oncolex logo
Utskriftsdato (24.3.2017)

Liver cancer

The most frequent kind of liver cancer is metastasis to the liver, often from colon or rectal cancer, but cancer can also originate in the liver.

Primary liver cancer is separated into:

  • Hepatocellular carcinoma – HCC (90 %)
  • Intrahepatic cholangiocarcinoma – IHCC (10 %)

The liver is the largest internal organ in the body and weighs about 1.5 kg in an adult. It is located in the upper right hypochondrium under the diaphragm. The liver is separated into two lobes, right and left, where the right lobe is the largest. The branches of the right and left portal vein indicate the right and left lobes of the liver. Most of the surface of the liver is covered by peritoneum.   

Liver - Essential facts

Incidence

HCC is is one of the most common cancer diseases on a global basis. HCC occurs most commonly among men. IHCC is not as common as HCC, however the frequency is increasing. Liver and intrahepatic cholangiocarcinoma represents 2.3% of all new cancer cases in the United States. In 2016, it is estimated that there will be 39,230 new cases of liver and intrahepatic cholangiocarcinoma in the United States. (10)

 

 

Age-specific incidence of liver cancer, 2009–2013.

Source: Cancer Registry of Norway

 

 

Incidence of liver cancer, 1954–2013.

Source: Cancer Registry of Norway

Etiology of liver cancer

Chronic inflammation, often in connection with a hepatotrophic virus, alfatoxin or alcohol, is observed in connection with the development of hepatocellular carcinoma (HCC).

A common estimate is that 80% of these patients have liver cirrhosis at the time of diagnosis. It is also known that HCC can develop without detectable liver disease.

For intrahepatic cholangiocarcinoma, (IHCC) the etiology is in most cases unknown, however chronic infections, hepatolithiasis, bile duct anomalies, and biliary cystadenoma can lead to development of IHCC.

Histology of liver cancer

The liver consists of hepatocytes, interstitial connective tissue, blood vessels, sinusoidal cells (endothelial and Kupffer cells), and biliary ductal epithelium.  Liver cancer can originate from all these different cell types. The most common is liver cell carcinoma, (hepatocellular carcinoma) originating from hepatocytes, and cholangiocarcinoma originating from biliary duct epithelium.

Precursor lesions

Similar to many other cancer types, there are precursor lesions in the liver possible to diagnose and prevent from further developing into manifest cancer.

  • Dysplastic nodules (adenomatous hyperplasia)
  • Hepatocellular adenoma
  • Biliary intraepithelial neoplasia

In countries with high incidence of hepatocellular carcinoma (HCC) there is a high prevalence of chronic hepatitis B or C virus infection. Despite treatment of patients with hepatitis,  some of them will develop cirrhosis that increases the risk of hepatocellular carcinoma. Chronic hepatitis B or C virus infections predispose to cirrhosis and HCC. Some patients with cirrhosis develop dysplastic nodules demonstrating atypical cellular morphology in regenerating hepatocytes. Radiological techniques can detect liver nodules, and needle biopsy might further determine the nature; whether they represent precursor lesions or manifest HCC.

Hepatocellular adenomas (HCA) are often difficult to separate from HCC, especially when using needle biopsy. Important differential diagnostic clues are cell morphology, number of mitotic figures and the presence of liver trabecula thicker than 2-3 cell layers. Adenomas are seen almost exclusively in non-cirrhotic livers. When multiple adenomas (>10) are seen, the condition is designated as adenomatosis. It is a paradox that HCA can be difficult to separate from HCC, although HCA seldom develop into HCC.

Besides HCC, intrahepatic cholangiocarcinoma is the most frequent primary malignant liver tumor. These are tumors that originate from intrahepatic biliary ducts. Precursor lesions are designated as biliary intraepithelial neoplasia (BIL-IN) grade I, II and III. These lesions can be seen in biliary ducts close to the hilum. Grade I represents epithelium with slight deviation from normal biliary epithelium, while grade III represent cellular changes corresponding to carcinoma in situ. Patients with sclerosing primary cholangitis, ‘inflammatory bowel disease’ (IBD), especially ulcerative colitis, and patients with either hepatholithiasis and dilatation of biliary ducts (Caroli syndrome) or hamartomas, predispose for BIL-IN and cholangiocarcinoma. Brush cytology from biliary ducts can be used to detect precursor lesions, and enables follow-up and consideration of relevant interventions.

Classification

  • Hepatocellular carcinoma (HCC)
  • Intrahepatic cholangiocarcinoma (IHCC)

HCC is the most frequent primary cancer in the liver followed by intrahepatic choloangiocarcinoma. HCC are classified according to the similarity to normal hepatocytes and ordinary liver trabecles. Immunohistochemical markers that determine the histogenetic origin are "hepato" or polyclonal CEA. Using the immunohistochemical markers and microscopic evaluation enable determination of whether metastasis or primary tumor in 95-100% of cases.

The same applies to cholangicarcinomas, where the use of cytokeratin CK7 and CK20 can separate intestinal cancer metastasis (CK 20 positive) from pancreaticobiliary cancer (CK 7 positive). The epithelium in pancreatic and intra- and extrahepatic biliary ducts are almost identical concerning morphology and immunohistochemical markers.

A type of HCC is important to recognize, the fibrolamellar type. This type is seen mainly in younger females, and have better prognosis compared to ordinary HCC. Histologically the fibrolamellar types are characterized by large eosinophilic tumor cells and a lamellar connective tissue.

Other cancer types

  • Mixed hepatocellular carcinoma and cholangiocarcinoma
  • Cystadenocarcinoma in intrahepatic biliary ducts
  • Hepatoblastoma (children)
  • Undifferentiated carcinoma
  • Epitheloid hemangioendothelioma
  • Angiosarcoma
  • Embryonal sarcoma (children)
  • Rhabdomyosarcoma

These are rare tumors that can be difficult to diagnose and separate from metastasis, especially in needle biopsies.

Benign tumors

Benign tumors are hemangiomas, focal nodular hyperplasia, hamartomas (von Meyenburg complex) cysts and angiomyolipomas. The three first mentioned are frequently seen, and are often suspected to be metastases in imaging techniques.

Fixation

Majority of liver specimens are needle biopsies to determine whether the lesion represents primary malignant tumor or metastasis. These small specimens are always adequately fixed in formalin. The larger liver operation specimens, such as resections of metastasis and primary tumors, must be adequately handled in order to be properly fixed. Thus, enough formalin (10 parts more formalin than specimen volume) should be used after cutting slices (not completely through the specimen) and there must be put some soft substance in between the slices.

Pathology reports

A liver removed due to a primary liver tumor should be examined and reported with the following information:

  • Tumor localization (segment)
  • Tumor size (millimeter)
  • Histological type (WHO)
  • Grading (1–3 (4))
  • Penetration of liver capsule
  • Resection borders in hilum close/extrahepatic biliary duct
  • Tumor infiltration in blood vessels
  • Lymph node metastasis
  • Extrahepatic spread (diaphragm/vena cava/metastases to other organs)
  • ”Milan” criteria:
    • Low risk for tumor progression: 1 tumor ≤ 5cm or 1–3 tumors < 3 cm
    • High risk for tumor progression: > 3 tumors > 3 cm or 1 tumor > 5 cm

Metastatic patterns of liver cancer

Spreading of hepatocellular carcinoma occurs primarily hematogenously.

Hepatocellular carcinoma and intrahepatic cholangiocarcinoma metastasizes mainly to lymph nodes, the lungs, and skeleton.

Staging of liver cancer

TNM Classification

The TNM system describes the extent of the disease at the time of diagnosis. "T" describes the extent of the local tumor. "N" expresses whether there are metastases to lymph nodes. "M" expresses metastasis.

The TNM classification differentiates between clinical classification (TNM) and the pathology classification (pTNM).

This classification is intended primarily for hepatocellular carcinoma (HCC). It can also be used for intrahepatic cholangiocarcinoma (IHCC).

Primary Tumor (T)

  • TX – primary tumor cannot be assessed
  • T0 – no evidence of primary tumor

 

  • T1 – solitary tumor without vascular invasion.
  • T2 – solitary tumor with vascular invasion; or multiple tumors none more than 5 cm in greatest dimension.

 

  • T3 – multiple tumors more than 5 cm or tumor involving a major branch of the portal or hepatic vein(s).
  • T4 – tumor(s) with direct invasion of other organs other than gallbladder or with perforation of visceral peritoneum. 

Regional lymph nodes (N)

  • NX – regional lymph nodes cannot be assessed
  • N0 – no regional lymph node metastasis
  • N1 – regional lymph node metastasis

Metastasis (M)

  • MX – metastasis cannot be assessed
  • M0 – no metastasis
  • M1 – metastasis

 

Stage Division

Stage I

Stage II 

Stage III

Stage IV

T1 N0 M0

 

     A   B  C

   T1–4 NX–1 M1

 

T2 N0 M0

 

 

T3 N0 M0

 

 

T4 N0 M0

 

 

T1–4 N1 M0

 

 

Symptoms of liver cancer

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (IHCC) often start with uncharacteristic symptomology. IHCC often causes few symptoms and first presents itself when the tumor has reached a considerable size.  

When liver cancer progresses, these symptoms will often appear over time:

  • weight loss 
  • reduced general health
  • diffuse discomfort in the area
  • lack of appetite 
  • jaundice
  • enlarged abdomen 
  • swollen ankles
  • possibly fever 

HCC is often discovered during follow-up of patients with a benign liver disease. It is detected by CT or ultrasound. A rise of α-fetoprotein (tumor marker) serum level also causes suspicion of HCC, but only half of those who develop HCC in Norway have a raised α-fetoprotein level.

Differential diagnoses of liver cancer

The differential diagnosis for primary liver cancer is other tumor types in the liver:

  • Cystadenocarcinoma in intrahepatic bile ducts
  • Hepatoblastoma (children)
  • Undifferentiated carcinoma
  • Epitheloid hemangioendothelioma
  • Angiosarcoma
  • Embryonal sarcoma (children)
  • Rhabdomyosarcoma
  • Metastasis from other primary tumors

Benign tumors: 

  • Hemangiomas
  • Focal nodular hyperplasia
  • Hamartoma (von Meyenburg complex)
  • Angiomyolipoma

Regenerating nodules from liver cirrhosis are another differential diagnosis.

Prognosis of liver cancer

Poor prognostic factors:

  • Large tumors > 10 cm
  • Infiltration through tumor capsule
  • Blood vessel invasion
  • Lymph node metastasis

 

 

Five-year relative survival of patients with liver cancer, in percent, during the diagnosis period 1974–2013.

Source: Cancer Registry of Norway

 

References on liver cancer

  1. Cancer in Norway 2013, Cancer Registry of Norway, Institute of Population-based Research. Oslo, Norway
  2. Mazzaferro V, Regalia E, Dolci R, Andreola S, Pulvirenti A, Bozzetti F et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrohosis. New Engl J Med. 1995 334 (11) 693–699  
  3. Gish RG, Porta C, Lazar L, Ruff P, Feld R, Croitoru A et al. Phase III randomized controlled trial comparing the survival of patients with resectable hepatocellular carcinoma treats with nolatrexed doxorubicin. J Clin Oncol 2007;25: 3069–75
  4. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF et al. Sorafenib in advanced hepatocellular carcinoma. N Eng J Med 2008; 359: 378–90.
  5. Abou-Alfa GK et al. Final results from phase II randomized double-blind study of sorafineb plus doxorubicin versus placebo plus doxorubicin in patients with advanced  hepatocellular carcinoma. 2008 Gastrointestinal Cancers Symposium. Abstr no: 128
  6. Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002, 35; 1164–71
  7. Llovet JM , M Real , X Montaña , R Planas , S Coll , J Aponte et al. Arterial embolization or chemoembolization versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomized controlled trial. Lancet 2002, 359, 1734–39.
  8. Seong J, Park HC, Han KH, Chon CY. Clinical results and prognostic factors in radiotherapy for unresectable hepatocellular carcinoma. IJRBP 2003, 55, 329–336.
  9. Chiba T, Tokuuye K, Matsuzaki Y, Sugahara S, Chuganji Y, Kagei K et al. Proton beam therapy for hepatocellular carcinoma: a retrospective review of 162 patients Clin Can Res 2005, 11, 3799–805
  10. U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute, USA.gov.

Diagnostics of liver cancer

The diagnosis is achieved using a combination of:

  • ultrasound with contrast
  • MRI/CT, possibly with contrast (3 phases)
  • blood tests (AFP, PIVKA II)

In 9 of 10 cases, radiology (characteristic charging patterns in two modalities) and blood tests are sufficient to make the diagnosis. In 10% of cases of HCC, where there are multiple small lesions and liver cirrhosis, a fine-needle or core biopsy may be necessary. 

Treatment of liver cancer

A large proportion of these patients have a primary liver disease, for example viral hepatitis, alcohol-related cirrosis, non-alcoholic steatohepatitis or chronic autoimmune disease, which is critical for the choice of treatment. 

In some cases, the cancer can be treated surgically. The prerequisite for this is that the tumor is not too large to be surgically resectable. The operation may be extensive. 

  • During a liver resection, the part of the liver involving the primary tumor or metastasis is removed.
  • liver transplantation is assessed according to special criteria.
  • Radiofrequency ablation of smaller tumors is a new treatment option. The method represents an advance in treatment of multicentric liver cancer. Up until now, multicentric liver cancer has been very difficult to treat. 

The hepatic cells have a high sensitivity to radiation. Radiation therapy therefore plays a modest role in treatment of multiple large liver lesions as the liver parenchyma is easily damaged by radiotherapy. However, large doses of radiation may be delivered to small liver volumes with curative intent (stereotaxtic body radiation therapy, SBRT).

Surgery/Intervention of liver cancer

The liver has a great ability to regenerate. If 50% of the liver is removed, the remaining liver cells will divide and the liver will increase in volume. After a few months, the liver will be close to its original size. The ability of the liver to regenerate is poorer in patients with cirrhosis, or liver damage from alcohol, or hepatitis B or C.

Hepatocellular carcinoma (HCC) is often associated with cirrhosis. In the planning for a liver resection, it is often feasible to perform a biopsy from the healthy party of the liver to determine the degree of cirrhosis. It is also recommended to assess the degree of cirrhosis based on the Child-Pugh score.

Child-Pugh score classification
Parameter Points
1 2 3
Bilirubin mmol/l < 25 25–30 > 40
INR < 1.3 1.3–1.8 > 1.8
Albumin g/l > 35 28–35 < 28
Ascites None Easily treatable Difficult to treat
Encephalopathy None Mild–moderate Stupor–coma

Child-Pugh A: < 6 points, Child-Pugh B: 7–9 points, Child-Pugh C: > 10 points

Primary liver surgery

The main focus is to assess whether the patient can be treated with a liver resection or a liver transplant. A study indicates that patients with a cancer occurring with the Milan Criteria have the best recurrence-free survival after a liver transplantation, and this is comparable to other indications for liver transplantation (> 75% 5 year survival) (2):

  • Single tumor < 5 cm
  • Maximally 3 tumors < 3 cm

In Norway, access to a liver transplant is better than in most other countries. A liver transplant can therefore be offered based on extended criteria:

  • Single tumor < 10 cm
  • Maximally 5 tumors < 5 cm
  • More than 5 tumors < 2 cm

Data are available indicating that the result after a transplant with respect to recurrence is better than after a resection, even if the liver tissue is normal. The assessment of whether a liver resection or transplant should be performed is done at a competent with a transplant surgeon as member of the multidisciplinary team. It is recommended that patients with Child B and C are not resected since the results are very poor. A transplantation should only be carried out if there is no extrahepatic spread.

The problem with a liver resection is unfortunately the high recurrence, which is 60-80% within 5 years. After a transplantation according to the criteria, a lower frequency of recurrence can be expected. However, there are no prospective studies available, and the patient populations of resected/transplanted cases differ. This applies especially to the frequency of blood vessel invasion and the size of the tumor.

Spread from HCC occurs mostly hematogenously. Microscopic vessel infiltration is a poor prognostic sign. Therefore, some believe that a formal anatomical liver resection provides better long-term survival than non-anatomical, however there are no results from controlled studies. The usual recommendation is therefore that patients with HCC who have a healthy liver, or patients with a liver disease classified as Child A, have a liver resection. For recurrence, a liver transplantation should seriously be considered.

Patients in category Child B and C should primarily be assessed for a liver transplantation.

Currently, patients with intrahepatic cholangiocarcinoma (IHCC) are not offered a liver transplantation since existing data shows very low or no long-term survival.

Radiofrequency ablation

Radiofrequency ablation (RFA) is used at larger treatment centers. This treatment is only an alternative when the patient's liver function is determined to be too poor to tolerate a resection or the patient for some other reason cannot be operated. Size is the limitation.

Radical ablation can be achieved if the tumor is less than 3-4 cm. If the tumor is located close to another organ, for example the stomach, this may contraindicate RFA due to the risk of thermal damage and perforation. An alternative local ablation technique may be a percutaneous ethanol injection (PEI) which is performed using ultrasound guidance. This method, however, is not frequently used in Norway.

PROSEDYRER

Liver resection

General

The liver is an organ which is richly vascularized and has a double blood supply. Arterial blood originates from the hepatic artery and venous blood from the large portal vein which drains blood from the bowels. The liver blood is drained via the three hepatic veins into the vena cava close to the right atrium of the heart. It is therefore important to know the course of these vascular structures when surgically dissecting the liver. The remaining liver tissue must have an intact venous outlet. The choice of operation method is decided after accurate assessment of the tumor's size and relation to these large blood vessels.  

A liver resection can either be performed by a traditional open resection or by laparoscopy. Both methods allow for both wide, formal resections following anatomical structures such as blood vessels and biliary ducts, as well as smaller local (tissue-sparing) resections where the procedure is limited to removing the tumor with a minimum of surrounding healthy liver tissue.

At Oslo University Hospital, Rikshospitalet, most of the large resection procedures are performed as open surgery. This always applies when involvement of blood vessels requires vessel reconstruction. Laparoscopic surgery is recommended in most local resections, including lateral left-sided resection (segment 2/3) and in selected cases of wider, formal resections. Previous liver resections are not a contraindication for laparoscopic surgery.  

Depending on the size of the liver and quality of the surrounding tissue, up to 80% of the liver can be resected. Regeneration of the liver occurs after a few months.

Formal resection

The liver is divided into 8 segments. The left lobe of the liver includes segments 2-4 while the right lobe includes segments 5-8. Segment 1 (caudate) overlies the inferior vena cava. The division between the two lobes is defined by the separation of the portal vein into the right and left portal veins. The falciform ligament defines the separation between left liver lobe segment 4 and segment 2/3.

A formal resection (anatomical resection/segmentectomy/lobectomy) is performed according to the liver's vascular and biliary anatomy. The traditional resections are defined as follows:

  • Lateral left-sided resection: Removal of segment 2 and 3 (Resection of about 20% of the liver's volume)
  • Formal left-sided resection: Removal of segment 2-4. (about 40% resection)
  • Formal right-sided resection: segment 5-8 including the gallbladder are removed (about 60%) 
  • Extended right-sided resection: segment 5-8 plus all or parts of segment 4 are removed (up to 80% is removed, often after pre-treatment with portal vein embolization)

Non-formal resection

The tumor is removed with a margin of around 1 cm (local, non-anatomical resection/wedge resection). This may be difficult when the tumor is located close to large vessels. This method may be applicable for multiple small metastases (multiple wedge resections).

Indications

  • Primary liver cancer
  • Cancer in intrahepatic biliary ducts
  • Liver metastasis

Goal

  • Complete removal of cancerous tissue 

Equipment

Identifying the resection margin

  • Diathermy

Division of the liver capsule

  • Ultrasound scalpel 
    • Harmonic Ace®
    • AutoSonix®
    • SonoSurge®

Dissect the parenchyma

  • CUSA® (cavitron ultrasonic surgical aspirator)
  • SonoSurge Aspirator®

Both of these are based on ultrasound.

Divide small vessels/biliary ducts

  • Liga Sure® 

Divide larger vessels

  • Staple machine
  • Clips 

Preparation

  • All open surgery is performed with the patient in the supine position.
  • For laparoscopic surgery, the position of the patient depends on the location of the tumor. For lateral right-sided tumors, the patient lies on the left side with a 45° angle. 
  • The procedure is carried out under general anesthesia.

Implementation

  • For open surgery, a curved transverse incision is made on the right side of the abdomen and further extended in the midline up to the xiphoid process. Sometimes, the transverse incision must be extended over to the left subcostalregion forming a three-armed "star." For laparoscopic resections, 4 ports of about 1 cm are generally used. Location on the abdominal wall depends on the location of the tumor. Sometimes, 1-2 additional ports are needed.  
  • For formal resections, the blood vessels and the bile ducts are dissected and preferably divided at the point of the entrance and exit of the liver. This will reduce the blood loss during the procedure.
  • The capsule is separated either with diathermy or with an ultrasound scalpel.
  • The division of the liver tissue is identically performed for both local and formal resections. The principle is to identify and secure small blood vessels and bile ducts during the dissection. The liver tissue is divided by controlled crushing, either manually or mechanically with ultrasound equipment (CUSA® or SonoSurge Aspirator®), and blood vessels and bile ducts are ligated or stapled.
  • In some cases, it is necessary to stop all blood supply to the liver due to bleeding from inflow blood vessels. This is done by the Pringle's maneuver where over the hepatoduodenal ligament is clamped with its large blood vessels (portal vein and hepatic arteries). The duration of this procedure is monitored. If prolonged clamping is needed, breaks are taken to provide the liver cells with oxygen.
  • When the involved part is separated from the remaining liver, careful hemostasis of the resection margin is performed. During laparoscopic surgery, the specimen is placed in a bag which is retrieved by extending the laparoscopy ports incisions. For wider resections, the incision must be extending 6-8 cm while in most cases an incision up to 3-4 cm is sufficient. 
  • To avoid a hernia, all layers of the abdominal wall are approximated before the skin is closed. Sometimes, a self-absorbing intracuticular suture is used while other times a normal skin suture or metal staples are used.

Follow-up

Observations

  • For open surgery, all patients receive an epidural (EDA). This provides good pain relief and allows for almost full mobilization from the first day after the operation.  
  • Rehabilitation occurs gradually during reduction of EDA. For laparoscopic surgery, EDA is not used. Despite this, the patient is often able to stand up a few hours after the operation and can start to eat and drink when they wish.
  • The operation occurs right under the diaphragm. Right-sided atelectasis and pleural fluid are not uncommon. The patient is also susceptible to a lung infection. 
  • With an open technique, the patient has a subcostal incision which can influence/inhibit respiration.
  • Damage to liver cells leads to increased breakdown of proteins which subsequently leads to increased formation of ammonia. The reduced number of liver cells may not be able to adequately convert ammonia to urea which can be excreted by the kidneys. This may lead to cerebral disturbance (encephalopathy) and the patient's mental state may be affected. The patient may also experience drowsiness, confusion, and even coma. 
  • Large liver resections prevent the liver from metabolizing medications as quickly as normal. Pain medication must therefore be adjusted/reduced and the patient's individual response to medication must be assessed carefully to identify the proper dosage.  
  • Fever, pain, increasing illness occurring a few days after the operation and may be sign of an abscess, either subphreneic or subhepatic.  

Follow-up

The patient will have an outpatient follow-up with an abdominal CT scan after 3 months.

Radiofrequency ablation of liver tumors

General

During radiofrequency ablation, the tumor is destroyed by radiofrequency energy. High-frequency alternating current (400,000 –1,250,000 Hz) is charged through the tumor via a needle electrode either by percutaneous, laparoscopic or open access, with the help of ultrasound guidance.

The needle consists of the outer part and one inner moveable part. When the inner part is pushed forward, multiple expanding metal rays come forward like an umbrella. The needle is isolated, except for the apical centimeter and the expanding rays. Current is applied to the needle from a generator. This produces high-frequency alternating current, which moves back and forth between the needle and 4 disc-shaped electrodes attached to both thighs of the patient.  When the generator is turned on, ionic agitation occurs in the tissue, as a result of the ions attempting to follow the directional changes caused by the alternating current. Frictional heat occurs close to the needle leading to necrosis of cells.  

It is assumed that all tumor tissue heated above 50–55 ºC for 5–10 minutes becomes necrotic.

Radiofrequency ablation is different from other types of tissue ablation in that the tissue around the needle warms up, not the needle itself.

Radiofrequency ablation is used as a supplement to liver resection or as primary treatment.

Indications

  • Liver tumors which are less than 4 cm in diameter.
  • Patients who either have too poor liver function or too poor general health.
  • Patients with liver metastases from colorectal cancer or neuroendocrine tumors where metastasis is limited in size and number.

Goal

  • Cure the disease
  • Palliation

Equipment

  • Radiofrequency generator
  • Electrode needles
  • Grounding pads on the patient

Preparation

  • The patient lies in the supine or lateral position.
  • The procedure is performed under general anesthesia.

Implementation

Radiofrequency ablation is carried out using ultrasound guidance either by percutaneous, laparoscopic, or open access.

  • 2 grounding pads are attached to each thigh and connected to the alternating current generator.
  • A small active needle electrode is inserted in the tumor.
  • The needle electrode is connected to the generator and establishes a circuit through the patient.
  • The alternating current leads to frictional heating of the tissue near the active electrode.
  • The liver tissue is heated twice for 5-10 minutes. The tumor and a small border of normal tissue are destroyed.
  • Ultrasound contrast is given to evaluate if the amount of necrotic tissue is adequate compared to the original tumor. About 1 cm margins of necrotic tissue around the tumor is the goal.

Follow-up

  • A few days of fever is normal due to breakdown products after tissue damage. If the fever occurs/lasts after the 3rd postoperative day, this may be due to an abscess (rare). 
  • A CT scan is performed the day after the ablation procedure to assure complete tumor destruction.

Follow-up

The patient should be seen 1 month after the procedure. The patient is followed-up every 3 months for 2 years and thereafter annually.

Drug therapy of liver cancer

There is no documented benefit by the use of adjuvant chemotherapy in HCC.

Hepatocellular carcinoma (HCC) has been considered a chemo-resistant cancer type. Still, weekly treatment with Adriamycin in patients with an inoperable cancer who are in good general health has been commonly applied. In a recent randomized phase III study, Adriamycin increased survival time compared to an interactive experimental medication (3).

Sorafenib is a new multi-kinase inhibitor which interacts with both cell proliferation and angiogenesis. A large randomized phase III study has shown that sorafenib increases survival time from 7.9 to 10.7 months compared to placebo (4).

Sorafenib was given only to Child-Pugh A patients, causing diarrhea and hand-foot syndrome as the most important side effects. In a recent randomized phase II study, a combination of sorafenib and Adriamycin showed a survival time of 13.7 months versus only 6.5 months median survival for Adriamycin alone (5).

Based on available literature, it is believed to be reasonable that HCC patients with Child-Pugh A status should initially be assessed for palliative treatment with sorafenib.

Inoperable HCC/metastatic illness

Many patients have a metastatic or inoperable illness at the time of diagnosis. Patients without significant liver failure can be given palliative oncology treatment.

Chemoembolization

Chemoembolization (TACE) is a combination of embolization of a hepatic artery branch supplying the tumor and chemotherapy administered in a hepatic artery. The method exploits the fact that in normal liver tissue, the arteries supply only 20–25% of the circulation versus 85–100% in HCC. Chemoembolization of locally advanced HCC is controversial partly due to lack of an international standard procedure. The two randomized studies available (80 and 112 patients) have shown an increase of survival for chemoembolization at 3 years from 3% to 26% and at 2 years from 27% to 63% (6,7).

In a meta-analysis of randomized and non-randomized studies, it was concluded that TACE improves long-term survival (3 year survival increased by 28%) and reduces the frequency of recurrence (28%).

Substances used are doxorubicin, mitomycin C, and cisplatin. Internationally, it is assumed that about 10% of patients with HCC will be suitable for chemoembolization.  

The following criteria for TACE treatment apply:

  • The patient is inoperable.
  • No tumor trombi in the portal system.
  • The main stem of the portal vein must be open. 
  • Tumor < 10 cm (cases with a diameter greater than this are assessed individually)
  • Multifocal tumors with diffuse liver involvement: relative contraindication
  • Child A-B, not Child C

At Oslo University Hospital, a protocol for TACE, with drug eluting beads loaded with doxorubicin is used. The advantage of this technique is the higher local concentration of doxorubicin and less systemic side effects.

TACE as pre-treatment to a resection or transplantation may be considered.

TACE can also be combined with RFA.

Radiation therapy of liver cancer

External radiation treatment is considered when the disease is localized and limited, and will cause regression of the tumor and improve survival (7). The treatment requires a high radiation dose.

Side effects are:

  • liver failure
  • hypoalbuminemia
  • ascites

Proton treatment for HCC appears to be promising (8).

Complication treatment of liver cancer

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

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

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.

Celiac Plexus Neurolysis

General

Neurolytic procedures can produce long-term blocking by destroying nerve tissue. This kind of nerve blockage lasts until the nerves regenerate. Pain is not only conducted by the afferent and sensory nerve fibers, but also the sympathetic nerve system. Most neurolysis procedures are directed toward the sympathetic nerve structures.

Today, by means of CT guidance, the neurolytic drug can be injected with high precision with a minimal risk of exposing the surrounding structures to the neurolytic chemicals. CT guidance also provides for a better possibility for optimal placement of the needle in cases where tumor masses have changed the normal anatomical conditions of the retroperitoneal room. The procedure is performed in cooperation with interventional radiologists.

Invasive techniques still play an important role in treating cancer pain in a correct selected group of patients. The quality of the blockages increases when the procedure is guided by imaging and with the help of an interventional radiologist. Neurolytic blockades should never be considered an isolated treatment form, but as part of a broader treatment strategy, where one of the goals is to reduce the need of strong opioids and other analgesic.

Celiac plexus neurolysis is the most common neurolytic blockage for patients with pain associated with cancer. It has been shown that patients with pancreatic cancer can obtain significant pain relief from a single (sympathetic nerve) blockade for the remainder of their life, on condition that distribution to sympathetic nerves are satisfactory.

Access to the celiac plexus is reached by:

  • Posterior antecrural or retrocrural access. May be done with C-bow, but preferably CT.
  • Endoscopic ultrasound-guided access (via gastroscopy with ultrasound.)
  • Open abdominal.  Neurolysis can be performed preoperatively (in connection to exploratory laparotomy.)

Indications

Pain, often deep, diffuse and localized to the upper abdomen with radiating pain to the back. This treatment is primarily for patients with pancreatic cancer, but also those with malignant tumors in the upper abdomen, suffering from visceral pain, may benefit from this blockage.

Refractory nausea for the same patient group.

Neurolysis of the celiac plexus (sympathetic nerves) may be appropriate for different cancer types in the upper abdomen, but is mostly utilized for pancreatic cancer. Visceral pain is the one that can be alleviated by this blockade. Sensory and sympathetic nerve fibers from all organs in the upper part of the abdominal cavity, including bowel up to and including proximal part of colon, goes through the celiac plexus.

Goals

Improved pain control and reduced side effects from opioid pain relievers due to dosage reduction.



Equipment

  • Needles (22 G) and equipment for local anesthesia.
  • Contrast medium to confirm correct position before the neurolysis.
  • Local skin anesthetic also for testing effect ahead of the neurolysis.
  • Alcohol, concentration minimum 50%.
  • Intensive care with vital signs (pulse rate, blood pressure, EKG and SaO2).
  • Medications for sedation and pain relief.

Preparation

  • Blood tests: INR, thrombocytes and  hematological tests, leukocytes, CRP, electrolytes and kidney function.
  • Agreement for possible cessation of anticoagulants and antiplatelet agents is made individually.
  • Any fasting ahead is agreed individually for each patient. Some sedation is common in addition to local anesthesia. If the patient requires deep sedation/sleep, fasting for 6 hours before the procedure is necessary.
  • Prone, supine, or lateral position. Anterior access is primarily used when the patient cannot lie on their abdomen or the lateral decubitus position or when anatomical conditions do not allow posterior access.

Implementation

The celiac plexus (sympathetic nerve fibers) lies retroperitoneal at the level of the L1 vertebra. The fibers are arranged as a network in front of the aorta and around the celiac trunk.

  • With the patient in the prone or lateral position, the needle is inserted at level of the T12 and L1 vertebrae using local anesthesia.
  • The direction of the needle is guided by CT. The needle is guided a few cm to the side of the midline on each side of the spine with the tip close to both sides of the aorta.
  • After a test dose of  local anesthesia, and confirmation of correct position by injection of contrast medium, 75-95% alcohol is injected, 20-30 ml on each side.
  • In some cases it may be difficult to achieve good dispersion of the neurolysis because of tumor masses filling up the retroperitoneal space. In such cases the blockade may be inserted  retrocrurally, also at level of the T12 and L1, but with less volume. The effect is then substantially as a result of blockade of the splanchnic nerves proximally to the celiac plexus.

Follow-up

Complications can occur but are uncommon.

  • Temporary side effects in the form of orthostatic hypotension and diarrhea are relatively common the first 24-48 hours.
  • Back pain, usually in the form of soreness for 2-4 days is experienced by some.
  • Retroperitoneal bleeding, aortic dissection and paraplegia are very rare, but have been reported.
Celiac plexus neurolysisCeliac plexus neurolysisCeliac plexus neurolysis

Febrile Neutropenia

General

Febrile neutropenia occurs in compromised immune systems due to a low number of leukocytes, especially granulocytes. Patients with a declining number of granulocytes after chemotherapy, can during bacterial sepsis, quickly develop extensive neutropenia and become critically ill. Febrile neutropenia can be a life-threatening condition.

A patient with neutropenia and simultaneous fever or clinical suspicion of systemic infection should be treated as quickly as possible with broad spectrum antibiotics including gram-negative and gram-positive coverage as soon as the required microbiological samples are taken.

The clinical situation is most critical in patients who have not yet started antibiotic treatment. When broad-spectrum antibiotic treatment is started, monitoring the fever may be permitted.

Fever is often the only symptom. Some have septicemia without fever. One should therefore also be aware of other symptoms such as lethargia, diarrhea, or visible sign of infection. The local clinical symptoms and signs (redness, pain, temperature increase, swelling (boil), and reduced organ function) are most often very much reduced or completely absent during neutropenia.

Indications

  • A patient with neutropenia and simultaneously fever or clinical suspicion of systemic infection

Goals

  • Avoid septicemia.
  • The patient is able follow the planned scheme of treatment.

Definitions

Fever is defined as:

  • a single (rectal) temperature ≥ 38.5 °C or
  • temperature ≥ 38 °C for more than 2 hours or
  • temperature ≥ 38 °C measured three times during 24 hours

There is a known increase of infections when neutrophil < 1.0 x 109/l.  The infection risk increases with degree and duration of neutropenia. The neutropenia is considered severe when granulocytes are ≤ 0.5 x 109/l.

Preparation

The following diagnostic tests should be performed:

  • Adequate microbiologic tests: blood culture x 2-3, throat/nasopharynx, urine, catheter opening any surgical incisions. All blood cultures should be taken simultaneously to avoid losing valuable time.
  • Blood culture and other microbiological samples should be taken before antibiotic treatment is started
  • Blood tests with differential count of leukocytes, thrombocytes, Hb, CRP, SR, creatinine
  • X-ray of chest

Information

Before initiation of chemotherapy, the patient should be extensively informed, both verbally and in writing, of febrile neutropenia and  its consequences.

A patient who can develop febrile neutropenia should obtain a written statement of the condition to present to other treatment providers.

Use of an isolated or private room

Patients with neutrophil granulocytes ≤ 0.3 x 109/l should have a private room if possible. Guidelines for protective isolation should be followed. Thorough washing of hands is especially important.

 

Implementation

  • Treatment is started as soon as possible.  Treatment may be postponed a maximum of 30 minutes to complete microbiological testing.
  • Start septicemia treatment for fever if neutropenia is expected, regardless of granulocyte value.

Antibiotic regimen

  • Benzylpenicillin sodium 5 mg IE x 4 tobramycin or gentamicin 5-10 mg/kg x1
  • Tazocin® 4 g x 3
  • Cefotaxime® 1 g x 4 if aminoglycoside should be avoided
  • Ceftazidim® 1 g x 4  with suspicion of pseudomonas infection
  • Meronem ® 0.5 g x 4 usually 2nd or 3rd choice

When using aminoglycoside, the first dose should be high. Keep in mind the following:

  • age
  • sex
  • kidney function
  • fat index   

Otherwise, the dose should be decided from concentration of aminoglycoside determined after the second day and thereafter monitored 2x per week. 

Serum concentration of tobramycin and gentamycin

For single dose in 24 hours

  • Trough concentration (0-test = 24 hour test) < 0.5 mg/l
  • Top concentration (30 minute after infusion is completed) > 12 mg/l

For multiple doses in 24 hours

  • Trough concentration < 2 mg/l, top concentration (30 minutes after the infusion is completed) preferably > 8-10 mg/l 
  • Avoid aminoglycoside :
    • If kidney function is reduced. Avoid aminoglycoside if cisplatin is used. If cisplatin has been previously used, many patients will have subclinically reduced kidney function. If necessary, use aminoglycoside for a short period and monitor kidney function closely.
    • If carboplatin is used, determine glomerulus filtration rate (GFR) for each new treatment. Penicillin/aminoglycoside can be used if GFR is stable (has not declined more than 15% if initial value is in the normal range)
    • With sarcoma: Protocols with very high doses methotrexate and ifosfamid (> 5 g/m2) should be used in sarcoma treatment. It is not abnormal for these patients to have an increase in creatinine.
    • with massive ascites
    • with suspicion of or documented myeloma kidney (myelomatosis)
    • If aminoglycoside has been used in the past two weeks
  • Suspicion of staphylococcus aureus as a cause of infection (relatively rare)
    • Give penicillinase-stable penicillin, cloxacillin, or dicloxacillin, possibly clindamycin instead of ordinary penicillin. Yellow staphylococci are also killed by cefotaxime and by merop
  • Gram-positive cocci in multiple blood cultures and if the patient has clinical signs of infection
    • Use vancomycin 500 mg x 4 until resistance determination is available
  • Poor patient condition and suspicion of gram-negative septicaemia
    • Use “double gram-negative” with for example ceftazidim or tobramycin
    • Other preparations with good effects against most gram-negative bacteria are meropenem and ciprofloxacin
  • Suspicion of anaerobic infection
    • Use an anaerobic drug: Metronidazol 500 mg x 3, clindamycin 600 mg x 4, piperacillin/tazobactam 2g x 4 or meronem 500 mg x 4.  This especially applies if there is suspicion of anaerobic infection under the diaphragm such as gallbladder, intestines, perforation, abscess.
    • penicillin is often adequate for anaerobic infections above the diaphragm.

With continuing clinical signs of infection, adjust the antibiotic treatment according to resistance determination in blood culture. Maintain gram-negative coverage.

Systemic fungal treatment

By persistent fever after multiple days with broad spectrum antibiotic treatment, one should consider empirical treatment of possible candida-sepsis, for example with fluconazole 600 mg the first 24 hours, and thereafter 400 mg x 1.

If candida is documented without adequate response to fluconazole, a fungicide drug should be used, for example amphotericin B.

If suspected infection with Aspergillus apply voriconazole, amphotericin B or caspofungin.

Follow-up

Observe for symptoms of a new infection.

Bone Marrow Stimulation with G-CSF

General

Bone marrow stimulation with G-CSF (Neupogen®, Granocyte®) is only recommended for febrile neutropenia which does not respond to antibiotic treatment, severe neutropenia (granulocytes < 0.5 x 109 /L for more than 1 week), and in cases where it is necessary to administer curative treatment with sufficient dosage intensity.

Indications 

  • To maintain dosage intensity for curative treatment; when a reduction in dosage will significantly reduce the chance of cure.
  • As prophylaxis for treatments associated with a high risk for febrile neutropenia (> 40 %)
  • Febrile neutropenia that does not respond quickly to antibiotic treatment
  • Long-lasting neutropenia

Goal

  • Maintain treatment intensity

Preparation

The patient should be adequately informed about the treatment.

Implementation

  • The dosage of Neupogen® is 5 µg/kg daily. The treatment is initiated, at the earliest, 48 hours after the treatment is completed. The treatment continues for 10 days.
  • The dosage of Neulasta® is 6 mg subcutaneously administered 24 hours after chemotherapy is completed. The neutrophil cells are counted on day 15.
  • The subsequent course is started on day 21, if the neutrophil count is 0.5 or higher, and the patient has not had febrile neutropenia.
  • It is important not to postpone the treatment if the neutrophil count is 0.5 or higher. The neutrophil count will compulsory decline after ending Neupogen® stimulation. Low values at the start of treatment should not be alarming if the values during hospitalization have been high enough to avoid febrile neutropenia.
  • Stimulation late in the cycle should only be performed for long-lasting, severe neutropenia. At least 48 hours should pass after completed stimulation treatment before the next chemotherapy course  is started. In these cases, it is always important to check that the doses are correct and to recalculate GFR etc. Continuation of chemotherapy will either require a drastic dosage reduction or secondary prophylaxis with G-CSF.

 

Follow-up Care

It is of utmost importance that the patient is informed of the risk of infections associated with a low neutrophil count.

Patients at risk for developing  very low values, must be  informed to take their temperature if they feel unwell or  febrile. In case of  a temperature above 38 °C they should contact their doctor immediately.

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.

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

Intravenous Extravasation of Cytotoxic Drugs

General

Intravenous extravasation occurs when there is an accidental leak of intravenous cytotoxic fluid (chemotherapy drug) from the vein to surrounding tissue.  

If chemotherapy is given in a peripheral vein, a large vein should be used, which is preferably in the underarm. Before the infusion begins, the vein should be checked for leaks by injecting NaCl 9 mg/ml or glucose 50 mg/ml. Backflow should also be checked. The patient must be informed that pain or burning in the area is not normal and they must inform the doctor.

Cytotoxic chemotherapy drugs should always be given through a central vein catheter to reduce the risk of intravenous extravasation.

Risk factors for intravenous extravasation:

  • Small veins (infants and children)
  • Brittle veins (elderly patients)
  • Reduced physical health (cancer patients)
  • Sclerosizing veins
  • Rolling veins
  • Poor circulation (if the needle is placed in an arm with edema)
  • Obstructed vena cava (raised venous pressure may cause leakage)
  • Conditions such as diabetes and radiation damage
  • Obesity

Chemotherapeutic drugs are separated into three groups according to the degree of toxicity:

  • Non-cytotoxic/irritating
  • Tissue irritant
  • Cytotoxic

Cytotoxic drugs can cause blisters or ulcerations leading to skin necrosis if extravasation occurs. If intravenous extravasation is left untreated, it can lead to permanent tissue damage, necrosis, scar formation around ligaments, nerves and joints, infections, abscesses, contractures, and in the worst case, amputation.

Indication

  • Intravenous extravasation of cytotoxic drugs. 

Goal

  • Limit damage of tissue from intravenous extravasation.

Definitions

Non-cytotoxic drugs or non-irritants

Non-cytotoxic/non-irritant drugs normally do not cause skin necrosis.

Irritants

Drugs that are tissue irritants can cause pain in and around the injection site and along the vein. They can also cause inflammation. Some tissue irritating drugs cause ulceration if a large amount leak extravasally.

Cytotoxic drugs

Cytotoxic drugs are categorized into subgroups according to the mode of damage. This categorization is important for the choice of treatment.

DNA-binding

DNA binders absorb locally into the cells, bind to DNA, and cause cell death. After cell death, the drug molecule can be liberated from the dead cell and start killing healthy cells. This group is divided into these subgroups:  

  • Anthracycline
  • Alkylating drugs
  • Other

For doxorubicin and mitomycin, progrediating tissue damage has been reported over weeks, and in some cases, months after intravenous extravasal injection.

Non DNA-binding

This group of medications can lead to cell death through other mechanisms than DNA binding drugs. This group is divided into:

  • Vinca alkaloids
  • Taxanes

 

Chemotherapy cytotoxicity (1)
Cytotoxic, necrosis

Irritant, can cause flaking or inflammation

Non-cytotoxic or non-irritant
Amsacrine Cisplatin Aldesleukin
Decarbazine Doxorubicin liposomal Alemtuzumab
Dactinomycin Estramustine** Asparaginase
Docetaxel**** Etoposide Bleomycin
Doxorubicin* Floxuridine Bevacizumab
Epirubicin* Florouracil Bortezomib
Daunorubicin* Irinotecan Cetuximab
Idarubicin* Carboplatin Cyclophosphamide**
Irinotecan Carmustin** Cytarabine
Kloremtin** Oxaliplatin Fludarabine
Mitoguazon Pemetrexed Gemcitabine
Mitomycin-C Ralitrexed Ibritumomab tiuxetan
Mitoxanthrone Temoporfin Ifosfamide**
Paclitaxel**** Teniposide Interferon
Plicamycin Topotecan Cladribine
Streptozocin Methylene blue***** Clofarabine
Verteporphin   Melfalan**
Vinblastine***   Methotrexate
Vindesine***   Rituximab 
Vincristine***   Tiotepa**
Vinorelbine***   Trastuzumab

 * = Anthracycline

** = Alkylating agents

*** = Vinca alkaloids

**** = Taxanes

*****= Methylene blue is not a chemotherapy drug, but is used for ifosfamide-induced encephalopathy, and is therefore included on the list.  

All chemotherapy drugs can damage tissue in high concentrations.

References

 

  1. Allwood M, Stanley A WP. The Cytotoxics Handbook. Ed. 4th ed. 2002. 2001
  2. Ekstravasation Guidelines Implementeringsværktøj [Online] 2007 [hentet 10. mars 2009]; Tilgjengelig fra URL: http://www.cancerworld.org/CancerWorld/getStaticModFile.aspx?id=2726

Preparation

Identification of an extravasal injection

  • A burning, stinging pain or other acute change of the puncture site.
  • Local redness or inflammation of the skin around the puncture site.
  • The infusion rate slows/stops.
  • Swelling of the puncture site.

Extravasation has probably also occurred if blood cannot be aspirated, resistance is felt on the plunger when a syringe is used, and/or there is no current if the drug is infused. 

 

Implementation

Flow chart for treatment of intravenous extravasation of cytotoxic drugs:

Emergency response:

  • Stop the infusion immediately.
  • Allow the needle to remain and aspirate with as much water as possible. Avoid applying direct pressure on the area of extravasation.  
  • The volume, type, and time of extravasation should be recorded.
  • A doctor/plastic surgeon should be called for to examine the patient.
  • The damaged area and skin manifestations should be marked/photographed.
  • The affected area should be kept elevated.
  • The remaining chemotherapy should not be discarded.
  • The patient should be informed about what is happening and what must be done. 
  • The needle is removed while aspirating.
  • Pain medication is administered if necessary.

Based on which medication has leaked extravasally, the doctor or plastic surgeon will decide whether conservative treatment or primary surgery is necessary.

Conservative treatment

Conservative treatment consists of two different treatment strategies to limit the damage by extravasation: localize/neutralize and spread/dilute (2).

Localize and neutralize:

  • Place an ice pack on the area for 15-20 minutes, at least 4 times daily for multiple days. A coldpack is used to limit spreading of the drug. Studies have indicated that there is reduced cellular uptake of drugs at lower temperatures (2).
  • The drug that has leaked extravasally is neutralized by a specific drug if the instructions are followed.
  • The affected area of the body should be kept elevated.

Spread and dilute (applies to vincristine, vinorelbine, vindesine, and vinblastine):

  • Warm compresses are placed on the area for 15–20 minutes, at least 4 times daily, for multiple days.
  • To dilute the drug that has leaked extravasally, many subcutaneous injections are given with hyaluronidase diluted with sterile water.

If the patient has lasting pain or blisters, surgical treatment should be considered by excising the area with direct sutures, skin transplant, or flap reconstruction.

Another type of reconstruction may be necessary at a later time. 

Treatment 

Dexrazoxan (Savene®)

Dexrazoxan is an EDTA analong used to treat extravasation of anthracycline (doxorubicin, daunorubicin, epirubicin, idarubicin). The mechanism of action is not fully understood, but it is believed that it may work through two mechanisms. By chelating iron, the formation of the iron-doxorubicin complex and  iron-mediated hydroxy radicals are hindered, which cause oxidative damage to cell membranes and proteins. Another possible mechanism is inhibition of topoisomerase II (3).

Treatment lasts for 3 days. In all cases of extravasation of anthracycline, this treatment should be assessed by an oncologist and surgeon/plastic surgeon.

  • The first infusion should start as soon as possible and within 6 hours after extravasation. 
  • On the following two days, the infusions should occur at the same time as the previous infusion (+/- 3 hours).
  • If possible, the infusion should be placed in a vein where there is no extravasation.
  • An ice pack or cooling element used on the area must be removed at least 15 minutes before the infusion starts to ensure sufficient blood circulation.

Cost

A package costs about NOK 100,000.-. If the expiration date runs out, the drug is replaced by the pharmaceutical company free of cost.

Dimethylsulfoxide (DMSO)

DMSO (70–90% solution) quenches free radicals and prevents formation of sores. The solution can be used after extravasation of cytotoxic drugs (anthracycline, mitomycin C, doxorubicin, idarubicin, epirubicin andactinomycin D) together with cooling of the area when other treatment methods cannot be used (5, 6). DMSO cannot be used in combination with dexrazoxan (3, 4).

  • An area twice as big as the affixed area is treated with the solution every 8 hours for one week.(6)

Hyaluronidase

Hyaluronidase is an enzyme that breaks down hyaluronic acid found in connective tissue. This leads to permeability and increased diffusion of the drug that is leaking extravasally, and is used only to spread the drug out into the tissue (spread and dilute).  

  • Hyaluronidase is administered subcutaneously or intradermally in 5-10 locations on the border of the area where the drug has leaked extravasally (7).

Surgical treatment

"Wash-out"

The washing out technique can be used with chemotherapy drugs when tissue damage is likely. When used with anthracycline, it is important that this is performed before the chemotherapy drug goes intracellularly.

In most cases, this is a very successful method if it is performed within 6 hours after the extravasation.

  • The patient receives regional anesthesia.
  • Multiple small incisions must be made to ensure sifficient access to the damaged subcutaneous tissue.
  • With an infiltration needle, which is usually used for liposuction, isotonic NaCl is flushed through the tissue and drains through the incisions.
  • The infiltrated fluid is then carefully removed by suction through a small needle used for liposuction.
  • The procedure is repeated until 300-500 ml fluid is used.

References

  1. Ekstravasation Guidelines Implementeringsværktøj [Online] 2007 [hentet 10. mars 2009]; Tilgjengelig fra URL: http://www.cancerworld.org/CancerWorld/getStaticModFile.aspx?id=2726
  2. Hasinoff BB. Dexrazoxane use in the prevention of anthracycline extravasation injury. Future Oncol 2008; 2006: 1–15.
  3. Statens legemiddelverk. Preparatomtale. 2008
  4. Langstein HN, Duman H, Seeling D, Butler CF, Evens GR. Retrospective study of the management of chemotherapeutic extravasation injury. Ann Plastic Surg 2002; 49: 369–74. 
  5. Bertelli G, Gozza A, Forno GB, Vidili MG, Silvestro S, Venturini M et al. Topical dimethylsulfoxide for the prevention of soft tissue injury after extravasation of vesicant cytotoxic drugs: A prospective clinical study. J Clin Oncol 1995; 13: 2851–5.
  6. Clinical Pharmacology© 2008 database. Hyaluronidase. 2008.

Follow-Up

For conservative treatment 

The damaged tissue should be observed for multiple weeks (with mitomycin at least 13 weeks) since necrosis can occur after months.

For emergency surgical treatment

Patients treated by a plastic surgeon should receive follow-up care by the surgeon until the wound has healed.

 

Intravenous extravasation of cytotoxic drugs.Intravenous extravasation of cytotoxic drugs.Extravasation of tissue toxic chemotherapy

Follow-up care after treatment of liver cancer

Patients who have completed treatment intended to cure primary liver cancer should be seen every 3 months for the first year, thereafter every 6 months. The frequency and duration of follow-up is individualized according to treatment modality type of cancer.  

In the first year, the patient should be checked at the center where treatment was carried out. Later checks should be done in dialog with the patient's local hospital if geographical circumstances allow. 

All patients with liver transplants are included in Rikshospitalet's special follow-up program. For a resection or radiofrequency ablation, there is a significant risk of recurrence. Checks should therefore continue for 5 years. 

Checks include: 

  • CT scan of liver (3 phase)/possibly MRI
  • Ultrasound of liver with contrast reinforcement
  • CT scan of thorax
  • Blood tests (liver tests, cancer markers). In patients having raised cancer markers before treatment (AFP/CA19-9), these levels will provide postoperative prognostic information.

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