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Utskriftsdato (25.5.2017)

Penile cancer

Penile cancer is rare, occurring mostly in older men. In Europe and North America, penile cancer constitutes less than 1% of malignant tumors in men, while in some South American countries, Africa, and Asia, this cancer type constitutes up to 10%, where cervical cancer also occurs more frequently.  

95% of penile cancers are squamous cell carcinomas. Carcinomas originates from the epithelial cells of the glans or the preputium (inner fold). The cancer development often starts under non-retractable preputium (phimosis). 

About 20% of AIDS patients with Kaposi's sarcoma have lesions on the penis, and about 3% of AIDS patients debut with penile Kaposi's sarcoma. Malignant melanoma and basal cell carcinoma are rare forms of penile cancer.

Incidence

Most cases of penile cancer occur in men from age 60 to 70, but the disease also occurs in younger men.

In Europe and the USA, the incidence of penile cancer is about 1 per 100,000 per year. In certain areas of South America, Asia, and Africa, penile cancer represents 10-20% of all cancer forms in men. The disease rarely occurs in countries where ritual circumcision is performed in childhood. In Israel, there are less than 0.1 new cases per 100,000 per year.

 

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

Source: Cancer Registry of Norway

 

 

Incidence of penile cancer, 1954–2013.

Source: Cancer Registry of Norway

Etiology of penile cancer

The etiological circumstances of penile cancer are now better understood, but still not as well documented as cervical cancer in women.

Risk factors

  • Poor hygiene
  • Phimosis
  • Infections
  • Smoking
  • Many sexual partners

Specific diseases such as Lichen Sclerosus, (undifferentiated PeIN and differentiated PeIN) are also associated with an increased risk for developing penile cancer. In countries where ritual circumcision of boys is performed, the incidence of penile cancer is low.

The human papilloma virus (HPV), which is a very common sexually transmitted viral infection, seems to play an important role in developing penile cancer. A systematic analysis of published studies shows that HPV is detected in 50% of penile carcinomas in Nordic countries with a low incidence of penile carcinoma. The incidence varies among different histologies.

As in women, the highest incidence of HPV in men is found in the pre-stages and in squamous cell carcinomas of basaloid and chondylomatous types. In half of the HPV positive tumors, HPV 16/18 is detected, which there is a vaccine for. It is therefore assumed that the HPV vaccine will protect against penile carcinomas and precursors, however, this is still not documented by clinical studies.

Histology of penile cancer

Punch biopsies, resected  tissue, or amputation specimens are the most common type of specimens from the penis.

Operation specimens are usually photo documented before  and after  a gross procedure. The pathology report should include tumor diameter, tumor thickness, and whether the following tissues are infiltrated: Lamina propria, corpus spongiosum, urethra, and preputium, and whether resection borders are free of tumor. Whole-organ microscopic sections are often used to better evaluate tumor extension and resection borders . Malignant tumors are classified according to WHO 2016.

Benign tumors

Apart from genital warts the benign tumors are rare. Genital warts (Condyloma Acuminata)  are very common and appear in 5-10% of sexually active younger people. The area is generally small (a few mm up to 2-3 cm) and localized on the glans, in the urethra, or on the preputium. They are caused by low risk HPV (Human Papilloma Virus) types (6 or 11), and transmitted through sexual activity. It has not been documented that they can develop into malignant tumors. Giant condyloma (Buschke-Lowenstein tumor) is very seldom and is also caused by HPV. They often exceed 5 cm and can be difficult to microscopically separate from well differentiated squamous cell carcinomas. Giant condyloma must be removed completely and can recur. Rare benign tumors also occur such as hemangioma, lymphangioma, and leiomyoma.

Image 1. Photomicrograph of condyloma. Click to enlarge. Magnification from image 1 showing the condyloma with koilocytes in upper epithelial layer. Click to enlarge.

Precursor lesions

The majority of penile carcinomas develop through a series of epithelial changes (percursor lesions) usually in the squamous epithelium of glans. What earlier was classified as dysplasias, carcinoma in situ and squamous epithelium hyperplasia, are now classified as Penil Intraepitelial Neoplasi (PeIN). PeIN is not graded.

There are two types of PeIN with different etiology. One is associated with HPV and is now called undifferentiated PeIn formerly called moderate/severe dysplasia and carcinoma in situ. Undifferentiated PeIN can be divided into a condylomatous and basaloid type but this has no clinical significance, both are associated with high-risk HPV infection (image 2a and 2b). Precursors that are not associated with HPV but often Lichen Sclerosus (formerly called atypical squamous epithelium hyperplasia) are now classified as differentiated PeIN. If doubts pathologists  may use immunohistochemistry and HPV analysis for correct classification of precursors.

Differentiated PeIN has minimal atypia (image 3) and is negative for p16 and positive for p53 basal and parabasal. Undifferentiated PeIN has rough atypia throughout the thickness of the epithelium (image 2a and 2b) and is throughout the epithelium thickness sharply positive for p16. Immunohistochemical examination for p16 is a surrogate marker for high-risk HPV infection and less expensive to perform than PCR.

Bowenoid papulosis, Erythroplasia Queyrat and Bowen's disease is clinical diagnoses where the light microscopic findings are identical with undifferentiated PeIN (image 2a and b). Bowenoid papulosis is caused by HPV and appears in younger sexually active men (16-35 years old) and usually regress spontaneously within one year without treatment. Erythroplasia de Queyrat and Bowen's disease appear in older men and is increasingly associated with cancer development. These lesions should be treated. What has previously been classified as light dysplasia and HPV changes are now classified as flat condyloma (image 4).

Lysmikroskopisk bilde av udifferensiert PeIN, kondylomatøs type Lysmikroskopisk bilde av udifferensiert PeIN, basaloid type Lysmikroskopisk bilde av differensiert PeIN

Image 2a. Photomicrograph of undifferentiated PeIN  condylomatous type. Click to enlarge

Image 2b. Photomicrograph of undifferentiated PeIN  basaloid type. Click to enlarge

Image 3. Photomicrograph of differentiated PeIN   Click to enlarge 

Image 4. Photomicrograph demonstrating a low-grade dysplasia with koilocytes in squamous cell epithelium. Click to enlarge.
Image 5. Photomicrograph demonstrating lichen sclerosis. Click to enlarge.

Lichen Sclerosus (Balanitis Xerotica Obliterans) (Fig. 6) is a degenerative condition also appearing in the vulva of older women. It is also a relatively common condition in older men, affecting the preputium and glans sometimes causing phimosis. Light microscopy does not reveal any atypia in the squamous epithelium, however, these findings are associated with squamous cell carcinoma, and is observed relatively frequently in the mucosa in patients with differentiated PeIN and cornified squamous cell carcinoma (usual type), verrucous carcinoma and papillary carcinoma.

Malignant tumors

Image 6. Photomicrograph showing a well differentiated squamous cell carcinoma. Click to enlarge.

Most of the penile squamous cells originate from the glans or preputium, but they  may also originate from transitional epithelium in urethra.( urothelial carcinomas), supporting tissue (sarcomas) or lymphoid tissue (lymphomas). Metastasis to the penis occurs very rarely.

More than 95% of penile squamous cells originate from the glans, preputium, or sulcus coronarius. On the skin of the penis shaft,  the same type of tumors that are common in skin may be developed. (These tumors are not included here). There are several subtypes of squamous cell carcinomas of varying etiology and prognosis (28,29), it is therefore important that pathologists subclassify properly so the patient receives the correct prognosis and treatment. Up to 50% of penile carsinomas are caused by HPV. Other risk factors include poor hygiene, phimosis, smoking, chronic inflammation, Lichen Sclerosus, immunosuppression and PUVA treatment.

Variants of squamous cell carcinomas not caused by HPV

Usual type (45-65%) are associated with differentiated PeIN, Lichen Sclerosus and phimosis (Image 6). According to WHO, these types are graded as high (grade 1), intermediate (grade 2) and poorly differentiated (grade 3) based on grade of nuclear atypia and keratinization. At the time of diagnosis, most of these tumors are grade 2.

Verrucous carcinoma (2-3%) occurs in older men. When performing a clinical examination, verrucous carcinoma, Giant cell condyloma, papillary carcinoma and condylomatous carcinoma are difficult to tell apart. Punch biopsies are therefore not suitable for the correct diagnosis;  the complete tumor must be removed to find the correct diagnosis.  It occurs more often in combination with usual type (hybrid verrucous carcinoma), the prognosis is then worse. The pure form (Image 9) has very little nuclear atypia papillary growth pattern with broad invasion front (not infiltrative) and has a very good prognosis. Metastases are not described, but local recurrence is a problem if the tumor and differentiated PeIN are not being removed with free resection margins.

Papillary carcinomas (5-10%) occurs in older men. This is also tumors with little nuclear atypia but with infiltrative basis and papillary growth pattern without koilocytosis. Infiltration of blood vessels and perineural infiltration may occur, but metastases are rare and the prognosis is good. Local recurrence may occur if tumor and differentiated PeIN are not removed with free resection margins.

Cuniculatum, pseudoglandular carcinoma, pseudohyperplastic carcinoma, adenosquamous carcinoma and sarcomatoid carcinoma are rare variants of squamous cell carcinoma that is not associated with HPV. Sarcomatoid carcinoma is a highly aggressive tumor which immunohistochemistry may be needed to exclude sarcoma.

Variants of squamous cell carcinomas associated with HPV

Basaloid carcinoma (10%) occurs in younger men and if sufficient number of sections of tumor are taken, there will always be  undifferentiated PeIN side of invasive tumor (Image 7 and 2b). This is a ulcero infiltrative with necrosis, large nuclear atypia and many mitosis. Keratinization is missing or very limited and without maturation. At the time of diagnosis more than half of the patients have  lymph node metastases. The tumor is not graded; this is an aggressive tumor with high mortality.

Condylomatous carcinoma (Image 8) is a more slowly growing verrucous tumor with moderate nuclear atypia and koilocytosis. Not invasive variant occurs, on the side by the tumorundifferentiated PeIN is observed. (Image 2a). This type is graded, they are often grade 1-2. Intermediate prognosis with relatively low mortality.

Plateepitelkarsinom av kondylomatøs type
Image 7. Photomicrograph showing basaloid carcinoma. Click to enlarge.
Image 8. Squamous cell carcinoma of condylomatous type. Click to enlarge.
Image 9. Photomicrograph showing verrucous squamous cell carcinoma. Click to enlarge.

Staging of penile cancer

TNM classification of primary penile cancer

  • TX: Primary tumor cannot be assessed
  • T0: No evidence of primary tumor
  • Tis: Carcinoma in situ
  • Ta: Noninvasive verrucous carcinoma
  • T1: Tumor invades subepithelial connective tissue

 

 

  • T2: Tumor invades the corpus spongiosum or cavernosum
  • T3: Tumor invades the urethra or prostate

 

 

  • T4: Tumor invades other adjacent structures

 

 

Regional lymph nodes

  • NX: Metastasis to regional lymph nodes is not assessed or cannot be assessed 
  • N0: No regional lymph node metastasis
  • N1: Metastasis to a single superficial inguinal lymph node
  • N2: Metastasis in multiple or bilateral superficial inguinal lymph nodes 
  • N3: Metastasis to deep inguinal and/or pelvic lymph nodes 

Metastasis

  • MX: Metastasis cannot be assessed
  • M0: No suspicion or detection of metastasis
  • M1: Metastasis

Metastatic patterns of penile cancer

Penile cancer always starts on the glans or the inner fold of the prepuce. It begins as a precursor (differentiated or undifferentiated PeIN) developing into a clinical tumor infiltrating through the basal membrane and into the lamina propria, corpus spongiosum  and possibly corpus cavernosum. When both glans and prepuce are affected, it may be difficult to determine where the cancer originates from. Type of tumor and grade of malignancy decide the growth and risk of proliferation.

If left untreated, penile cancer destroys the glans and the prepuce, invades the corpus spongiosum and corpora cavernosa, and may destroy the entire penis. Buck's fascia serves as a barrier in the beginning, but eventually the tumor will invade the corpora cavernosa.

Penile cancer spreads lymphatically to lymph nodes in the groin in all stages (also cis), but most commonly, invading cancer exists before metastasizing. Penile cancer can also cause hematogenous metastasis, but this is atypical and occurs rarely.

Typically, spreading occurs to the lymph nodes in the groin, where the cancer can establish a large metastatic tumor before spreading further lymphatically to the intrapelvic lymph nodes. Dissemination can then stop before further spreading. This is therapeutically very important to be aware of.

Metastasis is observed in the lungs and liver, but also occurs in the bone, brain, and skin.

Primary tumors in the urethra, prostate, bladder, and rectum can metastasize to the penis.

 

Symptoms of penile cancer

Any combination of phimosis and balanitis in adult men is suspect of cancer. The phimosis should be corrected surgically to facilitat washing and inspection of the glans.  

  • The earliest symptoms in men with a normally movable prepuce are ulcers, warts, redness, itching, burning, scab formation, or discomfort.
  • Later, ulceration of the glans or prepuce starts. During the tumor growth, the surface will become necrotic. This will then be infected with anaerobic bacteria causing a foul smell, especially in the presence of phimosis. 
  • Pain is not dominating with penile cancer, but in younger men, very intense pain from touch may be prominent.

It is not uncommon for a primary tumor to go unnoticed due to phimosis, or that the tumor is not visible (cis). The patient usually seeks medical help after a metastatic tumor in the groin can be seen or felt.

Differential diagnoses of penile cancer

Benign changes can occur on the penis which are not easy to distinguish from malignant tumors. Some of these are considered premalignant.

  • Lichen sclerosis (Balanitis xerotica obliterans) is a skin condition localized to the glans and the prepuce which presents as white atrophic patches. The condition may lead to phimosis and meatal stenosis. The association between balanitis xerotica obliterans and penile cancer is slight, and the disease is most common in elderly men. The secondary development of phimosis inhibits washing and prevents early diagnostics of possible malignancy development on the glans or inside of the prepuce. A radical circumcision should therefore be performed for this disease.
  • Condyloma acuminata is a common sexually transmitted disease caused by a virus belonging to the human papilloma virus group. The lesions normally grow as a papilloma and are usually found on the glans, prepuce, or shaft of the penis. These lesions are benign, caused by low-risk HPV 6/11, but mixed infections with high-risk HPV types are relatively common. Malignant transformation is not documented.
  • A variation of condyloma acuminata is giant condyloma acuminata. This disease is rare but shares the same histology as regular condylomas and grows very rapidly reaching grotesque sizes.These tumors may be similar to malignant tumors (verrucous carcinomas, papillary carcinomas and condylomatous carcinomas). These tumors do not metastasize, but may destroy the glans and prepuce, and become so large that a partial penis amputation is necessary. These patients usually seek medical help quickly because of the rapid tumor growth. Normal treatment is local extirpation without a mutilating effect.
  • Leukoplakias on the glans are rare. They appear as a white hypertrophic or atrophic patch and usually occur secondary to chronic irritation. The condition usually develops in the meatus. Biopsy is necessary to exclude cancer and intraepithelial neoplasia. (PeIN).
  • Bowen's, Erythroplasia de Queyrat and Paget's disease are  premalignant skin diseases that can occur on the shaft of the penis and scrotal skin, they must be biopsied and treated.
  • Bowen's disease is a clinical diagnosis which the pathologists now classify as undifferentiated PeIN. It manifests as a solitary, pigmented, scaly or scab-covered area that affects the penis shaft, scrotum, perineum, and the suprapubic area.
  • Erythroplasia de Queyrats is a clinical diagnosis which the pathologists now classify as undifferentiated PeIN, it grows on the glans and the prepuce where it presents as a well-defined, red patch.
  • Bowenoid papulosis is characterized by multiple, slightly elevated, red to violet or brownish papules, preferably on the penis shaft and scrotum. The condition, which is very rare, is preferably seen young men and going to regress without treatment. These are caused by high-risk HPV, most commonly HPV 16. Morphologically this cannot be separated from undifferentiated PeIN.

Prognosis of penile cancer

The prognosis for squamous epithelial cancer on the penis depends on the type of tumor (see Table), extent of the tumor (T stage) at diagnosis, treatment, and follow-up. Early diagnosis of malignant conditions is important.  

  • For localized cancer without metastasis, the 5 year survival is about 80%.
  • With metastasis to the groin but not the pelvic nodes, radical surgery of lymph nodes can cure the disease (5 year survival is 40-50%). 
  • If pelvic nodes are invaded, it may still be possible for successful surgery to cure the disease (5 year survival is 20%).

Recent publications show that the different variants of squamous cell carcinomas in the penis can be divided into three risk groups.

Risk groups at squamous cell carcinoma
Low risk Intermediary risk
High risk
Usual type, grade 1
Usual type, grade 2
Usual type, grade 3
Papillary carcinoma
Condylomatous carcinoma
Basaloid
Verrucous carcinoma
Mixed
Sarcomatoid
Pseudohyperplastic carcinoma.


Cuniculatum

 

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

Source: Cancer Registry of Norway

 

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References on penile cancer

  1. Cancer in Norway 2015, Cancer Registry of Norway, Institute of Population-based Research. Oslo, Norway
  2. Sandez DF et al. HPV- and non-HPV-related subtypes of penile squamous celle carcinoma: morphological features and differential diagnosis according to the new WHO classification 2015. Sem Diagn Pathol 2015; 32(3): 198-221
  3. Sandez DF et al. Pathological factors, behavior and histological prognostic risk groups in subtypes of penile squamous cell carcinomas.  Sem Diagn Pathol 2015; 32(3): 222-31
  4. Chaux A et al Seminars in Diagnostic Pathology. The role of human papillomavirus infection in the pathogenesis of penile squamous cell carcinomas 2012;29:67-71
  5. Velazquez EF el al Sem in Diag Pathol. Hostologic classification of penile intraepthelial neoplasia 2012;29:96-102
  6. Chaux A et al Human Pathology. Distribution and characterization of subtypes of penile intraepithelial neoplasia and their association with invasive carcinomas: A pathological study of 139 lesions in 121 patients 2012; 43(7):1020-7
  7. Chaux A et al Seminars in Diagnostic Pathology. New pathologic entites in penile carcinomas: an update of 2004 world health organization classification 2012;29(2):59-66
  8. Chaux A et al Am J Surg Pathol. Distinctive immunohistocheical profile of penile intraepithelial lesions: A study of 74 cases 2011; 35 (4):553-562
  9. AFIP Atlas of tumor pathology: series 4(14). Tumor of the prostate gland, seminal vesicles, penis and scrotum, Washington, DC 2011
  10. MCG Bleeker et al. World J Urol. Penile cancer: epidemiology and prevention 2009;27:141-150
  11. F. Algaba, S. Horenblas, G. Pizzocaro. Guidelines on penile cancer, Brussel ,European Association of Urologi 2009; 13
  12. WHO classification of tumours; Tumours of the Urinary system and male genital organs, IARC Press, Lyon 2004
  13. von Krogh G, Horenblas S. Diagnosis and clinical presentation of premalignant lesions of the penis. Scand J Urol Nephrol 2000; 34 (suppl 205): 201–14
  14. Horenblas S, von Krogh G, Cubilla AL, Dillner J, Meijer CJLM, Hedlund PO. Squamous cell carcinoma of the penis: premalignant lesions. Scand J Urol Nephrol 2000; 34 (suppl 205): 187–8
  15. Dillner J, Meijer CJLM, von Krogh G, Horenblas S. Epidemiology of human papillomavirus infection. Scand J Urol Nephrol 2000; 34 (suppl 205): 194–200
  16. Circumcision policy statement. Pediatrics 1999; 103: 686–93
  17. Iversen T, Tretli S, Johansen A, Holte T. Squamous cell carcinoma of the penis and of the cervix, vulva and vagina in spouses: is there any relationship? An epidemiology study from Norway, 1960–92. Br J Cancer 1997; 76: 658–60
  18. Hermanek P, Hutter RVP, Sobin LH, Wagner G, Wittekind C, red. TNM Atlas. 4. utg. Heidelberg: Springer, 1997: 264–71
  19. Windahl T, Hellsten S. Laser treatment of localized squamous cell carcinoma of the penis. J Urol 1995; 154: 1020–3
  20. Opjordsmoen S , Fosså SD. Quality of life in patients treated for penile cancer. A follow-up study. Br J Urol 1994; 74: 652–7
  21. Crawford ED, Daneshgari F. Management of regional lymphatic drainage in carcinoma of the penis. Urol Clin North Am 1992; 19: 305–17
  22. Gerbaulet A, Lambin P. Radiation therapy of cancer of the penis: indications, advantages, and pitfalls. Urol Clin North Am 1992; 19: 325–32
  23. Eisenberger MA. Chemotherapy for carcinomas of the penis and urethra. Urol Clin North Am 1992; 19: 333–8
  24. Grossman HB. Premalignant and early carcinomas of the penis and scrotum. Urol Clin North Am 1992; 19: 221–6
  25. Chaux A et al Am J Surg Pathol. Distinctive immunohistocheical profile of penile intraepithelial lesions: A study of 74 cases 2011; 35 (4):553-562 Grossman HB. Premalignant and early carcinomas of the penis and scrotum. Urol Clin North Am 1992; 19: 221–6
  26. Burgers JK , Badalament RA, Drago JR. Penile cancer: clinical presentation, diagnosis and staging. Urol Clin North Am 1992; 19: 247–56
  27. Canabas RM. Anatomy and biopsy of sentinel lymph nodes. Urol Clin North Am 1992; 19: 267–76
  28. Fosså SD, Hall KS, Johannessen NB, Urnes T, Kaalhus O. Cancer of the penis. Experience at the Norwegian Radium Hospital 1974–1985. Eur Urol 1987; 13: 372–
  29. Blandy JP. Penis and scrotum. I: Blandy J, red. Urology. Oxford: Blackwell, 1976: 1049–9

Diagnostics of penile cancer

Fifty percent of patients with penile cancer have had symptoms for a year before the diagnosis is made and treatment is started. Many early symptoms resemble benign lesions that can easily lead to delays in the diagnosis. 

In patients with changes on the penis that appear to be benign and do not respond to short-term conservative treatment, a biopsy should always be taken. The biopsy should be deep enough to evaluate the depth of invasion (T stage). This is a simple punch biopsy and can be performed by any doctor.
If the patient has phimosis, a radical circumcision must be performed with the biopsy. 

Examinations for detected cancer:

  • Physical assessment of the primary tumor:
    • The diameter of the tumor in millimeters and the depth of invasion is evaluated.
    • Prepare a plan for surgery and inform the patient of planned surgery.

Examinations for regional metastasis

Spreading of penile cancer occurs primarily lymphatically to lymph nodes and further to the intrapelvic lyph nodes. Lymph node spreading must be diagnosed as early as possible since it has a significant impact on the cure rate.  

  • Palpation of the groin. Enlargement of the inguinal nodes may be reactive.
  • Ultrasound of lymph nodes with fine needle cytology is done the day before planned surgery.
  • The sentinal node for penile cancer is situated near the branch of the superficial epigastric vein and the great saphenous vein. In the last seven years, sentinel node has been performed with isotopes (dynamic sentinel node biopsy). This is beneficial to the patient because the method is surgically minimal with few complications. The biopsy from the sentinel node is usually taken during surgery on the primary tumor. If cancer is present in the biopsy, an extended lymph node dissection is performed as a separate session.  
  • If there is suspicion of metastasis to intrapelvic lymph nodes on a CT, a robot-assisted laparoscopic iliacal node dissection is performed.

PROSEDYRER

Punch biopsy for penile cancer

General

With superficial tumors (Tis-T1), it is clinically impossible to assess the depth of infiltration without performing a punch biopsy. In order to safely choose organ-saving surgery, it is necessary to know whether the tumor is infiltrating and how deeply it expands.  

With advanced penile cancer (T2-T4), determination of the depth of infiltration is not problematic.

A biopsy from the glans or prepuce may be done under local anesthesia.

Equipment

  • biopsy punch with needle
  • forceps
  • knife
  • sutures
  • local anesthesia

Implementation

  • Inject the local anesthesia at the base of the tumor.
  • Resect a biopsy with a 2 or 4 mm needle.
  • Retrieve the cylindrical biopsy tissue.
  • Mark the superficial end of the biopsy tissue.
  • If necessary, insert a suture.
  • Request for the depth of infiltration in the referral to the pathologist.

Follow-up

  • Consult with the patient when the histology result is available.
Punch biopsy for penile cancer. Punch biopsy for penile cancer. Punch biopsy for penile cancer.

Biopsy of sentinel lymph node for penile cancer

General

A sentinel node is the first lymph node the cancer cells metastasize to. At the biopsy, the sentinel node is resected and examined for pathology. If lymph node metastases are not deceted by light microscopy, an immunohistochemistry is perfomed  to exclude sub- micrometastases. If there is no metastasis, the surgeon will limit the operation as if there is not tumor spreading (N0).

Dynamic sentinel node staging

In dynamic sentinel node staging, radioactive istopes are injected into the base of the primary tumor. The isotopes are then transported in the lymphatic system from the tumor to the first lymph node where they gather. This lymph node is identified with a gamma camera and peroperatively with a gamma detector. The sentinel node can be resected via a small incision.

The benefit of dynamic sentinel node staging is that the morbidity is low for the operative procedure. It is assumed that the sensibility and specificity is also higher than in anatomical sentinel node staging.

A close cooperation between the department of nuclear medicine and the surgeon is neccessary.

Indication

  • Diagnose penile cancer.

Goal

  • Examine for lymph node metastasis. 

Preparation

  • One hour before the radioactive isotope is injected, Emla® is applied to the skin where the injection will be made.
  • Usual preparations for the operation day.

Implementation

The injection is performed at the department of nuclear medicine in the morning of the operation day.  

  • The patient lies in the supine position.
  • 99m Tc-labeled colloidal human albumin is injected into the base of the tumor.  
  • Images are taken after 30 minutes with a gamma camera to localize radioactivity in the nodes.

In the operating theater 

  • A gamma camera is used for precise preoperative localization of the sentinel node.
  • A small incision is made in the skin over the node.
  • The node is retrieved through the incision.
  • The skin is sutured with absorbable sutures.
  • The node is sent unfixed for frozen sectioning to the pathologist.

Follow-up

  • Allergic reactions to human albumin can occur.
  • Otherwise, the usual postoperative observations apply.
Biopsy of the sentinel node in penile cancer. Biopsy of sentinel node in penile cancer.

Treatment of penile cancer

Treatment can be chosen when the tumor type and stage have been diagnosed. The European Association of Urology (2009) has guidelines for treatment of penile cancer (5).

Therapeutic schedule for penile cancer

Tumor- stage

Treatment 

Recommendations

Strong Optional  Investigational
Primary tumor Conservative therapy Primary/recurrent
PeIN, Ta-1 G1-2
T1 G3, T ≥ 2 (patients fit for surveillance) with metastasis to < 50% of nodes After chemotherapy, according to tumor response
Total/partial amputation Primary/recurrent
T1 G3, T ≥
Primary/recurrent Ta-1 G1-2 (conservative therapy not feasible)  
Radiation therapy Tumor invasion < 4 cm Primary T1-2 < 4 cm
(Patient refuses amputation)
In combination with chemotherapy
Regional (non-palpable nodes) Surveillance (Follow-up) PeIN, Ta G1-2, T1 G1, T1 G2 superficial growth T2 G2-3 (Patients prefering and fit for close follow-up) Negative dynamic sentinel node
Modified LND1 T1 G2 nodular or vascular growth, T1G3 or any T2. T1 G2 no vascular growth, no papillary growth (patients unfit for "follow-up". Positive dynamic sentinel node
Regional (palpable nodes) LND2 Postive nodes at presentation or positive nodes after "follow-up". Adjuvant chemotherapy or radiation therapy (> 1 positive node). Unilateral LND on nodal site (disease-free interval > 3-6 months)   
Chemotherapy + LND3 Fixed inguinal masses, pelvic nodes > 2 cm (patients fit for chemotherapy)       
Radiation therapy4 + LND     Fixed masses (patients unfit for chemotherapy)   
Distant metastases       Chemotherapy or palliative therapy (according to performance status, age, etc.)   

LND = lymphadenectomy

1. Modified LND can be extended to radical in cases where there are positive nodes.
2. If unilateral with non-papable nodes on the opposite side, modified LND can be carried out. Pelvic LND should be carried out only if there are >1 positive inguinal node. 
3. Chemotherapy should be discussed with oncologist and preferably be given in the context of clinical trials.
4. Radiation therapy has inconsistent results and high morbidity associated with surgery.

Surgery of penile cancer

Conservative surgical treatment of primary tumor

Conservative treatment is strongly recommended, but not at the cost of impairing the prognosis.

Surgical resection

  • When differentiated/undifferentiated PeIN on the inner fold of the prepuce and the epithelial cells of the glans are healthy, a radical circumcision is recommended.
  • When differentiated/undifferentiated  PeIN on the glans without evidence of change on the prepuce, a local resection on the glans may be performed, and epithelia on the inner fold of the prepuce can be used for coverage, or epithelia may be transplanted from the mouth/skin.
  • This method may also be applied if it is a superficially invading tumor. (Ta and T1/ grade 1 and 2).
  • If grade 3, surgical resection may be acceptable treatment for primary tumors T ≤ 1, but only on small tumors in fit patients.  
Collaboration with the pathologist is essential for conservative treatment because the surgical margins all around the specimen must be definitely free of cancer.

If there are multiple of the above conditions, YAG laser therapy is an alternative. The downfall is that this causes high morbidity for many weeks (months) after treatment and also uncertainty, since there is no assessment by a pathologist of margins of the specimen (14). If the lesion is premalignant, photodynamic therapy is also an alternative.

Radical surgical treatment of primary tumor

  • If the primary tumor invades the corpora spongiosa and/or cavernosa regardless of grade < T3, a partial or total penis amputation must be performed according to the extent of the tumor. There is no consistent consensus on the width of the margins required for the level of amputation. A 2 cm distance (palpable) from the tumor to the level of amputation has been recommended. If grade 1 and grade 2 tumors, 0.5 to 1.0 cm is sufficient.

Recurrence after conservative treatment of the primary tumor

  • If there is local recurrence after conservative treatment of the primary tumor, conservative treatment may still be considered, at any rate after primary surgery and YAG laser therapy.
  • Regular follow-up is critical after conservative primary surgery for early diagnosis of recurrence.

Nodular growth

Spreading of penile cancer occurs primarily lymphatically. There are very good treatment options available intended to cure the disease, even in cases where there are positive inguinal nodes. Spreading to inguinal nodes can be predicted statistically based on the grade and T stage of the primary tumor. This is also used in evaluation of indication of diagnostic procedures in the groin.

If inguinal nodes are palpable, ultrasound-guided biopsy is performed.

Dynamic sentinel node biopsy (DSNB) is performed if nodes are not visible with UL but grade 2-3, T>1. This procedure should be done bilaterally. If positive nodes are found during the procedure, a radical lymphadenectomy is performed in a separate session. DSNB has been shown to be valuable for other cancer types (for example, breast cancer) and the method has been improving for penile cancer for years.

A radical lymphadenectomy is a procedure with significant morbidity and should only be carried out on patients with positive nodes either subsequent to FNAC or DSNB.

Pelvic node surgery can be performed with laprascopic technique and should be done if there is suspicion of metastases on CT or PET scan.

PROSEDYRER

Penis Resection

General

If the penile cancer is localized, conservative treatment is recommended, especially in younger, sexually active men, however, treatment should be chosen for the best prognosis. 

Penile cancer is a multifocal disease in the epithelium of the glans and inner fold of the prepuce . With conservative surgery where parts of the glans with epithelium are conserved, the patient must have thorough follow-up for many years. If this is not possible, a partial amputation is recommended with removal of the entire glans.  

Indications

  • Squamous epithelial penile cancer, PeIN - T1
  • T2 fit for resection and the patient is fit and motivated for frequent follow-up after treatment.

Goal

  • Conservative treatment to cure penile cancer.

Equipment

  • Chlorhexidine 5mg/ml
  • Drape
  • Local anesthesia
  • Sterile rubber elastic 
  • Scalpel blade 
  • Absorbable sutures
  • Sterile vaseline compress
  • Cup with formalin
  •  

    Preparation

  • The patient must be informed about the nature of the surgery and follow-up routines.
  • A punch biopsy of the tumor should be completed with result from pathologist available.
  • If an epithelial skin transplantation will be performed, the donor site must be prepared. 
  • Antibiotic prophylaxis (anaerobic and aerobic bacteria)
  • Implementation

    Small tumors are removed under local anesthesia, block anesthesia, or general anesthesia/spinal anesthesia.

    • A penile block is performed. The anesthesia is injected at the root of the penis.
      • Find the edge of the pubic bone.
      • Perform the injection deep into the pudendal nerve and the dorsal nerve of the penis. Inject slowly.
      • Allow the anesthesia to work for 10 minutes.
      • Inject local anesthesia around and under the tumor. Allow it to work for 2 minutes.
      • Check with forceps whether the anesthesia is adequate.
    • Squeeze the glans/distal penis and apply a tourniquet to stop blood flow. 
    • Mark the borders of the resection (free margins) to the sides and in depth).  
    • Resect with good margins around the tumor.
    • Inspect the specimen for macroscopically involved margins.
    • Orient the specimen and mark with sutures toward the meatus and dorsally.
    • Place the specimen in a cup with formalin.
    • Assess whether it is necessary to repair the defect on the glans with a transplant.
    • Release the tourniquet and stop blood flow with diathermy, or possibly with small suture ligatures.
    • Suture the incision or transplanted epithelia from the prepuce/mouth/skin.
    • Apply a vaseline bandage.
    • Pull the prepuce forward.
    • Insert a thin catheter. (Ch 10 -14)
    • Bandage with mild compression.   

     

    Follow-up

  • Observe for hematoma. If present, it must be opened.
  • The catheter is removed the day after the operation.
  • Inform the patient on the pathology result.
  • The sutures should dissolve within 3–5 weeks.
  • Penile resectionPenile resectionPenile resectionPenis resection
    Penis resection

    Drug therapy of penile cancer

    Cisplatin and fluoruracil are recommended as adjuvant treatment if > pN1. 

    For very advanced cases, multimodal treatment with neoadjuvant chemotherapy before surgery may be an option. 

    PDT (Photo dynamic treatment)

    For differentiated and undifferentiated PeIN (CIS and atypical hyperplasia) without visible tumor and no histological suspicion of invading growth, photo dynamic therapy (PDT) may be considered. The principle of this treatment is that the malignant/premalignant cells are sensitized to light of specific wavelength and are destroyed by this light. In principle, this is the same treatment used in some types of superficial skin cancer.

    PROSEDYRER

    Sun Exposure under Drug Therapy

    General

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

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

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

    Indication

    Sun exposure in connection with drug cancer treatment.

    Goal

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

    Definitions

    Photosensitivity

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

    Phototoxicity

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

    Photoallergy

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

    Photoinstability

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

    PPE ( palmoplantar erythrodysesthesia = Acral erythema )

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

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

    Acne-like rash

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

    Hyperpigmentation

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

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

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

    Radiation Recall Dermatitis (RRD)/Photo Toxic recall reaction

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

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

    Preparation

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

    Implementation

    General Precautions

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

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

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

    Medicaments that most commonly cause skin reactions

    Medicament Common reactions Remedial action
    Dakarbazin (DTIC)


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

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

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

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

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

    (2, 9)

    Fluorouracil (5-FU®)

     

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

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

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

    Radiation recall
    Treatment as with phototoxic

    Kapecitabin (Xeloda®)

     

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

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

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

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

    Vinblastin

     

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

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

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

    Tegafur

     

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

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

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

    EGFR-hemmere

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

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

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

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

    References


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

    Preparation of Chemotherapy, Spills, and Cleaning a LAF Bench

    General

    Preparation of chemotherapy outside of a pharmacy

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

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

    Designated room with LAF-bench to dilute/mix chemotherapy

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

    Goal

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

    Handling of chemotherapy spills

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

    Goal

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

    Cleaning of LAF-bench

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

    Goal

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

    Source

    Applicable directives and guidelines (www.lovdata.no)

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

    Equipment

      Preparation of chemotherapy in a hospital

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

    Handling of chemotherapy spills

    Spill kit includes:

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

    Washing of LAF-bench

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

     

     

    Preparation

    Preparation of chemotherapy outside of the pharmacy

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

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

    Handling of chemotherapy spills

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

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

    Washing of LAF-bench

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

     

     

    Implementation

    Preparation of chemotherapy drugs outside of a pharmacy

    Aseptic procedure

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

    Multiple additions

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

    Handling of chemotherapy spills

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

    Washing of LAF-bench

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

    Routine washing

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

    Follow-up

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

    First aid if contact with chemotherapy drugs

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

    Radiation therapy of penile cancer

    In most cases, radiation therapy will only be appropriate to consider

    • as palliative therapy
    • in combination with surgery and/or chemotherapy, for fixed positive nodes
    • at necrotizing tumors where primary surgery alone poses a risk
    • if the the tumor is inoperable

    In these situations, multimodal treatment is necessary involving an oncologist, pathologist, radiologist, and an urologist.

    If the cancer is locally advanced, inoperable, or there are remaining tumor after surgery, radiation therapy is given with the guidance of CT. The pelvic field is irradiated with 50 Gy in 25 fractions and a boost of 14 Gy in 7 fractions to the macrotumor.

    Complication treatment of penile cancer

    Chemotherapy and radiation therapy cause varying degrees of side effects. It may be necessary to provide supportive care in order for the patient to complete and gain the full effect of planned treatment, or to reduce the burden of side effects.

    Chemotherapy may cause

    Radiation therapy may cause

    • Diarrhea and sometimes nausea.
      • Acute diarrhea can usually be kept under control with Imodium®.
      • Nausea is treated with Afipran®.
      • Skin soreness

      PROSEDYRER

      Treatment of Nausea Induced by Chemotherapy

      General

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

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

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

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

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

      Indication

      • Nausea induced by chemotherapy drugs.

      Goal

      • Prevention and treatment of nausea and vomiting.

      Definitions

      Chemotherapies according to emetic potential

      High emetogenicity   

      Group 1

      Moderate emetogenicity   

       Group 2

      Low/minimal emetogenicity

      Group 3

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

      CHOP (cyclophosfamide, doxorubicin, vincristine, prednisolone)
      Gemcitabine

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

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

      References

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

      Preparation

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

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

      Implementation

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

      Antiemetic regimens

      Mildly emetic chemotherapy

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

      Moderately emetic chemotherapy

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

      Highly emetic chemotherapy, or if other treatment does not help

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

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

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

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

      Delayed nausea

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

      Conditional nausea

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

      Follow-up

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

      Nutrition during Cancer Treatment

      General

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

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

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

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

      Indication

      • Cancer treatment (chemotherapy, radiation, surgery).

      Goal

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

      Definitions

      Subjective Global Assessment (SGA)

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

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

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

      Calculation of nutrition and fluid requirements

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

      Nutritionally enriched diet / enrichment of food and beverages

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

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

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

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

      Tube feeding

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

      Tube feeding is used in the event of

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

      Tube feeding must not be used for the following conditions.

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

      Tube feeding solutions

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

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

      Parenteral nutrition

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

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

      Preparation

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

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

      Tube feeding

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

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

      Parenteral nutrition

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

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

      Implementation

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

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

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

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

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

      Tube feeding

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

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

      For a running feeding tube:

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

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

      Bolus supply

      Initiation of tube feeding with bolus supply is only recommended

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

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

      Continuous supply

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

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

      Parenteral nutrition

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

      The patient must be monitored closely in relation to

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

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

      Follow-up

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

      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.

      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.

      Bone Marrow Stimulation with G-CSF

      General

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

      Indications 

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

      Goal

      • Maintain treatment intensity

      Preparation

      The patient should be adequately informed about the treatment.

      Implementation

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

       

      Follow-up Care

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

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

      Smoking cessation in connection with cancer treatment

      General

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

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

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

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

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

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

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

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


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

       

      Indication

      Weaning of nicotine in connection to cancer treatment. 

      Goal

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

      Preparation

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

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

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

      Implementation

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

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

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

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

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

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

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

      Treatment with nicotine replacement therapy

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

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

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

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

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

      Side effects

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

      Precautions

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

      Treatment with non-nicotine medications

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

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

      Side effects

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

      Precautions

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

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

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

      Side effects

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

      Precations

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

      Follow-up

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

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

      References

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

      Follow-up care after treatment of penile cancer

      Intervals

      Conservative treatment

      Patients having conservative treatment of the primary tumor either by surgery, YAG laser, or radiation therapy, and have remaining epithelial tissue on the glans or inner fold of the prepuce, have a high rate of recurrence.

      These patients must have regular follow-up:

      • every 2 months for the first 2 years.
      • every 3 months for the 3rd year and thereafter every 6 months.

      It is also very important that the patient learns how to perform self examinations (inspection and inguinal examinations ).

      Amputation

      Patients treated with a partial or total amputation rarely have local recurrence. During the first 2 years, the risk is greater for developing nodal metastasis.

      These patients must have regular follow-up:

      • Every 4 months for the first 2 years.
      • Twice a year in the 3rd year. 
      • Thereafter, yearly.

      Positive nodes and metastasis

      Patients with positive nodes and metastases when the primary tumor is removed should be monitored:

      • Every 2 months for the first 2 years.
      • Every 3 months the 3rd year. 
      • Every 6 months for the 2 following years.

      Inguinal lymphadenectomy

      If an inguinal lymphadenectomy has been performed (pN0), a physical examination should be performed:

      • Every 4 years for 2 years.
      • Every 6 months during the 3rd year.
      • Further follow-up is not necessary after the 3rd year.

      Inguinal metastasis

      Patients having inguinal metastasis at presentation or found during the follow-up period should have a CT of the pelvis/avdomen. Other cases must have follow-up that is individualized.

      Local physical examination

      • Anamnesis
      • Inspection of the organ (description, photos, meatus).
      • Palpation of the groins.

      Supplementary tests

      • Pelvic and abdominal CT for positive nodes.
      • Chest X-ray for distant metastasis.

      Delayed effects

      Many patients experience problems pertaining to sexual life after treatment, however, most patients describe their quality of life as satisfactory, according to a study on tumor-free patients in Norway (18, 19).

      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