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Utskriftsdato (24.3.2017)

Thyroid cancer

Cancer forms occurring in the thyroid gland differ biologically, which lead to differences in disease courses and prognoses after treatment.

About 90% of the cases originate from malignant tumors from the epithelial cells of the thyroid follicles. Most of the cases are papillary thyroid carcinoma (PTC).  

The incidence of palpable nodules is about 5% of the adult population, but with ultrasound, nodules are found in up to 70%. Only a small amount of these are malignant.

Increasing use of image diagnostics for other indications will detect tumors in the thyroid gland as a secondary finding.

Cancer types of the thyroid gland

  • Differentiated follicle epithelial-derived
  • Papillary thyroid carcinoma  (PTC)
  • Follicular thyroid carcinoma (FTC)
  • Undifferentiated anaplastic thyroid carcinoma and moderately differentiated thyroid carcinoma
  • Medullary thyroid carcinoma (MTC)
  • Other

Incidence

Thyroid cancer represents 3.8% of all new cancer cases in the United States. Approximately 1.2% of men and women will be diagnosed with thyroid cancer at some point during their lifetime.Thyroid cancer is most frequently diagnosed among people aged 45-54 and is more common in women than men.

In 2016, it is estimated to be 64,300 new cases of thyroid cancer in the United States. (1)

 

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

Source: Cancer Registry of Norway

 

 

Incidence of thyroid cancer, 1954–2013.

Source: Cancer Registry of Norway

 

Etiology of thyroid cancer

In most cases, the etiology for thyroid cancer is unknown.

In 20-30% of patients with medullary thyroid carcinoma (MTC), the disease is associated with genetic syndromes (mutation in the RET oncogene), which causes familial MTC. Some of these patients also develop disturbances in other hormone producing glands (multiple endocrine neoplasias (MEN)). Papillary thyroid carcinoma (PTC) can, in rare cases, also be familial.  

Risk factors

Patients who have received external radiation therapy to the neck have an increased risk of developing thyroid cancer.

Radiation may be a contributing factor in PTC. An example of this is the Chernobyl disaster. During the years after the catastrophy, the incidence of PTC among children and youth in the areas around Chernobyl increased. An equivalent increase has not been registered in Norway.

At the end of the seventies, it was discovered that the incidence of follicular carcinomas (FTC) was highest in areas of low iodine intake. Later research showed that addition of iodine in food reduced the risk of FTC, but the number of PTC increased in the same areas. Iodine supplementation has become more common in the western countries, and because the histopathological definition of FTC has become more specific, the collective incidence has decreased.  

There is also a correlation between thyroiditis and PTC.

Histology of thyroid cancer

Histologic classification (WHO)

  1. Papillary thyroid carcinoma (about 70%)
  2. Follicular thyroid carcinoma (about 15%)
  3. Poorly differentiated thyroid carcinoma (< 5%)
  4. Udifferentiated (anaplastic) thyroid cacinoma (< 5%)
  5. Medullary thyroid carcinoma (5-10%)
  6. others (lymphoproliferative neoplasias, metastases)

Group 1-4 originate from the follicular epithelium, while group 5 originates from C-cells (calcitonin-producing cells) localized between the follicles. 

Papillary thyroid carcinoma (PTC)

Extirpated thyroid gland with tumor in the right lobe. Click to enlarge. Cut surface from the right lobe in the specimen in the left-hand image. Click to enlarge. Photomicrograph of the same tumor. The tumor is growing in a papillary fashion in a colloid-filled lumen. Click to enlarge.


The microscopic diagnosis is based on evaluation of a combination of different aspects:

  • Growth pattern (papillary structures, solid nests, follicular structures in follicular variant of PTC).
  • Nuclear characteristics: ground glass nuclei, nuclear grooves and inclusions. These changes are, however, not specific for malignancy and are sometimes absent or very difficult to discern.

Papillary thyroid carcinomas (PTC) appear in many variants. To subclassify the tumor, the specific appearance/growth/nuclear features should dominate (>75%).

Grading is not generally recommended, but has been suggested by some investigators. The individual criterias that might indicate worse prognosis is, according to WHO 2004 are:

  • Marked nuclear atypia
  • Necrosis
  • Vascular invasion
  • Increased number of mitotic figures

PTC may be cystic and can then be difficult to diagnose, especially in fine needle aspirates (FNA).

Follicular neoplasia

Cut surface from a thyroid lobe with a follicular carcinoma and easily distinguishable capsule penetration. Click to enlarge. Photomicrograph of the same lobe and demonstrating the capsule penetration. Click to enlarge.


The follicular carcinoma diagnosis is based on detailed histological evaluation of tumor and its relation to the capsule and vessels. Thus, the presence of capsule- and/or vascular invasion is needed to establish the diagnosis, and not the tumor cell appearance.

Follicular carcinoma can be divided into low- and high-grade malignancy based on the extent of capsule- or vascular invasion. Those with focal capsule invasion (minimal invasive) have usually a low malignancy potential.

Follicular benign tumors (adenomas) will sometimes demonstrate nuclear variation and a few mitotic figures, but still they can be considered as benign. Atypical mitotic figures are, however, an indicator of malignancy.

Follicular carcinomas appear in two forms:

  • Minmal invasive
  • Widely invasive  

Carcinomas with oncocytic differentiation

Carcinomas with oncocytic differentiation can be very difficult to evaluate, concerning malignancy and classification.  

Medullary thyroid carcinomas

Photomicrograph showing a medullary thyroid carcinoma. Click to enlarge.

Medullary thyroid carcinoma originates from the calcitonin-producing C-cells in the thyroid gland. Medullary thyroid carcinoma appears as both a spontaneous and a familial variant. The finding of multiple tumors and/or C-cell hyperplasia, indicate a familial variant, while the finding of a solitary tumor frequently is consistent with the spontaneous variant.

Tumor cells are monomorphic with round, oval or spindle shape and a low nuclear/cytoplasmic ratio. These tumors often contain a characteristic amyloid substance.

Poorly differentiated thyroid carcinomas

Photomicrograph demonstrating a thyroid lobe with diffusely infiltrating anaplastic carcinoma. Click to enlarge. Cut surface from a thyroid lobe with diffusely infiltrating anaplastic carcinoma. Click to enlarge.


Poorly differentiated carcinomas are often categorized in two groups of which one is the insular growing carcinoma, and the other one showing features intermediate between differentiated thyroid carcinomas and undifferentiated anaplastic carcinoma. These are usually tumors with solid growth pattern, severe nuclear atypia (no ground glass nuclei), necrosis, mitotic figures and vascular invasion.

Undifferentiated anaplastic carcinomas

These tumors demonstrate severe nuclear atypia, multiple mitotic figures and extensive necrosis and, in addition, often spindle growth pattern eventually with giant cells. In most cases, only biopsy material is available. Differential diagnosis towards poorly differentiated of other origin can be very difficult. 

Papillary micro carcinoma (mPTC)

Papillary micro carcinomas display a diameter ≤10 mm. Tiny papillary carcinomas (2-3 mm) are regularly detected as an incidental finding (incidentaloma) in thyroid glands removed for other reasons. These tumors are, in most cases, considered as a finding of insignificant importance. If, however, the mPTC invades extrathyroidal tissue, the patient should be treated according to the same guidelines as the PTCs of clinical significant dimension.

Staging of thyroid cancer

The most commonly used classification for thyroid cancer is TNM (UICC).

The TNM system describes the extent of the disease at the time it is diagnosed.  

  • "T" describes the extent of the local tumor in and around the thyroid gland.
  • "N" (node) expresses whether there is spreading to lymph nodes. 
  • "M" describes the absence or presence of distant metastasis.

The TNM classification differentiates between the clinical classification (TNM) and the pathological classification (pTNM). For thyroid cancer, pTNM is used. This system is based on observations made before treatment, supplemented and modified according to observations made during the surgical treatment, and the subsequent histo-pathological examination.

In order to carry out the pTNM classification, sufficient tissue must be available for the histology examination.

pT-classification

  • pTx - primary tumor cannot be assessed 
  • pT0 - no evidence of primary tumor
  • pT1 - tumor ≤ 2 cm, intra thyroideal
  • pT2 - tumor > 2 cm, but  ≤ 4 cm, intra thyroideal

 

  • pT3 - tumor  > 4 cm intra thyroideal, or with minimal extra thyroideal growth (to m sternothyroideus or perithyroideal tissue)
  • pT4a - tumor regardless of size, outside thyroid capsule, with subcutaneous invasion, in the larynx, trachea, esophagus, recurrence
  • pT4b - tumor regardless of size, with invasion in prevertebral fascia, carotis, mediastinal vessel tumor

 


Undifferentiated carcinoma

  • pT4a - intra thyroideal tumor
  • pT4b - extra thyroideal tumor

pN-classification

  • pNx - tumor cannot be assessed 
  • pN0 - no regional lymph node metastasis
  • pN1a - metastasis in level VI
  • pN1b - metastasis to unilateral, bilateral, or contralateral cervical or superior mediastinal lymph nodes 

pM-classification

  • pMx - cannot be assessed 
  • pM0 - no distant metastsis 
  • pM1 - metastasis (provide localization)

Assessment of risk

  • Risk assessment before treatment is critical for the choice of the primary treatment.
  • Risk assessment after treatment is over is critical for the choice of follow-up plan.

Metastatic patterns of thyroid cancer

Papillary thyroid carcinomas spread lymphatically. It is not uncommon to find metastasis in lymph nodes on the neck locally and regionally, even next to small primary tumors. Up to 50% of patients have metastasis at the time of the diagnosis. Distant metastasis mainly localize in the lungs and bone.  

Follicular thyroid carcinomas spread mainly hematogenically and usually to the bone and/or lungs.

Anaplastic thyroid carcinoma metastasizes to local lymph nodes regionally, mediastinally, as well as to the lungs and brain. 

Symptoms of thyroid cancer

Thyroid cancer rarely causes symptoms.

The first finding is usually a solitary tumor or multinodal tumors in the thyroid gland without any symptoms or sign.

Anaplastic thyroid carcinoma. Click to enlarge the image.

The disease may also be discovered by enlarged lymph nodes which present as metastasis to the neck.

Other symptoms may be:

  • hoarseness
  • voice changes 
  • stridor

Symptoms requiring expedient work-up

  • Fast-growing tumor
  • Hoarseness or changes in voice which cannot be explained in patients with struma.
  • Enlarged lymph nodes of the neck
  • Tumor in children under 10 years or elder patients over 60, especially men
  • Stridor, which is a late debut symptom. The patient must be referred immediately.

Tumors in patients with familial accumulation of thyroid cancer, or who were previously irradiated to the neck, must have an expedient work-up.  

Differential diagnoses of the thyroid cancer

The differential diagnostic challenge of nodes in the thyroid is to differentiate between benign and malignant.

Benign nodes

Non-neoplastic nodes:

  • hyperplastic
  • spontaneous
  • compensatorical after partial thyroidectomy

Inflammatory:

  • Hashimoto's thyroiditis/autoimmune thyroiditis
  • subacute thyroiditis
  • acute bacterial thyroiditis

Benign neoplasias

Adenomas:

  • solid
  • cystic

Hyperfunctioning nodules

Prognosis of thyroid cancer

In 2013, there were an estimated 637,115 people living with thyroid cancer in the United States. For thyroid cancer, 67.7% are diagnosed at the local stage and the 5-year survival for localized thyroid cancer is 99.9%. The number of thyroid cancer deaths is highest among people aged 75-84. Death rates have been rising on average 0.7% each year over 2004-2013. (1)

The prognosis is very good, with the exception of anaplastic thyroid carcinomas.

The incidence of papillary thyroid carcinoma has a biphasic distribution; there is one peak in children/youth and another for elderly. The prognosis for papillary thyroid carcinoma is good, especially for young adults.

 

 

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

Source: Cancer Registry of Norway

 

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References on thyroid cancer

  1. U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute, USA.gov.
  2. Nasjonale retningslinjer for diagnostikk og oppfølging av differensiert cancer thyroideae 2007
  3. The American Thyroid Association Guidelines Taskforce. Cooper et. al. Management for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2006;16(2):1-33.
  4. Pacini F, et al. European consensus for management of patients with differentiated thyroid carcinoma of the follicular epithelum. Eur J Endocinol 2006;154:787-803.
  5. Danmark: Guidlines for behandling av thyroidcancer i Danmark (2005). http://conman.au.dk/dahanca/guidlines
  6. Sverige (ikke nasjonale): www.oc.gu.se (2006) og www.ocsyd.lu.se (1999)

 

Diagnostics of thyroid cancer

Primary work-up

  • Thorough family anamnesis 
  • Clinical examination with inspection and palpation of the thyroid gland and neck.
  • Register sign of hyper/hypothyroidism.
  • Blood tests:
    • thyroid function including thyroid stimulating hormone (TSH) and free T4
    • anti TPO (thyroid antibody - positive for autoimmune thyroiditis)
    • s-calcium and s-albumin

If there is suspicion of malignancy, the patient should have a work-up performed by a specialist.

Ultrasound examination, other image diagnostics, or scintigraphy will delay and raise the price of the work-up for possible thyroid cancer, and should only be done in cooperation with a specialist. 

Work-up with specialist

Patients with normal thyroid function tests with a solitary node, suspect node in nodal struma, or change in detected nodal struma, should be referred to a specialist.

Triple diagnostics are performed consisting of:

  • clinical examination
  • image diagnostics - ultrasound examination
  • biopsy - fine needle cytology

Clinical examination    

  • Anamnesis and clinical examination
  • Examination of the vocal cords, if necessary

Image diagnostics

  • Ultrasound of the thyroid gland and neck with lymph node status.

In some cases, it may be necessary to carry out a MRI or CT if:

  • there are large strumas where the limits cannot be assessed well enough clinically or by ultrasound.
  • there are fixed tumors
  • there is suspicion of extensive cancer 

Thyroid scintigraphy is only performed in patients with low/suppressed TSH and for suspect autonomous adenoma.

At least two months should pass after iodine-containing contrast is given until testing or treatment with radioactive iodine (131I). Therefore, the use of iodine-containing contrast agents for CT should be avoided before testing or treatment with radioactive iodine.

Biopsy - fine needle cytology

An open biopsy should not be taken of the primary tumor or lymph nodes suspect for metastases if there is suspicion of thyroid cancer. A cytological or histological needle biopsy is ordinarily sufficient.

If there is suspicion of lymphoma or undifferentiated thyroid carcinoma, an open biopsy may be necessary if a core biopsy is indeterminate.

Routine testing for calcitonin in patients with a node in the thyroid gland is controversial, but should be done preoperatively in those to be operated, or where there is a clinical suspicion of medullary thyroid carcinoma.  

PROSEDYRER

Thyroid gland biopsy

General

An ultrasound-guided cytological biopsy, also called fine needle aspiration cytology (FNAC) is, in many cases, the most precise diagnostic method for work-up of a tumor in the thyroid gland. WIth today's ultrasound equipment, the point of the needle can be placed within an area of about 2-3 mm.

For ultrasound guided FNAC of the thyroid gland, it is important that a cytologist or screener is present to immediately evaluate the quality of the material. This facilitates collection of a high number of representative samples. It also allows opportunities for collecting material for supplementary examinations.

In certain cases, it will be necessary to take a supplementary tissue sample for a histological biopsy to make a more definite diagnosis.

Indications

  • Palpable tumor
  • Solitary or dominant tumor ≥ 1 cm detected by ultrasound examination
  • Diffuse and enlarged, rapid-growing tumor in the thyroid gland

For a tumor that is not palpable < 1 cm, FNA is indicated if: 

  • there is familial accumulation of the disease
  • the patient has previously been irradiated to the neck
  • there are detected suspect lymph nodes in the neck
  • ultrasound finding gives suspicion of malignancy

Goal

  • Diagnose a tumor in the thyroid gland

Equipment

For examination and puncture of the thyroid gland, a linear ultrasound (US) probe with high contrast is ordinarily used (10–15 MHz). Patients with large struma often require a US sound probe with better tissue penetration (lower ultrasound frequency) for a satisfactory result, however, this reduces the contrast detail significantly.

For the cytology biopsy, a 27 G needle is used, or sometimes a 25 G needle is used.

For the histological biopsy, a biopsy gun is used for automatic biopsy taking with a biopsy needle size 16-18 G.   

 

 

 

Preparation

  • Local anesthesia is ordinarily not necessary for cytological biopsies, but should always be used for histological biopsies because of the needle thickness.
  • The patient lies with their neck dorsally flexed by a pillow under the neck.

Implementation

Cytology biopsy

  • The patient must hold their head still and not swallow during the puncture. 
  • For the cytology biopsy, the sample is taken without aspirating. The capillary action of the needle alone collects the best material for cytology testing.
  • The needle is located in the tumor and moved in an out in the same plane.

Normally, there are two to four punctures made in the area to be tested. The exception is when it is necessary to aspirate and/or use a thicker needle (23 G) to, for example, drain a cyst or when there is fibrosis in the thyroid gland. 

It is recommended that a diagnostic sample contain at least six groups of follicle epithelial cells in each of at least two punctures.

If there are cysts, as much fluid should be evacuated as possible. A cell sample from the remaining lesion should be taken if necessary (without aspiration).

All cyst fluid should be examined (make at least 2-6 smears of fresh fluid).

The material should be immediately smeared on a slide to avoid coagulation. The slide should be air-dried, fixed, and stained.

Histology biopsi

For the histology biopsy, the skin area is washed and the procedure is carried out aseptically. After placing the local anesthesia using US guidance, a small incision is made to insert the larger needle. When the point of the needle is in the correct position, the shooting mechanism is triggered and the sample is taken automatically. Because local anesthesia is given, the procedure usually does not cause any discomfort.  

Follow-up Care

  • Complications from the procedure are rare.
  • Mild irritation at the puncture point may occur.
  • Cytology and histology biopsies can, in rare cases, cause bleeding in the thyroid gland or in surrounding tissue.
  • The result of the test is usually available after 2 days.
Thyroid biopsyThyroid biopsyThyroid biopsy

Treatment of thyroid cancer

Thyroid cancer is treated using:

  • surgery
  • thyroid suppression with medication
  • radioactive iodine
  • external radiation treatment

In 75-80% of the patients, the treatment is intended to cure the disease. Adjuvant treatment with radioactive iodine is given to the majority of patients to remove remaining tumor tissue.

For locally advanced cancer, all identifiable tumor tissue should be removed, even if this involves recurrence nerves, larynx cartilage, the trachea, and the esophagus. Loss of function and morbidity as a result of surgery must be assessed individually and related to other treatment possibilities. Locally advanced thyroid cancer should be treated on a regional level.

For undifferentiated (anaplastic) carcinoma without distant metastases, a combination of external radiation and chemotherapy before surgery may be the best choice of treatment. Medullary thyroid carcinoma is treated by a total thyroidectomy with lymph node dissection.

Radioactive iodine is part of primary treatment for differentiated thyroid carcinoma. Iodine scintigraphy shows uptake near the midline in the thyroid region, which is assumed to be microscopic remains of thyroid tissue. In such cases, an ablation dose of radioactive iodine is given to destroy the remaining thyroid tissue. The basis for using s-thyroglobulin as a biochemical marker for recurrence is optimal when the thyroid tissue is not present.

There are clinical and experimental evidence that TSH suppression inhibits development of recurrence and metastasis of differentiated follicle cell-derived carcinomas (FTC and PTC).

For advanced illness, treatment is palliative radiation therapy and sometimes palliative surgery.

Surgery of thyroid cancer

Standard treatment for differentiated thyroid cancer is a total thyroidectomy. A lobectomy (hemithyroidectomy) is considered sufficient for certain patients with low risk tumors. Lymph node dissections are performed to varying degrees of extensiveness and are a topic of discussion.

Clear definitions of surgical procedures are important, and the following terms should be used:

  • Lobectomy – complete resection of a thyroid lobe including the isthmus and the pyramidal lobe, if present.
  • Near total lobectomy – lobectomy where the least possible thyroid tissue remains (< 1 g tissue) if there danger of injury to the recurrence nerve or blood supply to the parathyroid.
  • Total thyroidectomy – complete resection of both thyroid lobes, isthmus, and pyramidal lobe.
  • Near total thyroidectomy – complete resection of thyroid lobe (lobectomy) on one side with near total lobectomy on the other side. 

If a total thyroidectomy is not performed, the extent of the resection of each lobe should be described. 

The lymph nodes and pre and paratracheal spaces should be inspected and thoroughly palpated for metastases, to determine whether a therapeutic lymph node dissection should be performed. 

Some groups routinely recommend prophylactical central lymph node dissection as standard treatment, but this is somewhat controversial in Norway. Arguments for carrying out this type of dissection are to reduce the necessity of reoperating which significantly increases the risk for injury to the recurrence nerve in the central compartment. The collective assessment is in line with international guidelines, which recommends a prophylactical lymph node dissections as part of the primary surgery, when it can be performed with low risk of complication.

A lymph node dissection in the lateral field of the neck should only be carried out if metastasis is found.

Thorough inspection of the lymph node status with ultrasound is an important part of the preoperative work-up.

Frozen section testing is not very sensitive for papillary thyroid carcinoma, therefore a negative result will not exclude malignancy. For follicular thyroid carcinoma, frozen section should not be performed when the preoperative cytological diagnosis is a follicular tumor, as there is a risk of a false positive cancer diagnosis.

Medullary thyroid carcinoma

Surgery is the only effective treatment for this disease. A total thyroidectomy should be performed with a lymph node dissection, and often up to four field dissections (neck and mediastinum), but preferably in multiple sessions.

In about 10% of patients with a primary tumor ≤ 1 cm, local and regional metastases are found, and for larger tumors, up to 90%. The metastases can be very small. Bilateral dissection of pre and paratracheal areas as well as antero-superior mediastinum should therefore always be performed. If metastases are found, a modified neck dissection should be performed. This should include section III and IV of the involved side, at minimum. If the there are midline metastases, the dissection should be carried out on both sides.  

Anaplastic thyroid carcinoma

For anaplastic thyroid carcinoma, a total thyroidectomy should be performed secondary to radiation therapy, if there is no presence of metastasis.

  

PROSEDYRER

Thyroidectomy

General

A total thyroidectomy is ordinarily the primary treatment for differentiated thyroid carcinoma, medullary carcinoma, and anaplastic thyroid carcinoma, based on certain criteria. During the same operation, the pre and paratracheal lymph nodes are removed (central lymph node dissection). 

If pathological lymph nodes are found in the lateral neck region before or during the operation, a modified radical lymph node dissection should performed in addition. This involves preservation of nerves, vessels, and muscles in the area.

The next level of treatment for differential thyroid carcinoma is usually ablation with radioactive iodine (131I). The patient will have life-long treatment of thyroid hormone suppression.

A hemithyroidectomy consists of a lobectomy as well as removal of the isthmus and pyramidal lobe, if present.

Indications

Total thyroidectomy

For papillary thyroid carcinoma, a total thyroidectomy is performed in the following situations:

  • tumor diameter > 1 cm
  • multifocal disease
  • infiltration of thyroid capsule
  • incidence of metastases
  • previously irradiated neck
  • familial accumulation of thyroid cancer
  • if the patient will be treated with radioactive iodine 

For follicular thyroid carcinoma, a total thyroidetomy is performed in the following situations:

  • infiltration of the thyroid capsule, especially in elderly
  • minimal invasive follicular thyroid carcinoma with diameter > 4 cm
  • follicular thyroid carcinoma with prominent invasive elements 
  • malignant Hürthle cell tumors (oxyphile)
  • if the patient will be treated with radioactive iodine 

For medullary thyroid carcinoma, a total thyroidectomy is performed.

For anaplastic thyroid carcinoma, a total thyroidectomy is performed secondary to radiation therapy if there is no metastasis.

Hemithyroidectomy

A hemithyroidectomy is usually performed when:  

  • there is a differentiated thyroid carcinoma tumor around 1 cm or less. That is, for low-risk patients.
  • the tumor has an ambiguous histology prior to surgery (mostly follicular neoplasia)
  • the patient is older with a shorter life expectancy
  • the patient is unable to take thyroid hormone replacement regularly

Goal

  • Cure the disease 
  • Palliative treatment

Equipment

  • Surgery tray
  • Ligasure (if necessary)
  • Nerve stimulator (if necessary) 
  • Preparation

  • Thrombosis prophylaxis
  • Antibiotic prophylaxis in special cases, for example, long surgery, contamination of the surgical field from the tracheaor esophagus.
  • The patient lies in the supine position with their arms and legs to the side and their head streched back with a pillow under the their knees. 
  • Implementation

    The following principles apply to all thyroid surgery.

    • Optimal access to the entire surgical field is important. 
    • Identification of anatomical structures is very important. It is considered impossible to perform a lobectomy without being able to identify anatomical structures, especially the recurrent laryngeal nerve and the parathyroid gland.
    • Bleeding should be minimal. Vigorous use of suction can damage the parathyroid gland or other structures. 
    • Diathermy should not be used in the vicinity of the recurrent laryngeal nerve. Mild handling of these nerves is important to avoid nerve damage.

    Total thyroidectomy

    • An incision is made in the anterior neck.

    Dissection of the thyroid lobes can begin either laterally or cranially. Lateral access facilitates mobilization of the thyroid lobes early in the operation and makes dissection of the upper pole vessels less difficult. This also provides better access to the outer branch of the superior laryngeal nerve. If the tumor is large, it may be difficult to identify the thyroid artery and the recurrent laryngeal nerve, without separating the upper pole vessels first and releasing the upper pole. 

    • Both polar arteries are separated.
    • The lobes are dissected laterally and flipped medially to identify the recurrent nerves.

    After the thyroid lobes are rotated medially, the recurrence nerves should be systematically and carefully dissected from the thyroid gland. There are multiple anatomical variations of routes to the recurrent laryngeal nerve, inferior thyroid artery, and the thyroid gland. The nerve can run in front or behind the inferior thyroid artery, and more than 30 variations have been described. There is therefore no "safe" method for manuevering without identifying the recurrent laryngeal nerve.  

    • The parathyroid gland is dissected.

    In some cases, it is impossible to dissect the parathyroid from the thyroid capsule and maintain intact vessel supply. In these instances, the gland is taken out, cut into small pieces, and implanted into surrounding muscle, for example, the sternocleidomastoid muscle. The area is marked with non-absorbable thread for later identification. 

    • The thyroid is separated and removed.

    It is recommended to remove the entire specimen en bloc. That is, after the lobectomy is performed, the surgeon should continue to dissect on the opposite side without separating the isthmus. The thyroid gland is then removed in one piece. If there are metastases in lymph nodes in the central compartment of the throat, these should be removed together with the thyroid gland.  

    • A vaccuum drain is placed.
    • The incision is closed with intracutaneous sutures and a bandage is applied.

    A small bandage should be used for easier observation of possible postoperative bleeding. 

    Follow-up

    • The patient must be observed for sign of postoperative hypocalcemia
    • The vaccuum drain is removed when recommended by the surgeon, which is usually when < 50 ml has drained in a day. 
    • The day after the procedure, treatment with thyroid hormone substitution is started for patients having the entire thyroid gland removed and who is not treated with radioactive iodine.  
    • The patient is discharged after about one week.

    Patients with highly differentiated thyroid carcinoma are usually readmitted after about six weeks for treatment with radioactive iodine.

    Thyroxine

    After ablation treatment with radioactive iodine for follicular and papillary thyroid carcinoma, life-long thyroid suppression treatment is started with thyroxine.

    Substitution treatment with thyroxine is given to patients operated for medullary or anaplastic thyroid sarcoma.

    The maintenance dose of thyroxine (usually 125-150 µg daily) is managed according to the TSH value, which should lie around 1 mIE/l, and based on physical symptoms. The daily dosage should increase by 25 µg (or less) every 6-8 weeks until the normal TSH level is reached and there are no symptoms.

    Follow-up examinations

    For medullary thyroid carcinoma, the patient will have a follow-up examination with the surgeon after 6-8 weeks.

    Close follow-up is very important for diagnosing recurrence.

    Nerve injury

    Nerve damage rarely occurs with experienced surgeons (often given as 1%). The extent varies depending on which diseases the treatment center usually operates.

    Nerve damage which can occur:

    Partial recurrent damage

    Total or partial paralysis of the ipsilateral vocal cord, which will take on a paramedian or intermediary position. This will lead to incomplete closure of the voice glottal gap, which causes reduced voice quality, ability to cough, and speech and exertion dyspnea. 

    The patient is encouraged to use their voice and is referred to a speech therapist, if necessary. Less than half of patients will have spontaneous improvement of voice function even if more have improved voice quality. For chronic reduction of voice quality, the patient should be referred for assessment of compensatorical surgery. 

    Bilateral recurrent damage

    If there is bilateral recurrent damage, the symptoms will depend on the position of the vocal cord. The voice is better the closer the voice cords are to the midline, but stridor and dyspnea are simultaneously more significant. For postoperative stridor, reintubation or a tracheotomy should be considered. For lasting bilateral paralysis, a posterior cordectomy (extirpation of posterior part of vocal cord) will reduce dyspnoe, but will also reduce voice function. For these patients, voice training with a speech therapist is indicated.   

    Superior laryngeal nerve damage

    Damage to the superior laryngeal nerve, which innervates the cricothyroid muscle to adduct and tighten the vocal cord, can give rise to a lower tone pitch and reduce the upper part of the tonal register. Sensory fibers are important to protect reflexes, and damage can cause tendency to aspiration.  

    When the upper pole vessels are cut, they must be carefully isolated while the laryngeal nerve is seen, or at least has been actively looked for, to avoid damage to this nerve. The physical examination and stroboscopic laryngoscopy with detection of an increased glottis wave amplitude are basis for the diagnosis.  

    Accessory nerve damage

    Damage to the accessory nerve causes hanging shoulders and problems lifting the arms over the horizontal plane in a lateral or posterior position, due to paralysis of the trapezius muscle. During a lateral lymph node dissection, the nerve should be identified. Differentiated thyroid cancer is seldom an indication to sacrifice the nerve. Reduced function can still occur and is easily identified immediately after surgery. During extensive scar formation, gradual reduction of function can occur. Shoulder exercises are important to maintain as much shoulder function as possible.

    Horner's syndrome

    Horner's syndrome consists of hanging eyelids and constant small pupils, thereby impairing vision. Horner's syndrome can occur as a result of nerve damage (sympathetic trunk), or after a modified lateral lymph node dissection.

    Drug therapy of thyroid cancer

    All thyroidectomy patients will have either suppression treatment or substitution treatment with thyroid hormones.

    Growth of thyroid tissue is stimulated by TSH, therefore, inhibition of TSH secretion reduces the risk for recurrence and increases the chance of survival.

    Most patients operated for differentiated thyroid carcinoma must take thyroid hormone (thyroxine) as suppression treatment to reduce endogenous TSH stimulation of remaining tissue/cancer. For papillary and follicular thyroid carcinoma, suppression of TSH is also part of treatment.  

    The degree of suppression depends on the likelihood of recurrence or remaining cancer.

    • TSH should be < 0,1 and preferably under the laboratory detection limit (usually 0,03 mIE/l).
    • TSH should be in the lower reference area for patients with a very low risk for recurrence. One should be aware of patients with low a tolerance for thyroxine. 

    When starting thyroxine, TSH should be monitored after 6-8 weeks and the daily dose increased by 25 µg or less every 6-8 weeks until the desired TSH level is reached. The blood test for TSH and free T4 should be taken before the daily dose of thyroxine and 6-8 weeks after a dosage adjustment. Thyroxine sodium should be used rather than T3 for suppression treatment.   

    The patient's primary care doctor should be informed of the suppression treatment, and changes to the treatment strategy should not take place unless consulting the treating physician.  

    Radiation therapy of thyroid cancer

    Radiation therapy is given predominantly as an intravenous injection of radioactive iodine (131I), on the premise the patient has cancer cells and/or normal thyroid tissue that absorbs iodine.

    Radioactive iodine therapy is given alone, usually after surgery, or in combination with external radiation therapy.

    External radiation therapy plays a small role in thyroid cancer treatment, except for anaplastic thyroid carcinoma, in which it is an important part of treatment.

    PROSEDYRER

    Radioactive Iodine Therapy of thyroid cancer

    General

    Nuclear medical examinations play an important part in differentiated thyroid cancer, both for therapy follow-up and for localization of local recurrence. Radioactive iodine is important for postoperative ablation, treatment of small metastases, and diffuse lung metastases. Postoperative radioactive iodine (131I ) therapy is given to patients with a high risk of recurrence after surgery. 

    Examinations with radioactive iodine play a small role in the primary work-up of thyroid cancer. The diagnostic total-body scan with 200-700 MBq 131I is no longer performed before therapy, because the diagnostic dose may inhibit the subsequent uptake of the therapeutic dose (stunning), and also because a diagnostic scan has much less sensitivity for detection of remaining tissue compared to a post therapy scan. A diagnostic scan with123I can be utilized without the danger of stunning, but the medication is costly.

    A diagnostic scan with131I /123 I in addition to a post-therapy scan can be taken advantageously as a SPECT/CT.

    Indications

    Differentiated thyroid cancer after a thyroidectomy in the presence of one of the following factors: 

    • solitary papillary thyroid carcinoma 1-2 cm in largest diameter 
    • multifocal papillary thyroid carcinoma
    • papillary cancer with metastases to regional lymph nodes
    • papillary cancer with extra thyroidal growth and vessel infiltration and with Tall cell variant
    • invasive follicular cancer with or without regional or distant metastasis 
    • minimally invasive follicular cancer > 4 cm
    • minimally invasive follicular cancer with regional or distant metastases. Generally more liberal for patients between 20-45 years and with Hûrthle cell variation. 
    • iodine-concentrating metastases
    • diffuse lung metastases

    Goal

    Postoperative diagnostics

    • Inspect whether there is surrounding iodine contentrating tissue concentrated in the neck, or if there is iodine-concentrating in metastases.

    Postoperative radioactive iodine therapy

    • Ablation of remaining thyroid tissue to better monitor the level of s-tyroglobulin.
    • Minimize the frequency of recurrence by ablation of microscopic remains of cancer tissue.
    • Treatment for metastases.

    Treatment for metastasis

    •  Ablation of metastases (iodine-concentrating)

    Preparation

    If an ultrasound examination for lymph node metastases in the neck has not been performed preoperatively, this must be done before diagnostics and treatment with radioactive iodine. 

    Measurement of thyroglobulin (Tg) before or immediately after a thyroidectomy is preferable to have as a reference value.

    All examinations and treatment with radioactive iodine should occur under TSH (thyroid stimulating hormone) stimulation. In low risk patients having an ablation dose, rhTSH can be used as an alternative to thyroxine discontinuation.

    Normally, the patient must be without thyroxine for 4-5 weeks before ablation and therapy with radioactive iodine. After stopping thyroxine or a postoperative period without thyroxine, TSH must be > 30 mIE/l. The patient should not have taken triiodothyreonine in the last 10 days before testing and treatment.

    It is recommended to eat a diet low in iodine for 1-2 weeks before testing and treatment.

    The patient should not have an X-ray with an iodine-containing contrast agent, or take supplements high in iodine in the last two months before testing and treatment with radioactive iodine.  

    The patient should fast for at least 4 hours before taking radioactive iodine orally for optimal absorption.

    Other considerations

    The antiarrhythmic agent, Amiodarone, can inhibit iodine uptake for six months after discontinuation.

    Implementation

    Patients are normally hospitalized for 2-3 days after radioactive iodine therapy.

    To reduce radiation exposure to other organs, the following is recommended:

    • Copious fluid intake to frequently empty the bladder to reduce radiation exposure to the bladder/urinary tract.
    • From day two or three, the patient should suck on acidic pastilles to increase the excretion of radioactivity from saliva. Be aware that sucking on acidic pastilles already on day one leads to an increased uptake of radioactivity in saliva glands, which should be avoided.  
    • Bowel emptying in case of a post therapy scan due to high bowel uptake of radioactivity.

    The more remaining iodine-concentrating tissue, the higher the likelihood of radiation-induced thyroiditis, causing tenderness and discomfort in the neck.

    Thyroid scintigraphy and iodine uptake testing after total thyroidectomy

    3 MBq 131I  has sufficient activity for imaging (and possible uptake measurement) to determine the amount of remaining tissue before ablation. Imaging and uptake testing can take place as early as four hours after the dosage is given, even if 24 hours is more optimal, and sometimes necessary, for a satisfactory image and uptake.

    A negative scan after four hours may be due to delayed uptake, small amount of or poor uptake by remaining tissue, and does not indicate an absence of remaining tissue. Repeated image and uptake testing 20-24 hours after uptake must be performed. With a negative scan after 24 hours without a known iodine exposure, the amount of iodine in urine should be measured. The most common cause is that the patient has recently had an X-ray with an iodine-containing contrast agent.

    Even with Tg < 0.2 μg/l, small remains of normal gland tissue can be found in the throat.

    Diffuse lung metastases can be detected even with iodine activity as low as 3 MBq.

    Postoperative radioactive iodine therapy

    Activity

    • In low risk patients without suspicion of lymph node metastases, standard activity (3.7 GBq) is used.
    • In patients at higher risk for metastases and remaining localized disease, as well as iodine-concentrating metastases, higher activity is used (4.5-8 GBq).

    Radioactive iodine therapy for metastases

    Radioactive iodine therapy for metastases is given only when the metastases are concentrating iodine, and preferably only for small metastases with high uptake. 

    • The treatment effect is very good for diffuse microscopic lung metastases with high uptake ("black lungs" on scintigraphy). 
    • Bone metastases will often respond poorly to treatment with radioactive iodine despite high uptake.
    • With a raised Tg, but where the preceding post therapy scan was negative, repeated treatment with radioactive iodine is given if Tg showed a significant increase after preceding therapy (seen rarely). 

    Optimization with endogenous TSH stimulation and a diet low in iodine is important.

    Patients with metastases are treated with higher activity (6-8 GBq) than ablation of low risk patients.

    Radioactive iodine therapy is of little therapeutic value for large metastases with low iodine uptake.

     

    Follow-up

    The patient can be discharged when the dosage rate measured 1 m from the patient is < 30 µSv/hour. The age and dosage to which the patients' family/friends are exposed is more important than the dosage rate.

    Postoperative radioactive iodine therapy

    A post therapy scan can be completed 3-5 days after intake of the ablation dose. 

    Thyroxine is started on the third day after intake of radioactive iodine.

    Triiodothyronine is given for 10 days in addition to thyroxine to patients under 60 years without a known problem of chronic or paroxycystic atrial fibrillation. 

    Side effects

    Acute radiation induced thyroiditis in remaining tissue will cause tenderness, swelling, and discomfort in the throat starting 6-8 hours after the treatment dose (duration 3-5 days). It is important to inform the patient that this does not pose a threat of airway obstruction.

    Acute radiation induced gastritis with nausea and pain starting 6-8 hours after the treatment dose lasting for 3-5 days is normal.

    Reduced/change in sense of smell sometimes occurs and may last up to 6 months.

    Reduction of saliva secretion occurs and can be permanent after an activity accumulation >10GBq.

    Follow-up examination and possibly new ablation therapy

    The patient should have a follow-up examination normally 6-8 months after postoperative ablation (at least 4 months).

    Suppression therapy for follicular and papillary thyroid carcinoma

    Three days after treatment with radioactive iodine, the patient will start thyroid hormone treatment. The starting dosage is 125-150 µg, or the same dose as the thyroxine sodium (Levaxin®) before treatment. In addition,10-20 µg triiodothyronine is given 2-3 times daily for 1-2 weeks (caution in elderly and heart disease patients).

    Background

    Mechanism for Radioactive Iodine Therapy

    Cancer developing from follicular thyroid cells are often highly differentiated carcinomas. The cancer cells maintain specific functions such as thyroglobulin production and the ability to take up iodine. The absorption of iodine by cancer cells delivers the radiation right to the target. This is taken advantage of in postoperative diagnostics and treatment.

    Normal thyrocytes take up iodine via NIS (sodium-iodide symporter) and protein bind to thryoglobulin which is stored in the follicle lumen. In a euthyreoid person, 22% of the radioactive iodine test dose can be found in the thyroid after 24 hours.  

    The uptake in thyroid cancer cells depends on the grade of differentiation. It is assumed that uptake of thyroid cancer cells may be around 100 times less than in normal thyroid cells. Follicular cancer has a higher uptake than papillary cancer.

    Radioactive iodine therapy

    External radiation therapy of thyroid cancer

    General

    Radiation therapy can be given postoperatively, in combination with radioactive iodine therapy, or alone, and is central in the treatment of anaplastic thyroid carcinomas.

    Radiation therapy is effective for symptom-causing metastases which do not take up iodine. The dose per fraction and total dose depends on the expected lifetime of the patient and the localization of the metastasis. Fractions vary between 8 Gy x 1 to 2 Gy x 35.

    Indications

    • Undifferentiated (anaplastic) thyroid carcinomas
    • Papillary and follicular thyroid carcinoma in
      • stage IV - with macroscopic tumors with symptoms or life-threatening disease progression after surgery or treatment with radioactive iodine (131I)
      • locoregional recurrence - inoperability or nonradical surgery

    Goal

    • Cure the disease 
    • Reduce the volume of the tumor
    • Remove or limit the extent of metastases

    Definitions

    Target volume

    Target volume definitions according to ICRU
    (International Commission on Radiation Units and Measurements)
    GTV (Gross tumor volume) Palpable or visible/identifiable area of malignant growth.                               
    CTV (Clinical target volume)

    Tissue volume containing GTV and/or subclinical microscopic malignant disease.

    ITV (Internal Target Volume)

    Volume containing CTV and inner margin taking into account inner movement and revisions of CTV. 

    PTV (Planning Target Volume)

    Geometric volume containing ITV and one set-up margin taking into account patient movement, variation in patient positioning, and field modeling.

    OAR (Organ-at-Risk) Normal tissue in which radiation sensitivity may influence planning and/or dose.

    PRV (Planning organ-at-risk volume)

    Geometric volume containing risk volume with set-up margin.
    TV (Treated Volume) The volume within an iso-dose surface considered sufficient based on intent of treatment.
    IV (Irradiated Volume) The volume to receive a significant dose relative to normal tissue tolerance.
    CI (Conformity Index) The relationship between the planning target volume and the treated volume (PTV/TV).

    Preparation

    The target volume and dosage are adapted individually.

    Ideally, the dosage distribution is uniform in the target volume and no radiation will reach any critical organs. This is realistically impossible to achieve, therefore, a compromise must be made between what is possible and what is the goal.  

    Preparation for radiation therapy includes:

    • individual customization of a plastic mask to immobilize the head/neck
    • repeat CT
    • tracing of the tumor and risk volume on each section
    • preparation of dosage plan
    • approval of dosage plan
    • tracing for field limits

    This will take about one week after which radiation therapy can begin.

    Risk organs

    In the region around the thyroid gland, there are risk organs with limited radiation tolerance such as:

    • medulla spinalis
    • brain stem
    • parotid gland

    Implementation

    All fields should be treated with each fraction. It is very important that the planned time of treatment is carried out.

    For unforseen discontinuation of the treatment, no more than one extra fraction can be given per week, and a skipped treatment should be given within one week. 

    Anaplastic thyroid carcinoma

    • 60 Gy to GTV   / ITV  
    • 10 fractions per week (2x daily weekdays), fraction dosage 1.8 Gy  
    • The radiation treatment is often given together with weekly doxorubicin 20 mg

    Postoperative treatment of papillary and follicular thyroid carcinomas T4 tumors

    • 50-60 Gy to GTV, possibily 50 Gy to ITV
    • 5 fractions per week, fraction dosage 2 Gy

    Locoregional recurrence and inoperable papillary and follicular thyroid carcinomas

    • 60-70 Gy tol GTV, possibly 50 Gy to ITV
    • 5 fractions per week, fraction dosage of 2 Gy

    Follow-up

    The patient must have regular follow-up at least once per week at the radiation clinic.

    Side effects of radiation therapy

    Acute

    • Mucositis
    • Salivary gland dysfunction 
    • Dry mouth due to reduced saliva production
    • Taste disturbances
    • Painful swallowing
    • Pain
    • Thick mucus
    • Thrush 

    Regular follow-up of the oral cavity is very important with fields reaching higher up.

    Delayed

    • Salivary gland dysfunction 
    • Dry mouth
    • Taste disturbances
    • Cavities
    • Periodontal disease
    • Osteo (radio) necrosis
    • Trismus
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    Treatment of omplications of thyroid cancer

    Cancer treatment causes varying degrees of side effects.

    It may be necessary to provide supportive care in order for the patient to complete and gain the full effect of planned treatment.

    Supportive care can also be provided to reduce side effects and improve the patient's quality of life during and after treatment.

    PROSEDYRER

    Treatment of Nausea Induced by Chemotherapy

    General

    The majorities of chemotherapy drugs are emetic to varying degrees and may cause nausea and vomiting. Today, there are efficient antiemetic drugs that can significantly reduce the side effects.

    Other factors that can aggravate or prolong the presence of nausea and vomiting are: pain, anxiety, electrolyte disturbances, constipation, dyspepsia, and ulcers.

    There is a distinction between acute nausea, which occurs within the first 24 hours, and late nausea, which occurs later than 24 hours after the treatment.

    Acute nausea can be effectively treated with 5HT3-antagonists (ondansetron, tropisetron, palonosetron), and possibly combined with steroids. Dopamine antagonists (metoklopramid, metopimazine) also have some effect on acute nausea. If this treatment is not effective, it may be improved with aprepitant.

    If standard prophylaxis and treatment of nausea is not satisfactory, other nausea regimens should be tried.

    Indication

    • Nausea induced by chemotherapy drugs.

    Goal

    • Prevention and treatment of nausea and vomiting.

    Definitions

    Chemotherapies according to emetic potential

    High emetogenicity   

    Group 1

    Moderate emetogenicity   

     Group 2

    Low/minimal emetogenicity

    Group 3

    All cisplatin-containing regimens (CiFu, GemCis, BEP, TIP, VIP, PV, AP, EDP, DHAP, ECX, weekly dose cisplatin, and others) BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosfamide, vincristine, prokarbazine, prednisolone)
    Doxorubicin/epirubicine weekly dose
    Doxorubicin/ifosfamide Bendamustine
    Docetaxel
    FEC-60 og FEC-100
    (fluorouracil, epirubicin, cyklophosfamide)
    Carboplatin
    ENAP (etoposide, mitoxsantrone, cytarabine, prednisolone)
    ABVD (doxorubicin, bleomycin, vinblastine, dakarbazine Carboplatin/pemetrexed
    FLv (fluorouracil)
    FOLFIRINOX
    Carboplatin/vinorelbine
    FuMi (fluorouracil, mitomycin)

    CHOP (cyclophosfamide, doxorubicin, vincristine, prednisolone)
    Gemcitabine

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

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

    References

    1. Lehne G, Melien Ø, Bjordal K, Aas N, Mella O. Kvalme og oppkast ved cytostatikabehandling i: Dahl O, Christoffersen T, Kvaløy S, Baksaas. Cytostatic Medication cancer treatment. 7. edition. Oslo. Department of Pharmacotherapeutics and The Norwegian Cancer Society, 2009, p 119-130.

    Preparation

    Nausea regimens are selected according to the emetogenicity of the relevant drugs.

    • Inform about the risk for and treatment of nausea. 
    • In the event of anxiety or conditional nausea, give tranquilizers if necessary.

    Implementation

    • Start with an optimal antiemetic regimen starting with the first cycle of chemotherapy in order to counteract the amplification of the nausea that often occurs with a new treatment.
    • Start the oral antiemetic regimen 1-2 hours before chemotherapy and approx. 15-30 minutes before an intravenous injection.
    • If the patient is already nauseous, the medication should be administered parenterally or rectally.

    Antiemetic regimens

    Mildly emetic chemotherapy

    • Metoclopramide 10 mg is given intravenously before treatment with cytostatic agents.
    • Metoclopramide 10 mg is given orally uptil 3 times.

    Moderately emetic chemotherapy

    Ondansetron 8 mg orally 2 x daily. In the event of nausea before treatment, give ondansetron intravenously. If this has little effect, try ondansetron 8 mg x 3 or change to a 5HT3-antagonist, for example, tropisetron 5 mg orally/intravenously or palonosetron 250 µg intravenously.

    Highly emetic chemotherapy, or if other treatment does not help

    For highly emetic chemotherapy drugs, or if other treatment is not adequate, a 5HT3-antagonist can be given orally or intravenously. It should be combined with dexamethasone 8-16 mg intravenously ½-1 hour before treatment, and further, 8 mg x 2 intravenously or orally on the first day.

    In addition, dopamine antagonists may be given, for example, metoclopramide 10 mg x 3.

    In some cases, traditional nausea treatment is not sufficient. In this case, the patient can be treated with aprepitant. Aprepitant is used for highly emetic regimens and for patients where the usual antiemetic treatment has failed during moderate emetogenic treatment. Aprepitant is given orally 1 hour before chemotherapy and is combined with dexamethasone and 5HT3-antagonists:  125 mg capsules orally on day 1, then 80 mg orally on days 2-5, depending on the duration of the treatment. Aprepitant can enhance the effect of taxane and etoposide, as well as vinorelbine, and can reduce the effect of warfarin.

    The regimen is repeated daily if highly emetic treatment is given over a number of days.

    Delayed nausea

    Aprepitant in combination with dexamethasone and 5HT3-antagonists is preferable if there is a high risk of delayed nausea and vomiting. This is offered especially to patients who have previously experienced delayed nausea.

    Conditional nausea

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

    Follow-up

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

    Nutrition during Cancer Treatment

    General

    Monitoring the patient's nutritional status is an important part of cancer treatment. The goal is to identify malnutrition as early as possible in order to initiate treatment as quickly as possible.

    Measures include diet according to symptoms and the nutritional condition. The patient should be offered nutrition-rich food, snacks, nutritional drinks, tube feeding and intravenous nutrition.

    Because cancer treatment breaks down both cancer cells and normal cells, the body requires an adequate supply of nourishment to increase growth of new cells. 

    In cancer patients, the sensation of hunger is not always present to the necessary degree. In these cases, it is important to take actions to improve the nutritional status of the patient. The nutritional condition is easiest followed by monitoring body weight over time.

    Indication

    • Cancer treatment (chemotherapy, radiation, surgery).

    Goal

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

    Definitions

    Subjective Global Assessment (SGA)

    Subjective Global Assessment (SGA) is a scheme for classifying the patient's nutritional status.

    Other tables that are frequently used are Malnutrition Universal Screening Tool (MUST), Mini Nutritional Assessment (MNA) and Nutrition Risk Score (NRS). In principle, these schemes are prepared in the same way as SGA, but they are not validated for patients with cancer.

    Weight loss is one of the most important signs of change in nutritional status. A weight loss of more than 15% over the past 6 months or more than 5% over the last month is a significant and serious weight loss. If the weight loss occurs in combination with low BMI (body mass index) (< 20 kg/m2 for adults) and/or a food intake of less than 60% of the calculated requirement over the past 10 days, the patient will be malnourished or be at nutritional risk.

    Calculation of nutrition and fluid requirements

    • Ambulatory patients:  30-35 kcal/kg/day
    • Bed-ridden patients:  25-30 kcal/kg/day
    • Elderly above 70 years:  Recommended amount is reduced by 10%
    • Fluid requirement:  30-35 ml/kg/day

    Nutritionally enriched diet / enrichment of food and beverages

    Nutritional beverages may be used as a meal in itself or between meals. Nutritional drinks can be a more valuable snack than "normal" food, because it is often easier for the patient to drink than to eat. It has been shown that if nutritional drinks are introduced as snacks, it does not affect the energy intake during the main meals.

    There are a number of ready-made nutritional drinks on the market. Some of the products are of nutritionally complete. They contain carbohydrates, protein and fat and are supplemented with all the necessary vitamins, minerals and trace minerals and possibly fiber. Some of these products can be used as the sole source of nutrition. The energy content varies from 85-200 kcal/100 ml and some products have a high protein content. Other nutritional drinks are supplement drinks adjusted to individual needs such as allergies, intolerance and special conditions associated with illnesses.

    The products are also adapted to age, and the dose is determined individually by a clinical dietician/doctor.

    Many patients prefer homemade nutritional drinks based on full fat milk, cream, ice cream, fruit and possibly flavor supplements. These are free of additives and have a fresher taste. The energy and protein content is close to the commercial products and at the same time they are more sensibly priced.

    Tube feeding

    Tube feeding is preferable to total parenteral nutrition (TPN) when the digestive system is working. Nutrition supply to the intestine is more physiological. It protects against bacterial growth, maintains the intestine's mucous membrane structure and function, and promotes motility. Tube feeding involves less risk of metabolic complications.

    Tube feeding is used in the event of

    • insufficient food intake (less than 60% of energy requirements) over the past 5-7 days despite oral intake
    • weight loss >2 % over the past week, >5 % over the past month or >10% over the past 6 months
    • danger of weight loss due to planned treatment
    • low albumin values (under 35 g/l, lower limit for normal area)
    • stenosis with feeding obstacles in pharynx/gullet

    Tube feeding must not be used for the following conditions.

    • Paralysis or ileus of the alimentary tract
    • Short bowel syndrome
    • Serious diarrhea
    • Serious acute pancreatitis
    • Obstruction of the intestine
    • Serious fluid problems

    Tube feeding solutions

    The tube feeding solution must be nutritionally complete because they shall be used as the sole source of nourishment. The most frequently used are standard (1 kcal/ml), fiber-containing (1 kcal/ml) or energy-rich (1.5 kcal/ml). There are also tube feeding solutions which are adapted to patients with digestion and absorption problems, patients with diabetes or lactose allergy, and intensive care patients.

    Tube feeding solutions, which are adapted to cancer patients are energy-rich (1.5 kcal/ml). They contain extra omega-3 fatty acids, rich in MCT acid and enriched with extra vitamins and minerals. Recommended dosage is 500 ml/day.

    Parenteral nutrition

    Parenteral nutrition should only be used if food by mouth or tube feeding cannot be maintained. Parenteral nutrition can also be used as a supplement to tube feeding or ordinary food. 

    Precautions must be taken for kidney failure, heart failure, lung failure, large fluid and electrolyte loss, diabetes mellitus and liver failure.

    Preparation

    The patient is classified as well-nourished, somewhat malnourished or seriously malnourished on the basis of information about weight development, food intake, symptoms and physical functioning. This classification has been shown to correlate well with more objective measurements of nutritional status and morbidity, mortality and quality of life.

    Actions include individual adjustment of diet according to symptoms and nutritional status.

    Tube feeding

    The end of the tube is often inserted into the stomach. In the event of poor gastric function, total gastrectomy or pancreatic resection, the feeding tube should be inserted in the duodenum or jejunum. The position of the feeding tube is vital for the choice of feeding-tube solution and mode of administration.

    The most common solution is to insert the tube nasogastrically, but it can also be done through the abdominal wall (PEG).

    Parenteral nutrition

    It is preferable to use intravenous or parenteral nutrition as a supplement to oral/tube feeding instead of only TPN (total parenteral nutrition).

    • Central veins must be used for TPN with high osmolality.
    • Peripheral veins can be used for short-term parenteral nutrition. In this case, a large vein on the forearm is used and a small needle. Nutrition is then given as more diluted solutions.

    Implementation

    All patients are weighed regularly (1–2 times each week). This is a prerequisite to being able to register changes in the nutritional status.

    Varied and healthy food contributes to the growth of new cells and enhances the immune system.

    • Fruit, berries and vegetables are rich in vitamins, minerals, antioxidants and fiber, which contribute to enhances the immune system and contributes to keeping the digestive system working.
    • Fish, shellfish, poultry, meat, eggs, cheese, milk, beans and nuts are rich in proteins, which are the building blocks of new cells.
    • Bread, rice, pasta, porridge and breakfast cereals supplement the diet with proteins, carbohydrates, fiber, vitamins and minerals.
    • Oil, margarine, butter, mayonnaise products, nuts, cream, heavy cream, desserts etc. are fat and energy rich products, which are important to maintain the energy intake at a satisfactory level.
    • Cancer patients also have a requirement for plenty of fluid, especially during treatment, to discharge waste.

    Often, the patients must have an individually adjusted diet. In the event of lack of appetite, it is generally more important that you eat (enough food) than what you eat (the right food). It is beneficial to have small portions and for the food to be as abundant in energy as possible. These patients will often have a need for 6–8 small meals everyday to obtain their energy requirements.

    Enrichment of food and drink is done in order to increase the energy content of the food product without increasing the volume. Full-fat products such as full-fat milk, cream, butter, heavy cream, mayonnaise, sugar, honey, eggs and cheese etc. are primarily used. Enrichment powders from pharmacies may also be used. Some powders are nutritionally complete, i.e. they contain everything the body requires in terms of energy and nutrients, while others only contain pure energy (carbohydrates, fat and/or protein). 

    Tube feeding

    Tube feeding is given continuously with a low drop rate or by interval/bolus administration (individually adapted meals with high drop rate).

    When the patient's energy and fluid requirements are fulfilled, it will be decided whether the patient will be given bolus or continuous supply at night, in order to increase mobilization during the day. However, this requires that the patient does not have diarrhea, nausea or other complaints associated with the supply of nutrition.

    For a running feeding tube:

    • Every 4-8 hours, it should be aspirated in order to monitor the gastric emptying. This applies especially to immobile and weak patients.
    • Weekly or more often, the nutrition program/fluid balance, evaluation, edema control, blood tests (albumin, K, Mg, P, blood glucose) should be monitored weekly or more often.
    • Every 4-6 weeks, the tube should be changed. Alternate the uses of nostrils avoid irritation in the nose through prolonged feeding.

    Experience shows that the use of infusion pumps causes fewer side effects and ensures correct volume and rate.

    Bolus supply

    Initiation of tube feeding with bolus supply is only recommended

    • if the patient been taking any food until the last 24 hours
    • if the patient is taking some food and requires tube feeding for additional nourishment

    It is recommended to use pumps for bolus supply for the first 1–2 days.

    Continuous supply

    If the patient cannot tolerate bolus supply (vomiting, abdominal discomfort, nausea, diarrhea), reverting to continuous supply should be considered.

    Tube feeding should always be administered continuously to very malnourished patients or if the tube end is located distally to the pylorus.

    Parenteral nutrition

    If the patient has a satisfactory nourishment status, begin with 100% of the requirement. If the patient is seriously malnourished, start with 80 % of the requirement and increase slowly to 100% over the course of three days.

    The patient must be monitored closely in relation to

    • electrolytes (potassium, phosphate and magnesium).
    • infusion rate.
    • twenty-four hour urine sample and fluid balance should be calculated daily.
    • glucose in the blood and urine, and electrolyte in the blood should be examined daily at the start.
    • liver tests, kidney function tests and triglycerides should be taken examined at least once every week.

    For TPN treatment longer than 1 month, vitamins and trace elements should be examined.

    Follow-up

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

    Transfusions

    General

    Transfusions of blood components are often necessary for the patient to complete the planned cancer treatment.

    Blood transfusions are appropriate for low hemoglobin (Hb) and thrombocyte transfusions for low thrombocytes (trc) which also poses a risk for serious bleeding.

    Normal values

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

    Indications

    Blood transfusion

    Assessment for a blood transfusion based on:

    • Hb/hct
    • symptoms/sign/function level
    • underlying disease (heart/lung, serious infection)
    • expected development of anemia (marrow function, current bleeding)
    • acute blood loss > 15% of total blood volume
    • Hb < 8.0 g/dl and symptom causing chronic anemia
    • Hb < 8.0 g/dl and reduced bone marrow production without sign of regeneration
    • Hb < 8.0 g/dl in perioperative period
    • Hb < 7.0 g/dl in patients without symptoms of other disease
    • Hb < 10.0 and receiving radiation therapy

    Platelet transfusion

    The patient is assessed for thrombocyte transfusion based on:

    • clinical status (bleeding, bleeding tendency, or fever/infection)
    • ongoing bleeding and thrombocytopenia < 50x19/l
    • degree of thrombocytopenia and cause of thrombocytopenia (reduced production or increased consumption)

    Prophylactic platelet transfusion

    • For values < 10x109/l secondary to previous chemotherapy
    • Before invasive procedures
    • For spinal puncture and installation of central vein catheter, thrombocytes should be 30x109/l and 
    • Puncture biopsies (liver/kidney/tumor) > 40x109/l
    • For major surgeries, thrombocytes should be > 50x109/l. After surgery, thrombocytes should be monitored and transfusion repeated, if necessary.

    Remember clinical evaluations: possible bleeding, other risk factors for bleeding, diagnosis, treatment, prognosis.

    Goal

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

    Definitions

    Blood

    For a blood transfusion for anemia, SAGMAN erythrocytes are used. One unit is obtained from 450 ml blood. Most of the plasma is removed and replaced with 100 ml SAGMAN solution (Saltwater-Adenine-Glucose-Mannitol). Hematocrit is about 0.60%.

    Platelets

    One unit contains 240-300 x 109 platelets and is prepared from blood donors with type O and A. In acute situations, the receiver's blood group is of minor importance.
    Two kinds of platelet products are available:
    • Apheresis platelets produced from thrombophereses from one donor
    • Buffcoat platelets produced from buffy coat from 4 donors

    All cellular blood products should be leukocyte filtered. Leukocyte filtration is done to remove antigen-presenting and virus-bearing cells. 99.99% of leukocytes in the unit are removed.

    Radiation

    Blood and thrombocytes are irradiated to a minimum of 25 Gy in the blood bank to eliminate T-lymphocytes.

    This is done for:

    • Bone marrow transplant or stem cell transplant (1 month before or 3 months after HMAS until 1 year after allogeneic stem cell transplant)
    • For use of HLA-compatible platelet concentrations
    • For all transfusions from relatives
    • For use of fresh blood
    • For use of fludarabine

    Preparation

    Blood tests

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

    Compatibility

    Erythrocyte concentration—Rh(D) negative products can usually be given to everyone while Rh(D) positive can only be given to Rh(D) positive receivers.

    Thrombocyte concentration—Rh(D) negative girls and women in fertile ages who obtain Rh(D) positive thrombocyte products should be given a prophylaxis for Rh immunization. Boys/men and women who are over the fertile age may obtain thrombocytes regardless of Rh(D) type.

    Implementation

    Blood components should never be given together with other medications.
    • Premedication if the patient has reacted to previous transfusions.
    • Secure venous access
    • The blood product is checked to ensure the correct unit is given to the correct patient.
    • Use blood set with filter
    • Give SAGMAN over 1 hour and thrombocytes 20-30 minutes per unit.
    • Rinse the set with NaCl 9 mg/ml at the end of the infusion
    • Store the blood product bag for one day before discarding

    Observations

    The patient should be observed during the transfusion with emphasis on reactions. Most serious transfusion reactions occur within the first 20 minutes.

    Symptoms of transfusion reaction:
    • chills
    • fever
    • feeling of heat in the face
    • breathing difficulty
    • itching
    • nervousness
    • fall in blood pressure
    • shock
    Suspect/manifest blood transfusion reaction:
    • Stop transfusion immediately
    • Start treatment if necessary (intravenous fluid, adrenalin, steroids, oxygen, respirator)
    • Check blood bag and compatibility form. The residue should be sent to the blood bank.

    Follow-up

    Hemoglobin and thrombocytes are checked.

    If poor effect of platelet transfusion, platelet value should be checked after approximately one hour. The value should have increased by approximately 30x109/l or more after a standard dose.

    If the increase is drastically less, the cause may be:
    • Abnormally high consumption. This is an indication for more frequent transfusions.
    • Antigens against HLA or platelet-specific antigens. The patient must be examined in cooperation with the blood bank to find compatible donors.

    Postoperative Hypocalcemia

    General

    After a total thyroidectomy, it is not uncommon to have symptoms of hypocalcemia for a short period. Acute hypocalcemia occurs most often during the first postoperative days.  

    In some cases, the condition is permanent. If hypocalcemia continues for more than one year, the patient has permanent postoperative hypocalcemia.

    The incidence of permanent postoperative hypocalcemia is about 0.5 - > 2% depending on the experience of the surgeon and the extent of the local disease. With a reoperation, the risk for postoperative hypocalcemia is significantly greater, which is why it is very important that the first surgery is radical.

    Indication

    • Postoperative hypocalcemia

    Goal

    • Normalize calcium level

    Background

    Causes may be:

    • Operation trauma with edema following the surgery.  
    • The vessel supply to the parathyroid gland may be damaged or temporarily reduced.
    • The parathyroid glands were difficult to identify and were included in the resected specimen.

    Preparation

    Acute postoperative hypocalcemia is often a scary and traumatic experience for the patient. It is therefore important that the patient is informed before the operation.

    Symptoms:

    • tingling and numbness in the extremities and face
    • seizures can occur from severe hypocalcemia

    Implementation

    Oral calcium supplementation is recommended. If calcium treatment is started early, intravenous treatment can usually be avoided.

    Treatment is calcium tablets/fizz tablets 500 mg x 1-8 (sometimes more) daily. The risk of overdose with calcium tablets is very small.

    With serious hypocalcemia, a slow calcium infusion should be given intravenously. Some may require a calcium infusion for multiple days.

    Mild hypocalcemia

    Calcium tablets 500 mg 1-2 as needed, possibly 6-8 (10) tablets daily to treat symptoms. The patient should be followed-up closely until stable.

    If the symptoms last for more than 4 weeks, treat with a vitamin D analog and 500 mg calcium or more, if needed.

    Calcium with D vitamin should be discontinued gradually. It is important not to overtreat. Ca2+ should be in the lower normal range, since it will stimulate the remaining parathyroid tissue.

    Follow-up Care

    Check ionized calcium with two week intervals until a stable level is reached. Ionized calcium should be maintained in the lower normal limit to maintain the endogenous stimulation of the parathyroid gland.

    PTH should be measured every two months for parathyroid function. If PTH is measureable in the normal area and all symptoms of hypcalcemia disappear, treatment should be stopped, since the parathyroid glands may have been restored.  

    Permanent hypocalcemia

    If the patient has permanent hypocalcemia, they will need life-long treatment with vitamin D and regular follow-up of calcium status.  

    Calcium (ionized or albumin) should be checked every 3-6 months when levels have stabilized.

    Calcium and phosphate secretion in urine should be monitored. Vitamin D treatment poses a risk for high calcium secretion from the kidneys, which increases the risk for developing kidney disease, especially if the s-calcium and s-phosphate values are high. The vitamin D dose should be kept low, avoid high phosphate values, and reduce renal secretion by supplementing with magnesium, thiasid, or a phosphate binder.

    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.

    Smoking cessation in connection with cancer treatment

    General

    In patients treated with surgery, radiation and/or chemotherapy, the treatment efficacy may be affected by smoking. Smoking has an impact on both metabolism and pharmacokinetics.

    Smoking may inhibit wound healing after surgery and increase the probability of surgical site infections. Because smokers generally have more mucus in the airways and are less able to remove it, they also may have a increased risk of serious lung complications during anesthesia. However, it is disputed whether or not it is beneficial to quit smoking directly prior to surgery and this should be considered in each case individually. (28,30-33). Smokers are more prone to stagnation of bronchial secretion than non-smokers and rapid postoperative extubation is important. 

    Patients who continue smoking during radiation therapy have a lower risk of complete respons, development of secondary cancer, increased toxicity and several other side effects compared to non-smokers and smokers that quit before treatment. Continued smoking during radiation therapy is also associated with oral mucositis, impaired ability to taste, dry mouth, reduced voice quality, weight loss, cachexia, fatigue, pneumonia, bone-and soft tissue necrosis.

    Tobacco may have an effect the metabolism and the mechanisms of chemotherapy and in this way may make the treatment less effective. Smokers undergoing chemotherapy may also experience a weakened immune system, increased rates of infection, exacerbation of common side effects, weight loss, cachexia, fatigue and cardiac or pulmonary toxicity. Some findings suggest that it may also apply to monoclonal antibodies.

    Cancer patients who quit smoking before chemo- and radiation therapy get a total symptom burden equal to that of non-smokers, but those who continue to smoke state a higher symptom burden. Targeted measures in smoking cessation may increase quality of life and lead to less treatment interruptions.

    A lot of patients wonder if there is any point to quit smoking after receiving a cancer diagnosis. tudies show that continued smoking is associated with increased treatment-related toxicity, increased risk of second primary cancers, reduced quality of life, reduced treatment effect and reduced survival in patients with cancer. This applies to both cancer diagnoses where smoking is a known causal factor, as with lung- and head and neck cancers and in cases where smoking has no known correlation with the diagnosis. Studies conducted on smoking and cancer diagnoses such as breast cancer, prostate cancer, colorectal cancer, esophageal cancer, cervical and ovarian cancer as well as leukemia and lymphoma cancers show that to continuation of smoking after a proven cancer diagnosis is associated with increased risk of mortality.

    Studies support that quitting smoking improves cancer, and emphasizing the potential importance of targeted smoking cessation in cancerpatients during and after treatment. The link between tobacco and impact on cancer and cancer treatment is a complex matter.

    Regarding the significance of the various components much is still unkown. When it comes to tobacco use in cancer treatment research is primarily done on the link between cigarette smoking and efficacy of cancer treatment. Nevertheless, it cannot be excluded that using other smokeless tobacco products such as snuff and chewing tobacco, may also impact the cancer treatment. According to international guidelines all tobacco use should be stopped during cancer treatment.


    Benefits of smoking cessation and risks of continued smoking in patients with cancer
    Quitting smoking results in the following benefits: Continued smoking results in a risk of :
    • improved treatment results.
    • less side effects
    • fewer infections
    • improved respiration and circulation
    • increased survival
    • reduced efficacy of treatment.
    • postoperative complications and longer recovery.
    • cardiovascular and respiratory complications.
    • recurrence of cancer, and secondary cancer.
    • shortened life expectancy.

     

    Indication

    Weaning of nicotine in connection to cancer treatment. 

    Goal

    Healthcare providers should convey evidence-based information to patients about how smoking affects cancer treatment, the risk of side effects and prognosis and also provide guidance and relevant treatment for smoking cessation.

    Preparation

    Patients require clear, formalized and fact-based guidance and continuous follow-up. Many patients want encouragement for smoking cessation early in the disease. Being hospitalized is a good opportunity because patients have access to support and help to reduce nicotine withdrawal symptoms and discomfort.

    A patient recently diagnosed with cancer is often motivated to quit smoking and also receptive to conversations about how to do this. Motivation or willingness to quit often changes during the treatment, and use of tobacco and motivation should therefore be discussed at every consultation.

    Clarifying the patient´s smoking habit is important. The time of day the patient lights their first cigarette says something about the degree of addiction. Making the patient aware of the situations in which he or she smokes most; at work, at home or in social settings, can help break unwanted patterns of behavior.

    Implementation

    The best and most direct approach to motivate the patient is telling that tobacco use will decrease the effectiveness of treatment and the most important thing the patient can do himself is to stop using tobacco.

    • Speak directly to the patient about how tobacco use may decrease the effectiveness of treatment.
    • Discuss smoking cessation with the patient at each visit.
    • Clarify any misunderstandings about the risks of tobacco use. Point out the importance of quitting.

    Sometimes there may be misunderstandings about what kind of health risk smoking during and after cancer treatment may entail.

    Advice to those who are not ready for smoking cessation
    The smokers statement The response of health care professionals
    Justifications
    The damage from smoking is already done.
    Some damage is done, but continued smoking will still damage your health and reduce the effects of treatment. Quitting smoking is more important now than ever.
    This response tells the patient that it is not too late to quit smoking, and the effect of treatment will be positive.

    I have reduced smoking.
    That is great, and now you need to focus on quitting completely. What do you think keeps you from quitting altogether?
    This response tells the patient the importance of quitting completely, as the benefits of quitting at baseline are documented.
    This is not a good time to quit smoking.
    The benefits of quitting are greatest now, before treatment begins. What is needed to make you feel ready to quit smoking?
     
    This response make the patient aware of the fact that quitting smoking optimizes the cancer treatment.

    Health professionals must assist the patient identifying realistic expectations and goals for smoking cessation. For some, it may feel easier to scale down the number of cigarettes than to quit completely. The patient should know that every puff affects their health, and that the total health benefits can only be achieved through smoking cessation. For patients unable to stop completely, a gradual reduction may be a step in the right direction.

    The probability of success for smoking cessation significantly increases for those who receive professional help in combination with nicotine replacement therapy (NRT) or non-nicotine based products. For the best possible effect of NRT the patient needs professional guidance to find the right product and dosage. For some patients combining two products or receiving a higher dosage than recommended will give the best effect. Sometimes the product must be replaced during the treatment.

    Treatment with nicotine replacement therapy

    Topical products are patches (Nicorette®, Nicotinell®), chewing gum (Nicorette®, Nicotinell®), lozenges (Nicorette®, Nicotinell®), inhalator (Nicorette®) or a combination of these. These products contain nicotine and therefore reduce the withdrawal symptoms experienced after smoking cessation.

    • Patch: Nicorette® 5 mg,10 mg and 15 mg/16 hours up to 6 months or Nicotinell® 7 mg,14 mg og 21 mg/24 hours up to 3 months.
    • Chewing gum: Nicorette®/Nicotinell® 2 mg and 4 mg, 8-12 pcs/day up to 12 months.
    • Lozenges: Nicorette® 2 mg and 4 mg, typically 8-12 pcs/day, maximum respectively 15 pcs/day up to 9 months or Nicotinell® 1 mg and 2 mg, typically 8-12 pcs/day, maximum is respectively
      25 and 15 pcs/day up to 12 months.
    • Inhalator: Nicorette® 10 mg/dosage container, 4-12 pcs/day up to 6 months.

    Combination therapy means combining patches with chewing gum, lozenges or an inhalator.

    • Nicorette® patch15 mg/16h and Nicorette chewing gum 2 mg. 5-6 chewing gums daily. Maximum 24 pcs/day
    • Nicorette® patch 15 mg/16h and Nicorette® inhalator 10 mg: 4-5 dosage-container daily. Maximum 8 pcs/day

    Nicotine replacement therapy increases the chance of smoking cessation by 50 to 70% after six months. Two products used in combination increase the chance of smoking cessation compared to the use of only one product.

    Side effects

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

    Precautions

    • Precaution in acute cardiovascular disease, peripheral arterial disease, cerebrovascular disease, hyperthyroidism, diabetes mellitus, kidney- and liver failure and peptic ulcers.
    • Should not be used during pregnancy, unless the potential benefit outweighs the potential risk.
    • The products should not be used during breastfeeding.

    Treatment with non-nicotine medications

    Bupropion (Zyban®) is a selective reuptake inhibitor of dopamine and norepinephrine. The mechanism behind why the ability to refrain from smoking increases by using bupropin is unknown. A should be set for smoking cessation for the second week of treatment.

    Bupropion increases the chance of smoking cessation after 6 months by nearly 70%.

    Side effects

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

    Precautions

    • Contraindicated in people with disease that can cause convulsions,  people with substance abuse or other circumstances lowering the seizure threshold.
    • Depression, which in rare cases includes suicidal thoughts and – behavior including  suicide attempt.
    • Safety and efficacy have not been established for people under 18 years.
    • Should not be used during pregnancy.

    Varenicline (Champix®) is a partial agonist by a subtype of nicotinic receptors. It has both agonistic activity with lower intrinsic efficacy than nicotine and antagonistic activity in the presence of nicotine.

    A date for smoking cessation should be set. Treatment should start 1-2 weeks, or up to 35 days, before that date. The starting dose is 0,5 mg one time daily on days 1-3, then 0,5 mg two times daily on days 4-7, then 1 mg two times daily on day 8 and until the end of treatment. The treatment should last for 12 weeks.

    Side effects

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

    Precations

    • Links have been reported between the use of varenicline and an increased risk of cardiovascular events, suicidal thoughts, depression and aggressive and erratic behavior
    • Safety and efficacy have not been established for people under 18 years of age
    • Should not be used during pregnancy

    Follow-up

    If the patient experiences a relapse, it is important to inform them that this is completely normal, and encourage them to continue. If the most common measures do not work,
    consideration should be given both to increase the NRP and to provide closer follow-up by health care providers.

    Guidance in smoking cessation is described in the literature as brief and clear advice and then further follow-up with a telephone helpline offering treatment for addiction and behavior change/issues. It is not necessary for the patient to have decided to quit smoking in order to be referred to a quitline. If the patient agrees to receive a call from quitline, he or she will be followed up by a supervisor. Supervisors are bound by confidentiality, are up-to-date professionally and offer free follow-up counseling calls for up to a year.

    References

    1. Gritz E, Fingeret M, Vidrine D. Tobacco control in the oncology setting. American Society of Clinical Oncology, eds Cancer Prevention An ASCO Curriculum Alexandria, VA: American Society of Clinical Oncology. 2007.
    2. ASCO ASoCO. Tobacco Cessation Guide for Oncology providers,. 2012 (02.12.2014).
    3. Zevallos JP, Mallen MJ, Lam CY, Karam-Hage M, Blalock J, Wetter DW, et al. Complications of radiotherapy in laryngopharyngeal cancer: Effects of a prospective smoking cessation program. Cancer. 2009;115(19):4636-44.
    4. Obedian E, Fischer DB, Haffty BG. Second malignancies after treatment of early-stage breast cancer: Lumpectomy and radiation therapy versus mastectomy. Journal of Clinical Oncology. 2000;18(12):2406-12.
    5. Park SM, Lim MK, Jung KW, Shin SA, Yoo K-Y, Yun YH, et al. Prediagnosis smoking, obesity, insulin resistance, and second primary cancer risk in male cancer survivors: National Health Insurance Corporation Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007;25(30):4835.
    6. Van Den Belt-Dusebout AW, De Wit R, Gietema JA, Horenblas S, Louwman MWJ, Ribot JG, et al. Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer. Journal of Clinical Oncology. 2007;25(28):4370-8.
    7. Warren GW, Kasza KA, Reid ME, Cummings KM, Marshall JR. Smoking at diagnosis and survival in cancer patients. International Journal of Cancer. 2013;132(2):401-10.
    8. Hooning MJ, Botma A, Aleman BMP, Baaijens MHA, Bartelink H, Klijn JGM, et al. Long-term risk of cardiovascular disease in 10-year survivors of breast cancer. Journal of the National Cancer Institute. 2007;99(5):365-75.
    9. Li CI, Daling JR, Porter PL, Tang M-TC, Malone KE. Relationship between potentially modifiable lifestyle factors and risk of second primary contralateral breast cancer among women diagnosed with estrogen receptor–positive invasive breast cancer. Journal of Clinical Oncology. 2009;27(32):5312-8.
    10. Kenfield SA, Stampfer MJ, Chan JM, Giovannucci E. Smoking and prostate cancer survival and recurrence. JAMA - Journal of the American Medical Association. 2011;305(24):2548-55.
    11. Joshu CE, Mondul AM, Meinhold CL, Humphreys EB, Han M, Walsh PC, et al. Cigarette smoking and prostate cancer recurrence after prostatectomy. Journal of the National Cancer Institute. 2011;103(10):835-8.
    12. Phipps AI, Baron J, Newcomb PA. Prediagnostic smoking history, alcohol consumption, and colorectal cancer survival: The Seattle Colon Cancer Family Registry. Cancer. 2011;117(21):4948-57.
    13. Kountourakis P, Correa AM, Hofstetter WL, Lee JH, Bhutani MS, Rice DC, et al. Combined modality therapy of cT2N0M0 esophageal cancer. Cancer. 2011;117(5):925-30.
    14. Waggoner SE, Darcy KM, Fuhrman B, Parham G, Lucci J, Monk BJ, et al. Association between cigarette smoking and prognosis in locally advanced cervical carcinoma treated with chemoradiation: A Gynecologic Oncology Group study. Gynecol Oncol. 2006;103(3):853-8.
    15. Schlumbrecht MP, Sun CC, Wong KN, Broaddus RR, Gershenson DM, Bodurka DC. Clinicodemographic factors influencing outcomes in patients with low-grade serous ovarian carcinoma. 2011. p. 3741-9.
    16. Nagle CM, Bain CJ, Webb PM. Cigarette smoking and survival after ovarian cancer diagnosis. Cancer Epidemiol Biomarkers Prev. 2006;15(12):2557-60.
    17. Ehlers SL, Gastineau DA, Patten CA, Decker PA, Rausch SM, Cerhan JR, et al. The impact of smoking on outcomes among patients undergoing hematopoietic SCT for the treatment of acute leukemia. Bone Marrow Transplant. 2011;46(2):285-90.
    18. Talamini R, Polesel J, Spina M, Chimienti E, Serraino D, Zucchetto A, et al. The impact of tobacco smoking and alcohol drinking on survival of patients with non-Hodgkin lymphoma. International Journal of Cancer. 2008;122(7):1624-9.
    19. Toll B, Brandon T, Gritz E, Warren G, Herbst R. AACR Subcommittee on Tobacco and Cancer. Assessing tobacco use by cancer patients and facilitating cessation: an American Association for Cancer Research policy statement. Clin Cancer Res. 2013;19:1941-8.
    20. Arntzen A, Sandvold B. Hvordan veilede om røykeslutt? Sykepleien Forskning. 2010;5(3):182-90.
    21. Dresler CM. Is it more important to quit smoking than which chemotherapy is used? 2003. p. 119-24.
    22. Hsu CCT, Kwan GNC, Chawla A, Mitina N, Christie D. Smoking habits of radiotherapy patients: Did the diagnosis of cancer make an impact and is there an opportunity to intervene? J Med Imag Radiat Oncol. 2011;55(5):526-31.
    23. Richards J. Words as Therapy: Smoking Cessation. The journal of family practice. 1992;34(6):687-92.
    24. Cooley ME, Lundin R, Murray L. Smoking cessation interventions in cancer care: opportunities for oncology nurses and nurse scientists. Annual review of nursing research. 2009;27:243.
    25. Mazza R, Lina M, Boffi R, Invernizzi G, De Marco C, Pierotti M. Taking care of smoker cancer patients: a review and some recommendations. Annals of Oncology. 2010;21(7):1404-9.
    26. Waller LL, Weaver KE, Petty WJ, Miller AA. Effects of continued tobacco use during treatment of lung cancer. 2010. p. 1569-75.
    27. Peppone LJ, Mustian KM, Morrow GR, Dozier AM, Ossip DJ, Janelsins MC, et al. The Effect of Cigarette Smoking on Cancer Treatment-Related Side Effects. Oncologist. 2011;16(12):1784-92.
    28. Kuri M, Nakagawa M, Tanaka H, Hasuo S, Kishi Y. Determination of the duration of preoperative smoking cessation to improve wound healing after head and neck surgery. Anesthesiology. 2005;102(5):892.
    29. Krueger JK, Rohrich RJ, Mustoe TA. Clearing the smoke: The scientific rationale for tobacco abstention with plastic surgery. 2001. p. 1074-5.
    30. Nakagawa M, Tanaka H, Tsukuma H, Kishi Y. Relationship between the duration of the preoperative smoke-free period and the incidence of postoperative pulmonary complications after pulmonary surgery. Chest. 2001;120(3):705-10.
    31. Barrera R, Shi W, Amar D, Thaler HT, Gabovich N, Bains MS, et al. Smoking and timing of cessation: Impact on pulmonary complications after thoracotomy. Chest. 2005;127(6):1977-83.
    32. Mason DP, Subramanian S, Nowicki ER, Grab JD, Murthy SC, Rice TW, et al. Impact of Smoking Cessation Before Resection of Lung Cancer: A Society of Thoracic Surgeons General Thoracic Surgery Database Study. Annals of Thoracic Surgery. 2009;88(2):362-71.
    33. Gajdos C, Hawn MT, Campagna EJ, Henderson WG, Singh JA, Houston T. Adverse Effects of Smoking on Postoperative Outcomes in Cancer Patients. Ann Surg Oncol. 2012;19(5):1430-8.
    34. Alsadius D, Hedelin M, Johansson KA, Pettersson N, Wilderang U, Lundstedt D, et al. Tobacco smoking and long-lasting symptoms from the bowel and the anal-sphincter region after radiotherapy for prostate cancer. Radiother Oncol. 2011;101(3):495-501.
    35. Chen AM, Chen LM, Vaughan A, Sreeraman R, Farwell DG, Luu Q, et al. Tobacco smoking during radiation therapy for head-and-neck cancer is associated with unfavorable outcome. International Journal of Radiation Oncology Biology Physics. 2011;79(2):414-9.
    36. Eifel PJ, Jhingran A, Bodurka DC, Levenback C, Thames H. Correlation of smoking history and other patient characteristics with major complications of pelvic radiation therapy for cervical cancer. Journal of Clinical Oncology. 2002;20(17):3651-7.
    37. Bjarnason GA, MacKenzie RG, Nabid A, Hodson ID, El-Sayed S, Grimard L, et al. Comparison of Toxicity Associated With Early Morning Versus Late Afternoon Radiotherapy in Patients With Head-and-Neck Cancer: A Prospective Randomized Trial of the National Cancer Institute of Canada Clinical Trials Group (HN3). International Journal of Radiation Oncology Biology Physics. 2009;73(1):166-72.
    38. Browman GP, Wong G, Hodson I, Sathya J, Russell R, McAlpine L, et al. Influence of Cigarette Smoking on the Efficacy of Radiation Therapy in Head and Neck Cancer. The New England Journal of Medicine. 1993;328(3):159-63.
    39. Browman GP, Mohide EA, Willan A, Hodson I, Wong G, Grimard L, et al. Association between smoking during radiotherapy and prognosis in head and neck cancer: A follow-up study. Head Neck-J Sci Spec Head Neck. 2002;24(12):1031-7.
    40. Travis LB, Gospodarowicz M, Curtis RE, Clarke EA, Andersson M, Glimelius B, et al. Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease. Journal of the National Cancer Institute. 2002;94(3):182-92.
    41. Ford MB, Sigurdson AJ, Petrulis ES, Ng CS, Kemp B, Cooksley C, et al. Effects of smoking and radiotherapy on lung carcinoma in breast carcinoma survivors. Cancer. 2003;98(7):1457-64.
    42. Dresler CM, Gritz ER. Smoking, smoking cessation and the oncologist. 2001. p. 315-23.
    43. Balduyck B, Nia PS, Cogen A, Dockx Y, Lauwers P, Hendriks J, et al. The effect of smoking cessation on quality of life after lung cancer surgery. Eur J Cardiothorac Surg. 2011;40(6):1432-8.
    44. Hamilton M, Wolf JL, Rusk J, Beard SE, Clark GM, Witt K, et al. Effects of smoking on the pharmacokinetics of erlotinib. Clinical Cancer Research. 2006;12(7 I):2166-71.
    45. Helsedirektoratet. Forberedelse til røykeslutt 2011. Available from: http://helsedirektoratet.no/publikasjoner/forberedelser-til-roykeslutt/Publikasjoner/forberedelse-til-roeykeslutt.pdf   
    46. Brunnhuber K, Cummings KM, Feit S, Sherman S, Woodcock J. Putting evidence into practice: Smoking cessation: BMJ Publishing Group; 2007.
    47. Helsedirektoratet. Røyketelefonen 2013 [updated 12.12.201102.12.2014]. Available from: http://www.helsedirektoratet.no/folkehelse/tobakk/snus-og-roykeslutt/royketelefonen/Sider/default.aspx.
    48. Legemiddelverk S. Legemidler A-Å 2013 [02.12.2014]. Available from: http://www.legemiddelverket.no/Legemiddelsoek/Sider/Legemidler_A-AA.aspx.
    49. Hughes JR, Stead LF, Lancaster T, Rev CDS. Antidepressants for smoking cessation. Cochrane Database of Systematic Reviews: Reviews 2007. 2014 (1).
    50. Stead LF, Perera R, Bullen C, Mant D, Hartmann-Boyce J, Cahill K, et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2012;11(11).
    51. Cahill K, Stead LF, Lancaster T, Polonio IB. Nicotine receptor partial agonists for smoking cessation. Sao Paulo Med J. 2012;130(5):346-7

    Follow-up care after treatment of thyroid cancer

    The center responsible for treatment is also responsible for follow-up of the patient. This should be in collaboration with the primary care doctor.

    A risk assessment is performed at least six months after treatment is concluded and is based on:

    • the physical exam
    • results from the image testing
      • post therapy scan
      • ultrasound of the neck
      • eventually CT/MR of the thorax, and in some patients PET
    • stimulated Tg in TgAb nevative patients

    Risk assessment after completing primary treatment is very important in choosing the long-term follow-up plan.

    The low risk group is defined as patients:

    • without metastasis at diagnosis
    • with tumors less than pT3 at diagnosis
    • without a low differentiated histology at the primary diagnosis
    • who have had adequate surgery and radioablation
    • without sign of disease at the follow-up examination 6-12 months after primary treatment (including stimulated Tg < 0,2 µg/l)
    • who have not been previously irradiated to the throat

    Patients who do not fit into the low risk group are considered high risk patients.

    Patients with advanced disease at the time of the diagnosis have more frequent follow-up checks than patients in the low risk group, even if both groups are classified as low risk after treatment. 

    All patients who have had a thyroidectomy will either have suppression treatment or substitution treatment with thyroid hormones, and must have life-long follow-up with at least an annual monitoring of s-TSH, s-FT4 and s-calcium.

    Low risk patients without thyroglobulin-antibodies (total thyroidectomy)

    The follow-up plan for low risk patients without thyroglobulin-antibodies is available in an interactive flow chart, which provides overview of follow-up for different patient groups.

    Click here to open the flow chart:

    Hemithyroidectomy patients

    Patients having a hemithyroidectomy have a follow-up yearly with Tg testing. The Tg value must be monitored closely. The baseline value may be measurable (up to 10 µg/l, rarely higher). An elevation may be due to cancer or a change in normal remaining gland tissue, and will depend on the TSH level.

    A clinical examination and ultrasound of the neck should be performed every 2-3 years.

    Conditions requiring other types of follow-up testing

    Increasing Tg

    With an elevated Tg (stimulated or unstimulated), Tg and TgAb must be monitored in combination with FT4 and TSH. An ultrasound of the neck should also be performed. Radioactive iodine is given as a diagnostic scan, or possibly as a direct therapy dose. A thoracic CT is done and possibly a PET/CT directly.  

    Low risk patient with TgAb

    These patients, as long as they are TgAb positive, must be examined with:

    • measurement of Tg and TgAb
    • ultrasound
    • rhTSH or endogenous stimulated whole body scintigraphy (WBS)
    • CT thorax, possibly PET/CT

    Uptake outside the thyroid bed on whole body scintigraphy after ablation dose

    Patients with uptake outside the thyroid bed on the post ablation scan must have further testing. An ultrasound, CT, MRI, and possibly PET/CT are taken to ensure localization of metastases/cancer remains for surgery, or radioactive iodine therapy if surgery is not possible. PET/CT scan should be performed stimulated.

    Tg positive -  radioactive iodine-negative patients

    Patients with an elevated Tg level in the blood but no iodine uptake on whole body scintigraphy have a high probability of cancer remains/metastases that are not concentrating iodine. These pose a diagnostic and therapeutic challenge.   

    An explanation of the lack of iodine uptake is that the disease has dedifferentiated and lost its ability of iodine accumulation. These patients therefore require further testing with ultrasound, CT, PET, and possibly MRI to localize the disease and to evaluate for treatment (surgery, possibly external radiation therapy). Metastatic foci that are smaller than the resolution of the camera may also be present. In these cases, Tg will rise 3-5 days after radioactive iodine therapy, and Tg will fall after each treatment with radioactive iodine.  

    Pregnancy after primary treatment

    If the patient is planning on becoming pregnant, differentiated thyroid carcinoma is not a contraindication. However:

    • it is not recommended to become pregnant before treatment is completed and the planned therapy doses are given
    • one year should pass from the last radioactive iodine ablation/therapy dose
    • thyroid hormones should be stable

    It is very important for fetal development that thyroid hormones are optimal and stable through the entire pregnancy. The need for thyroxine increases during pregnancy, mostly in the first half (10-80% increase), but in those undergoing suppression treatment, it is normally not necessary to increase the dosage. Pregnant patients must be monitored closely through the entire term. Both overdosing and deficiency of thyroxine is harmful to the fetus.

    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

    Positron Emission Tomography (PET)

    General

    Positron Emission Tomography (PET) is a nuclear medical examination method. PET is a well-documented, well-established and very useful tool in oncological imaging.

    Indications

    Oncological imaging for:

    • Staging the primary diagnosis and recurrence
    • Evaluating the effect of aggressive chemotherapy treatment
    • Evaluating the effect of completed treatment, including differentiating scar tissue from viable residue tissue
    • Suspicion of recurrence (for example, increased level of tumor marker in the blood)

    Goal

    • To provide concrete diagnostic information that will provide a basis for the choice of the best possible treatment.

    Definitions

    PET has a very high sensitivity and can register absorption of radiopharmaceutical agents in extremely low concentrations. Since the central atoms in biochemical compounds (carbon, oxygen, nitrogen) all have positron-emitting isotopes that can be produced in small hospital cyclotrons, it is possible to mark a number of central molecules such as oxygen, water, amino acids, various metabolites, hormones, and neurotransmitters.

    For clinical PET, dextrose is usually used where a hydroxide group is replaced by 18F (18-flourine), a compound that is called 18F-FDG (flourine-18 labeled deoxyglucose). 18F-FDG has a high affinity for cells with increased metabolism, for example cancer cells. The substance is transported into the cells and phosphorylates glucose to 18F-FDG-phosphate, but no further break-down occurs. Because cell membranes are impermeable to phosphorylated deoxyglucose, an intracellular accumulation of the substance occurs.

    Limitations

    • Small tumors ( < 0,5 cm) and tumors with low to moderate absorption can escape detection.
    • Inflammatory conditions will produce increased absorption.
    • For patients with diabetes (especially those requiring insulin) and non-fasting patients, high muscular absorption will reduce the sensitivity for tumor detection.
    • Some tumor types have low FDG absorption (for example, prostate and bronchoalveolar carcinoma).

    Sources of error

    • Infections and inflammatory conditions (including post-operative changes) will result in increased absorption.
    • Normally, the intestine can have a high absorption.
    • Myocardium often displays high absorption, also in fasting patients.
    • 18 F-FDG is excreted through the kidneys and FDG in the urinary tract can be misinterpreted.
    •  Absorption in brown fat tissue can be misinterpreted as a tumor if PET is not compared with CT. PET/CT combined in the same apparatus gives better specificity than PET alone.

    Equipment

    • PET/CT-scanner  
    • Radio-pharmaceutical agent: 18F-FDG is formed by radiating a heavier natural variant of oxygen with protons. This occurs in a cyclotron. Fluorine-18 (18F) is produced at the hospital cyclotron located at Rikshospitalet .

    Preparation

    Patient preparation depends on the clinical diagnosis.

    • Fast for at least 6 hours before the examination in order to increase the absorption of 18F-FDG. But the patient should drink plenty (2-4 glasses per hour. Water, tea, or coffee without sugar or cream/milk added can be substituted for water.
    • Measurement of s-glucose is performed before injection of 18F-FDG.
    • After intravenous injection of 18F-FDG, it is very important that the patient lies relaxed in a quiet room without talking and avoiding all forms of stimuli, in order to avoid non-specific absorption of 18F-FDG in the muscles.
    • Tranquilizers and painkillers are often administered prior to the injection.
    • The patient should be warm and comfortable prior to the injection in order to prevent absorption in the brown fat, which may affect the interpretation.

    There will be other precautions for neurological and cardiological diagnoses.

    Implementation

    • The patient must lie completely still while the images are being taken.
    • A whole-body examination takes approximately 25 minutes.
    • For PET, tissue absorption is displayed by positron-emitting, radiopharmaceutical preparations.

    Registration of emission

    • The positron is considered a positively charged electron.
    • When the positron leaves the radioactive core, it will travel up to a few millimeters before it collides and fuses with an electron and is transformed into energy; this is called annihilation.
    • The mass of the positron and the electron is transformed into energy in the form of two photons, each of 511 keV, which are emitted in diametrically opposing directions (180°).
    • A ring detector around the patient will catch the photons.
    • The two photons will encounter the ring detector at the same time (coincident detection), and because they have moved in exactly opposite directions, the detection will precisely localize the radiation focus (for example, a lymph node with tumor tissue).
    • A modern PET-camera with ring detector can map the entire body in 20 minutes.
    • The PET-scanners have integrated CT, so that the information from PET is accurately localized anatomically.

    Examples of findings

    • Anal cancer: Anal tumor and metastasis in lymph node
    • Hodgkin's lymphoma (HL): HL with involvement of: soft tissue in the larynx , vertebra L4 ,  os pubis L  and femur
    • Cancer of the rectum: Adenocarsinom in rektosigmoideum liver metastases
    • Intracranial tumors: Astrocytoma grade II/III, left parietal lobe  high-grade glioblastoma, right frontal lobe 
    • Lung cancer: Lung tumor  lung cancer with lymph node spread
    • Sarcoma: Soft tissue sarcoma in the left thorax
    • Cancer in the esophagus: Tumor in the distal esophagus
    • Colon cancer: Metastasis-suspect lesion in adrenal gland

    Follow-Up

    • At the end of the examination, the radioactivity is small, but the patient should keep a distance (about 3 meters) from children and pregnant ladies the day of the scan.
    • The result will normally be available the following day.
    Postitron emission (PET) with <sup>18</sup>F-FDGPostitron emission (PET) with <sup>18</sup>F-FDGPostitron emission (PET) with <sup>18</sup>F-FDGPostitron emission (PET) with <sup>18</sup>F-FDG
    Postitron emission (PET) with <sup>18</sup>F-FDGPositron emissions tomografi (PET) with <sup>18</sup>F-FDGPositron emission tomography (PET) with <sup>18</sup>F-FDGPositron emission tomography (PET) <sup>18</sup>F-FDG
    Positron emission tomography (PET) with <sup>18</sup>F-FDGPositron emission tomography (PET) <sup>18</sup>F-FDGPositron emission tomography (PET) with <sup>18</sup>F-FDGPostitron emission (PET) with <sup>18</sup>F-FDG
    Postitron emission (PET) with <sup>18</sup>F-FDGPostitron emission (PET) with <sup>18</sup>F-FDGPostitron emission (PET) with <sup>18</sup>F-FDGPostitron emission (PET) with <sup>18</sup>F-FDG
    Positron emmissions tomography (PET) with<sup>18</sup>F-FDGPositron emission tomography (PET) with <sup>18</sup>F-FDGPositron emission tomografi (PET) with <sup>18</sup>F-FDG