and are immunhistochemically positive for gastrin.

Small cell carcinoma is similar to corresponding tumors in the lung and esphagus.

Large cell endocrine carcinoma consists of large cells often with rosette formations and pallisading features. Both small cell and large cell carcinomas are rarely observed in the gastric wall.

Tumor-like lesions (hyperplasia/dysplasia) are generally seen in autoimmune gastritis/hypergastrinemia with ”simple”, linear and micronodular ECL-hyperplasia. When nodules exceed 0.5 mm they are designated as endocrine neoplasms.

Small intestine

Endocrine tumors in the small intestine are divided according to localization: those within duodenum and proximal part of jejunum and those in the distal part of jejunum and ileum.

Endocrine tumors of the duodenum and proximal part of jejunum comprise 23% of all gastrointestinal endocrine tumors where > 90% are in the duodenum. The most common among these tumors are the gastrinomas (62%), somatostatin cell tumors (21%), and gangliocystic paraganglioma (9%).  Most tumors are less than 2 cm in diameter, although some can reach 5 cm. The microscopic appearance is similar to other well-differentiated endocrine neoplasias with trabecular, tubulo-glandular and nodular growth patterns. General neuroendocrine markers and specific hormone markers (gastrin, somatostatin) confirm the diagnosis. Gangliocytic paraganglioma is a rare tumor with mixed microscopic appearance consisting of three different cell types: spindle, epithelial, and ganglion cells. EC-cell serotonin-producing tumors (classic ”mid-gut” carcinoid) are rare in the duodenum and proximal part of the jejunum.

Photomicrograph demonstrating a lymph node metastasis from an endocrine carcinoma of the cecum. Click to enlarge. Immunhistochemical staining for Synaptophysin in primary tumor (same patient as left image). Click to enlarge. Immunhistochemical staining for Ki-67 in primary tumor (same patient as left image). Click to enlarge.

Endocrine tumors in the distal part of jejunum comprise about 30% of all endocrine GI neoplasms. They are mainly classical ”mid-gut” carcinoid (EC-cell endocrine neoplasms) . They are often multiple, and more than half of them exceed 2 cm in diameter when diagnosed and grow in submucosa or deep in the mucosa. In some instances these tumors infiltrate muscularis propria or serosa. Extensive infiltration in the mesenterium which is often dependend on lymphatic spreading stimulates fibroblastic activity with desmoplasia. This can cause intestinal obstruction. EC-cell endocrine neoplasms are more aggressive than other well-differentiated endocrine carcinomas. They metastasize mainly to regional lymph nodes or to the liver. Patients are usually cured  when complete local resection has been performed, tumors are less than 1 cm, tumors are localized within mucosa/submucosa, no vascular invasion has been documented and Ki-67 score is less than 2%.

Appendix veriform

Endocrine tumors in the appendix vermiform comprise 50–75% of all tumors in this localization. The most common type of well-differentiated endocrine neoplasms in appendix is EC-cell neoplasias with similar appearance as in the ileum. They are generally less than 1 cm in diameter and are seen in the tip of the appendix. The majority of tumors are found incidentally during appendectomy. These tumor are less aggressive compared similar tumors in the ileum. This may be partly due to smaller size.
Photomicrograph demonstrating tumor cells with goblet appearance infiltrating the appendix wall. Click to enlarge. Immunhistochemical staining for Synaptophysin (same tumor as left image) confirms the diagnosis of goblet cell carcinoid. Click to enlarge. Immunhistochemical staining for Ki-67 (same tumor as left image). Only scattered positive nuclei. Click to enlarge.

Apart from  EC-cell endocrine neoplasias, there are variants of mucus-producing endocrine neoplasias and tubular endocrine neoplasias. The first group is represented by the goblet cell carcinoid that is characterized by groups of cells growing in the submucosa centrical around the lumen without forming a distinct tumor. The cell groups contain cells comparable to mature goblet cells in the intestinal mucosa. In these cell groups, immunohistochemical staining for neuroendocrine marker shows positivity. Earlier it was believed that goblet cell carcinoid were less aggressive, although today they are considered to be represented by a spectrum of well-differentiated to poorly differentiated signet ring carcinomas.

Tubular carcinoid is a rare entity and grows in tubular structure in the submucosa almost like an adenocarcinoma. Immunhistochemical neuroendiocrine markers and limited involvement of mucosa generally confirm the diagnosis.

Non-angioinvasive endocrine neoplasias in the appendix vermiform (except for goblet cell carcinoid) less than 2 cm in diameter, not infiltrating mesoappendix or resection borders may be cured by appendectomy.

Colon and rectum

Well-differentiated endocrine tumors appear mostly in the rectum (about 50%) followed by the cecum (20%).  EC-cell neoplasia appear more frequently in colon and less frequently in rectum. They are similar to those in well-differentiated endocrine carcinomas with varying malignancy potential depending on size, depth of infiltration and mitiotic count/Ki-67% activity. About 40% demonstrate local spread. L-cell, glucagon-like peptide and PP/PYY-producing tumors often demonstrate a typical trabecular growth pattern and are usually seen in the rectum. When they are smaller than 2 cm in diameter and do not infiltrate muscularis propria they have a benign clinical course. Four of five endocrine tumors in the rectum demonstrate positivity for PSA. Poorly differentiated endocrine neoplasms (small cell carcinoma and large cell endocrine carinoma) rarely appear in colon or rectum.

Anal canal

Endocrine tumors are very rare in the anal canal. Most of them are L-cell type.

Metastatic patterns of neuroendocrine tumors

Like other tumors, neuroendocrine tumors spread principally by:

  • local infiltration
  • lymphogenic spreading
  • hematogenic spreading

Besides spreading to local lymph nodes, spreading to the liver is the most common. Spreading to the skeleton and peripheral lymph nodes occurs relatively seldom.

Octreotide scan showing massive metastasis to the liver, spinal column, and pelvis. Click to enlarge the image. MRI of patient with skeletal metastasis in the sacrum and bodies of vertebrae Th6, S2 and S3. (virvelcorpora). Click to enlarge image.

Grading of neuroendocrine tumors

WHO's classification is based on Ki-67%, which is an immunohistochemical test of tumor tissue. The MIB-1 (Mindbomb homologue 1) antigen binds to the Ki-67% protein, which is expressed in cells undergoing division. This antigen stains the cell nucleus. Thus, dividing cell nuclei can be differentiated from non-dividing nuclei. Ki-67% expresses the percent of cells in the tumor which are stained or in the division phase. If Ki-67% is 5%, this means that 5% of the cells are undergoing mitosis.

Ki-67% may be different in different areas of the tumor and is often higher in metastasis cells than the primary tumor. The area with the highest Ki-67 (”hot spots”) in the primary tumor provide the basis for classification. 

WHO classification (2010)
Ki-67% < 3% Low gradeneuroendocrine tumor
Ki-67%  3–20% Intermediate grade neuroendocrine carcinoma
Ki-67% > 20% High grade neuroendocrine carcinoma

In the American database SEERS (Surveillance, Epidemiology and End Results), there is metastasis at the time of diagnosis in 21% of patients with well differentiated tumor, 30% with a moderately differentiated carcinoma, and 50% with a poorly differentiated carcinoma.

(4)

Symptoms of neuroendocrine tumors

Highly differentiated tumors

These tumors are often slow-growing and symptoms occur gradually, sometimes over years. Symptoms depend on the primary organ and the extent to which the tumor produces symptom-causing peptides. 

Metastatic symptoms are often the first manifestation. Even non-symptom causing primary tumors of 1–2 cm in diameter may cause extensive metastasis. A mesenterial metastasis from neuroendocrine intestinal and colon carcinomas can induce a fibrotic process around the metastasis, which by itself can cause significant symptoms from surrounding structures drawn into the fibrotic process (desmoplastic reaction). This can lead to ileus/subileus by traction on the bowel, hydronephrosis by stenosis of the ureter, or to thrombosis in intestinal blood vessels due to compression. 

CT scan of patient with neuroendocrine intestinal tumor. Click to enlarge the image. CT scan showing extensive liver metastasis originating from a small intestinal tumor. Click to enlarge the image.

Tumors in the intestines and upper part of the colon can cause "carcinoid syndrome", diarrhea, redness (most common in the face/upper body, not normally accompanied by a feeling of warmth), diarrhea, and difficulty breathing. In these patients, the valves on the right side of the heart may become fibrotic and damaged due to substances released by the tumor. Cardiac valve surgery may be indicated to prevent cardiac failure. Lung tumors can also cause similar hormonal symptoms.

Common symptoms are:

  • pain
  • weight loss   
  • lethargy
  • hormonal symptoms

Peptides produced by neuroendocrine tumors can, but not necessarily, cause symptoms. In the stomach-intestinal tract, the peptides do not cause symptoms until the tumor has spread outside the intestinal system, most often to the liver. This is because peptides which enter the bloodstream from tumors in the stomach-intestinal tract are usually degraded in the liver before they enter the systemic circulation.

Examples of peptides produced by neuroendocrine tumors and subsequent symptoms

Neuroendocrine tumor Peptide  Symptom
Pancreas Insulin Hypoglycemia
Gastrin Peptic ulcer (Zollinger Ellison's syndrome)
Glucagon Hyperglycemia, rash
VIP Intense diarrhea
Intestines Serotonin Diarrhea, flushing, dyspnoe (”carcinoid syndrome”)
Lungs Serotonin Diarrhea, flushing
Histamine Angioedema
 ACTH Cushing's syndrome

Poorly differentiated carcinomas

The most common symptom is pain, often combined with and reduced performace status.

Differential diagnoses of neuroendocrine tumors

Because neuroendocrine tumors can, in principle, occur in all of the body's organs, the differential diagnosis is other solid tumors from the same organ.

In hormone production, the differential diagnostic considerations involves applies to other endocrine diseases.

Prognosis of neuroendocrine tumors

At Oslo University Hospital (Rikshospitalet), the registered patients with:

  • intestinal tumors have a 5 year survival rate of 88% with local disease at the time of diagnosis
  • pancreatic tumors have a 5 year survival rate of 57%
  • metastasis at the time of diagnosis have a 5 year survival rate of 64% (intestinal tumors) and 42% (pancreatic tumors)

The tumor is often so advanced at the time of diagnosis that radical surgery is not possible.

Based on the SEERS database from the US, survival varies with differential degrees and with primary focus. The 5 year survival in highly differentiated tumors, with distant metastases, from the intestines is 54%, coecum 48%, followed by lungs 27%, pancreas 27%, and appendix 25%.

Few patients with poorly differentiated carcinomas that is not radically resected are a live one year after diagnosis.

 (5)

References on neuroendocrine tumors

About neuroendocrine tumors

  1. Modlin IM, Lye KD , Kidd M . A 5-decade analysis of 13, 715 carcinoid tumors. Cancer: 2003; 15;97(4): 934–59
  2. Cancer in Norway 2010, Cancer Registry of Norway, Institute of Population-based Research. Oslo, Norway

    Etiology

  3. Toumpananakis CG, Chaplin ME. Molecular genetics of gastroenteropancreatic neuroendocrine tumors. Am J Gastroenterol 2008; 103: 729–32

    Histology

  4. Hamilton SR, Aaltonen LA. WHO Classification of Tumors. Pathology and Genetics of Tumours of Digestive System. Lyon, France: IARC Press, 2000:204 

    Staging/Prognosis

  5. Yao JC, Hassan M, Phan A et al. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35.825 cases in the United States. J Clin Oncol. 2008; 26: 3063–72

    Diagnostics

  6. Taupenot L, Harper KL, O'Connor DT. The chromogranin-secretogranin family. N Engl J Med. 2003; 348: 1134–49
  7. Betchen SA, Cirigliano M, Furth EE et al. Tubulovillous adenoma of the duodenum, a new etiology for flushing and urinary 5-HIAA elevation. DigDisSci 1998; 43: 1447–81

    Surgery

  8. van Vilsteren FG, Baskin-Bey ES, Nagorney DM et al. Liver transplantation for gastroenteropancreatic neuroendocrine cancers: Defining selection criteria to improve survival. Liver Transpl. 2006 Mar; 12(3): 448–56

    Drug Therapy

  9. Vilar E, Salazar R, Pérez-García J et al. Chemotherapy and role of the proliferation marker Ki-67 in digestive neuroendocrine tumors. Endocr Relat Cancer. 2007; 14: 221–32

    Radiation Therapy

  10. Kwekkeboom DJ, de Herder WW, Kam BL et al. Chemotherapy and role of the proliferation marker Ki-67 in digestive neuroendocrine tumors. Endocr Relat Cancer. 2007; 14: 221–32

Title is not translated!

Chapter does not contain text!!

Diagnostics of neuroendocrine tumors

Some tumors first cause symptoms only after metastasizing. It is not uncommon that a neuroendocrine tumor is discovered coincidentally while performing a work-up for another condition.

The paitent´s medical history may cause suspicion of a neuroendocrine tumor especially if there are hormone-related symptoms. The symptoms are however often unspecific and vague. Symptoms having lasted for many years do not usually lead to a comprehensive work-up.

Blood tests such as hematological status and liver tests are often normal even when the disease is extensive. No laboratory or image diagnostic examinations provide a 100% certain diagnosis. The final diagnosis is therefore based on the histological examination of the tumor tissue.

Chromogranin A

Around 90% of all highly differentiated neuroendocrine tumors release the protein chromogranin A, which is detected in the serum. The level increases with the size of the tumor. The test can therefore be used for both the work-up and to monitor treatment progress. Increasing values after treatment intended to cure the disease may be a sign of recurrence. 

Chromogranin A in serum can, however, be raised for a series of other conditions such as medications for ulcers/dyspepsia (proton pump inhibitors, H2 antagonists), gastritis, renal failure, hepatic failure, and disturbances of other hormone-producing organs. Certain other cancer types can also cause elevated chromogranin A in serum. 

Interpretation of raised chromogranin A values can therefore be difficult. The test should not be taken randomly, but only if there is suspicion of a neuroendocrine tumor (6).

Urinalysis

5-hydroxyindoleacetic acid (5-HIAA), which is a byproduct of serotonin, can be detected in raised levels in urine in 24 hours from patients with serotonin-producing tumors. These patients often have diarrhea and flushing. Elevated 5-HIAA is also found from tumors originating from the small intestines and first part of the colon. Raised levels are also observed after intake of certain foods such as bananas, tomoatoes, avocadoes, chocolate, pineapple, certain medications, and other diseases (7). 5-HIAA can be analyzed in a morning spot urine sample, 24-hour collection does not seem to be necessary.

Image diagnostics

A CT scan with oral and intravenous contrast is the most sensitive radiological examination. Images of both the arterial and potovenous phase are very important. Neuroendocrine tumors are normally hypervascular and are sometimes visible:  

  • only in the arterial phase
  • only in the venous phase
  • on MRI but not CT
  • only on ultrasound

A patient with liver metastasis may have some metastases which are only visible on CT and some which are only visible on MRI or ultrasound.

Intestinal MRI or X-ray with contrast can detect neuroendocrine tumors. The tumors can be <1 cm, and for the detection, the radiological procedures and interpretations must be of good quality.

Image examples:

  • CT
  • CT lungs 
  • Ultrasound
  • X-ray  

Endoscopic examinations

  • Gastroscopy is a useful work-up for neuroendocrine tumors in the stomach and duodenum . Small tumors in the stomach can be removed endoscopically.
  • Endoscopic ultrasound can detect tumors in the pancreas/duodenum which are not visible by CT/MRI/ordinary ultrasound.
  • Coloscopy may detect tumors in the colon and rectum. Small tumors can be removed during the procedure.

Octreotide scan

This type of scan is based on a radioactive isotope (as 111Indium) which is injected intravenously. This isotope which is attached to a somatostatin analogue (octreotide) binds to somatostatin receptors in the body. An increase of this tracer is detected by scanning the patient with a gamma camera. Over 50% of all neuroendocrine tumors have somatostatin receptors and will only be visible on octreotide scintigraphy . The tumor should normally be 1 cm or greater to be detected. Octreotide scintigraphy is not very specific for neuroendocrine tumors. Uptake is observed in a series of cancer forms such as lung cancer, lymphomas, and breast cancer. Inflammatory processes may also give rise to positive scans.

PET 

PET with 18F-FDG as a tracer is not very sensitive for neuroendocrine tumors and does not have a place in routine work-up. Some tracers, for instance 68Gallium, has a very high sensitivity for neuroendocrine tumors. 

PROSEDYRER

Esophago/gastro/duodenoscopy

General

Esaphago-gastroduodenoscopy (also called upper gastrointestinal scopy) is an examination of the esophagus, stomach, and duodenum.  The examination is carried out by means of a gastroscope, which is a flexible tube equipped with a camera on the end, a light system, and one or two work canals. The mucosa can be inspected and the images are transferred to a monitor.  

During a scopy, the following can also be carried out:

  • biopsy
  • polyp removal
  • treatment for bleeding
  • injection of medication
  • laser treatment of lesions 
  • dilatation of the esophagus

The examination is simple and is carried out at most hospitals. It is important the stomach is empty before the exam.

Indications

  • Diagnose changes in the mucosa (soreness, inflammation, benign or malignant tumors)
  • Monitor a sore in the stomach/duodenum
  • Find source and treat acute bleeding in the upper gastrointestinal tract. 

Goal

  • Diagnose and possibly definitive treatment

Equipment

  • Gastroscope with equipment for biopsy and treatment.
  • Preparation

    Before the examination:

    • Anamnesis:
      • With known valve defect, endocarditis prophylaxis should be considered. 
      • Diabetes requiring insulin should be treated according to guidelines. 
      • Anticoagulation or antiphlogistic drugs should be stopped 5 days before the examination.
    • The stomach should be empty.
    • The patient should fast, starting 6 hours before the examination. Clear fluids are allowed up to 2 hours before the examination.
    • Daily medications can be taken the same day with a sip of water.

    The day of the examination:

    • Premedication with local anesthetic in the pharynx.
    • Possibly general anesthesia.

    Implementation

    • The gastroscope is inserted in through the mouth, down the esophagus and further down to the stomach and duodenum. How far the scope is inserted depends on which organs are inspected or which organ is suspect of tumor growth.
    • Air is blown in to clear the esophagus/stomach and get a better view during insertion of the scope.
    • The mucosa is inspected for abnormalities.
    • Perform necessary procedure.

    The examination usually lasts around 10-30 minutes.

    Follow-up

    Vomiting, pressure, and bloating are normal discomforts during/after the exam.

    The patient should be observed for:

    • bleeding if a biopsy is taken or polyps are removed
    • vomiting blood, black and tar-like stool, or intense stomach pain. If the patient has returned home, the patient is recommended to contact the hospital immediately.

    The patient may eat/drink 1 hour (at the earliest) after the exam due to the local anesthetic in the throat. For an outpatient exam, the patient may return home after 1-2 hours.

    Tissue sample results are available after 1-4 weeks. Further follow-up and treatment should be scheduled, if necessary.

    Colonoscopy

    General

    Colonoscopy is performed when:

    • proven blood (visible or occult), or other symptoms suggestive of colorectal cancer.
    • screening of asymptomatic patients with known hereditary risk of colorectal cancer.
    • postoperative control after colon cancer surgery.
    • control in inflammatory bowel disease (IBD).

    Purpose

    • Uncover polyps or infiltrating cancer of the colon and rectum.
    • Postoperative control of the anastomosis areas concidering recurrence of cancer or stricture formation.
    • Postoperative control to check whether new polyps or cancer (metachronous) has occurred.
    • Assessing disease activity and any development of dysplasia by IBD.

    Equipment

    • Coloscope with associated equipment
    • Biopsy forceps
    • Sling for removal of polyps

    Preparation

    • Fasting is not necessary. High-fiber bread, cereals, linseed or fruits/vegetables with a lot of seeds should be avoided the last five days before the examination.
    • Patients should avoid iron supplements in the last seven days before the examintaion.
    • Bowel emptying through taking oral laxative solutions (an abundant bowel emptying is necessary).
    • If the patient uses anticoagulants and it is necessary to take biopsies or slinging polyps (usually), the patients should consult their doctor to ensure the safety of taking a break in the medication according to the following rules:
      • Plavix® and equivalent antiplatelet is not to be discontinued if they have been in use < 1 year, otherwise stop may be considered.
      • Pradaxa®, Xarelto® and Eliquis® must be stopped two days before the examination, earlier if renal impairment.
      • Restarted after two days if a sling resection or another examination that can cause bleeding is performed.
      • Marevan® (warfarin) is stopped five days before the examination. INR is measured an hour before the procedure and should be below 1,8. If the patient has a high risk of thrombosis (heart valve and others) low molecular weight heparin must be considered. Start with double dose of Marevan® (warfarin) the same evening.
      • Albyl-E® (Acetylsalicylic Acid) can be continued.

    If it is contraindicated to discontinuate (for example dual antiplatelet agent), and there is an indication to perform the examination as soon as possible, a tailored program should be made in collaboration with the general practitioner and possibly a cardiologist/haematologist.

    • Any other medications in the morning can be taken as usual.
    • If the patient has diabetes and use insulin, an appointment early in the day can be made.
    • The bladder should be empty before the examination.

    Implementation

    • Before total colonoscopy premedication with intravenous analgesics and possibly sedation are usually administered.
    • The patient is located in a left lateral position.
    • The anal canal is lubricated and palpated with a finger to ensure that the canal is open.
    • The coloscope is being inserted and it is attempted to use as little air as possible during insertion to minimize discomfort.
    • As the scope is inserted upwards the patient turns into a supine position, possibly another position.
    • If there is difficulties during the insertion the assistant will "stabilize" the intestine by holding his hands on the patient´s stomach.
    • If the patient experiences the examination as painful, more medications are administered.
    • The scope is rapidly, but gently inserted to the cecum, possibly into the terminal ileum. Then more air is filled in and the scope is slowly pulled down while all parts of the intestine are being visualized.
    • Any lesions are being biopsied, or possibly removed.

    The examination lasts for about 15 - 60 minutes.

    Follow-up

    • The patient can eat and drink immediately after the procedure, unless otherwise indicated.
    • The patient can usually go home quite immediately. If he/she is tired after the examination/medications, or a procedure that leads to increasing risk for complications is performed, the patient may be in the hospital for observation in one to three hours before going home.
    • The patient is informed about possible complications:
      • Bleeding from the rectum if polyps are removed.
      • Abdominal pain which do not disappear quickly after a completed examination, may lead to suspicion of bowel perforation. This may occasionally occur during diagnostic colonoscopy, while it is more common after biopsy/sling resection.

    The physician in charge of the examination is following up test results and informs the patient about any further investigation and control.

    Ultrasound-guided needle biopsy in the abdomen

    General

    CT and other radiological examinations are often used for assessment of possible spreading of different cancer types. For these examinations, it is possible to find enlarged lymph nodes or unspecific lesions where it is necessary to confirm or exclude metastases. If the lesion is visible on ultrasound, ultrasound-guided biopsy is the optimal method for clarification. The exception is for suspicion of sarcoma which should be adequately reported with pictures before sample collection. The indication assessment is done by a sarcoma specialist.

    Ultrasound-guided biopsy is a quick method for diagnosing possible pathology of suspect lesions/changes deep in the abdomen. We always use fine-needle aspiration initially. The cell sample is stained immediately and assessed by a cytologist. In many cases, the diagnosis for metastasis or reactive lymph node is certain after rapid staining and microscopy. When relevant, a pistol biopsy is performed as well. In these cases, it is necessary to wait 4-6 days to initiate treatment while awaiting the result.

    Indication

    • Lesions of unknown type in the abdomen evident by radiological examinations.

    Goal

    • Confirm or exclude metastases of suspect lesions in the abdomen evident by radiological examinations.

    Equipment

    • Ultrasound apparatus with (transducer) for the procedure.
    • Local anesthetic (5 ml Xylocain 10 mg/ml). (Not always for cytological biopsies - always for histological biopsies.)
    • Syringe (5 ml) and needle for anesthesia. (22 G B&D spinal needle)
    • Needle for cytology material. (22 G B and D spinal needle)
    • 4 specimen slides for the material 

    For a histological biopsy with biopsy pistol, the following is used additionally:

    • separate 18 G or 16 G needle + pistol, possibly disposable  
    • glass slides for storage of histological material (formalin, Ringer solution, McCoy, dry glass slides for freezing etc. – depending on tentative diagnosis).

    For sterile bandaging (used for local anesthesia)

    • Sterile cover
    • Sterile disposable tweezers
    • Sterile compresses 5 x 5 cm
    • Chlorhexidine colored 1 mg/ml
    • Sterile gloves
    • Sterile condom for UL-head
    • Sterile gel
    • Mepore bandage 6 x 7 cm

    Preparation

    • For ultrasound-guided puncture in the abdomen, the patient should fast the last 4 hours before the exam for best possible access.
    • Depending on the localization and localization of the lesion, normal blood tests should be done beforehand for bleeding parameters (hemoglobin, thrombocytes, possibly INR).
    • The patient is informed about what will happen.
    • The patient should lie comfortably on the examination table.
    • Inform the patient during the procedure.   

    Implementation

    Ultrasound-guided biopsy is taken with or without local anesthesia depending on depth, localization, and patient cooperability.

    • Localize the lesion with the ultrasound probe.
    • Determine the best puncture point and direction.
    • Wash the point of puncture with colored chlorhexidine 1 mg/ml.
    • Allow the skin to dry.
    • Inject the local anethesia with the help of ultrasound in the entire puncture canal, especially the skin, muscle fascia, peritoneum, and organ surfaces. It is important the patient does not experience any pain when the biopsies are taken. If the puncture is painful, it is easy to lose control of the needle, and small lesions are difficult to reach.
    • Puncture the spinal needle quickly through the skin.
    • Insert the the needle with the help of ultrasound through the peritoneum and into the lesion.
    • Retrieve the mandrin.
    • Move the needle back and forth 2-3 times per second. Due to capillary action, the cells will be collected in the needle.  
    • When the material is evident in the upper part of the needle, it is retrieved.
    • Deposit the material onto a specimen slide.

    Spread for cytology

    • Spread the material out with a specimen slide.
    • Dry the material under a fan or similar.
    • Staining: fixation fluid with methanol + haemacolour + rinsing in water:
      • 5 dips in fixator: allow the solution to drip off the paper.
      • 3 dips in color solution 1.
      • 6 dips in color solution 2. Allow the solution to drip off the paper.
      • Rinse in 2 baths of clean water.
      • Examine the specimen under a microscope with 10x or 20x objective.

      Microscopic assessment of cell material is done by a cytologist to determine if supplementary tests are necessary.

      Histological biopsy (pistol biopsy)

      • Place local anesthesia in the entire puncture canal down to the lesion. This is done with the help of ultrasound.
      • Make a small incision in the skin.
      • Insert the biopsy needle up to the lesion, preferably a little ways in, depending on the size of the lesion and type of tissue in front and behind the lesion.
      • Pull the trigger to take the sample.
      • Retrieve the needle and open it.
      • Place the piece of tissue in a holder with transfer medium, for example formalin.

      Follow-up

      • After uncomplicated biopsies, outpatients must remain at the hospital for 1 hour before going home.
      • Depending on the localization of the lesion and nature, bleeding may occur after the biopsy procedure.
      • For intense pain or bleeding, the patient must be observed at the post or intensive unit, depending on severity, while necessary measures are taken.
      Ultrasound-guided needle biopsy in abdomenUltrasound-guided needle biopsy in the abdomenUltrasound-guided needle biopsy from abdomen
      Ultrasound-guided needle biopsy from the abdomenUltrasound-guided needle biopsy in the abdomenUltrasound-guided needle biopsy from abdomenUltrasound-guided needle biopsy in the abdomen

      Treatment of neuroendocrine tumors

      Today, surgery is the only treatment which can cure the patient. All other treatment is palliative. Tumor-reducing treatment, such as hepatic artery embolization and radiofrequency ablation of liver metastases may reduce tumor size and symptoms and might omprove the prognosis.  

      Biological treatment with interferon and/or somatostatin analogues may stop further growth, and in some cases, reduce the size. The effect of this type of treatment is normally best when treating tumors with low Ki-67%, preferably < 5 %.

      Chemotherapy may have an effect, preferably on tumors with high Ki-67%.

      External radiation usually has little or no effect, particularly when metastases are located in the skeleton.

      Peptide receptor radionuclide therapy (PRRT) may be very effective on subgroups of neuroendocrine tumors, both to reduce the tumor size and to prevent further growth.

      Surgery/Intervention of neuroendocrine tumors

      Neuroendocrine intestinal carcinoma. Click to enlarge the image.

      The goal of a curative resection is complete removal of all of the diseased tissue. However, the tumor is often so advanced at the time of diagnosis that radical surgery is not possible. In these cases, some patients will benefit from a palliative resection or de-bulking operation, where most of the tumor tissue is removed. Debulking surgery is not recommended in poorly differentiated carcinomas.

      Ileum

      Primary treatment for a tumor in the ileum is an intestinal resection, often with resection of a larger or smaller part of the intestinal mesentery. These tumors are often surrounded by a large fibrotic process. The tumor should be removed radically, if possible. It may be necessary to remove more of the intestines than the primary tumor, as removal of mesentery will involve blood circulation to more of the intestines than the tumor-bearing part. 

      Appendix

      It is estimated that a neuroendocrine carcinoma in the appendix is found in about 1 in 300 appendectomies. If the tumors are greater than >2 cm, or is located at the basis of the appendix or infiltrates the mesoappendix, it is recommended to perform a right-sided hemicolectomy.

      Rectum

      The surgical treatment is, in principle, the same as for rectal tumors. The size and localization determines whether a resection can be performed with a primary bowel anastomosis, or if a rectum amputation with permanent sigmoideostomy must be performed. 

      Duodenum

      Depending on the size and localization, different surgical approaches are chosen, from a simple resection of the intestinal wall, to a large operation including both the stomach and pancreas.

      Pancreas

      Treatment depends on the type of tumor, size, and localization. Generally, tumors lying on the surface of the organ may be resected locally or by nucleation. 

      The risk of complications for this type of treatment is usually relatively small. However, such local treatment cannot usually be carried out.

      If the tumor is located in the body or the caudal area of the pancreas, a distal pancreas resection should be considered. If the tumor is located in the head area, the possibility of performing Whipple's operation (pancreatico-duodenectomy) is assessed. A distal pancreas resection can, in some cases, be carried out laparascopically in departments specializing in this type of surgery. Whipple's operation is a comprehensive operation with significant risk of complications.

      Lungs

      Operation methods vary based on size and localization. Most often, treatment will involve wedge resections, a segment resection, or resection of an entire lung flap. Normal lung tissue is conserved as much as possible. Laser treatment is only an alternative for very small tumors, or when other types of procedures are contraindicated.

      Liver metastases

      The surgical approach depends on the localization of the tumor(s). The operative method is a liver resection of some form, either local resections or more comprehensive resections in parts of the liver. Surgical treatment is evaluated against embolization or radiofrequency ablation. A liver resection is mainly recommended if the tumor can be completely removed. Palliative operations (de-bulking procedure) are only recommended if > 90% of the tumor tissue can be removed. It is then evaluated whether the rest of the tumor can be treated with embolization or ablation, possibly drug therapy. 

      For small tumors, it is recommended to monitor the patient's status over some time before choosing the operation. This is because these tumors develop very differently, from very slowly to rapidly giving rise to massive, diffuse spreading.

      A liver transplantation may be an alternative for patients who, after surgical removal of the primary tumor, solely have liver metastasis which progresses despite medical treatment (8).

      Radiofrequency ablation

      Radiofrequency ablation is carried out by inserting electrodes into the tumor with the help of ultrasound. Electricity is use to heat the tumor to about 100°C, which destroys the tumor cells. This can be performed as an open operation, laparascopy, or as a percutaneous procedure with the patient under general anesthesia.

      There are limitations for when the method can be used. The tumors should not be greater than 4 cm in diameter. This method can be used on tumors in the liver where liver surgery is technically difficult.

       

      PROSEDYRER

      Hepatic artery embolization

      General

      The cells of the liver receive blood partly from the hepatic artery and partly from the hepatic portal vein. The cancer cells receive blood mainly from the hepatic artery. By embolizing the arteries to the tumor with small particles, it is possible to stop blood supply to the tumor tissue. By doing this, all or parts of the tumor becomes necrotic  . The normal cells in the area survive since they also receive blood from the hepatic portal vein. This treatment is appropriate if there are many large metastases in the liver. Generally, only one liver flap is embolized at a time. 

      Liver embolization is also used for patients without serious symptomology since the procedure can be repeated, but the effect diminishes with repeated embolizations of the same lobe. This is mainly due colateral formation of arteries making effective embolization of arterial supply difficult for later procedures. 

      The procedure is carried out by an interventional radiologist.

      The treatment may be appropriate at an early stage to reduce tumor size, or later when liver metastases increase in size despite treatment. The treatment often relieves symptoms, especially for those with hormonal symptoms such as flushing and diarrhea. A life-prolonging effect can also be attained with this treatment.


      Indications

      • Multiple liver metastases
      • Symptom-causing disease despite other treatment

      Contraindications

      Absolute:

      • Central port vein thrombosis

      Relative:

      • Poor general health status
      • Enterobiliar anastomosis (increased risk for infection)
      • Little remaining liver parenchyme (risk of hepatic failure)

      Goal

      • Relieve symptoms
      • Reduce amount of tumor tissue in the liver

      Equipment

      • Angiography equipment (equipment for X-ray)
      • Selective catheters, microcatheters
      • Embolization materials

      Preparation

      • Hepatic work-up with CT scan or MRI
      • Premedication (Sandostatin®)

      Implementation

      • The catheter is inserted into the hepatic artery via the femoral artery.
      • Local anesthesia is placed.
      • The femoral artery is punctured using Seldinger's technique: the artery is punctured at the level of the head of the humerus. A leader probe is inserted through the needle and the needle is removed. An introducer casing is inserted into the artery over the leader probe.
      • A catheter is inserted in over the guidewire and up to the liver using X-ray.
      • Contrast fluid is used to visualize the hepatic artery. 
      • An angiograph with intra-arterial contrast is used to obtain more exact visualization and overview.
      • A microcatheter is inserted into the catheter. The embolization substance is placed through this. Polyvinyl alcohol particles are used (150-200 microns) and mixed in the contrast fluid before the injection. 
      • The particles are injected using X-ray. The microcatheter is gradually removed as the arteries block.
      • Finally, the result is checked with an overview angiography. The catheter and casing are removed and the puncture wound in the groin is closed. 
      • Embolization takes from 30 minutes to multiple hours.

      Follow-up

      The patient is checked with a CT scan or MRI usually 6 months after the procedure

      Complications

      In the days following the procedure, the patient may be very sick with a high fever, abdominal pain, and nausea due to edema in the liver and significant release of necrotic material from the destroyed metastasis. Hospitalization of 1-2 weeks is normal.

      Incidental embolization of the cystic artery can lead to necrosis of the gall bladder and peritonitis. Both dissection and thrombosis of the common hepatic artery can occur. 

      Hepatic artery embolizationHepatic artery embolizationHepatic artery embolization

      Drug therapy of neuroendocrine tumors

      Molecular targeted therapy

      Today there are two main types of biological medications used to treat neuroendocrine tumors:

      • Somatostatin analogues
      • Interferon

      Both medications work by inhibiting growth or reducing the size of the tumor. Interferon is more effective than somatostatin medications, but has significantly more side effects.

      Somatostatin analogues

      Most neuroendocrine tumors have somatostatin receptors. Somatostatin is an inhibiting peptide having exocrine, endocrine, paracrine, and autocrine effects. Somatostatin analogues are generally most effective on tumors which are somatostatin receptor positive on an octreotide scan.

      The treatment is usually well tolerated. The most common side effects are diarrhea, nausea, and a tendency for gallstones .

      The most common somatostatin analog is octreotide, which has a half-life of about 90 minutes. For treatment of neuroendocrine tumors, the slow-release formulation is used preferably (Sandostatin LAR® or Ipstyl Autogel®). These substances are usually administered every 28 days as an intramuscular (Sandostatin LAR®) or subcutaneous (Ipstyl Autogel®) injection.

      Administration of somatostatin analogues usually has an immediate effect on hormonal symptoms such as diarrhea and flushing. Somatostatin analogues can also cause growth inhibition. In 0-5%, the tumor shrinks, and growth stops in 30-40% . The effect of growth inhibition appears to be proportional to the dose. Median time to progression is as for interferon, about 12 months. 

      Interferon

      Interferon influences a number of processes in cells including inhibition of growth factor and cell division. Interferon also activates parts of the immune system, especially the cellular part. The normal start dose is subcutaneous interferon alfa-2b (IntronA®) 5 x 106 IU daily. The dose is adjusted according to side effects and blood test results, often down to 3 x 106 IU 3–4 times weekly. Alternatively, peg-interferon alfa-2b (PegIntron®) is administered as 1–1.5 micrograms per kg as a weekly subcutaneous injection.

      Approximately 30–40% of the patients must stop taking interferon due to the side effects. The most common are muscle pain, psychological problems and depression, lethargy, blood disturbances, especially leukopenia.

      Studies indicate that in 40–50% of treated patients, the tumor stops growing. In 10-15%, the tumor is reduced in size. Interferon may be effective for hormonal symptoms from neuroendocrine tumors, but usually not as effective as somatostatin analogues. The median time to progression is about 12 months. After starting treatment, regular blood tests are important (after 1 week, 2 weeks, 4 weeks, and thereafter every 8 weeks after starting) to discover leukopenia, especially.  

      Other

      Studies are in progress with a series of other biological therapies, among others, angiogenesis inhibitors, mTor inhibitors, and tyrosine kinase inbibitors. Everolimus and sunitinib has been approved for treatment of highly differentiated tumors originating from the pancreas. These medications are increasingly used in Norway, most often as 3. or 4. line of therapy. In other countries they are often used in 1. or 2. line. 

      Chemotherapy 

      Chemotherapy is effective on small tumors, especially with KI-67 % in the upper levels. Tumors originating in the pancreas are often more sensitive to chemotherapy than tumors originating in the intestines. Relatively few studies are available involving chemotherapy for neuroendocrine tumors. They often include few patients, and inclusion criteria and effect indicators vary greatly.

      Most common regimens

      5- Flurouracil (5-FU) combined with streptozocin

      This is the first-line chemotherapy combination for tumors originating from the intestines and pancreas. The treatment is given as 5 day treatment, followed by 1 day treatment every 3-4 weeks. Treatment is usually monitored by CT scan every 3 months. For effect beyond 1 year, the interval between 1 day treatments is extended up to 6 weeks.

      • For neuroendocrine pancreatic tumors, a regression is observed in 40–60%. The median time to progression is 4–12 months. 
      • For neuroendocrine tumors orginating from the colon, regression is observed in 6–33%. The median time to progression is 3–8 months.

      Cisplatin (or carboplatin) combined with etoposide

      This combination is 2. or 3. lie chemotherapy treatment for tumors and 1. line chemotherapy treatment for poorly differentiated carcinomas. The treatment is given as a 3 day treatment in 3 week intervals. For response, 4-6 treatments are given with a break until progression, and then starting with new 3 day treatments with 3 week intervals.

      • Regression is observed in 9.4–81%. The median time to progression is 3–9 months.

      Temozolomid/capecitabine

      This combinations seems to have good effect on poorly differentiated carcinomas, the studies are, however small and few. This combination is less nephrotoxic than the other combinations.  

      Other regimens

      There are studies indicating varying degrees of effectiveness of a series of different chemotherapy drugs and combinations, including doxorubicin, temozolomide, gemcitabine, dacarbazine/paclitaxel, leucovorin, and docetaxel.

      (9)

      PROSEDYRER

      Sun Exposure under Drug Therapy

      General

      Correct information about the possibility of sunbathing may affect patients health and quality of life.

      Precautions in connection with sunbathing should be followed under medical cancer treatment and for 2-3 weeks after end of treatment.

      Drug cancer treatment includes chemotherapy, antibodies and other drugs used in cancer treatment.

      Indication

      Sun exposure in connection with drug cancer treatment.

      Goal

      Prevent sun damage of the skin during and after cancer drug treatment.

      Definitions

      Photosensitivity

      Increased sensitivity to ultraviolet light have been associated with certain drugs used in cancer treatment. Photosensitivity reactions can be expressed in various ways. They can be phototoxic, which is by far the most common, or photoallergic (8,14). Druginduced photosensitivity is mainly caused by wavelengths in the UVA range, but UVB rays may also be involved (8).

      Phototoxicity

      A phototoxic reaction is reminiscent of a reinforced sunburn, with redness, edema, pain and increased sensitivity in sun-exposed areas of the skin. This is caused by a photochemical reaction of a photosensitive drug and irradiation of sunlight on the skin, which leads to skin cell death. In severe cases, blistering can occur (14). Symptoms may appear immediately or as a delayed inflammatory reaction (3). Higher doses of medication will give an increased risk of skin reaction (14). Healing of skin area will often lead to a hyperpigmentation that can last from weeks to months before they might disappear (8). Although the incidence of drug-induced photosensitivity is unknown, phototoxic reactions is possibly more common than is diagnosed or reported.

      Photoallergy

      An immunological reaction usually occurring 24-72 hours after sun exposure. The reaction degenerates as an itchy, eczema-like eruptions. In acute cases, one can see rash liquids. The prevalence of eczema is usually limited to sun-exposed skin, but can in severe cases spread to larger areas of the body. Unlike a phototoxic reaction, photoallergy is less dependent on the dose of the causative drug (8).

      Photoinstability

      Some drugs can be degraded when exposed to light. This can happen both before administration and when the drug is circulating in the body. This degradation can cause redness/rash and edema of the skin. This applies especially for dacarbazine (9). It is unknown whether the effect of the drug is affected and it is therefore recommended that one avoids direct sunlight as long as the drug is active in the body.

      PPE ( palmoplantar erythrodysesthesia = Acral erythema )

      PPE is also called hand-foot syndrom. The condition starts with altered skin sensation that develops into burning pain, swelling and redness of palm of the hands and soles of the feet. The symptoms can also occur in other parts of the body that is subjected to pressure, for example under tight clothing. In severe cases large blisters and ulceration can develop. The pain can be so severe that daily activities is limited.

      PPE is often seen with liposomal doxorubicin (Caelyx®) and high dose cytarabine, but may in principle occur with any anthracyclines, taxanes and fluorouracil (5- FU® ) (9,14) .

      Acne-like rash

      Pimple-like eruptions in skin areas with a lot of sebaceous glands such as the face, scalp, chest and neck. In contrast to common acne, the liquid-filled blisters does not contain any bacteria (9,10,15).

      Hyperpigmentation

      Hyperpigmentation is a common side effect in patients receiving chemotherapy, especially alkylating drugs and antibiotics with cytostatic effect. The area that has increased pigmentation may be localized or diffusely distributed. It can occur in the skin, mucous membranes, hair and nails. Pigment changes can be normalized upon discontinuation of the drug, but it may also persist.

      Fluorouracil is one of the most common drugs which can provide hyperpigmentation. Others are; metotrexate, busulfan, doxorubicin liposomal, Hydroksyurea®, procarbazine, bleomycin, cyclophosphamide, doxorubicin , ifosfamide, tegafur, mitoxantrone, daunorubicin, fluorouracil, cisplatin, carmustine, thiotepa, docetaxel, vinorelbine, vincristine, imatinib and combination regimens (14).

      An increased pigmentation in sun-exposed areas with the use of methotrexate, fluorouracil and capecitabine is described (16,17,18). Beyond that there is little evidence in the literature  that hyperpigmentation aggravates by sun exposure.

      Radiation Recall Dermatitis (RRD)/Photo Toxic recall reaction

      Flares of an inflammatory skin reaction in an area of ​​previous radiation damaged skin resulting from sunburn or external radiation. RRD can occur from months to years after the initial radiation damage.

      Drugs that can provide RRD are; bleomycin, capecitabine, cyclophosphamide, dactinomycin, cytarabine, daunorubicin, docetaxel, doxorubicin liposomal, doxorubicin, etoposide, fluorouracil, gemcitabine, Hydroksyurea® , idarubicin, lomustine, melphalan, methotrexate, paclitaxel, tamoxifen and vinblastine (14). EGFR inhibitors (cetuximab , gefitinib and erlotinib) may also cause other skin reactions that may be exacerbated by sun exposure (9,10,19).

      Preparation

      The patient is given written and verbal information by the medical responsible doctor and nurse at the start of the drug cancer treatment, and it is repeated as necessary.

      Implementation

      General Precautions

      Prevention and protection:
      • Limit sun exposure during the first days after the cure.
      • Observe skin daily to detect any skin reactions early.
      • Avoid getting sunburned.
      • View extra care between 12.00-15.00 (2).
      • Wear protective clothing and headgear (2,3,4,5,6).
      • Wide-brimmed hats protect better than caps (2.4).
      • Please note that the window glass does not protect against UVA rays (7).
      • Use sunscreen; to protect against UVA and UVB rays, a minimum SPF 15 (3,4,6,8) is applied several times daily.
      • Use mild skin care products without perfumes.

      In case of an eruption, sun exposure (including solarium) should be avoided until the skin is healed. Adverse skin reactions can be alleviated with moist and cooling compresses. Mild cortisone salves can also be highly effective. For very severe cases, systemic cortisone might be necessary (3,6,7,9).

      When a photosensitive reaction occurs, it is important to consider what other medications the patient is receiving which can also trigger such reactions. For example, steroids, some antibiotics, diuretics and NSAIDs.

      Medicaments that most commonly cause skin reactions

      Medicament Common reactions Remedial action
      Dakarbazin (DTIC)


      Phototoxic/photoinstability
      See general precautions
      Redness in skin, tingling of the scalp and general unwellness
      Avoid sunlight completely the day of the treatment (9)
      Methotrexate
      Phototoxic

      See general precautions
      Acne-like rash
      Avoid direct sun exposure, heat and humidity (9,10). Avoid soap, alcohol based skin products (9). Use moisturizing products and oil bath (4,9,10).
      Palmoplantar erythrodysesthesia = Acral erythema (PPE)

      Preventive: Pyridoxin (vitamine B6) (2,6,9)

      Avoid sunlight, heat, pressure against the skin and tight clothing can according to some studies have an effect (11,12,13). Use moisturizer.

      Treatment/relief: Cortisone salves, cortisone tablets, cold compress, cold baths

      (2, 9)

      Fluorouracil (5-FU®)

       

      Phototoxic See general precautions
      Palmoplantar erythrodysesthesia = Acral erythema (PPE) Preventive: Pyridoxin (vitamin B6) (2,6,9)

      Avoid sunlight, heat, pressure against the skin and tight clothing can according to some studies have an effect (11,12,13). Use moisturizer.

      Treatment/relief: Cortisone salves, cortisone tablets, cold compress, cold baths   (2, 9)

      Radiation recall
      Treatment as with phototoxic

      Kapecitabin (Xeloda®)

       

      Phototoxic See general precautions
      Palmoplantar erythrodysesthesia = Acral erythema (PPE)

      Preventive: Pyridoxin (vitamin B6) (2, 6, 9). Preventive: Pyridoxin (vitamin B6) (2, 6, 9)

      Avoidance of sunlight, heat, pressure against the skin and tight clothing can according to some studies have an effect (11,12,13). Use moisturizer.

      Treatment/relief: Cortisone salves, cortisone tablets, cold compress, cold baths (2, 9)

      Vinblastin

       

      Phototoxic
      See general precautions
      Radiation recall Treatment as with phototoxic
      Doxorubicin liposomal (Caelyx®)
      Palmoplantar erythrodysesthesia = Acral erythema (PPE) Preventive: Pyridoxin (vitamin B6) (2, 6, 9)

      Avoidance of sunlight, heat, pressure against the skin and tight clothing can according to some studies have an effect (11,12,13). Use moisturizer.

      Treatment/relief: Cortisone salves, cortisone tablets, cold compress, cold baths (2, 9)

      Tegafur

       

      Phototoxic
      See general precautions
      Palmoplantar erythrodysesthesia = Acral erythema (PPE) Preventive: Pyridoxin (vitamin B6) (2, 6, 9)

      Avoidance of sunlight, heat, pressure against the skin and tight clothing can according to some studies have an effect (11,12,13). Use moisturizer.

      Treatment/relief: Cortisone salves, cortisone tablets, cold compress, cold baths    (2, 9)

      EGFR-hemmere

      (Cetuximab, panitumab, erlotinib, gefitinib, lapatinib, vandetanib)

      Phototoxic
      See general precautions
      Acne-like rash
      Avoid direct sun exposure, heat and humidity (9,10). Avoid soap, alcohol based skin products (9). Use moisturizing products and oil bath(4, 9, 10).

      Beyond the medications listed in the table the literature gives som evidence that these substances may cause phototoxic skin reactions :

      • paclitaxel (Taxol®)
      • docetaxel (Taxotere®)
      • hydroxycarbamide ( Hydroksyurea® )
      • imatinib ( Glivec® ) and Dapson® and that paclitaxel can provide radiation recall .

      References


      1. LOV-1999-07-02-63 Pasientrettighetsloven - pasrl. Lov om pasientrettigheter.
      2. Polovich M, White JM, Kelleher LO. Chemotherapy and biotherapy guidelines: recommendations for practice. Pittsburgh, PA: Oncology Nursing Society; 2005.
      3. González E, González S. Drug photosensitivity, idiopathic photodermatoses,and sunscreens. J Am Acad Dermatol 1996;35:871-85;quiz 886-7.
      4. Liffrig, JR. Phototrauma prevention. Wilderness Environ Med 2001;12:195-200.
      5. Tan E. Skin toxicity of chemotherapy drugs [created 2007, last updated  2010 Mar 5]. Hentet 1. desember 2010 fra: http://dermnetnz.org/reactions/chemotherapy-toxicity.html
      6. Gould JW, Mercurio MG, Elmets CA. Cutaneous photosensitivity diseases induced by exogenous agents. J Am Acad Dermatol 1995;33:551-73.
      7. Payne, AS & Bernandin, RM. Sunburn [topic last updated 2010 Oct 06]. I: BMJ Best Practice. Hentet 23. november 2010 fra http://bestpractice.bmj.com
      8. Zhang AY, Elmets CA. Drug-induced photosensitivity [updated 2010 Jan 15]. Hentet 1. desember 2010 fra: http://emedicine.medscape.com/article/1049648-overview
      9. Ulrich J, Hartmann JT, Dörr W, Ugurel S. Skin toxicity of anti-cancer therapy. J Dtsch Dermatol Ges 2008;6:959-77.
      10. Agero AL, Dusza SW, Benvenuto-Andrade C, Busam KJ, Myskowski P, Halpern AC.Dermatologic side effects associated with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol 2006;55:657-70
      11. Alley E, Green R, Schuchter L. Cutaneous toxicities of cancer therapy. Curr Opin Oncol 2002;14:212-6.
      12. Mangili G, Petrone M, Gentile C, De Marzi P, Viganò R, Rabaiotti E. Prevention strategies in palmar-plantar erythrodysesthesia onset: the role of regional cooling. Gynecol Oncol 2008;108:332-5.
      13. Tanyi JL, Smith JA, Ramos L, Parker CL, Munsell MF, Wolf JK. Predisposingrisk factors for palmar-plantar erythrodysesthesia when using liposomal doxorubicin to treat recurrent ovarian cancer. Gynecol Oncol 2009;114:219-24.
      14. Payne AS, Savarese DMF. Cutaneous complications of conventional chemotherapy agents. I: UpToDate [version 18.2 2010]. Hentet 1. desember 2010 fra: http://www.uptodate.com
      15. Heidary N, Naik H, Burgin S. Chemotherapeutic agents and the skin: an update. J Am Acad Dermatol 2008;58:545-70.
      16. RELIS Sør. Hyperpigmentering av cytostatika og forverring av sollys. I: RELIS database 2010, Spm.nr 4736. Hentet 1. desember fra: http://relis.arnett.no/Utredning_Ekstern.aspx?Relis=2&S=4736
      17. Hendrix JD Jr, Greer KE. Cutaneous hyperpigmentation caused by systemic drugs. Int J Dermatol 1992;31:458-66.
      18. Schmid-Wendtner MH, Wendtner CM, Volkenandt M, Heinemann V. Clinical picture: leopard-like vitiligo with capecitabine. Lancet 2001;358(9293):1575.
      19. Segaert S, Tabernero J, Chosidow O, Dirschka T, Elsner J, Mancini L, et al. The management of skin reactions in cancer patients receiving epidermal growth factor receptor targeted therapies. J Dtsch Dermatol Ges 2005;3:599-606.

      Preparation of Chemotherapy, Spills, and Cleaning a LAF Bench

      General

      Preparation of chemotherapy outside of a pharmacy

      At Oslo University Hospital, the pharmacy primarily prepares chemotherapy for each patient. If it is necessary to dilute/mix the medicine at the department, then this should occur in a designated room with a LAF bench (laminar airflow bench). Many chemotherapy drugs are carcinogenic and teratogenic, and it is extremely important for health personnel to follow directions for preparation of of these medications. At Oslo University Hospital, all chemotherapy should be prepared and administered by a nurse who has completed a cytostatic treatment course at Oslo University Hospital, or by nurses who are certified cancer nurses from Oslo University College.

      Pregnant women and employees under physician orders not to temporarily or permanently work with chemotherapy drugs, should not handle or be exposed to these chemicals. Nursing mothers may handle chemotherapy drugs as long as they follow the general guidelines for chemotherapy handling. For each work place, there should be written guidelines for handling of chemotherapy drugs and for first aid for spills and maintenance of fume hoods etc..

      Designated room with LAF-bench to dilute/mix chemotherapy

      • The ventilation should be separate from the main ventilation and fumes should be vented to the outside and if necessary, filtered.
      • The room should be well illuminated for visual control of the fluid.
      • The LAF bench should be a workbench having sterile, filtered air from the ceiling with defined speed and an approved fume hood. The bench should be routinely tested and approved.

      Goal

      • To protect nurses and surroundings from exposure to cytotoxic chemicals and to preserve the sterility of the drug.

      Handling of chemotherapy spills

      Chemotherapy drugs are a heterogeneous group of drugs in which many are known mutagens, teratogens and/or carcinogens. Allergic reactions have also been reported. Studies show that there is a health risk during exposure of chemotherapy drugs and there are guidelines for minimizing exposure of health personnel to these chemicals. Workers in daily contact with these drugs will be more at risk due to the increasing use of chemotherapy. Chemotherapy spills refers to spills during preparation and leakage from infusion bags.

      Goal

      • To ensure that spills of chemotherapy drugs or waste materials that contain these chemicals are handled in a safe way to protect health and safety.

      Cleaning of LAF-bench

      The Norwegian Work Authority recommends that each workplace should have written guidelines for handling chemotherapy drugs, first aid for spills, and maintenance of fume hoods etc. A LAF-bench (laminar airflow bench) is a bench protecting workers from the drug being prepared and also protects from microbiological organisms. Those who carry out cleaning should have training and knowledge of the risk for exposure to chemotherapy drugs.

      Goal

      • Maintain a clean LAF bench
      • Avoid contamination and preserve the sterility of the drug 
      • Protect people and surroundings from exposure

      Source

      Applicable directives and guidelines (www.lovdata.no)

      • Warn against exposure to chemicals at the workplace (Kjemikalieforskriften §24), mandated by The Norwegian Labour Inspection Agency from 5 May 2001, last edition from 26 April 2005.
      • Guidance for chemical directives attachment VII Cytostatica from September 2003 (www.arbeidstilsynet.no).

      Equipment

        Preparation of chemotherapy in a hospital

      • 2 pairs of gloves: vinyl gloves inside and sterile, powder-free latex gloves outside
      • Protective coat with long arms/plastic apron
      • Arm protectors
      • LAF bench
      • Dilution fluid
      • Syringes and cannulas
      • Sterile compresses
      • Disposable cloths
      • 70% ethanol
      • Absorbent benchcoat with plastic underside for the work bench
      • If a LAF bench is not used, use a protective mask with aerosol filter and protective goggles.

      Handling of chemotherapy spills

      Spill kit includes:

      • 2 pairs of nitrile gloves, long
      • 2 pairs of latex gloves, long
      • 2 pairs of shoe covers
      • Plastic coat\apron
      • 1 mask
      • 2 diapers
      • 1 bed absorbent bed sheet
      • 2 plastic bags with zippers (30 x 40 cm)
      • 4 thin, white plastic bags (60 x 90 cm)
      • Absorbant material   
      • 8 disposable wash cloths

      Washing of LAF-bench

      • Plastic apron
      • Arm protectors
      • Gloves: either double vinyl gloves or special gloves
      • Disposable cloths
      • 70% ethanol
      • Bucket and soapy water
      • Waste container with plastic bag for chemotherapy waste (biohazardous waste)

       

       

      Preparation

      Preparation of chemotherapy outside of the pharmacy

      For preparation of chemotherapy drugs, use gloves and a protective lab coat with long arms or tight-fitting cuffs.   Use two pairs of gloves where the inner pair is vinyl or other latex-free material. The outer glove should be sterile and of latex or other material which is impenetrable.  The gloves are recommended to be changed every half hour for preparation of chemotherapy drugs, and right away with spills.

      • Start the LAF-bench a minimum of 30 minutes before use.
      • Wash hands
      • Put on the inner gloves
      • Disinfect the work surface with 70% ethanol
      • Cover the work surface with a benchcoat. This should not cover the vent; otherwise, the bench will not function properly.
      • Read the dilution directions and find the necessary equipment and medications as described.
      • Choice of dilution system/fluids
        • A transfer cannula should be used in preference to a syringe where possible to maintain a closed system as much as possible.
        • If a syringe is used: use a syringe with Luer lock connection. These have a better connection between the syringe and the cannula.
      • Check the expiration on the drug packaging and infusion fluid.
      • Check that the drug in liquid form does not contain particles or visible solids.
      • Check that the packaging does not have any cracks or leakages.
      • Perform necessary calculations, date, and sign the work form.
      • Obtain another nurse to double check: right patient, work form, drug, dosage, fluid type and volume, as well as calculations.  All checks should be against the original ordination. The person doing the check should sign and date it.
      • Set out necessary equipment on the LAF-bench or where the work will take place. The equipment should be placed in the corner within the ventilation of the LAF-bench.  Remove the outer packaging of the sterile gloves and lay the gloves on the bench.
      • Put on the protective clothing (coat/apron and arm protectors)
      • Put on the sterile gloves in the bench
      • Disinfect the rubber membrane on the infusion bag and hood windows as well as the ampules.
      • Make sure the protective glass on the LAF-bench is pulled down to the correct work level as recommended by the manufacturer of the bench.

      Handling of chemotherapy spills

      All, except the workers who clean the spill, should leave the room.  Preferably, two people should help each other to remove the spill.  This way, one can ensure that proper precautions are taken.

      At Oslo University Hospital, a packet is available from the pharmacy for chemotherapy spills.

      Washing of LAF-bench

      • The LAF-bench should be operating under cleaning.
      • The sash should be down, as under normal working conditions.
      • Use a plastic apron, arm protectors, and gloves.

       

       

      Implementation

      Preparation of chemotherapy drugs outside of a pharmacy

      Aseptic procedure

      •   To avoid turbulence of the sterile, laminar air stream:
        • Work at least 15 cm inside the perforation with steady movements
        • Avoid hands or other objects from coming between the airflow and the medicine.
      • Make only one medicine at a time.
      • A full syringe or finished bag should be labeled for the next preparation.  The label should be labeled with the patients name, birthdate, drug and dosage, preparation date, expiration, and the name of the person who prepared and checked the medicine.
      • Avoid spills and aerosol formation
        • Use a dry, sterile compress around neck of the ampule when it is broken.
        • When the cannula is removed from the syringe, hold a sterile compress around the barrel neck to catch any spills.
        • Hold the syringe/ampule such that the opening is directed away from the face.
        • For solid substances, solvent should be added along the glass wall to avoid whirling of particles.
        • With positive/negative pressure in the hood glass: apply a filter cannula first to reduce pressure.
        • With use of adapter: place adapter first in the infusion bag and connect to the hood glass with medicine.
        • When the air is removed from the syringe, place the cannula cap on the cannula again while the syringe is held vertically with the cannula upright. A sterile compress should be held around the opening between the cannula and the syringe to collect spillage.
        • Clean up spills at once
      • After each addition, the contents of the infusion container should be mixed well by inverting and repeating 5-6 times.
      • Infusion fluid which has been added to should be marked satisfactorily.
      • The finished solution should be scrutinized for solid or foreign particles. All solid should be dissolved.
      • If visible changes occur under the mixing procedure, the physician should be contacted and the fluid should not be used. Store the infusion fluid and packaging of the added drug and contact the pharmacy (chemist) for further clarification.
      • All used equipment should be rolled up in the benchcoat (alternatively, all used equipment can be placed in a plastic bag which can be tied or closed with zipper) and disposed of in box with plastic bag for chemotherapy waste/biohazardous waste.
      • LAF-bench should be stopped at least 30 minutes after use.

      Multiple additions

      • Addition of multiple drugs for chemotherapy solutions should be avoided. If it is still appropriate, there should be clear documentation of the mixture.
      • Different chemotherapies can mix if their mixing properties are documented (and checked with pharmacist).

      Handling of chemotherapy spills

      • Use two pairs of disposable latex\nitrile gloves, plastic coat, mask, shoe covers (used with floor spills) and protective goggles.
      • Lay the smallest diaper in the middle of the spilled fluid. Then, place the absorbent bed sheet over the diaper and the rest of the fluid. Use more diapers and absorbent material if necessary.
      • Dispose of used diapers, absorbent material, bed sheets, and gloves is appropriate waste container, which can be closed.
      • Use new gloves and wash thereafter with soapy water and disposable wash cloths a minimum of three times. Use a new cloth before each wash. Used cloths should not be put back in the wash solution.  Used cloths and gloves should be disposed in the appropriate waste containers (in plastic bags which can be closed).
      • The plastic bags with used equipment should be disposed of in the appropriate containers which are properly labeled.

      Washing of LAF-bench

      • Other than a cannula bucket, nothing should be stored in the bench after the last preparation.
      • Washing with 70% ethanol is sufficient if there are no visible spills.
      • For visible spills, wash the bench with soapy water and spray afterwards with 70% ethanol (see procedure under). Soapy water is the most effective for removing chemotherapy spills.

      Routine washing

      • Washing should be done every 1-4 weeks depending on frequency of use.
      • Spills and dust pose risks for washing.
      • It is important that any remaining solution of chemotherapy is not spread under washing.
      • Use disposable cloths.
      • To avoid contamination of washing water, the washing hand should not be dipped in the water.
      • Wash with slow movements and use a new cloth as needed.
      • Cloths that have been in contact with the bench should not be put back in the washing water and should be discarded in proper waste container.
      • Wash first the walls from top to bottom with soapy water (the cleanest to the most contaminated) – place the cloth on a squeegee for hard-to-reach areas.
      • The filter in the ceiling of the bench should not be washed.
      • Wash the work surface in the bench – wash from back to forward (from the cleanest to the most contaminated).
      • Raise the work surface.
      • Wash the work surface on the underside, especially the closest, perforated part.
      • Then wash the underside bottom of the work surface.
      • Wash thereafter all surfaces (not the ceiling) with 70% ethanol.
      • Remove protective clothing.
      • Discard all protective clothing for one-time use and washcloths in the appropriate waste container.
      • Wash hands.
      • Replace the cannula bucket.
      • There should be a record for bench washing; the employee who washes should sign and date the record.

      Follow-up

      Aerosol formation with spraying or squirting can occur:
      • when a syringe is used and cannula is retracted for transfer
      • when an ampule is broken
      • when air is removed to measure volume
      • with a leak in a syringe or IV catheter
      • with waste handling

      First aid if contact with chemotherapy drugs

      • Skin: Rinse well with water for 15 minutes. Wash contacted area with regular soap.
      • Eyes: Rinse well with water, or use spray bottle with NaCl 9 mg/ml (at least 20-30 minutes of continual rinsing).
      • Contact a doctor.

      Radiation therapy of neuroendocrine tumors

      External radiation therapy may relieve symptoms from skeletal metastases. External radiation therapy otherwise does not have a place in treatment of neuroendocrine tumors.

      Radioactive isotope treatment (Peptide receptor radionuclide therapy)

      If a tumor is detected by an octreotide scan with somatostatin receptors, it can be treated with radioactive isotopes (radionuclides). These are attached to an octreotide analog which binds to receptors on the tumor thereby the radionuclide can deliver local radiation. A series of different radionuclides are used. The most common are 111Indium and 177Lutetium. 177Lutetium has given the best results.

      This treatment option is not currently available in Norway. Patients who require this treatment are referred to Uppsala University Hospital in Uppsala, Sweden, where mainly 177Lutetium in used.

      Treatment is given 1–8 times in 4–6 week intervals. The patient is isolated for the first 24 hours to protect others from radiation. The patient stays at the hospital or patient hotel for 4–7 days for each treatment.

      Of those treated, 80% have a positive effect: 35% stabile disease, and 45% regress. The median time to progression is 40 months. The effect appears to be best for neuroendocrine tumors in the pancreas. 

      Examples of treatment effect:

      • CT scan 
      • Octreotide scintigraphy

      Common side effects are nausea and pain, which occur early in the treatment course. Cytopenia, myelodysplastic syndrome, and renal failure are side effects which are considered delayed/rare.

      Indications

      • Other treatments should be tried first
      • There is strong uptake by the tumor on octreotide scan
      • Good general health status
      • Good bone marrow function 
      • Good renal function
      • Ki67 less than 40-50% 

      (10)

      PROSEDYRER

      Complication treatment of neuroendocrine tumors

      Surgery, chemotherapy, and radiation therapy cause side effects to varying degrees.

      It is usually 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.

      PROSEDYRER

      Treatment of Nausea Induced by Chemotherapy

      General

      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.

      Indication

      • Nausea induced by chemotherapy drugs.

      Goal

      • Prevention and treatment of nausea and vomiting.

      Definitions

      Chemotherapies according to emetic potential

      High emetogenicity   

      Group 1

      Moderate emetogenicity   

       Group 2

      Low/minimal emetogenicity

      Group 3

      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
      Doxorubicin/ifosfamide Bendamustine
      Docetaxel
      FEC-60 og FEC-100
      (fluorouracil, epirubicin, cyklophosfamide)
      Carboplatin
      ENAP (etoposide, mitoxsantrone, cytarabine, prednisolone)
      ABVD (doxorubicin, bleomycin, vinblastine, dakarbazine Carboplatin/pemetrexed
      FLv (fluorouracil)
      FOLFIRINOX
      Carboplatin/vinorelbine
      FuMi (fluorouracil, mitomycin)

      CHOP (cyclophosfamide, doxorubicin, vincristine, prednisolone)
      Gemcitabine

      CHOEP (cyclophosfamide, doxorubicin, vincristine, etoposide, prednisolone)
      Methotrexate weekly dose
         Dakarbazine
      Navelbine
            ECO/ACO (epirubicin/doxorubicin, cyclophosfamide, vincristine)
      Paclitaxel
             EOX (epirubicin, oxaliplatin, capecitabine)
      Pemetrexed
            EPOCH-F (etoposide, prednisolone, vincristine, cyclofosfamide, doxorubicin, fludarabine)

          EPOCH-F (etoposide, prednisolone, vincristine, cyclophosfamide, doxorubicin, fludarabine)
       
          FLIRI (fluorouracil, irinotecan)
       
          FLOX (fluorouracil, oxaliplatin)    
         Gemcitabine/carboplatin      
         HD-Cytarabine
         
          HD-Methotrexate    
        IGEV (ifosfamide, gemcitabine, vinorelbine)
        
         IME (ifosfamide, methotreksate, etoposide)  
         Irinotecan  
         Streptozocin  
         Vorphase (cyclophosfamide)
       

      References

      1. 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.

      Preparation

      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.

      Implementation

      • 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.

      Antiemetic regimens

      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.

      Delayed nausea

      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.

      Conditional nausea

      In the event of conditional nausea, diazepam or other tranquilizers may be considered. Diversion or desensitization can be tried in more serious cases.

      Follow-up

      Ondansetron can have a constipating effect. Use of a laxative for several days should be considered.

      Nutrition during Cancer Treatment

      General

      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.

      Indication

      • Cancer treatment (chemotherapy, radiation, surgery).

      Goal

      • Maintain nutritional status in order for the patient to have the best possible conditions for implementing treatment.

      Definitions

      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

      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 diarrhea
      • 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

      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.

      Preparation

      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.

      Tube feeding

      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).

      Parenteral nutrition

      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.

      Implementation

      All 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

      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.

      Bolus supply

      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.

      Continuous supply

      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.

      Parenteral nutrition

      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.

      Follow-up

      The patient's nutrition status should be monitored at follow-up visits after the end of treatment.

      Transfusions

      General

      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.

      Normal values

      • Hemoglobin 13.4–17 g/dl
      • Platelets 145–348 109/l

      Indications

      Blood transfusion

      Assessment for a blood transfusion based on:

      • Hb/hct
      • 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

      Platelet transfusion

      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.

      Goal

      • Complete the planned treatment
      • Ensure hemostasis 
      • Ensure adequate oxygen transport to peripheral tissue.
      • Maintain intravascular fluid volume for adequate circulations of vital organs

      Definitions

      Blood

      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%.

      Platelets

      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.

      Radiation

      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

      Preparation

      Blood tests

      Before the first blood transfusion, the following blood tests are performed:
      • Virus antigens
        • HCV
        • HBV
        • HIV
      Every three days, and as needed, pre-transfusion tests are taken.

      Compatibility

      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.

      Implementation

      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

      Observations

      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:
      • chills
      • fever
      • feeling of heat in the face
      • breathing difficulty
      • itching
      • nervousness
      • fall in blood pressure
      • shock
      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.

      Follow-up

      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.

      Smoking cessation in connection with cancer treatment

      General

      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.

       

      Indication

      Weaning of nicotine in connection to cancer treatment. 

      Goal

      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.

      Preparation

      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.

      Implementation

      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
      Justifications
      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.

      Side effects

      • Headache, dizziness, nausea, flatulence and hiccup.
      • Irritation in the mouth and esophagus using chewing gum/ lozenges/inhalator
      • Skin irritations while using patches.

      Precautions

      • 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%.

      Side effects

      • Dry mouth, nausea, insomnia, hypersensitivity reactions and seizures (convulsions)

      Precautions

      • 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.

      Side effects

      • Nausea, sleep disturbances, headache, constipation, flatulence and vomiting

      Precations

      • 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

      Follow-up

      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.

      References

      1. Gritz E, Fingeret M, Vidrine D. Tobacco control in the oncology setting. American Society of Clinical Oncology, eds Cancer Prevention An ASCO Curriculum Alexandria, VA: American Society of Clinical Oncology. 2007.
      2. ASCO ASoCO. Tobacco Cessation Guide for Oncology providers,. 2012 (02.12.2014).
      3. Zevallos JP, Mallen MJ, Lam CY, Karam-Hage M, Blalock J, Wetter DW, et al. Complications of radiotherapy in laryngopharyngeal cancer: Effects of a prospective smoking cessation program. Cancer. 2009;115(19):4636-44.
      4. Obedian E, Fischer DB, Haffty BG. Second malignancies after treatment of early-stage breast cancer: Lumpectomy and radiation therapy versus mastectomy. Journal of Clinical Oncology. 2000;18(12):2406-12.
      5. Park SM, Lim MK, Jung KW, Shin SA, Yoo K-Y, Yun YH, et al. Prediagnosis smoking, obesity, insulin resistance, and second primary cancer risk in male cancer survivors: National Health Insurance Corporation Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007;25(30):4835.
      6. Van Den Belt-Dusebout AW, De Wit R, Gietema JA, Horenblas S, Louwman MWJ, Ribot JG, et al. Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer. Journal of Clinical Oncology. 2007;25(28):4370-8.
      7. Warren GW, Kasza KA, Reid ME, Cummings KM, Marshall JR. Smoking at diagnosis and survival in cancer patients. International Journal of Cancer. 2013;132(2):401-10.
      8. Hooning MJ, Botma A, Aleman BMP, Baaijens MHA, Bartelink H, Klijn JGM, et al. Long-term risk of cardiovascular disease in 10-year survivors of breast cancer. Journal of the National Cancer Institute. 2007;99(5):365-75.
      9. Li CI, Daling JR, Porter PL, Tang M-TC, Malone KE. Relationship between potentially modifiable lifestyle factors and risk of second primary contralateral breast cancer among women diagnosed with estrogen receptor–positive invasive breast cancer. Journal of Clinical Oncology. 2009;27(32):5312-8.
      10. Kenfield SA, Stampfer MJ, Chan JM, Giovannucci E. Smoking and prostate cancer survival and recurrence. JAMA - Journal of the American Medical Association. 2011;305(24):2548-55.
      11. Joshu CE, Mondul AM, Meinhold CL, Humphreys EB, Han M, Walsh PC, et al. Cigarette smoking and prostate cancer recurrence after prostatectomy. Journal of the National Cancer Institute. 2011;103(10):835-8.
      12. Phipps AI, Baron J, Newcomb PA. Prediagnostic smoking history, alcohol consumption, and colorectal cancer survival: The Seattle Colon Cancer Family Registry. Cancer. 2011;117(21):4948-57.
      13. Kountourakis P, Correa AM, Hofstetter WL, Lee JH, Bhutani MS, Rice DC, et al. Combined modality therapy of cT2N0M0 esophageal cancer. Cancer. 2011;117(5):925-30.
      14. Waggoner SE, Darcy KM, Fuhrman B, Parham G, Lucci J, Monk BJ, et al. Association between cigarette smoking and prognosis in locally advanced cervical carcinoma treated with chemoradiation: A Gynecologic Oncology Group study. Gynecol Oncol. 2006;103(3):853-8.
      15. Schlumbrecht MP, Sun CC, Wong KN, Broaddus RR, Gershenson DM, Bodurka DC. Clinicodemographic factors influencing outcomes in patients with low-grade serous ovarian carcinoma. 2011. p. 3741-9.
      16. Nagle CM, Bain CJ, Webb PM. Cigarette smoking and survival after ovarian cancer diagnosis. Cancer Epidemiol Biomarkers Prev. 2006;15(12):2557-60.
      17. Ehlers SL, Gastineau DA, Patten CA, Decker PA, Rausch SM, Cerhan JR, et al. The impact of smoking on outcomes among patients undergoing hematopoietic SCT for the treatment of acute leukemia. Bone Marrow Transplant. 2011;46(2):285-90.
      18. Talamini R, Polesel J, Spina M, Chimienti E, Serraino D, Zucchetto A, et al. The impact of tobacco smoking and alcohol drinking on survival of patients with non-Hodgkin lymphoma. International Journal of Cancer. 2008;122(7):1624-9.
      19. Toll B, Brandon T, Gritz E, Warren G, Herbst R. AACR Subcommittee on Tobacco and Cancer. Assessing tobacco use by cancer patients and facilitating cessation: an American Association for Cancer Research policy statement. Clin Cancer Res. 2013;19:1941-8.
      20. Arntzen A, Sandvold B. Hvordan veilede om røykeslutt? Sykepleien Forskning. 2010;5(3):182-90.
      21. Dresler CM. Is it more important to quit smoking than which chemotherapy is used? 2003. p. 119-24.
      22. Hsu CCT, Kwan GNC, Chawla A, Mitina N, Christie D. Smoking habits of radiotherapy patients: Did the diagnosis of cancer make an impact and is there an opportunity to intervene? J Med Imag Radiat Oncol. 2011;55(5):526-31.
      23. Richards J. Words as Therapy: Smoking Cessation. The journal of family practice. 1992;34(6):687-92.
      24. Cooley ME, Lundin R, Murray L. Smoking cessation interventions in cancer care: opportunities for oncology nurses and nurse scientists. Annual review of nursing research. 2009;27:243.
      25. Mazza R, Lina M, Boffi R, Invernizzi G, De Marco C, Pierotti M. Taking care of smoker cancer patients: a review and some recommendations. Annals of Oncology. 2010;21(7):1404-9.
      26. Waller LL, Weaver KE, Petty WJ, Miller AA. Effects of continued tobacco use during treatment of lung cancer. 2010. p. 1569-75.
      27. Peppone LJ, Mustian KM, Morrow GR, Dozier AM, Ossip DJ, Janelsins MC, et al. The Effect of Cigarette Smoking on Cancer Treatment-Related Side Effects. Oncologist. 2011;16(12):1784-92.
      28. Kuri M, Nakagawa M, Tanaka H, Hasuo S, Kishi Y. Determination of the duration of preoperative smoking cessation to improve wound healing after head and neck surgery. Anesthesiology. 2005;102(5):892.
      29. Krueger JK, Rohrich RJ, Mustoe TA. Clearing the smoke: The scientific rationale for tobacco abstention with plastic surgery. 2001. p. 1074-5.
      30. Nakagawa M, Tanaka H, Tsukuma H, Kishi Y. Relationship between the duration of the preoperative smoke-free period and the incidence of postoperative pulmonary complications after pulmonary surgery. Chest. 2001;120(3):705-10.
      31. Barrera R, Shi W, Amar D, Thaler HT, Gabovich N, Bains MS, et al. Smoking and timing of cessation: Impact on pulmonary complications after thoracotomy. Chest. 2005;127(6):1977-83.
      32. Mason DP, Subramanian S, Nowicki ER, Grab JD, Murthy SC, Rice TW, et al. Impact of Smoking Cessation Before Resection of Lung Cancer: A Society of Thoracic Surgeons General Thoracic Surgery Database Study. Annals of Thoracic Surgery. 2009;88(2):362-71.
      33. Gajdos C, Hawn MT, Campagna EJ, Henderson WG, Singh JA, Houston T. Adverse Effects of Smoking on Postoperative Outcomes in Cancer Patients. Ann Surg Oncol. 2012;19(5):1430-8.
      34. Alsadius D, Hedelin M, Johansson KA, Pettersson N, Wilderang U, Lundstedt D, et al. Tobacco smoking and long-lasting symptoms from the bowel and the anal-sphincter region after radiotherapy for prostate cancer. Radiother Oncol. 2011;101(3):495-501.
      35. Chen AM, Chen LM, Vaughan A, Sreeraman R, Farwell DG, Luu Q, et al. Tobacco smoking during radiation therapy for head-and-neck cancer is associated with unfavorable outcome. International Journal of Radiation Oncology Biology Physics. 2011;79(2):414-9.
      36. Eifel PJ, Jhingran A, Bodurka DC, Levenback C, Thames H. Correlation of smoking history and other patient characteristics with major complications of pelvic radiation therapy for cervical cancer. Journal of Clinical Oncology. 2002;20(17):3651-7.
      37. Bjarnason GA, MacKenzie RG, Nabid A, Hodson ID, El-Sayed S, Grimard L, et al. Comparison of Toxicity Associated With Early Morning Versus Late Afternoon Radiotherapy in Patients With Head-and-Neck Cancer: A Prospective Randomized Trial of the National Cancer Institute of Canada Clinical Trials Group (HN3). International Journal of Radiation Oncology Biology Physics. 2009;73(1):166-72.
      38. Browman GP, Wong G, Hodson I, Sathya J, Russell R, McAlpine L, et al. Influence of Cigarette Smoking on the Efficacy of Radiation Therapy in Head and Neck Cancer. The New England Journal of Medicine. 1993;328(3):159-63.
      39. Browman GP, Mohide EA, Willan A, Hodson I, Wong G, Grimard L, et al. Association between smoking during radiotherapy and prognosis in head and neck cancer: A follow-up study. Head Neck-J Sci Spec Head Neck. 2002;24(12):1031-7.
      40. Travis LB, Gospodarowicz M, Curtis RE, Clarke EA, Andersson M, Glimelius B, et al. Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease. Journal of the National Cancer Institute. 2002;94(3):182-92.
      41. Ford MB, Sigurdson AJ, Petrulis ES, Ng CS, Kemp B, Cooksley C, et al. Effects of smoking and radiotherapy on lung carcinoma in breast carcinoma survivors. Cancer. 2003;98(7):1457-64.
      42. Dresler CM, Gritz ER. Smoking, smoking cessation and the oncologist. 2001. p. 315-23.
      43. Balduyck B, Nia PS, Cogen A, Dockx Y, Lauwers P, Hendriks J, et al. The effect of smoking cessation on quality of life after lung cancer surgery. Eur J Cardiothorac Surg. 2011;40(6):1432-8.
      44. Hamilton M, Wolf JL, Rusk J, Beard SE, Clark GM, Witt K, et al. Effects of smoking on the pharmacokinetics of erlotinib. Clinical Cancer Research. 2006;12(7 I):2166-71.
      45. Helsedirektoratet. Forberedelse til røykeslutt 2011. Available from: http://helsedirektoratet.no/publikasjoner/forberedelser-til-roykeslutt/Publikasjoner/forberedelse-til-roeykeslutt.pdf   
      46. Brunnhuber K, Cummings KM, Feit S, Sherman S, Woodcock J. Putting evidence into practice: Smoking cessation: BMJ Publishing Group; 2007.
      47. Helsedirektoratet. Røyketelefonen 2013 [updated 12.12.201102.12.2014]. Available from: http://www.helsedirektoratet.no/folkehelse/tobakk/snus-og-roykeslutt/royketelefonen/Sider/default.aspx.
      48. Legemiddelverk S. Legemidler A-Å 2013 [02.12.2014]. Available from: http://www.legemiddelverket.no/Legemiddelsoek/Sider/Legemidler_A-AA.aspx.
      49. Hughes JR, Stead LF, Lancaster T, Rev CDS. Antidepressants for smoking cessation. Cochrane Database of Systematic Reviews: Reviews 2007. 2014 (1).
      50. Stead LF, Perera R, Bullen C, Mant D, Hartmann-Boyce J, Cahill K, et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2012;11(11).
      51. 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 neuroendocrine tumors

      The patient is initially followed up with 6 month intervals, sometimes more frequently.

      In patients treated with radical surgery, it is important to continue monitoring for up to 10–15 years, since long-term recurrence after curative operations has been registered. Regular interval between follow-up for this group imight be 6 months, 1 year, 2 years, 3 years, 5 years, 7 years, 9 years, 12 years and 15 years.

      For a stable disease over 1-3 follow-up visits, the intervals are extended between follow-up visits often to 1 year, but rarely over 1 year.

      Examinations at follow-up visit 

      • Clinical status
      • Ordinary blood tests, as well as chromogranin A in serum
      • Image diagnostics, most often a CT scan. In younger patients who are expected to be monitored for many years, use of MRI is appropriate to reduce radiation exposure.

      PROSEDYRER

      Fatigue before, during, and after Cancer Treatment

      General

      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.

      Definition

      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.

      Preparation

      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.

      Implementation

      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.

      General advice
      • 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.  

      Sleep

      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.

      Nutrition

      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.

      Work situation

      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.

      Drug therapy

      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.

      Follow-up

      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.

      Some articles/books:

      • 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