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Utskriftsdato (27.6.2017)

Bladder cancer

Ninety-five percent of all malignant diseases of the urinary tract originate from the urothelium (2).

The urinary tract lined with urothelium (transitional cells) includes calyses, renal pelvis, ureters, urinary bladder and upper urethra.

Urothelial cancer occurs most frequently in the bladder. Primary urothelial cancer in the urethra is rare. Urothelial cancer in the urethra is often secondary to cancer originating in the bladder, which grows down into the urothelium in the upper part of the urethra. 

Urothelial cancer is often multifocal and the disease is considered a general disease of all the urothelium. It is a heterogenous disease that varies in aggressiveness, which plays a significant role for the choice of treatment and follow-up care. The disease is easy to diagnose when localized to the bladder, and has a high cure rate, but also a high rate of recurrence.

Usually, urothelial cancer arises from a malignant transformation of cells in an apparently normal-looking urothelium (carcinoma in situ). Depending on the malignancy potential of these primary cells, they can form papillomatous tumors that do not infiltrate for a long time. Papillomatous tumors do not usually cause early symptoms of hematuria. Tumors that grow solid and nodular usually begin to infiltrate from an early stage. Flat infiltrating carcinoma in situ is a tumor type that does not necessarily appear like a tumor, but can metastasize without the patient having noticeable hematuria.   

Incidence

Bladder cancer represents 4.6% of all new cancer cases in the United States and is more common in men than women. Bladder cancer becomes more common with age and is more frequently diagnosed among people aged 75-84. In 2017, it is estimated to be 79,030 new cases of bladder cancer in the United States (4).

 

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

Source: Cancer Registry of Norway

 

 

Incidence of urothelial cancer, 1954–2013.

Source: Cancer Registry of Norway

 

Etiology of bladder cancer

In most cases, the cause of urothelial cancer is unclear. However, it is known that this cancer type was previously an occupational disease associated with certain chemical industries before environmental policies were adapted, mostly in the paint and color industry.

Certain medications are suspected to have a detrimental effect on developing urothelial cancer. Molecular biology techniques have identified mutations on chromosome 9 and 17, as significant etiological and prognostic factors for developing urothelial cancer (2).

Carcinogens 

It is likely that different types of pollution contain carcinogens that are excreted in urine and involve urothelial cells, causing mutations. The bladder, where urine is stored the longest, is clearly the most frequent location for primary tumors. 

Smoking

Urothelial cancer is diagnosed most often in people who smoke or were smokers. In heavy smokers, aggressive urothelial cancer occurs more frequently (6).

Chronic irritation/infections

Chronic irritation of the urothelium due to calculi and chronic infections (especially Bilharzia) can develop into cancer. In these cases, squamous epithelial cancer develops (2).

Previous radiation therapy/chemotherapy 

Patients who, at a young age, had radiation therapy to the bladder region as part of treatment of another cancer type (sarcoma, testicular cancer, gynecological cancers) have an increased risk of developing bladder cancer in the long run (1).

Histology of bladder cancer

Tumors found in the urinary tracts are classified according to WHO/ISUP 2004 guidelines (5). More than 99 % of the tumors found in the urinary tracts originate from the urothelium, which covers mucosa of the calyses, renal pelvis , ureters, urinary bladder and the upper part of the urethra.

Benign tumors are uncommon; urothelial papillomas may be papillary or inverted . Infection with the Human Papillomavirus may cause squamous cell papillomas .

More than 95% of urothelial tumors are malignant and are known as urothelial carcinomas. They are either non-invasive and papillary, or invasive (images 1 and 2).

Image 1: Low-grade, papillary non-invasive carcinoma. Click to enlarge.
Image 2: High-grade invasive urothelial carcinoma. Click to enlarge. 

Different variants of urothelial carcinomas exist (images 3,4) and some of these are very aggressive (micropapillary and sarcomatoid type). High-grade urothelial carcinomas can have both squamous differentiation and glandular differentiation. Primary adenocarcinomas in the bladder occur, which are often associated with intestinal metaplasia in the urothelium and adenocarcinoma in situ . Adenocarcinomas originating from embryonal remains in the urachus often produce mucus. 

Primary squamous cell carcinomas in the bladder are uncommon in Norway, but do occur in patients with chronic infections and keratinizing squamous metaplasia in bladder mucosa. In countries with endemic infections with Schistosoma haematobium, squamous cell carcinomas in the bladder are much more common . Small-cell carcinomas in the bladder are very aggressive tumors. This diagnosis is confirmed by immunohistochemistry . Correct classification of this tumor type is crucial because patients are treated primarily with chemotherapy and not surgery.

Image 3: Photomicroscopic image of micropapillary urothelial carcinoma. Click to enlarge.
Image 4: Photomicroscopic image of urothelial carcinoma, sarcomatoid type. Click to enlarge. 

Tumors occuring in supporting connective tissue are uncommon (images 5-8); they may be benign (leiomyoma) or malignant (sarcomas of different types). Malignant tumors which occur in lymphoid tissue are called lymphomas; these can originate primarily in the urinary tracts, but are uncommon. Metastases occur also in the urinary tracts despite the more common direct invasion from malignant tumors into adjacent organs (prostate, uterus or rectum). 

Image 5: Photomicroscopic image of leiomyosarcoma of the urinary bladder. Click to enlarge.
Image 6: Photomicroscopic image of leiomyoma of the urinary bladder. Click to enlarge.

 

Image 7: Specimen from a radical cystectomy of the urinary bladder with leiomyosarcoma. Click to enlarge.
Image 8: Photomicroscopic image of leieomyosarcoma of the urinary bladder. Click to enlarge.

Histological diagnostics 

If the patient has hematuria with suspicion of a urinary tract tumor, the diagnosis must be verified by histological diagnostics before treatment is started. The pathologist plays a key role in diagnosing tumors of the urinary tracts. The pathologist must inspect the tissue samples and surgical specimens by microscopy to determine whether the tumor is benign or malignant, as well as the malignancy potential. It is also necessary to confirm whether the tumor in the urinary tracts represents spread from other tumors. Typing, grading and description of extent of tumor spread is time-consuming and of great significance for choice of treatment and the patient's prognosis. The pathologists work together in a team, and there are often multiple pathologists assessing the tissue sample before the final diagnosis is made. Additional analyses such as immunohistochemical and molecular analysis may be necessary to sub-classify the tumor. The diagnosis is made on mucosal biopsies from the urinary tract taken by cystoscopy, TUR-B or larger surgical specimens .

Mucosal biopsies from the bladder 

The urologist may take selected mucosal biopsies from the bladder to determine pre-stages (dysplasia and carcinoma in situ) for classification of small tumors or to detect recurrence of tumors . Mucosal biopsies rarely contain tissue from the bladder wall musculature, which inhibits staging of infiltrating carcinomas.

Transurethral Bladder Resection (TUR-B)

With this procedure, much more tissue of the bladder and urinary tracts can be examined. The urologist shaves away tumor tissue with laser via a cystoscope. The pathologist receives multiple tissue samples preserved in formalin. After fixation, the material is weighed and random shavings are cast for examination with a photomicroscope (up to 8 blocks). When the pathologist examines these shavings using a photomicroscope, the presence of papilloma, carcinoma, or carcinoma in situ in flat mucosa is indicated. The type and grade of tumor tissue must also be determined. The pathologist must also indicate if there is infiltration of the lamina propria and muscularis propria. In some instances, there may be too much thermal damage and the pathologist is not able to make a reliable diagnosis . If infiltrating carcinoma is present and the material lacks muscle from the bladder wall, a new tissue sample must be taken from the tumor area (TUR-B) before final staging can be done.

Partial or radical cystectomy

Patients with carcinoma in situ, high-grade and muscle-invasive carcinomas are candidates for partial or radical cystectomy. In men, the bladder is removed with surrounding adipose tissue, the prostate, and seminal vesicles. In women, the uterus as well as both ovaries, fallopian tubes and parts of the vagina are removed. 

If there is carcinoma in situ, the pathologist will often not see any changes in the bladder mucosa (image 9). Bladder carcinomas may grow exophytic (image 10) or infiltrating (image 11) and they may originate from bladder diverticula .

The pathologist removes many sections from the bladder wall with surrounding tissue to investigate the extent of the tumor. The pathologist will then determine the type of tumor, whether the tumor has infiltrated the bladder wall and into adipose tissue, the status of the resection renders, and the presence of growth into vessels or spread to lymph nodes or adjacent organs. 

Image 9: Specimen from a radical cystectomy without visible tumor tissue. Click to enlarge.
Image 10: Specimen from a radical cystectomy with papillary bladder cancer. Click to enlarge.
Image 11: Infiltrating bladder carcinoma. Click to enlarge.

Grading

In 2004, a new grading system was introduced for urothelial tumors (WHO/ISUP) (5,6). This system includes a new category of papillary urothelial neoplasm of low malignant potential (PUNLUMP - see table). These tumors have a thicker, more disorderly urothelium with mild nuclear pleomorphia compared to papillomas, but not as pronounced nuclear atypia as observed in the low-grade non-invasive urothelial carcinomas. High-grade urothelial carcinomas have a thickened, disordered urothelium with moderate to severe nuclear atypia over the entire thickness of the urothelium, with increased amount of mitoses high up in the urothelium.

The new classification system is now used by all pathology laboratories in Norway (7). The hope is that the new system will facilitate in diagnosing malignant tumors with good versus poor prognoses and provide grounds for choice of treatment strategies. It has been important to reduce the amount of tumors which were previously classified as WHO grade 2, which have been a very heterogeneous group. The morphological criteria are now better characterized than previously. Some of the tumors that were previously classified as WHO grade 2 are now graded as low-grade, while some are graded as high-grade (see table). Pathologists no longer differentiate between tumors having moderate and severe nuclear atypia; they are now classified as high-grade. Pre-stages are not graded; they are separated into low-grade dysplasia and carcinoma in situ (which are are no longer graded) (5,6,8).

 

Grading of Urothelial Tumors (click to enlarge images)

WHO 1973
(old classification)

 

WHO/ISUP 2004
(new classification)

Papilloma

Papilloma

Urothelial carcinoma grade 1

Papillary urothelial neoplasm 
of low malignant potential
(PUNLUMP)

Urothelial carcinoma grade 1

Urothelial carcinoma grade 2

Low-grade urothelial carcinoma

Urothelial carcinoma grade 2

Urothelial carcinoma grade 3

High-grade urothelial carcinoma

 

Metastatic patterns of bladder cancer

In principle, urothelial cancer at all stages can metastasize to other organs. The most malignant (grade 3) metastasize earlier than grade ≤ 2. An advanced stage local tumor (T ≥ 2) metastasizes more frequently than superfical tumors (T ≤ 1).

WHO grade 1 tumors can become large and infiltrate locally. They have a great tendency for recurrence, but almost never metastasize to other organs.

WHO grade 2 tumors grow slowly locally, but infiltrating into mucosa (T1) and further through the basal membrans and into the bladder muscle, through this and out into adipose tissue or into neighboring organs (T ≥ 2). A grade 2 tumor can cause spread when it becomes infiltrating (T ≥ 1), but the risk of metastases usually increases only when it infiltrates muscle. The deeper infiltration of the local tumor, the higher frequency of metastases.

A WHO grade 3 tumor is the most aggresive tumor type and almost always infiltrates (T ≥ 1) at the time of diagnosis. This tumor does not necessarily become very large, but quickly infiltrates the bladder wall and neighboring organs. It spreads early to both regional lymph nodes and distant metastases. Metastases occur hematogenously to pelvic and retroperitoneal lymph nodes with distant spread to the lungs, bone, and liver. 

Metastasis occurs hematogenously to all organs, most frequently the lungs, liver, bone, or lymphatically to regional lymph nodes in the pelvis, or further to retroperitoneal lymph nodes.

Staging of bladder cancer

The T stage describes the extent of the tumor in the wall of the organ, depth of infiltration in the urinary bladder, ureter, and renal pelvis wall. The T classification is differentiated into clinical T stage (T), which is clinically diagnosed (with endoscopy, palpation, image diagnostics) and histopathological pT classification. In principle, the pathological stage (pT) can only be given after a histological examination of a cystectomy specimen, but a specimen from a transurethral resection will provide the pT stage for superfical tumors (≤ T1), as long as muscularis mucosa in included in the specimen.

The N stage describes whether there is metastasis to lymph nodes and how extensive the spread is. N0 and M0 indicate that distant metastasis has not been found.

 

 

 

 

TNM tumor classification for urinary bladder (13)
T/N category  Depth of growth (T)/size (N) 

Ta

Tis

T1

Non-infiltrating papillary

In situ (intraepithelial): "Flat tumor"

Infiltration of submucosal connective tissue (lamina propria)

T2

T2a

T2b

Muscle infiltration (muscularis propia)

Inner half

Outer half

T3

T3a

T3b

Infiltration of perivesical fat

Microscopically

Macroscopically (extravesical mass)

T4a

T4b

Tumor invades prostate, uterus, or vagina

Tumor invades pelvic wall or abdominal wall (fixed tumor)

N1

N2

N3

Solitary lymph node ≤ 2 cm

Solitary lymph node > 2 cm < 5 cm, or multiple ≤ 5 cm 

 > 5 cm

 

TNM classification of tumor in the renal pelvis and ureter

For tumors in the renal pelvis and ureter, the following are used: Ta, Tis, T1, T2, T3, T4, N1, N2 and N3.

Symptoms of bladder cancer

The most common tumor types in the bladder cause early symptoms, and the bladder is easily accessible for endoscopic examination and treatment. Ten percent of patients with bladder cancer develop urothelial cancer in other parts of the urinary tract. 

Urothelial cancer in the ureter and renal pelvis is not as easy to diagnose, and symptoms may occur later in the disease course. Cancer in this area is therefore often diagnosed at a later stage. 

When the tumor is localized in the bladder, the main symptoms are macroscopic hematuria, with or without different types of problems micturition. When the tumor is localized in the upper urinary tracts, colicky pain is the dominating symptom, in addition to hematuria. 

When urothelial cancer is advanced, the patient may also have colic pain and symptoms from already existing metastases such as back pain and weakened general health. 

 

Differential diagnoses of bladder cancer

Most symptoms from the urinary tract are caused by benign conditions. There are no specific cancer symptoms.

Patients with macroscopic hematuria without other symptoms are tested for malignant tumors, but this may also be due to:

  • bleeding from vessels in the prostate from benign prostate hyperplasia (BPH)
  • renal pelvic calculi
  • bladder calculi
  • kidney cancer with infiltration to renal pelvis
  • microhematuria from chronic kidney/urinary tract infections

Problems urinating are common from:

  • cystourethritis - many of these symptoms can occur from BPH
  • hormone-related dysuria in women during/after menopause

 

Prognosis of bladder cancer

Normal development and prognosis for urothelial cancer depends on the malignancy grade of the tumor (WHO grade).

Grade 1 tumor

Grade 1 tumors have a weak propensity to invade and metastasize, but grow exophytically and can become very large. The tumor can grow so large that it can fill the entire urinary bladder and obstruct urine from the ureters and bladder. The tumor can also be localized to the renal pelvis or ureters and obstruct these organs. This type of tumor usually causes periodic macrohematuria. A grade 1 tumor can change malignancy grade and become more agressive.

Grade 2 tumor

Grade 2 tumors can grow exfoliative and cause symptoms from the growing tumor occuing the bladder. All grade 2 tumors will infiltrate into the wall of the organ of origin, penetrate this, and infiltrate into neighboring organs (the pelvic wall (bladder), and retroperitoneal tissue (ureter/renal pelvis)). If left untreated, they will metastasize to lymph nodes and other organs (lungs, bone, liver, and others).

Grade 3 or undifferentiated tumor

Grade 3 tumors rarely grow exfoliative. They are highly malignant, grow infiltrative, and metastasize early.

In addition to WHO grading, the prognosis for patients with urothelial cancer depends on the TNM stage and whether the primary disease is multifocal. 

Superficial  (pT ≤ 1)

Superficial urothelial cancer has a 30% chance of developing muscle infiltration within 5-10 years after primary treatment, all WHO grades combined. The frequency of recurrence is about 70% after treatment. This requires resources for follow-up and detect recurrences as early as possible. Primary multifocal disease has a higher chance of recurrence than primary solitary disease.

Prognostic factors for recurrence are:

  • high histological malignancy grade
  • multiplicity of the tumors
  • presence of carcinoma in situ/dysplasia in surrounding urothelium 

Muscle infiltrating (pT ≥ 2)

Five year survival after radical treatment is 40–60%, and has not changed significantly in later years. The use of preoperative radiation or chemotherapy has not changed these numbers. 

The prognosis depends on:

  • the T-stage
  • tumor size > 7 cm
  • tumor invasion in small blood and lymphatic vessels
  • high malignancy grade (WHO grade 3)

In 2014, there were an estimated 696,440 people living with bladder cancer in the United States. The earlier bladder cancer is caught, the better chance a person has of surviving five years after being diagnosed. 34.4% are diagnosed at the local stage and the 5-year survival for localized bladder cancer is 70.2%. The number of bladder cancer deaths is highest among people aged 75-84. Death rates have been stable over 2005-2014 (4).

 

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

Source: Cancer Registry of Norway

 

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References on bladder cancer

  1. EAU Guidelines on Non-muscle-invasive Bladder Cancer, 2015,  M.babjuk (chair) et al.
  2. Nasjonalt handlingsprogram med retningslinjer for diagnostikk behandling og oppfølging av blærekreft (2013), Helsedirektoratet (National guidelines for diagnostic, treatment and follow-up care of bladder cancer, Norwegian Directorate of Health)
  3. TNM Atlas. Illustrated Guide to the TNM/pTNM Classification of Malignant Tumours. 7th Edition 2009.
  4. Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2014, National Cancer Institute. Bethesda, MD 
  5. Lopez-Beltran A, Sauter G, Gasser T, et.al., Tumours of the Urinary System. In Eble JN, Sauter G, Epstein JI, Sesterhenn IA (eds). WHO Classification of Tumours: Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. Lyon: IARC Press, 2004.
  6. Murphy WM, Grignon DJ and Perlman EJ. ATIP Atlas of Tumor Pathology. Series 4. Tumors of the kidney, bladder and related urinary structures. AFIP, Washington DC 2004.
  7. Epstein JI, Reuter VE and Amin MB. Biopsy interpretation of the bladder. Lippincott Williams & Wilkins, 2.ed. 2010

Diagnostics of bladder cancer

Diagnostics and work-up for urothelial cancer is based on specific symptoms causing suspicion of a tumor.

Patient anamnesis

The patient's anamnesis and physical examination will decide the further investigation strategy.

A change in urination pattern, such as imperious urination, or pollakisuria should be investigated on patients over 45 to 50 years. In women, urothelial cancer is usually more advanced when diagnosed. This is because hormonal changes cause changes in urination, which is a relatively common problem in women of this age group, and may delay the diagnosis.  

Urine testing

  • Urine stick supplemented with microscopy of the urine pathology is present 
  • Urine cytology x 2
  • Test for bacteria if there is suspicion of associated infection

In 85% of cases, the patient seeks medical help for hematuria, often as a single symptom. If hematuria is macroscopic, urothelial cancer should be suspected. If hematuria is present, without finding cancer or other cause for this, the patient should be considered for further consultations. 

If the patient has microscopic hematuria with < 3–5 red blood cells per visual field, and without other additional symptoms from the urinary tracts, the probability of finding cancer is so small that further examination is not indicated. If the patient has additional symptoms such as dysuria, pollakisuria, urgency, or urinary tract infection, further investigations must be considered.  

If malignant cells are detected in urine and the findings are normal from cystoscopy and possibly CT urography, a bilateral ureter catheterization with collection of urine from each side should be performed. The urine is collected selectively form the renal pelvis and distal ureter. This catheterization is an attempt to localize the malignant cells and may be supplemented with ureteropyeloscopy. 

Endoscopy

If the patient has symptoms and/or findings which indicate urothelial cancer, cystoscopy is carried out. In most cases, cystoscopy reveals tumor changes in the urinary bladder. Detection may be less certain in cases of carcinoma in situ (CIS).

A biopsy from visible tumors is unnecessary during simple cystoscopy under local anesthesia. A biopsy must be taken under general anesthesia to assess the depth of growth and stage. A biopsy under local/superfical anesthesia should only be carried out if changes identified by endoscopy are uncharacteristic for malignancy. PDD (Photo Dynamic Diagnostics) has been employed.

Image diagnostic examinations

Urothelial cancer is considered a disease general disease of the urinary system. It therefore should obligatory to examine the upper urinary tracts by imaging (urography or CT urography).

For muscle-infiltrating cancer (T ≥ 2), bone scintigraphy, abdominal CT, and thoracic X-ray should be done with regard to indication for multimodal treatment.

  • CT urography is used for tumors in the bladder, upper urinary tracts, as well as for hydronephrosis. Larger tumors are seen as defects in the contrast medium. Hydronephrosis may indicate a ureter tumor or muscle-infiltrating cancer in the bladder with ureter involvement.
  • MRI are used for investigation of invasive tumors and evaluation of lymph nodes in the pelvis and retroperitoneum. MRI after TUR-B may cause overstaging of a tumor due to TUR-induced perivesical changes.
  • The benefit of routine bone scintigraphy before radical treatment of infiltrating cancer is uncertain, with the exception for when the patient has elevated alkaline phosphatase in serum and/or has skeletal symptoms. MRI may clarify uncertain findings from bone scintigraphy or skeletal symptoms. 
  • If the conclusion is still uncertain, ureteroscopy should be considered.

Specific examinations for urothelial cancer

Bladder cancer

Most bladder cancers are easily diagnosed with cystoscopy. By examination under superficial anesthesia, it is relatively simple to biopsy with regular cold biopsy forceps to verify malignancy, but the test should be done preferably under general anesthesia/spinal anesthesia. The biopsy is taken with a resectoscope loop deep into the bladder muscle under the tumor, such that a histopathological assessment of depth infiltration (pT) can be made. 

The final work-up of bladder cancer is painful, and the patient should be examined under general anesthesia. This is because diagnostic biopsies are taken in consideration for the WHO grade, as well as deep biopsies to assess depth infiltration (T stage), and digital exploration to assess the clinical T stage. 

  • Carcinoma in situ in the bladder (Tis) may be difficult to diagnose with regular cystoscopy applying white light. Cystoscopy with photodynamic diagnostics (PDD) may be useful. 
  • Before the treatment plan can be made, an exact stage determination is necessary. CT and  MRI of the pelvis are performed as a routine for evaluation of T-stage.

Urethral cancer

The examinations for urethral cancer are more or less the same as for bladder cancer. Most cancers in the prostatic urethra are found in association with bladder cancer. It is therefore sensible for the evaluation of bladder cancer to take biopsies of mucosa from the upper part of the urethra, even if the mucosa appears normal on endoscopy.  

Renal pelvis/ureter cancer

Small tumors in the upper urinary tracts seldom cause symptoms other than hematuria. If no explanation for the hematuria can be found, the renal pelvis/ureters must be examined with urography (preferably CT urography). If defects in the contrast image or other X-ray findings are identified, such as strictures or hydronephrosis, an ureteroscopy should be performed. 

If maligant cells are present despite normal conditions in the bladder/urethra on cystoscopy, as well as normal upper urinary tracts on X-ray, then urine is collected selectively from both urethers via urether catheters. The best information is obtained by collecting urine from different levels (renal pelvis, middle and distal urethers). If malignant cells are found in the renal pelvis or ureters, the examination is supplemented with ureteroscopy.

PROSEDYRER

Cystoscopy with photodynamic diagnostics (PDD)

General

Hexaminolevulinate is a pharmaceutical product developed for diagnosing urothelial cancer in the bladder, and is used in combination with cystoscopy. An instillation of hexaminolevulinate before cystoscopy will identify changes in the urothelium by showing a change in color of the urothelium. This examination is called photodynamic diagnostics (PDD). 

There is very little toxicity associated with this substance.

Indications

  • Examination for superficial urothelial cancer of the bladder, especially for suspected cancer in situ in patients with confirmed or suspected urothelial cancer.
  • Monitoring of high risk patients
  • Support for TUR-B in special cases

Goal 

  • Diagnostics (better sensitivity for detection of cancer in situ)
  • Monitoring (more accurate for detection of recurrence)
  • Support during treatment (TUR-B)

Equipment

  • Catheterization set 
  • Hexaminolevulinate kit containing 85 mg powder and 50 ml fluid for dilution
  • Laparoscopy rack
  • CE brand cystoscopy equipment with necessary filter to allow both standard cystoscopy with white light and cystoscopy with blue light

Preparation

  • Prepare instruments for sterile catheterization. 
  • Prepare the hexaminolevulinate solution. The hexaminolevulinate powder is mixed together with fluid to prepare a solution. Each glass bottle of powder contains 85 mg of hexaminolevulinate in the form of 100 mg hexaminolevulinate hydrochloride.
  • Transfer 50 ml of the solution to a sterile 50 ml syringe. Add about 5 ml of the fluid to the glass bottle containing the powder.
  • Carefully shake the bottle to dissolve the powder.
  • Transfer the solution back to the 50 ml syringe and carefully mix. 
  • Add about 5 ml of the solution from the syringe to the glass bottle again and then aspirate the solution, repeating two more times. Check to make sure all the powder is transferred to the syringe.  
  • The final solution should be clear, colorless, or light yellow.
  • The solution should not be stored for more than two hours after mixing.
  • It is recommended to dispose of any unused solution.

Implementation

  • About one hour before cystoscopy:
    • Insert the disposable catheter by sterile procedure 
    • Empty the bladder
    • 50 ml the hexaminolevulinate solution is instilled in the bladder via the catheter 
    • The patient should keep the fluid in for about 60 minutes before emptying the bladder 
    • After emptying the bladder, cystoscopy with fluorescing light should be initiated within 60 minutes
  • The patient should be brought from the urology department where the solution was instilled to the operating room for cystoscopy. 
  • Cystoscopy with or without general anesthesia:
    • The cystoscopy instrument is inserted into the bladder via the urethra. 
    • Examine the changes in the bladder urothelium by examining the patient with the help of white and blue light. During the examination with blue light, any changes will emerge as a colored area in the bladder. 
    • If needed, biopsies are taken from suspect areas under white light.

Follow-up

Observations

  • The hexaminolevulinate rarely causes side effects.
  • Blood may be present in urine along with dysuria the first days after the procedure. 

Follow-up

  • Scheduled on an individual basis according to the diagnosis and treatment schedule. 
Cystoscopy with instillation of Hexvix in the bladder.  Cystoscopy with instillation of Hexvix in the bladder. Cystoscopy with instillation of Hexvix in the bladder.

Urine cytology of urothelial cancer

General

A constant rejection of cells from normal urothelium and malignant cells occurs in the bladder. These rejected cells can be isolated from a regular urine sample and assessed and classified as normal or malignant.

Urine cytology is most reliable for detecting tumors of higher grade (WHO grade 2 and 3) and Tis. A tumor of WHO malignancy grade 1 will give a positive cytology to a lesser degree. Due to a low cell count, degenerative -, irritative - (for example calculous disease or cystoscopy urine) and therapy-induced (BCG and radiation therapy) changes, the cytological interpretation of the specimen may be problematic.

Indications

  • Hematuria not explained at cystoscopy and urography  
  • Ambiguous finding at cystoscopy
  • Negative cystoscopy in patient with suspect UTI-symptoms
  • Negative cystoscopy and possible tumor in upper urinary tract from urography/ultrasound 
  • Follow-up of certain patients (for exmple Tis)

Goal

  • Diagnostic
  • Follow-up

Equipment

  • Reagent tube
  • Slide glass with matted end
  • 70% ethanol
  • Centrifuge
  • PreserveCyt solution
  • ThinPrep machine
  • Papanicolaou

Preparation

  • Urine for a cytology examination is taken from spontaneous urine, catheter, or ilium bladder.
  • Night urine should not be used.
  • The sample is fixed with 70% ethanol/urine (50/50) and sent as a regular postal package
  • At least two, preferably three samples should be taken for cytology, at different urinations.

Implementation

  • Pour the urine sample into a 50 ml reagent tube.
  • Centrifuge the sample for 10 minutes at 2000 rotations.
  • Remove the supernatant.
  • Preserve the sediment with PreserveCyt solution and allow to sit for at least 15 minutes.
  • Prepare the ThinPrep machine:
    • Insert the filter with holder
    • The "Fix-bath" holder should be filled with 70% ethanol.
    • Have a ThinPrep slide ready.
    • PreserveCyt solution container with the fixed material should be available.
  • Start the machine (program 2)
  • When the sample is finished rotating, remove the ThinPrep slide from the fix-bath holder.
  • Allow the sample to dry.
  • Stain by routine protocol in the staining machine with Papanicolaou. Remember: only one bath of hematoxylin.
  • Mount the smears immediately. If not, place them in Xylenes to avoid "Cornflakes."

Treatment of bladder cancer

Bladder cancer

Treatment of bladder cancer is separated into two groups:

  • superficial cancer (pT ≤ 1)
  • infiltrating cancer (pT ≥ 2)

For superficial cancer (pT ≤ 1), the patient is offered conservative (organ-sparing) treatment. For cancer infiltrating the muscle (pT ≥ 2), more invasive (radical) surgery is necessary.  

Surgery

  • Transurethral resection (TUR-B)
  • Bladder resection (rarely performed) 
  • Cystectomy

Radiation therapy

Curative radiation therapy is no longer recommended for infiltrating urothelial cancer in the bladder. For a small tumor volume and T ≤ 2, radical TUR-B supplemented with external radiation therapy may cure the disease, and may be used in patients not willing to have a cystectomy. However, these patients must be monitored closely, and if recurrence, a cystectomi must be performed.

Radiotherapy alone is not given to treat bladder cancer, but is used in multimodal treatment of bladder cancer and for palliative treatment. 

Drug therapy

  • Local
    • Intravesical chemotherapy
    • Intravesical immunological treatment (BCG)
  • Systemic chemotherapy

Multimodal treatment

Multimodal treatment involves a combination of drug therapy, radiation, and surgical treatment. Many studies on infiltrating bladder cancer are conducted, but the results are not unambiguously in favor of the patient.

Patients having a poor prognosis should be referred for treatment at institutions having a team including a surgeon, oncologist, pathologist, and radiologist to achieve optimal treatment results.

Renal pelvis and ureters

In most cases of cancer in the renal pelvis or ureters, the treatment is nephroureterectomy. Other treatments are rarely appropriate to consider, other than for single kidney or bilateral disease.

Most cancers in the renal pelvis/ureter must be treated by organ resection. For tumors in the lower third of the ureter, a resection of the distal ureter may be performed, including a bladder resection of the ureteral opening and subsequently reimplantation of the ureter into the bladder. The entire ureter can also be removed and be replaced with a segment of the small intestine, or an autotransplantation of the kidney can be performed where the renal pelvis is anastomosed directly to the urinary bladder. These treatment options are mostly appropriate for single kidney or bilateral disease. Conservative surgery with endoscopic coagulation in the renal pelvis and upper ureters can be attempted if the patient has a low WHO grade. However, the surgery is difficult to carry out and as there will be a lack of confidence in curing the disease. Therefore, it is seldom indicated. If the patient has Tis in the upper urinary tracts, it may be possible to treat by rinsing with BCG via pyelostomy catheter, but these patients must be monitored closely.

Surgery of bladder cancer

Transurethral resection of bladder (TUR-B)

The tumor localization must be described and a bimanual exploration should be performed on the patient before and after a TUR-B to determine the T-stage.

If there is CIS in areas of the urinary bladder, verified with biopsies or supplemented with fotodynamic diagnostics (PDD), it is agreed upon that a TUR-B alone is not adequate treatment. In such cases, local immunological treatment with BCG instillation in the bladder is recommended. For primary Tis, there is an 80% cancer reduction (normal cytology) after BCG instillation. If pT ≥ 2 or if a WHO grade 3 is present regardless of T-stage, additional treatment should be discussed and planned for.  

YAG laser

Laser destruction of superficial tumors can be performed as an alternative to TUR-B or electrocoagulation. The advantage of laser is that cells are destroyed deeper into the tissue. The disadvantage is that a pathology assessement of the radicality of the treatment cannot be performed. 

Radical cystectomy

If the tumor infiltrates the bladder wall musculature (pT ≥ 2) and TUR-B is the only treatment, experience shows that the prognosis will be poor. In most cases, a radical cystectomy with urine diversion is recommended. This operation is a mutilating surgery, and in elderly patients with a statistically short expected survival time and solitary tumor, a bladder resection can be chosen as suboptimal treatment, possibly in combination with radiation therapy. Significant contraindications against a cystectomy should be present to choose organ-sparing surgery in case of a muscle-infiltrating tumor.

In principle, a radical cystectomy with regional lymphadnectomy is the correct treatment for muscle-infiltrating urothelial cancer of the urinary bladder. This treatment should also be considered for superficial high risk cancers (multifocal WHO grade 3, possibly combined with CIS).

During a radical cystectomy on a man, the following organs are removed: the urinary bladder, prostate, vesicles, and distal ureters en bloc. In women, the following are removed: the bladder, distal ureters, urethra, uterus, and anterior vaginal wall. In postmenopausal or menopausal women, the ovaries are also removed. 

Principles for urinary diversion

There exist different methods for urinary diversion, ranging from a simple pyelostomy to complicated continent diversions. A clear goal for the choice of method must be that later urine collection must occur in a safe way that is easily maintained and will protect the kidneys. 

  • A pyelostomy catheter/cutaneous ureterostomy are very simple diversions. They are simple to carry out, but not much protective of the kidneys, and should therefore only by chosen as palliative treatment in patients with short expected survival, or with severe contraindications against safer alternatives. 
  • Cutaneous ureterileostomy ad modum Bricker is a simple diversion of urine and protects the kidneys. For the patient, the diversion is compatible with a good quality of life, as long as the surgeon constructs a nipple that functions well.
  • To avoid external collection into a urostomy bag, different methods for intraabdominal collection of urine have been developed over the years. Many different variations have been attempted including use of the small intestine (Studer) and large intestine (Lundiana). All of the methods are encumbered with a significant re-operation frequency. Therefore, these procedures should be used on patients with favorable prognoses. Such procedures should preferably not be used in patients who have previously irradiation to the pelvis/abdomen. 
  • An orthotopic bladder is a reconstructed bladder using tissue from either the large intestine or small intestine, which is connected to the urethra where it empties, either by abdominal pressure or using a catheter. There are multiple techniques for constructing an orthotopic bladder including Studer.   

The surgeon must always keep in mind the patient's quality of life and kidney function when choosing a method for urinary diversion. If the patient must be on dialysis after 5-20 years, the method of choice was not optimal.

Contraindications for continent urostomy and bladder substitution 

  • Neurological disease (must have help for catheterization)
  • Psychiatric disease
  • Short survival expectancy
  • Reduced kidney and liver function
  • Chronic diarrhea and malabsorption conditions
  • Previous irradiation of pelvis/abdomen
  • PROSEDYRER

    Radical cystectomy with construction of orthotopic bladder substitution ad modum Studer

    General

    A radical cystectomy is standard treatment for muscle infiltrating urothelial cancer in the bladder. This operation is also relevant for certain high risk groups of superficial tumors.  

    Orthotopic bladder substitute

    An orthotopic reconstruction using intestinal tissue connected to the urethra has been implemented mostly on male patients, but in later years, the operation has been increasingly used on female patients. The reconstruction is performed using a 50-60 cm long isolated intestinal segment. The intestinal reservoir is emptied using abdominal pressure, relaxation of the pelvic floor, or intermittent catheterization. The majority of patients will experience encumbant nighttime incontinence and lacking or incomplete emptying. In the long term, many develop difficulties emptying the bladder and require self catheterization.  

    Contraindications for an orthotopic bladder substitution are tumor involvement of the prosthatic urethra, extenstive Tis, high preoperative radiation dose to the pelvis, and longer urethral strictures. A bladder substitution is contraindicated if the patient is not willing to accept that self catheterization may be necessary as well as the risk of urinary incontinence.

    Indications

    The indications for a radical cystectomy are: 

    • T1 tumor with deep infiltration of lamina propria
    • T1 tumors with accompanying carcinoma in situ
    • Extensive T1 tumors
    • Recurring T1 tumors
    • Muscle-infiltrating urothelial cancer without detectable lymph node metastasis or distant metastasis 

    Goal

    • Curative treatment

    Equipment

    • Surgical laparotomy tray
    • Bookwalters retractor 
    • Pigtail catheters Ch. 7–9, x 2
    • Optionally robot


    Preparation

    • Antibiotic prophylactic
    • Thrombosis prophylactic
    • Preoperative hair removal for abdominal incision

    Preoperative preparation in the operating theatre

    • Operating table appropriate for patient and type of surgery
      • Men: square drape, penis free
      • Women: back/leg supports
    • Diathermy
    • Suction
    • Installation of catheter

    Implementation

    • The abdominal cavity is opened using a long midline incision, or the operation is performed with a robot with removal of the urinary bladder and lymph nodes before urinary diversion.  
    • The bowels are displaced cranially.
    • The ureters are identified on both sides and clamped towards the bladder.
    • Biopsies of both ureters are sent for frozen sectioning.
    • The peritoneum is opened around the bladder.
    • Proceed to the midline and identify the layer between the bladder and the rectum.
    • The vesicle arteries are clamped and divided.
    • Proceed to the front and open the endopelvic fascia.

    Removal of the primary specimen 

    • In men, the neurovascular bundle is cut on both sides of the prostate using a sharp scissors, and the nerves are spared as much as possible to preserve erectile function.  
    • In women, the length of the vagina is spared as much as possible.
    • Proceed back to the urinary bladder. Maintain a good margin until the specimen is removed. 
    • Take a biopsy of the urethra and put it in formalin.

    Iliacal bilateral lymph node dissection

    • First, empty the obturator space bilaterally.
    • Proceed in front of and lateral to the iliacal vessels out towards the ilioinguinal nerve. 
    • Isolate the internal and common iliac arteries up to the level of the aortic bifurcation. 

    Construction of the reservoir (ad modum Studer)

    • Tunnel the left ureter and attach it the right.
    • Isolate about 55 cm of distal small intestine. The anal division should be about 30 cm from the coecal opening. 
    • First, split the mesentery at the anal end of the instestinal segment.
    • Measure the correct length.
    • Split the mesentery at the oral end before the bowel is closed and divided at both ends with a suture apparatus. 
    • Restore the intestinal continuity with side-to-side anastomosis with a suture apparatus.
    • Invaginate the clips with suture.
    • Attach the ureters to the isolated intestinal segment and insert pigtail catheters to the renal pelvis on both sides.
    • Invaginate 45 cm (distale) of the removed intestinal segment.
    • Construct a reservoir ad modum Studer with continuous sutures.
    • Prepare an anastomosis between the urethral stump and the most caudal point of the reservoir with interrupted sutures over a Foley catheter nr. 18. 
    • Test the anastomosis for possible leakage using a 60 ml syringe with sodium chloride 9 mg/ml.
    • Insert a drain in the abdomen and lay the pigtail catheters out.
    • Close the abdominal cavity with monofilament continuous sutures.

    Follow-up

    • Remove pigtail catheter to the kidneys after 10 days
    • Foley catheter is removed after three weeks 

    The patient should be trained for self-catheterization before being discharged.

    Follow-up

    The risk of tumor progression after a radical cystectomy depends very much on the histopathological T stage. The risk gradually increases with tumor stage.

    Recommended follow-up routines

    A follow-up by a specialist should be performed 3 and 6 months after the operation. Thereafter, the patient should be monitored every 6 months for a period of 5 years. After 5 years, further follow-up can be done by a primary care doctor.

    Evaluation should include:

    • Physical examination with palpation of the abdomen and transrectal exploration.
    • Blood tests: Hb, creatinine, ALP, venous acid-base determination (should be followed closely for tendency of elevated creatinine), vitamin B12 (should be followed from 2 years)
    • Thoracic X-ray (after 2 years, once annually)
    • CT urography is performed after 3 months and 1 year. If these are satisfactory, CT urography is done later upon indication (hematuria, clinical UVI, flank pain). Somewhat more liberal CT urography is performed for Tis. For monitoring of hydronephrosis, ultrasound of the kidneys is an alternative. 
    • Endoscopy of urethra and bladder substitute should be performed once annually and possibly supplemented with "wash cytology". 
    • Measurement of residual urine in bladder substitute.
    • Endoscopy of remaining urethra in risk patients once annually if a urethraectomy was not performed.

    Radical cystectomy with construction of Bricker bladder

    General

    A radical cystectomy is standard treatment of muscle-infiltrating urothelial cancer of the bladder. This operation is also relevant for certain high risk groups of superficial cancer. 

    Construction of Bricker bladder (cutaneous uretero-ileostomy ad modum Bricker) may be performed with open surgery or robot-assisted laparoscopy.

    A segment of ileum about 25 cm long is used for bladder substitution. The ureters are anastomosized to the oral end of the ileum segment. The anal end is prepared as an abdominal stoma (incontinent), usually in the right iliac fossa. The urine will continually drain from the stoma and collect into a urostomy bag. An ideal stoma is about 2 cm high. This allows for easy attachment of the stoma bag and also keep urine from seeping out on the skin under the bag, causing skin problems. This can in turn also cause the bag to fall off.

    Indications for radical cystectomy

    • T1 tumor with deep invasion of lamina propria
    • T1 tumor with accompanying carcinoma in situ
    • Extensive T1 tumors
    • Recurring T1 tumors
    • Muscle infiltrating urothelial cancer in the bladder without detectable nodal metastasis 

    Goal

    • Curative treatment
    • Palliative treatment for local problems from the bladder and where there are bone or nodal metastases

    Equipment

    • Laparotomy tray  
    • Bookwalter's retractor 
    • Pigtail catheters Ch. 7–9, x 2
    • Optionally robot

     

    Preparation

    Preoperative preparation of the patient

    • Marking for stoma before the operation
    • Antibiotic prophylaxis
    • Thrombosis prophylaxis
    • Preoperative hair removal for abdominal incision

    Preoperative preparation in the operating theatre

    • Operating table appropriate for patient and type of surgery
      • Men: square drape, penis free
      • Women: back/leg supports
    • Diathermy
    • Suction
    • Insertion of Foley catheter

    Implementation

    • The abdominal cavity is opened using a long midline incision, or the operation is performed with a robot with removal of the urinary bladder and lymph nodes before urinary diversion. 
    • The ureters are identified on both sides and clamped towards the bladder.
    • The peritoneum is opened around the bladder.
    • Proceed to the midline and identify the layer between the bladder and the rectum.
    • The side ligaments are defined, ligated, and divided with a stapling instrument.
    • Proceed to the front and open the endopelvic fascia

    Removal of the primary specimen 

    • In men, the neurovascular bundle is cut on both sides of the prostate using a sharp scissors, and the nerves are spared as much as possible to preserve erectile function.  
    • In women, the length of the vagina is spared as much as possible.
    • Proceed back to the urinary bladder. Maintain a good margin until the specimen is removed. 

    Cutaneous u reteroileostomy ad modum Bricker

    • Isolate a segment of small intestine about 30 cm long.
    • Construct a Wallace anastomosis between the ureters and oral end of the segment. 
    • Construct a regular eversion ileostomy.
    • Pigtail catheters are inserted to the renal pelvis bilaterally and out through the intestinal segment during the procedure. 
    • Resume the intestinal continuity as a side-to-side anastomosis with a stapling instrument and reinforce with sutures, if necessary.
    • Check that the anastomosis lies without tension and that the color of the intestinal sections are acceptable. 
    • Insert the vacuum drain down in the pelvis.
    • Close the abdominal cavity with monofilament continuous sutures.
    • Send the specimen for a histological examination. 

     

     

    Follow-up

    Postoperative observations

    • Circulation in the stoma
    • Sutures, bandage, and skin around the stoma
    • Urine drainage
    • The vaccum drain can be removed as indicated by the surgeon
    • The pigtail catheters can be removed on the 10th postoperative day.
    • Sutures in the incision can be removed 12-14 days postoperatively (with the primary care doctor) 

    Training 

    On the second postoperative day, the patient's training on stoma care will be initiated. The patient should be trained every day or every other day according to the needs of the patient. The patient should be able to take care of the stoma alone upon discharge. Anbefalt kontrollregime

    Recommended follow-up

    The patient should have follow-up by a specialist 3 and 6 months after the surgery. Thereafter, checks should be with 6 month intervals over a period of 5 years. After 5 years, follow-up can be taken over by the primary care doctor.

    Evaluation should include

    • Clinical examination with palpation of the abdomen and transrectal exploration
    • Blood tests: Hb, creatinine, ALP, venous acid-base test (should be followed closely for tendency of increasing creatinine), vitamin B12 (followed from 2 years) 
    • Thoracic X-ray (after 2 years x 1 annually)
    • CT urography should be performed after 3 months and 1 year. If these are satisfactory, CT urography should be performed later upon indication (hematuria, clinical UVI, flank pain). Somewhat more liberal CT urography is performed for Tis. For monitoring of hydronephrosis, ultrasound of the kidneys is an alternative.
    • Urine for cytology

     

    Transurethral resection of the bladder (TUR-B)

    General

    A transurethral resection of the bladder is the initial treatment for all patients with urothelial cancer in the bladder, regardless of tumor stage.

    For all primary and recurring tumors, a TUR-B should be performed with the goal of obtaining tumor tissue for a histopathological assessment to determine the grade of the tumor (WHO grade and pT classification). For this diagnostic/treatment procedure, it is a requirement that the underlying bladder musculature is included in the tissue specimen from the tumor area. All tumors will be removed, and all suspect areas of mucosa will be biopsied separately. The base ofthe resection wound with surrounding mucosa will be electrocoagulated. After all of the visible tumor tissue is resected and the margin biopsies are taken, it is normal to conclude the procedure with intillation of a cytotoxic substance (epirubicin, adriamycin) to reduce the chance of recurrence.  

    The pathologist who investigates the tumor specimen will describe the tumor type (WHO grade) and the depth of infiltration (pT stage). If the T stage ≤ 1, pT stage ≤ 1, WHO grade ≤ 2, then the primary surgical treatment is finished. If multiple tumors are found in the bladder, these must be removed and coagulated, if necessary. This type of patient has a high risk of recurrence, therefore, instillation of BCG should be considered.

    Important factors of the procedure

    • While under general anesthesia, a bimanual palpation will be performed. This can preferably be carried out both before and after, but should always be performed after the resection. The goal is to identify palpable masses in relation to the bladder, and to determine whether they are fixed or mobile relative to the pelvic wall. After the resection, finding a palpable tumor increases the probability that an infiltrating tumor (≥ T2) is present. 
    • The resection must be carried out in such a way that the relation of the tumor to the bladder can be judged, and that the tumor tissue can be preserved for a histological assessment. By taking large enough segments and minimalizing current for cutting, heat damage of representative tumor areas can be avoided. Superficial and deep parts of an infiltrating tumor should be resected individually and be sent to pathology as separate specimens. 
    • In addition to the tumor resection, biopsies should be taken of suspect mucosal areas. If there is suspicion of infiltration into the bladder neck level and/or cancer in situ (Tis), a biopsy of the prostatic urethra down to the colliculus, preferably with the resection loop, is indicated. This type of biopsy should also be taken if a cystectomy is planned with construction of an orthotopic bladder substitute as additional treatment.
    • It is contraindicated to take random bladder biopsies in patients with solitary papillomatous tumors, since such biopsies will not provide additional information. It is also a danger that biopsy lesions of mucosa may be locations for implantation of cells from the tumor.
    • For superficial papillary tumors, a single instillation of chemotherapy is recommended immediately after a TUR-B. 

    Indications

    • Treatment of superficial tumors (Tis, Ta, T1)
    • Palliative treatment of T4b/metastatic tumors

    Goal

    • Curative treatment
    • Palliative treatment

    Equipment

    • Cystoscopy set
    • Resectoscope number 24 or 27  
    • Optic 30¤
    • Evacuator
    • 3-way catheter nr 20
    • Light source
    • Light cable
    • Diathermy cable
    • Diathermy
    • Diathermy pad with cable

     

    Preparation

    • The patient should be informed that presence of some blood and blood clots in urine is normal and will disappear during the first days after the procedure.
    • Urine stick - If positive, antibiotic prophylaxis will be given.  
    • Pretreatment according to schedule
    • The patient will lie with their legs in leg supports.
    • A diathermy pad will be applied to the thigh.
    • Sterile wash and draping 

    Implementation

    • Place Xylocaine® gel in the urethra
    • Insert the resectoscope via the urethra and into the bladder 
    • Inspect the bladder for pathological findings 
    • Resect tissue/superficial tumors in the bladder using an electrical loop . The pieces of tissue will remain in the bladder and the wound surfaces will bleed, therefore, it is important to flush the area. When the bladder is full of flushing fluid, the resection instrument should be pulled out of the resectoscope to drain the fluid. Alternatively, a suprapubic catheter can be used to provide continual drainage. 
    • Coagulate bleeding continually
    • Empty the bladder for resected tissue and clots using an evacuator .
    • Check hemostasis.
    • Insert a 3-way catheter in for continual flushing.

    Follow-up

    Postoperatively, the bladder is flushed using a 3-way catheter.  

    • The flush fluid/urine should be observed for: 
      • Amount
      • Color
      • Coagulation
    • The rate of flushing should be varied according to the amount of blood in the fluid. 
    • If the fluid stops due to clots, flushing should continue manually with a catheter syringe and sodium chloride 9 mg/ml.
    • Flushing is usually stopped the day after the procedure, but depends on the amount of bleeding. The doctor should determine when to stop flushing. 
    • Use of a catheter should be stopped according to the treating doctor. 
    • After removal of the catheter, observe for: 
      • Spontaneous urination 
      • Urination patterns after the procedure
    • Scanning of remaining urine and flowmetry is performed before discharge.  

    Shortly after undergoing a TUR-B, the patient will normally be able to return home, however, he/she must be informed that not until the histology result is available will it be known whether primary treatment is finished. The histology result will often show uncertain resection margins to the sides (margin biopsies) or in depth under the tumor. Not until the patient is considered tumor-free will he/she be able to start the follow-up schedule. The patient should be informed that the cancer may recur after many years and the malignancy (grade) of the tumor can also change when it recurs. When urothelial cancer is diagnosed, there will always be a risk for developing new tumors, especially in cases of malignancy grades.  

    Follow-up

    A follow-up with cystoscopy will take place after 3 months at the urology clinic.

    Transurethral resection of bladder (TUR-B)Transurethral resection of bladder (TUR-B)Transurethral resecion of bladder (TUR-B)Transurethra resection of bladder (TUR-B)

    Drug therapy of bladder cancer

    Drug therapy for treatment of transitional epithelial cancer can be given either intravesically via rinsing (BCG/chemotherapy) or as systemic treatment with chemotherapy.

    Supplementary treatment of superficial bladder cancer T1

    In the last 20 years, immunological treatment with BCG has been the dominating intravesical instillation treatment. Intravesicle instillation of chemotherapy aimed at reducing the chance of recurrence has also been used to treat urothelial cancer of the bladder for many years. Today, flushing is mainly performed as part of adjuvant treatment in combination with a transurethral resection (TUR-B) as a single treatment at the end of the surgery.

    Intravesical instillation treatment 

    Intravesical instillation of immune-modulating substances, such as BCG or cytotoxic drugs, are used to treat carcinoma in situ (Tis), or to prevent new recurrence after resection of recurring superficial tumors (≤ T1) with or without accompanying Tis.  

    A single instillation of a cytotoxic drug immediately after a TUR-B is used for all papillary superficial tumors.

    A single instillation with epirubicin (80 mg) or mitomycin C (40 mg) within 6 hours after TUR-B reduces the frequency of recurrence by about 50% in a two year period, and is recommended for all superficial tumors, except if the bladder is perforated or there is postoperative bleeding requiring treatment. The medication is instilled and the catheter is closed for 1-2 hours (anticholinergic drug for bladder tenesmus) and opened thereafter.

    The instillation regimen for high risk tumors consists of an induction cycle (usually 6 weekly instillations) and a maintenance cycle (different schedules over 1-3 years) with BCG or chemotherapy. 

    Chemotherapy is considered for:

    • Recurring tumors of grade 1-2
    • Intolerable side effects from BCG 
    • No response to BCG with Ta tumors ("cross over")
    • Contraindications for BCG

    In some patients, especially elderly, chemotherapy should be considered because of better tolerability than BCG, when there is no obvious need for the long-term effect of BCG.

    Systemic treatment of localized muscle-infiltrating bladder cancer T2-T4a, cN0M0

    As radical treatment, systemic chemotherapy has been attempted as neoadjuvant or adjuvant treatment. Multiple randomized studies have shown that neoadjuvant chemotherapy improves survival for muscle-infiltrating bladder cancer (1,2). All patients with muscle-infiltrating bladder cancer should therefore be assessed by a multidisciplinary team to optimize treatment. Normally, three cycles of cisplatin and gemcitabin are given and evaluated after two cycles.  In certain patients, HD-MVAC is indicated. However, the general condition of the patient and kidney status must be taken into consideration. Neoadjuvant chemotherapy is not recommended if ECOG function status is 2 and/or significantly reduced kidney function.

    For locally advanced disease, chemotherapy can be given as induction therapy to render inoperable tumors operable. After a radical operation with spreading to regional lymph nodes, adjuvant therapy may be considered, preferably within the framework of a clinical study.

    Systemic treatment for metastatic disease

    Systemic chemotherapy for urothelial cancer has not provided the results hoped for, but there is a clear indication to consider chemotherapy for metastatic disease, in addition to experimental multimodal treatment with surgery, chemotherapy, and radiation.

    Tumors of transitional epithelium are moderately sensitive to chemotherapy drugs such as cisplatin (Platinol®), methotrexate (Emthexat®/Metoject®), vinblastin (Velbe®), doxorubicin (Adriamycin®/Caelyx®), gemcitabine (Gemzar®), and paclitaxel (Taxol®). Vinflunine (Javlor®) is used as second-line treatment. Using a combination of these drugs, an objective response rate of 60-70% can be obtained. The most commonly used combination at Oslo University Hospital today is cisplatin and gemcitabine.

    Side effects

    The side effects are bone marrow inhibition with the danger of febrile leukopenia, as well as nausea and hair loss. Cisplatin is oto/nephrotoxic. In patients with heart and kidney failure, cisplatin is often contraindicated due to kidney toxicity and fluid accumulation during cycles. For reduced kidney function, replacing cisplatin with carboplatin may be considered. 

    Chemotherapy drugs

    Some of the drugs given for chemotherapy can be found in the National Registry for Chemotherapy Drugs. 

     

     

     

    PROSEDYRER

    BCG immunotherapy

    General

    Intravesical bladder immunotherapy with BCG (Bacillus Calmette-G uerin) is performed on all patients at a high risk for recurrence after a transurethral resection of the bladder (TUR-B). Upon instillation of BCG in the bladder, the bladder will start to produce antibodies, which will attack the cancer cells. 

    • Induction cycle: one instillation per week for 6 weeks
    • Maintenance/follow-up cycle: one instillation per week for 3 weeks  

    Up to 50% of those who do not respond to the induction cycle will respond to a repeated induction cycle. Repetition of maintenance cycles for up to three years should be considered based on tumor risk and tolerability. In general, patients with high-risk tumors (Tis, T1G3) receive a full maintenance cycle. The procedure is performed on an outpatient basis. At the Norwegian Radium Hospital, when and how often the maintenance cycle is carried out is determined on an individual basis.

    Indications

    • Three episodes of tumor recurrence within 18 months
    • Primary T1G2/3
    • Primary Tis, or possibly concomitant Tis in multiple localizations 
    • Multiple recurrences at the first or second follow-up after TUR-B, especially if there was primary multiplicity, or the primary tumor was large (³ 3 cm)

    Goal

    Treatment for superficial transitional epithelial cancer in the bladder (Ta, T1).

    • Reduce the chance of recurrence.
    • Prevent progrediation of the disease.

    Equipment

  • Catheterization set with sterile gloves, swabs, compresses, forceps, drape, and pus basin 
  • Chlorhexidine® 0.5 mg/ml
  • Syringe 50 ml
  • Sodium chloride 9 mg/ml, 50 ml
  • Transition tube
  • Closed system for mixing and instillation in bladder 
  • Disposable catheter
  • Xylocaine® gel
  • Vial with Onco TICE® 12.5 mg (store in refrigerator, tolerates only a few hours at room temperature)
  • Gloves, coat, mask
  • Yellow bag for waste
  • Preparation

    • Prepare equipment for a sterile procedure.
    • Mix Onco TICE® 12.5 mg in 50 ml sodium chloride 9 mg/ml using a closed transfer system or under a LAF bench.
    • Ask the patient to urinate and provide a urine sample to test for possible UTI.
    • If there is a sign of infection, confer with a doctor before instillation.

    Information for the patient

    During treatment and two weeks following:

    • Sit to urinate to avoid spillage of urine.
    • Dry the opening of the urethra with paper and dispose in the toilet before washing hands with soap and water.
    • Use a designated towel during the entire period.
    • Be aware of people with a reduced immune response and avoid direct contact to avoid transfer of BCG. 
    • Men should use a condom during sex. 

    Provide general information about the treatment and possible side effects (see follow-up/observations).

    Implementation

    • Insert the catheter sterilely.
    • Empty the bladder.
    • Place the catheter tip of the transition tube into the catheter.  
    • Instill the BCG solution from the syringe. The fluid should infused gradually over 2 minutes.
    • Remove the catheter.
    • Put all used equipment into a yellow bag and into a biohazardous waste receptacle.

    Follow-up

    • The patient may return home after the treatment.
    • The solution should be kept in the bladder for 2 hours (if he/she is able to) 
    • Then the patient should urinate.

    Observations

    • Frequent and burning urination during the first days after each treatment is normal. 
    • Urine tinged with blood may be present.
    • Influenza-type symptoms usually the day of the treatment and the following day are normal. 

    Sometimes the patient may experience such intense side effects that treatment must be stopped.

    Follow-up

    • The first years after treatment, the patient will have follow-up with cystoscopy every 3 months. 
    • Further investigations are assessed individually.
    BCG bladder instillationBCG bladder instillationBCG bladder instillationBCG bladder instillation
    BCG bladder instillationBCG bladder instillation

    Sun Exposure under Drug Therapy

    General

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

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

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

    Indication

    Sun exposure in connection with drug cancer treatment.

    Goal

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

    Definitions

    Photosensitivity

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

    Phototoxicity

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

    Photoallergy

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

    Photoinstability

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

    PPE ( palmoplantar erythrodysesthesia = Acral erythema )

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

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

    Acne-like rash

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

    Hyperpigmentation

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

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

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

    Radiation Recall Dermatitis (RRD)/Photo Toxic recall reaction

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

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

    Preparation

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

    Implementation

    General Precautions

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

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

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

    Medicaments that most commonly cause skin reactions

    Medicament Common reactions Remedial action
    Dakarbazin (DTIC)


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

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

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

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

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

    (2, 9)

    Fluorouracil (5-FU®)

     

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

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

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

    Radiation recall
    Treatment as with phototoxic

    Kapecitabin (Xeloda®)

     

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

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

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

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

    Vinblastin

     

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

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

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

    Tegafur

     

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

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

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

    EGFR-hemmere

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

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

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

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

    References


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

    Preparation of Chemotherapy, Spills, and Cleaning a LAF Bench

    General

    Preparation of chemotherapy outside of a pharmacy

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

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

    Designated room with LAF-bench to dilute/mix chemotherapy

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

    Goal

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

    Handling of chemotherapy spills

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

    Goal

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

    Cleaning of LAF-bench

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

    Goal

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

    Source

    Applicable directives and guidelines (www.lovdata.no)

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

    Equipment

      Preparation of chemotherapy in a hospital

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

    Handling of chemotherapy spills

    Spill kit includes:

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

    Washing of LAF-bench

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

     

     

    Preparation

    Preparation of chemotherapy outside of the pharmacy

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

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

    Handling of chemotherapy spills

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

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

    Washing of LAF-bench

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

     

     

    Implementation

    Preparation of chemotherapy drugs outside of a pharmacy

    Aseptic procedure

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

    Multiple additions

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

    Handling of chemotherapy spills

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

    Washing of LAF-bench

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

    Routine washing

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

    Follow-up

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

    First aid if contact with chemotherapy drugs

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

    Radiation therapy of bladder cancer

    Radiation therapy can be given as curative- or palliative treatment.

    The main prognostic factors considering the effect of radiation therapy are spread of tumor (T-stage), grade (low-grade or high-grade), level of hemoglobin in blood before treatment and the patient's general condition.

    Curative radiation therapy

    Curative radiation therapy may be given preoperatively, postoperatively or as radical treatment for patients with muscle-infiltrating cancer with not proven metastases to lymph nodes or distant metastases.

    Preoperative radiation therapy is not included in any standard program, but is performed to reduce the tumor size and make full or partial removal of the bladder technically easier. This will also reduce the risk of spreading cancer cells during surgery and prevent the risk of establishing new tumors.

    At local recurrence after cystectomy, radiation therapy may be considered, but as of today no studies show any gain of supplemental radiation therapy after cystectomy.

    Curative radiation therapy may be considered by:

    • small tumors with limited invasion into muscle (T2).
    • cases where the patient's general condition indicates that the bladder cannot or should not be completely removed.
    • in those cases where the patient does not want to remove the urinary bladder due to  reduced quality of life.

    For patients where the aim of radiation therapy is curative, tissue samples are taken from the tumor area after finishing the treatment. In Norway primarily external radiation therapy is used, brachytherapy is not common.

    External radiation therapy is given on the basis of CT-based dose planning. Special considerations is necessary to reduce radiation against the bowel, bowel movements are also considered  when the radiation field is planned. The treatment course is daily treatments with 2 Gy x 32, in other words a total dose of 64 Gy. In recent years it has often been attempted to provide cisplatin weekly as an adjunctive therapy in connection with radiation therapy. However, this requires good general condition and a good renal function.

    Palliative radiation therapy

    Radiation therapy with palliative intention may be offered to patients where the tumor is not technically available for surgery. The treatment will reduce the patient´s problems of bleeding and pain.

    Technique and dose/number of treatments may vary based on the patient's condition and the tumor´s biological growth. Alternatively the course of treatment may be 2 Gy x 25, 3 Gy x 10, 4 Gy x 5 or 7 Gy x 3. For spreading tumors the palliative radiation therapy are varying  depending on the location of the tumors and the purpose of treatment.

    Complication treatment of bladder cancer

    Both chemotherapy and radiation therapy cause varying degrees of side effects. Supportive treatment is often necessary in order for the patient to gain the full effect of treatment and/or to reduce bothersome side effects. During and after instillation of BCG in the bladder, the patient may experience different forms of discomfort. In such cases, it is necessary to provide the patient with supportive care to reduce discomfort. 

    Side effects of chemotherapy

    • Nausea to varying degrees. Good prophylaxis and treatment helps significantly.
    • Reduced bone marrow function, especially granulocytopoesis which may require stimulation to complete relevant treatment, in some cases. 
    • Anemia
    • Hairloss
    • Oto-/nephrotoxicity (cisplatin)

    Side effects of radiation therapy

    • Nausea. In combination with chemotherapy, nausea will increase. It is normal for the patient to lose 5-6 kg due to poor apetite during treatment. 
    • Anemia. A hemoglobin level over 11 g/dl should be maintained during treatment. 

    Side effects of BCG bladder instillation   

    • Dysuria and other symptoms of irritation and inflammation in the bladder/urinary tract. Frequent and burning urination is common during the first days after each treatment.  
    • Fever
    • Lethargia
    • Influenza-like syndrome. This is most common on the day of treatment or the following day.

    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.

    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.

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    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.

    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.

    Intravenous Extravasation of Cytotoxic Drugs

    General

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

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

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

    Risk factors for intravenous extravasation:

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

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

    • Non-cytotoxic/irritating
    • Tissue irritant
    • Cytotoxic

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

    Indication

    • Intravenous extravasation of cytotoxic drugs. 

    Goal

    • Limit damage of tissue from intravenous extravasation.

    Definitions

    Non-cytotoxic drugs or non-irritants

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

    Irritants

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

    Cytotoxic drugs

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

    DNA-binding

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

    • Anthracycline
    • Alkylating drugs
    • Other

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

    Non DNA-binding

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

    • Vinca alkaloids
    • Taxanes

     

    Chemotherapy cytotoxicity (1)
    Cytotoxic, necrosis

    Irritant, can cause flaking or inflammation

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

     * = Anthracycline

    ** = Alkylating agents

    *** = Vinca alkaloids

    **** = Taxanes

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

    All chemotherapy drugs can damage tissue in high concentrations.

    References

     

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

    Preparation

    Identification of an extravasal injection

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

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

     

    Implementation

    Flow chart for treatment of intravenous extravasation of cytotoxic drugs:

    Emergency response:

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

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

    Conservative treatment

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

    Localize and neutralize:

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

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

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

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

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

    Treatment 

    Dexrazoxan (Savene®)

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

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

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

    Cost

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

    Dimethylsulfoxide (DMSO)

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

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

    Hyaluronidase

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

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

    Surgical treatment

    "Wash-out"

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

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

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

    References

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

    Follow-Up

    For conservative treatment 

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

    For emergency surgical treatment

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

     

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

    Follow-up care after treatment of bladder cancer

    Patients who have undergone conservative treatment

    Most patients in this group have primarily had a superficial tumor (T ≤ 1). Some of these patients have received curative radiation therapy for a muscle-infiltrating tumor in the bladder, and others have undergone a bladder resection.

    After conservative treatment, there is over a 70% risk for recurrence, and 30% risk for development of an infiltrating tumor later. The risk is the highest for high/moderately high malignancy, and less for low grade malignancy. 

    Life-long follow-up has been normally recommended with urine cytology and cystoscopy, as well as urography every year or every other year. Tumors of higher malignancy have a greater risk for recurrence than low grade tumors, and primary multifocal tumors have a higher risk than solitary tumors. A combination of low grade and solitary primary tumors have a low risk for recurrence(grade 1, T ≤ 1) if all primary tumor tissue is removed (no remaining tumor tissue/recurrence at the first follow-up check after primary treatment). Studies show that frequent and long-term follow-up is not necessary for this patient group. About half of patients with ≥ T1 urothelial cancer have a low risk of recurrence and minimal risk of progression. Patients with highly malignant tumors (grade 3), and patients with recurring grade 2 tumors should have frequent follow-up.

    Follow-up should include

    • urine cytology x 2
    • cystoureteroscopy

    Recommendations for follow-up

    • Patients with low-grade TaG1 tumors should be checked with cystoscopy 3 months postoperatively. If the cystoscopy is negative, the next examination should be 9 months postoperatively. After this, annually for 5 years.
    • High risk patients should have cystoscopy 3 months postoperatively. If the result is negative, the exam should be repeated every 3 months over a period of 2 years. Then every 4 months in the third postoperative year. After this, every 6 months for 5 years after the operation. Cystoscopy testing is then offered once annually. Annual urography should also be performed.
    • Patients in transition stages between these two groups (about 1/3 of all patients) should have a designated follow-up schedule individualized according to personal and subjective factors.

    Patients with muscle-infiltrating urothelial cancer (≥ T2) after curative treatment

    Follow-up of patients with infiltrating urothelial cancer after a cystectomy or radiation must identify local recurrence/distant metastases as early as possible. Additional treatment should be started if indicated.  Additional treatment should include salvage cystectomy, ureterectomy, nephroureterectomy, and/or secondary surgery of residual tumor. 

    Intervention type (cystectomy/chemotherapy) and prognostic factors determine the follow-up regimen for the patient. The stage of pT and pN with additional risk factors such as pTis are the most important prognostic factors and are normal for the follow-up schedule.

    After cystectomy

    The first check 3 months postoperatively should include:

    • anamnesis 
    • serum creatinine and blood gas analysis to evaluate kidney function 
    • urine cytology
    • CT urography to check anastomosis function/ultrasound of kidneys, liver, and peritoneum 
    • thoracic X-ray

    The examinations should be repeated annually with emphasis on urinary diversion and kidney function. 

    After radiation therapy

    The first follow-up 3 months after radiation therapy should include:

    • anamnesis of complications
    • serum creatinine
    • urine cytology x 2
    • cystoscopy under general anesthesia in addition to deep biopsies from the tumor area 
    • thoracic X-ray
    Additional follow-up will resemble the schedule for superficial urothelial cancer.

    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