Malignant melanoma most often occurs in the skin, but can also occur in mucous membranes (nose, sinuses, mouth, genitals, urinary tract, bowel and esophagus), in eyes and lymph nodes.
In men, the most common localization of melanoma is the upper body and head/neck. Females previously had the highest incidence of melanoma on the extremities, but after around year 2000 the upper body is the most frequent localization also with them .
Malignant melanoma in the mucous membranes occurs primarily in the head/neck region. The most common localization is the nasal cavity.
Uveal malignant melanoma is the most common primary malignant tumor in the eye.
Malingnant melanoma - Essential facts
Compared to other cancers, malignant melanoma is fairly common and represents 4.5% of all new cancer cases in the United States. Approximately 2.1% of men and women will be diagnosed with malignant melanoma at some point during their lifetime. Malignant melanoma is most frequently diagnosed among people aged 55-64 and is more common in men than women and among individuals of fair complexion and those who have been exposed to natural or artificial sunlight (such as tanning beds) over long periods of time. There are more new cases among whites than any other racial/ethnic group.
In 2016, it was estimated to be 76,380 new cases of malignant melanoma in the United States. (1)
Age-specific incidence of skin melanoma, 2009–2013.
Source: Cancer Registry of Norway
Incidence of skin melanoma, 1954–2013.
Source: Cancer Registry of Norway
Histology of malignant melanoma
The microscopic diagnosis of pigmented lesions is based on the presence and localization of atypical melanocytes. Aggregation of atypical melanocytes may be seen in atypical/dysplastic nevi. These may sometimes be difficult to distinguish from superficial spreading malignant melanoma. There are also some more infrequent variants, as for instance desmoplastic melanoma, which may look similar to benign lesions, and thereby may give rise to diagnostic problems. These cases require experience and high professional skill.
For the diagnosis of malignant melanoma several other factors must be evaluated:
- Type of melanoma
- Infiltration of vessels
- Resection margins
- Mitotic rate, or Clark`s level if mitotic rate cannot be determined reliably.
- In addition, possible lymphocyte invasion, presence of necrosis, regression and neurotropism (tumor growth along nerves) should be commented.
Melanomas are divided into four types.
Superficial spreading malignant melanoma
In this tumor type (circa 70%), large atypical melanocytes are often found infiltrating epidermis in cooperation with a component growing into the underlying dermis. These atypical melanocytes become different, often smaller than those in epidermis. The melanocytes in epidermis spread peripheral around the dermal invasive part of the lesion. Thereby the name “superficially spreading.”
Nodular malignant melanoma
In this type (circa 15%) there is no growth of melanocytes in the epidermis outside the invasive part of the tumour. Secondary tumor infiltration may be seen centrally superficial to the lesion.
Lentigo malignant melanoma
In lentigo malignant melanoma (circa 10%) epidermis is thin and atrophic, indicating damage to actin. The melanocytes are spindle-shaped or epitheloid and grow linearly in one or more layers in the epidermis.
Acral lentiginous melanoma
Acral lentiginious melanoma (circa 5%) are observed in the sole of the foot, palm of the hand, toes, fingers and sublingually, the epidermis is thick with elongated rete ridges. In this type of melanoma, large single atypical melanocytes are seen in the basal part of the epidermis.
Amelanotic melanomas (without pigment) are rare and amount to 1-2% of the melanomas. The diagnosis is most frequently made after it has metastasized.
Light microscopic picture of in situ components beside the main tumor in a superficially spreading melanoma. Click to enlarge.
Light microscopic picture of nodular malignant melanoma. No infiltration of epidermis. Click to enlarge.
Light microscopic picture of superficial malignant melanoma infiltrating epidermis. Click to enlarge.
Thickness of tumor (ad modum Breslow)
Tumor thickness is the most important single factor for the histological evaluation. This is measured (in micrometer under the microscope) as the longest diameter from the top of the tumor to the deepest epidermal tumor cell. The length is given in mm with one decimal.
The pathologist must consider whether the pathological slides are representative for the type and extent of the growth, assuming the entire tumor is sent for examination. The slides must include the area with the expected deepest infiltration.
The histologic information is important for the choice of treatment and for the further evaluation of melanoma patients. Satellites in the dermis must be included. The evaluation of the tumor thickness may be uncertain or impossible when regressive changes in the tumor have taken place. In such cases, the length both with and without inclusion of the regressive zone may be given by the pathologist.
The following factors must be included in the pathology report:
- Histological type, invasive or in-situ
- Thickness of tumour, when invading (Breslow) in tenths of mm
- Ulceration (present/not present)
- Other factors (infiltration of vessels, infiltration of lymphocytes)
- Resection margins
For lymph node resection:
- Number of metastatic nodes
- Total number of resected nodes
- Perinodal growth of tumor
- Tumor in the resection margin
In malignant melanomas, a variable microscopic picture is seen. Lymphocyte filtration is less frequent compared to skin lesions. Around 1/3 of the melanomas in the nose and oral cavity are melanotic. This type of melanoma may be difficult to differentiate from other types of cancer in mucosal membranes. Immunohistochemistry may be helpful in this respect.
Etiology of malignant melanoma
5-10% of all cases have a familial disposition. To use the definition "melanoma family," at least two first-degree relatives or at least three family members must have developed the tumor.
People with accumulation of malignant melanoma in the family should be referred to a genetic evaluation. This also applies to people with two relatives with malignant melanoma, where one of them has had two or more melanomas. People with incidence of both pancreatic cancer and malignant melanoma among close relatives (possibly the same person) should also be offered genetic evaluation.
People with increased risk of malignant melanoma are offered follow-up. The aim is early diagnosis and treatment, which are believed to improve the prognosis.
About 1% of all newborns have birth marks, of which most are small. There is an increase in malignancy development in large birth marks. It has not been proven whether there is an increased risk for developing melanoma in small and medium-sized birth marks (4).
Atypical melanoma/dysplastic nevus syndrome
Familial incidence of atypical nevi is categorized as atypical mole syndrome (AMS). The National Institute of Health (NIH) defines AMS as:
- incidence of melanoma in one or more 1st or 2nd degree family members
- high number of moles, at least > 50 including atypical moles
- moles which meet criteria for atypical histology
Atypical moles pose an increased risk for developing melanoma. The greatest risk factor is atypical moles in people from families with one or two family members who have had melanoma. It is unclear whether isolated moles themselves can be considered pre-stages for melanoma, or whether these lesions indicate a skin type that more easily develops atypical moles and melanoma.
|Sun rays on the skin can, in addition to many beneficial effects such as vitamin D synthesis, suntan, and wellness, cause DNA damage in multiplying cells. Over time, this damage can lead to cancer.
Epidemiological studies provide evidence that sunlight influences the development of melanoma. Studies document that within the same population there is a higher incidence of melanoma within decreasing latitudes.
The incidence of melanoma is higher among people who work indoors and visit southern destinations causing intermittent, strong UV exposure.
Sunscreen has been shown to reduce:
- DNA damage in the skin after exposure to UV light
- UV induced immunosupression
- the development of moles (The strongest isolated risk factor for developing melanoma.)
- age-induced skin changes
- incidence of actinic keratosis and squamous cell carcinoma
There is also scientific evidence that regular use of sunscreen reduces the risk of developing melanoma . The Norwegian Cancer Society and Norwegian Melanoma Group recommends using sunscreen (at least SPF 15) if physical protection is not possible .
- Full agreement has not been reached whether the risk is increased by use of solarium, however, based on known skin damage from UV radiation and conclusions from different studies in the field, the Norwegian Melanoma Group does not recommend use of solariums. They recommend using strong precaution under 18 years of age as UV exposure in childhood is more detrimental. IARC published in 2007 a review article which concludes that the risk of melanoma increases by 75% for people who use solarium before 35 years of age (19). An 18-year age limit has been introduced from 1th of July 2012 in Norway. In addition, all tanning salons must be staffed with competent personnel from 1th of January 2014.
- A large number of benign moles are a risk factor for developing melanoma. (8)
- Studies associate the incidence of melanoma with the use of chemicals. (5)
Metastatic patterns of malignant melanoma
In 2/3 of the patients, the first metastases are locoregional while 1/3 have distant metastases.
- Local recurrence – relapse in the scar or under the scar after the primary operation
- In-transit metastases – metastases which occur along the lymph pathways between the primary tumor > 2 cm from the scar and the regional lymph nodes
- Satellites – new tumor within a radius of 2 cm from the scar after removal of primary tumor. Satellites may be caused by remains of the primary tumor.
Satellites and in-transit metastases should give suspicion of distant metastasis.
Malignant melanoma can metastasize to almost all the regions of the body. One-third of patients have distant metastases without previous spreading to regional glands. Malignant melanoma can spread both hematogenously and through the lymphatic vessels.
The most common metastatic localizations are the skin, lymph nodes, lungs, liver, bone, and brain. The first metastases usually appear in the skin or lymph nodes, but metastases to the lungs, liver, and brain are the most common causes of death in patients with advanced malignant melanoma.
Melanoma in mucous membranes commonly metastasize to the liver, lungs, brain, and dermis. Local growth of tumor may be extensive with bone destruction and growth into the sinuses. Local recurrences are very common. 10-23% have lymph node metastases at the time of diagnosis and up to 25% will develop lymph node metastases in the disease course. Lymph node metastases are more common in oral malignant melanomas than for sinonasal. Five to 10% have distant metastases at the time of diagnosis.
Spreading of melanoma in the eye occurs almost always hematogenously since the eye lacks lymph drainage. In > 90% of patients, liver metastases are the first sign of disease dissemination (11).
Staging of malignant melanoma
For skin melanoma, the TNM classification is used (13) for staging.
The TNM system describes the anatomical extent of the disease at presentation. “T” refers to the extent of the primary tumor. “N” (node) refers to the absence or presence and extent of regional lymph node metastasis. “M” refers to the absence or presence of distant metastasis.
The TNM classification differentiates between clinical classification (TNM) and pathology classification (pTNM). The staging is performed after removal and then according to pTNM.
pT classification of melanoma is based on three criteria:
- Thickness of the tumor (Breslow), the largest vertical diameter of the tumor in millimeters.
- Ulceration of primary tumor present or not
- pTX – primary tumor cannot be assessed
- pT0 – no evidence of primary tumor
- pTis – melanoma in situ
- pT1 – tumors 1 mm or less in thickness
- pT1a – without ulceration and mitoses <1/mm²
- pT1b – with ulceration or mitoses ≥1/mm²
- pT2 – tumors from 1,01 mm - 2 mm in thickness
- pT2a – without ulceration
- pT2b – with ulceration
- pT3 – tumors from 2,01 mm - 4 mm in thickness
- pT3a – without ulceration
- pT3b – with ulceration
- pT4 – tumors more than 4 mm in thickness
- pT4a – without ulceration
- pT4b – with ulceration
- NX – regional lymph node cannot be assessed
- N0 – no regional lymph node metastasis
- N1 – metastasis in regional lymph node
- N1a – only microscopic metastasis (clinically occult)
- N1b – macroscopic metastasis
- N2 – metastasis in two or three regional lymph nodes, satellites or in-transit metastasis
- N2a – only microscopic metastasis
- N2b – macroscopic metastasis
- N2c – satellites or in-transit metastasis without lymph node metastasis
- N3 – metastases in four or more regional lymph nodes, or coalescing metastatic regional lymph node, or the combination satellite-/in-transit metastasis and lymph node metastasis
- MX – distant metastasis cannot be assessed
- M0 – no distant metastasis
- M1 – distant metastasis
- M1a – distant metastasis in skin, subcutanous tissue or lymph nodes outside regional lymph nodes
- M1b – lung metastases
- M1c – metastasis in other sites, or any site and an elevated serum lactate dehydrogenase (LDH)
||Regional lymph node metastases
Symptoms of malignant melanoma
Characteristics of malignant melanoma are:
- growth - diameter often more than 6 mm
- two-tone color
- asymmetrical shape, uneven coloration, and irregular borders
In some cases, melanoma will:
- bleed or cause sores
Examples of moles with uneven color and black areas, uneven surface and irregular borders:
Malignant melanoma in the nose/sinuses may cause symptoms such as:
- nose bleeding
- unilateral nasal obstruction
- double vision
- facial pain
Malignant melanoma in the mouth may cause symptoms such as:
- pigmented lesions
- changes in fit of dentures
In the eye, a melanoma may cause:
- blurry vision in one eye
- distorted field of vision
- pressure in the eye
The symptoms depend to a large degree on the localization. There may be no symptoms.
Differential diagnoses of malignant melanoma
A series of conditions may resemble malignant melanoma:
- Verrucae seborrhoicae with secondary inflammation reaction
- Pyogenic granulomas
- Pigmented basal cell carcinoma
- Hemorrages in regular verruca
- Vascular changes
- Pigmented fibromas
- Addison's disease
- Blue nevus
- Kaposis sarcoma
- Oral nevus
- Amalgam tatooing
- Grafitti tatooing
- Melanotic macule
- Peutz-Jeghers syndrome
- Physiological pigmenting
Examples of differential diagnoses
|Angioma. Click to enlarge.
||Blue nevus. Click to enlarge.
||Seborrheic keratosis. Click to enlarge.
|Pigmented basalioma. Click to enlarge.
||Pigmented basalioma. Click to enlarge.
Prognosis of malignant melanoma
In 2013, there were an estimated 1,034,460 people living with malignant melanoma in the United States. The earlier malignant melanoma is caught, the better chance a person
has of surviving five years after being diagnosed. 83.8% are diagnosed at the local stage and the 5-year survival for
localized malignant melanoma is 98.4%. The number of malignant melanoma deaths is highest among people aged 75-84. Death rates have been stable over 2004-2013. (1)
Mortality is low compared to other cancers, but has increased in the last ten years. After removal of the primary tumor, over 80% of patients operated for malignant melanoma are cured. However, the prognosis depends on whether the disease is localized, regional, or metastatic at the time of diagnosis.
In-transit metastases and satellites should give suspicion of distant metastases and are associated with poor prognosis. For in-transit metastases and satellites, the expected five year survival is 50% without lymph node metastases, and 30% with lymph node metastases.
The prognosis with lymph node metastases is dependent on the number of glands containing tumor tissue. In patients with spreading to only one gland, the ten year survival is almost 50% after radical lymphadectomy. If there are metastases in 2-4 glands the prognosis is more serious, and the 10 year survival is 20-30% after surgery. (9)
The mortality rate is somewhat higher for men than for women.
Elderly patients have a poorer prognosis than younger patients.
The localization of the melanoma also has prognostic significance. For example, prognosis is better for melanoma localized to the face, neck and lower extremities. Melanoma localized on the foot, hand, and sublingually has the poorest prognosis.
For melanoma in the eye, the mortality rate is 30-50% depending on the size and localization of the tumor. (11)
Five-year relative survival for patients with melanoma (skin), in percent, during the diagnosis period 1974–2013.
Source: Cancer Registry of Norway
Prognostic factors for skin melanoma
- Vertical thickness of primary tumor. The Breslow thickness is the most important prognostic parameter as long as metastases are not present at the time of diagnosis.
- Ulceration. The prognosis is worse in cases of ulceration (9,10).
- Mitotic rate. Tumor cell proliferation measured by mitotic rate is an independent prognostic factor for the thinnest melanomas. The presence of > 1 mitosis / mm ² predicts a poorer prognosis.
- Regional and metastatic disease. Metastases to regional lymph nodes will lead to a drastic fall in five year survival. The number of metastatic glands greatly influences the prognosis. For distant metastases, the chance of survival is < 10%. The prognosis is best if the metastatic spreading is to the skin, subcutanous tissue, lymph nodes, and lungs. The prognosis is the poorest in cases of spreading to the brain and liver.
Prognostic factors for malignant melanoma in mucous membranes
- Tumor thickness. This is the most important prognostic indicator. Lesions with thickness < 0.75 mm metastases are rare. Lesions with thickness > 5 mm have a poor prognosis.
- Vessel infiltration. This is a significant prognostic factor and predicts local relapse, regional metastases, and distant metastases, as well as disease-free survival.
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Diagnostics of malignant melanoma
The dramatic increase in the number of malignant melanoma in the skin has lead to an increased awareness in the population of the association between sunbathing and malignant melanoma. People with moles seek medical advice earlier than in previous years.
A thorough anamnesis should always be performed, as well as adequate examination and dermatoscopy. For examination of suspect skin lesions, a systematic approach is beneficial.
Malignant melanoma which is asymmetric, has an uneven border, and irregular color. Click to enlarge.
ABCD rule is a helpful tool:
- A – Asymmetry
- B – Border. These lesions usually have an irregular, notched, ragged, or blurred edge.
- C – Color. The color is irregular and often with black parts.
- D – Diameter. Moles that are usually 6 mm in diameter or larger.
- E – Elevation
The final diagnosis is based on histopathological examinations of the lesion. In cases where the tumor is localized to the face in elderly, fragile individuals, or for suspicion of malignancy in a small part of a large lesion, it may be appropriate to take a biopsy for a histological diagnosis.
Tangential biopsies are contraindicated because specification of the Breslow tumor thickness is then not possible. Excisional biopsy of pigmented lesions, where malignant melanoma cannot be ruled-out, can be carried out by a dermatologist or general practitioner. For large lesions or in cosmetically sensitive locations such as the face, the excision should be carried out by a surgeon/plastic surgeon.
Sentinel node (sentinel lymph node) is a diagnostic and prognostic procedure. It is not proven to improve survival and is not used routinely in Norway. Norwegian Melanoma Group proposes to implement sentinel node procedure for cutaneous melanoma localized to lower extremities, initially stage 2a. To reduce the number of sentinel node procedures, it is proposed that this starts at university hospitals and that the patients initially are screened with cytology samples and by a radiologist with extensive experience in ultrasound.
The National Institute of Health separates birth marks according to size:
- small nevus < 1.5 cm
- medium nevus 1.5–20 cm
- large nevus > 20 cm
Moles can be described as atypical based on clinical and/or histological criteria. A clinically atypical mole:
- is at least 5 mm large
- is asymmetrical
- has irregular borders and color variation
An excision should be done of an atypical mole if there is suspicion of malignancy. The patient should be referred to a dermatologist if he/she has an atypical mole or a family member with malignant melanoma for information, instruction, and follow-up.
For suspicion of malignant melanoma in a mucous membrane in the head/neck region, a clinical examination should be supplied with:
- CT/MRI skull base/jugulum
- CT thorax
- ultrasound of liver
- blood status
Treatment of malignant melanoma
Early diagnosis and surgical treatment are decisive for survival of malignant melanoma.
Surgery is the only treatment modality having curation as a goal. Other treatment modalities are of a palliative and symptom-postponement nature.
Surgery of malignant melanoma
The primary surgery for a suspect melanoma may well be performed by general practitioners. Lesions in difficult locations as the face, ear, breast, fingers, toes and foot sole should be referred for plastic surgery. Resected pigment skin lesions should routinely be sent for histopathological examination, even if there is no suspicion of malignancy.
Exsision biopsy of a suspected melanoma should be performed with an eliptical inscision 2-5 mm into normal skin with a margin of subcutaneous fat. Thereby the whole lesion can be examined with determination of the thickness of the tumor (Breslow), which will determine further surgical treatment.
For histologically verified malignant melanoma smaller extended margins have been recommended in recent years. Most surgical defects can be closed directly. The extended resection should be performed to the underlying fascia.
Sometimes it may be necessary to cover the defect with a skin graft, or a skin patch with reconstructive surgical techniques. Who should perform the resection depends on localization, the need for margins and available expertise.
|Surgical margins determined by tumor thickness (Breslow)
|Melanoma type/tumor thickness
|In situ/Lentigo maligna
|Lentigo maligna melanoma
||1 cm and 2 cm for Breslow > 2 mm
|< 1 mm
||Minimum 1 cm, max 2 cm. Back 2 cm
||Minimum 2 cm
|> 4 mm / Desmoplastic type
Nowadays examination of sentinel node is recommended in the primary diagnostics of malignant melanoma. This is particularly for tumors with thickness 1-4 mm without ulceration and for thinner ulcerated tumors. In Norway the procedure is particularly recommended for locations in the extremities. These amounts to 40% of all melanomas of the skin with 10% in the upper and 30% in the lower extremities. The sentinel node examination should ideally be performed simultaneously with the extended resection.
The lymph nodes of the axilla or groin should be examined by ultrasonography and cutology to identify patients with clinical lymph node metastases, thereby reducing the need for sentinel node examinations.
Further identification of sentinel nodes is performed with lymphoscintigraphy and injection of blue dye.
As the melanoma originate in the dermis the isotope and dye must be injected intradermally, or around the scar if the melanoma has been excised previously. The injection should not be given subcutaneously.
The recommended dose of isotope is 60-70 MBq 99m Tc-Nanocoll intradermally, in 4 injections around the melanoma/ scar, total volume 0,1 ml. The isotope examination may be performed on the day of surgery as the circulation of lymph in the skin is rapid. Bue dye is injected at the start of the operation. The sentinel node is located by inspection for blue dye in lymphatic vessels and nodes and by Geiger counter /gamma probe.
Surgical treatment of local recurrence
Local recurrence is defined as growth of tumor in or deep to the scar after the primary operation. Wide surgical excision is recommended for isolated recurrence.
In-transit metastases are metastases originating between the location of the primary tumor and the regional lymph nodes, such single metastases are widely excised. For multiple metastases the treatment will depend on the localization and extent of the metastases.
If surgery is not possible for an extremity melanoma, isolated limb infusion (ILI) or isolated limb perfusion (ILP) is the next treatment option. Oslo University Hospital is national centre for this kind of treatment.
Amputation of extremity is seldom necessary. For tumors located in the truncus or on the extremities not available for ILI/ILP, local radiotherapy, CO2 laser or electrochemotherapy may be an alternative. This is particularly relevant for elderly patients.
Surgical treatment for lymph node metastases
All patients with invasive melanoma are in danger of having metastases to the local nymph nodes. Involved nodes are firm or hard, with a rounded or slightly buckled surface and most frequently is the lymph node nearest to the primary lesion. Lymph node metastases are rare for melanomas with a thickness of <1 mm. For melanomas of 1 mm or thicker the tendency for metastasizing increases with increasing thickness.
In cases of clinical suspicion of lymph node metastases, cytological examination (FNAC) can confirm the diagnosis. A negative FNAC should be repeated if the node is continuously suspicious during a short observation periode. Open biopsy may increase the risk for tumour soiling. When excision biopsy in rare cases has to be performed, the inscision should be put in a way that it is easily resected with the specimen in a later radical lymph node dissection. This is done in a curative intent or for local control.
For curative intention, meaning no distant metastases, an adequate local resection should be performed if at all possible. Local control is especially desirable when there is a danger of tumor perforation.
In a lymphadenectomy, all of the lymph node-containing tissue is removed from the region. Limited dissection does not guarantee adequate removal of positive nodes, therefore, a "node-picking" operation should not be performed. Adequate dissection reduces the chance for recurrence in dissected lymph node stations. Such recurrence are difficult to treat.
Extranodal growth, extensive tumor involvement, or tumor spillage during an operation, should often be treated with radiation to prevent local recurrence.
Lymphadenectomy is performed in the:
- Malignant melanoma with regional lymph node metastasis
Plastic surgery instruments
- Removal of hair in the area.
- Clyx the preoperative evening if the patient is to be bedridden postoperatively.
- Thrombosis prophylaxis the preoperative evening.
- Measure for long antithrombotic stocking.
- The operation is performed under general anaestesia.
- Groin: Supine position: The leg on the involved side is bended at the knee ("tailor position").
- Axilla: Supine position. The arm on the involved side in 70-90 degrees angle to the body.
- Neck: Supine position. The head turned laterally on a cushion to stretch the neck.
The superficial nodes are localized at least 5 cm above the inguinal ligament in the entire femoral triangle and spread on both sides of the great saphenous vein. Except for in very thin people, these lymph nodes are located under scarpa's fascia.
A vertical lazy-S incision is made starting 10 cm above the inguinal ligament, crosses the midpoint, and continues about 15 cm below the inguinal ligament . Alternatively, an incision is made a few centimeters below and parallel to the inguinal ligament and curved medially down in the femoral triangle.
- The skin flaps are dissected and the specimen is removed en bloc. The great saphenous vein is included in the specimen from the tip of the femoral triangle to the origin into the femoral vein. If metastatic lymph nodes are confirmed in the pelvis, the operation is extended to an ilio-inguinal dissection including iliac and obtural nodes.
- The wound is washed and a drain is installed.
- The wound is closed in two layers.
The incision is often made horizontally, lazy-S, or zig-zag, and extends from the lateral edge of the major pectoral muscle to the edge of the latissimus dorsi. An upper and lower skin flap is created. All 6 node groups are situated under the clavipectoral fascia, and an en bloc removal is performed. The axilla dissection should include levels 1, 2, and 3 .
To obtain sufficient access to the top of the axilla, it may be necessary to split the minor pectoral muscle by the coracoid process or remove it. It is rarely necessary to split the major pectoral muscle. The axillary vein can, if absolutely necessary, be removed since intact blood supply around the scapula prevents permanent stasis in the arm. The dissection continues down to the 6th rib while trying to conserve the large nerves in the area (the thoracodorsal and long thoracic nerves).
Neck dissections for malignant melanoma have changed in character in recent years. Selective and modified radical neck dissections are now performed more frequently. Which levels are dissected depend on the location of the primary tumor.
A neck dissection is a technically difficult operation with a high risk of complications and high relapse frequency. This type of operation should be centralized.
- The day of operation and 1. postoperative day the patient stays in bed (toilet leave prohibited).
- 2. postoperative day the patient may move by wheel-chair and careful walking to the toilet. Gradually mobilization till normal within a week.
- Thigh-long "white" stocking continuously during the hospital stay and every night for 3 months.
- Thigh-long "brown" stocking every day for 6 months.
- The day of operation the patient stays in bed.
- Mobilisation with mitella from 1. postoperative day.
The vacuum-drain (active) should be kept for 5-10 days or until the volume of fluid is reduced to 40-50 ml per 24 hours. The vacuum is neutralized and remains passive. At home the drain is shortened 1 cm daily by the nurse. This is to ensure that the wound heals from the inside- outwards.
- Postoperative seromas – these are drained aseptically
- Nerve pain and dysfunctions – often temporary
- Edge necrosis, lymphedema, and incision infections – more frequent for inguinal dissection
- Deep vein thrombosis in the leg
Lymphedema is a serious and persistent complication. Lymphedema after axilla dissection is rarely observed, but occurs in approximately 20% of patients after a groin dissection.
After an inguinal dissection, it is recommended that for the first three months after the operation, the patient elevates their feet while lying and sitting. In the same period, it is recommended to use elastic stockings day and night. Gradual decrease in the use of stockings should take place during the next three months. After an axillary dissection, it is not necessary to routinely use elastic stockings.
Physiotherapy after the operation is important for the patient to achieve an adequate rehabilitation process. Many do not need to go to sessions of physiotherapy, but rather, information and guidance will be adequate.
For some operations, it is necessary to perform skin flap reconstruction after a surgical resection to achieve coverage of the excised area, a better cosmetic result, and/or to restore functionality.
For the free flap technique, the skin tissue is transferred from one part of the body to another. The tissue's blood supply is divided and reestablished in the reconstructed area, using microsurgical techniques.
For the rotation flap technique, skin tissue, often with attached muscle, is dissected free while preserving the main blood supply. The flap may then be rotated from its original position to cover the defect. In these cases, the flap/tissue can only be used at a limited distance from the donor site.
- Closure of wounds after wide resection of skin.
Cover difficult defects
- Restore functionality
- Obtain the best possible cosmetic result
- Plastic surgery instruments
- Operation microscope (only for free flaps)
- The operation is carried out under general anesthesia.
- Local anesthesia with adrenalin is applied to reduce bleeding.
A free flap reconstruction can be technically difficult and the operation time can vary from 6 to 12 hours.
- The flap is dissected from the surrounding tissue, with at least one artery and vein intact.
- One artery and vein in the recipient location is marked.
- The vein and artery of the flap are ligated and the vessels divided.
- The blood vessels of the flap and recipient location are anastomosed using microsurgery.
- The flap is sutured to the area to be covered.
The donor area can usually be directly sutured.
- The flap is isolated with intact blood supply.
- The flap is rotated directly, or through a tunnel under the skin, to the recipient location.
- The flap is sutured to the desired location.
In the first days following the procedure, blood circulation in the flap should be observed closely. This is especially important for free flaps.
Wound cleaning/bandage changes should be carried out as needed.
- Loss of parts of or the entire flap if the blood circulation clots. For free flaps, this may require an emergency reoperation.
For wide excisions, additional tissue around the scar where a tumor has previously been removed, is excised. Wide surgical margins around the removed tumor may reduce the risk of relapse. In cases where a lot of skin has to be removed and it is difficult to close the wound primarily, it may be necessary to use a skin graft or flap reconstruction to cover the defect.
If the area to be covered is large, the risk for relapse is considered to be high or the patient's condition does not allow an operation with comprehensive flap reconstruction, and the condition of the patient permits it, the defect will usually be covered with a skin graft.
For a skin graft, the skin tissue is moved from one part of the body to another without preserving the tissue's blood supply. New blood vessels grow from the recipient area in a few days after the operation.
Skin grafts may be full-thickness or split-thickness:
- A full-thickness skin graft is used for small defects where the cosmetic and functional requirements are higher. This especially applies after excision of skin changes and skin tumors in the head/neck region. Full-thickness grafts consist of both the dermis and the epidermis.
- Split-thickness graft is often used for larger defects, and in cases where cosmetic considerations are not possible or needed. Split-thickness grafts consist of the epidermis and parts of the dermis.
Wide excision is carried out for:
- Tumors in the skin where a wider margin is needed to reduce the risk of relapse
- Cases in which all tumor tissue was not removed during the first operation
- Cure the disease
- Reduce the risk for recurrence
- Plastic surgery instruments
For skin grafts, the following are also used:
- The procedure is carried out under local or general anesthesia.
- The area to be removed is outlined on the skin followed by administration of local anesthesia with adrenalin along the edge of the lesion, to reduce bleeding. An interval of 10 minutes should be allowed before the incision is started.
- An incision is made along the outline.
- The area is dissected until an adequate margin of depth is reached.
- The tissue is lifted at one end with forceps and using a scalpel, the appropriate skin thickness is separated from the underlying tissue.
Hemostasis is maintained with diathermy. It is necessary to maintain sufficient hemostasis to prevent postoperative bleeding and formation of an underlying hematoma. Too much diathermy can lead to loss of tissue viability, which will compromise healing of the wound.
- The specimen is usually marked with a thread, at one end or at an area of interest, to facilitate the pathology evaluation of the specimen.
For small defects, the area behind the ear is often used as donor site. For larger defects, it is common to use skin from the groin, inside of the upper arm, or other places where the donor defect can be closed directly with sutures.
- The graft is dissected by separating the dermis from underlying fat tissue. It is important that the skin is free of fat before it is positioned onto the defect.
- The donor site is closed with sutures.
- The edge of the transplant is adapted as precisely as possible to the edges of the defect. The full-thickness graft heals by growth of blood vessels from the dermis into the edges of the defect.
- The graft is attached with "interrupted sutures" where 6 cm remain on each end of the sutures.
- A loop suture is placed around the edge of the graft.
- A compression bandage (buttoning) is placed on the graft and tied securely using ends from the interrupted sutures.
It is easiest to obtain donor skin from flat skin surfaces. A common donor site is the thigh.
- The skin is rubbed with oil.
- The skin is stretched. A compressed air dermatome or manual skin knife is used to harvest the skin. The instrument functions like a cheese slicer cutting the skin in very thin layers.
- The transplant is moistened and placed on a glass surface.
- It is then put through a mesher (aperture puncher). Depending on the size of the mesh surface, the harvested transplant will increase in size, to cover a larger wound surface.
- The transplant is positioned onto the defect and stapled/sutured in place.
- Excess donor skin is resected.
Dressing of split-thickness graft:
- The transplanted area may be covered my Mepitel or Jelonet.
- On top of this is put a compression bandage/sterile sponge or similar to maintain immobility of the graft.
- Alternatively a VAC pump may be applied (Vacuum Assisted Closure Device). Mepitel is similarly put onto the transplanted area and thereafter a sponge covered by a transparent plastic drape. This is connected to a vacuum pump. The vacuum extracts fluid and stimulates proliferation of blood vessels.
- If possible the operated area should be elevated to reduce postoperative edema and bleeding.
- The sutures are removed after 7-14 days.
- For a full-thickness graft, the compression bandage should remain untouched for about 1 week.
- For split-thickness transplants, the compression bandage is to remain untouched for one week if the recipient site is considered clean. If there is danger of infection, the compression bandage should be changed and the graft should be inspected after 2-3 days.
- VAC bandages are changed/removed after 3-5 days depending on the conditions.
- The skin graft should be protected from trauma and force for 2-3 weeks.
- Exercises and training which may lead to damage of the graft should be avoided for 3-4 weeks.
- Protect the graft and donor site from sun exposure.
Isolated limb perfusion (ILP) is a treatment in which the blood circulation is isolated in an extremity providing local treatment with chemotherapy using a heart/lung maching. The purpose is to give large doses of tumor-toxic medications which are 15- to 20-fold higher than can be given by systemic treatment. The treatment provides an increased cytostatic effect on the tumor with minimal systemic exposure.
Today, ILP is an established treatment method for regionally advanced malignant melanoma and for advanced soft tissue sarcoma limited to an extremity. In most cases, the treatment leads to complete remission of the tumor. In some cases, ILP leads to partial remission or stabilization of the illness.
In Norway, this treatment is centralized to Oslo University Hospital.
- For locoregional spreading and in-transit metastases which can no longer be treated by local excision
- To avoid amputation
- Curative treatment
- Heart/lung machine such as roll pump, oxygenator, and warming system
- Gamma detector
- Software for continual monitoring of possible leakage.
- Surgery tray
- Vein instruments
- Vascular cannulas
- Temperature probes
- Warming blanket
Melfalan is a suitable medication for ILP treatment because of its short half-life, low endothelial toxicity, limited cell cycle specificity, and relative linear dose response conditions of cytotoxicity.
- 10 mg/l extremity volume for upper extremity
- 13 mg/l extremity volume for lower extremity
Tumor necrosis factor (TNF-a) is used only for melanoma metastases with tumor size > 2 cm in diameter. TNF leads to selective endothelial damage to tumor veins and conserves normal ones. The medication is very toxic when given systemically and can lead to septic shock.
Dosage for both upper and lower extremity:
- 2–4 mg per perfusion regardless of extremity
Hyperthermia increases the toxicity effect of both melfalan and TNF.
Temperatures over 41°C lead to high regional toxicity, therefore mild hyperthermia with temperatures between 38.5-39.5°C are used.
- Vascular and neurological status must be assessed carefully.
- The volume of the extremity is calculated.
- The procedure is carried out under general anesthesia.
- Supine position with good access to the extremity to be treated.
ILP can be carried out via the following veins:
- Upper extremity:
- Axillary vein
- Brachial vein
- Lower extremity:
- External iliac vein
- Femoral vein
- Popliteal vein
Iliac access is used often for lower limb perfusions.
- A diagonal incision is made across the iliacal fossa.
- The fascia and muscles are cut.
- Dissection down to the external iliac veins.
- Vascular control is secured proximally and distally with vessel loop.
- The side branches are ligated.
- Anticoagulation with heparin is administered.
- Venous and arterial cannulas are inserted.
- A tourniquet is placed proximally on the thigh.
- Temperature probes are inserted in the extremity both in subcutaneous tissue and in the muscle distally and proximally.
- The cannulas are connected to the heart/lung machine.
- Perfusion is maintained at 400–500 ml/min for lower extremity and 150–300 ml/min for upper extremity.
- For large melanoma metastases TNF is added to the perfusion and circulated for 30 minutes.
- The perfusion is heated to 38.5–39.5°C.
- Melfalan is added.
- The duration of the perfusion with melfalan is 60 minutes. Total duration of the entire perfusion when TNF is added to melfalan is 90 minutes.
Monitoring of leakage
- Potential leakage is measured with radioactive-labeled albumin, which is injected into the perfusate.
- A gamma detector is placed over the heart.
- Radioactivity in perpheral plasma is monitored continually with specialized software.
- For leakage > 10 %, it must be decided whether the perfusion should be interrupted due to risk of systemic toxicity.
Completion of ILP
- The drug perfusion is stopped and the extremity is perfused with 3-5 L Macrodex.
- The pump is turned off and the tourniquet and cannula removed.
- The veins are sutured and the circulation is reestablished in the extremity.
- The incision is closed.
The patient is mobilized from the first postoperative day.
Normal postoperative stay is 3 to 7 days depending on side effects and/or complications.
Local side effects
Side effects are graded according to the Wieberdink's classification:
Mild edema and/or erythema
Prominent edema and/or erythema with blisters and some limited movement.
Comprehensive epidermolysis and/or visible damage to deep tissue leading to limited function,
threatening or developed compartmental syndrome.
Reaction requires amputation.
- Mild side effects develop usually after 2 to 3 days after ILP in 90% of patients. Moderate to serious side effects involve 25 to 40 % of patients.
- Extremity-threatening complications with serious tissue damage and edema occur in less than 10 % of patients. In rare cases, amputation is necessary.
Most side effects after ILP treatment spontaneously regress after 2 to 3 weeks.
Vascular complications such as thrombosis after arteriotomy occur in about 2.5 %. The incidence of DVT is about 10 % despite heparinization during the treatment. Nerve toxicity manifests itself as pain or paresthesia 2 to 3 weeks after treatment in 25 to 40 % of patients. These usually regress within a few months. Long-term neuropathy occurs more rarely.
Systemic side effects
Most systemic side effects are caused by leakage from the perfusion fluid to the circulation system during treatment. Despite complete isolation and thorough rinsing afterwards, there may still be remains of medication in the tissue or in intravascular components which can spread to the entire body when circulation is reestablished.
Systemic toxicity from melfalan perfusion is limited if the systemic leakage does not surpass 10%.
Systemic leakage of TNF can lead to serious cardiovascular, metabolic, and hematological complications.
The patient is checked clinically every other week for 3 months. Thereafter every third month for 1 year. Follow-up with MRI of the extremity is performed after 4 and 8 weeks and only when a large volume is involved.
For partial remission or locoregional relapse, new ILP treatment should be considered.
Drug therapy for malignant melanoma
Malignant melanoma is relatively resistant to chemotherapy (20). Adjuvant treatment with chemotherapy has not improved survival and is not an established therapy for melanomas (21). Except for controlled clinical trials, it is only appropriate to offer chemotherapy to patients with metastases which cannot be removed surgically or should be treated with radiation. No studies have shown improved survival after chemotherapy. Most objective remissions last only for some months. However, some patients are good responders (3-5%) and may achieve long-lasting remissions.
Dacarbazine® (DTIC) is the most commonly used chemotherapy for disseminated disease and objective remissions are achieved in 10-20% of the patients (22). DTIC is administered intravenously once every third week. The treatment has relatively few side-effects. If there is no effect after 2-3 courses it should be discontinued. With simultaneous brain metastases, Temodal® is considered since it most likely penetrates the blood-brain barrier better (14). Termodal® tablets are administered one daily for 5 days every 4th week. The effect is similar to DTIC (23).
For lack of effect of DTIC or Termodal®, other cytostatic drugs may be considered if BRAF inhibitor or immunotherapy is not relevant. Carboplatin® / Docetaxel® may be given intravenously every 3rd week, The regimen causes more side-effects and has no better effect than DTIC. Vinblastine is given intravenously once a week and 7-10% of the patients will benefit from the treatment. The same goes for Docetaxel® (intravenously once a week) and lomustin (CCNU) taken as tablets once every 6th week.
For inoperable local relapse and/or systemic illness in mucous membranes, it is appropriate to try chemotherapy. The regimens are the same as for malignant skin melanoma.
ILP – (Isolated limb perfusion) regional perfusion treatment
For multiple metastases located in the extremities where surgery is not appropriate, intensive regional perfusion treatment with melfalan, possibly in combination with tumor necrosis factor (TNF), under hyperthermia (heating of the extremity) should be considered. Studies have shown 90% total response after such treatment. Around 70% have complete remission with a combination of melfalan and TNF (33). Oslo University Hospital, The Radium Hospital is the national centre for such treatment.
For cutaneous metastases electrochemotherapy my be tried. The technique takes advantage of electrical impulses to enhance the permeability of cytostatic drugs, usually Bleomycin®; into the tumor cells. Good results are often achieved (34,35). Oslo University Hospital is the national centre for this treatment.
Melanoma is an immunogenic tumour well suited for immunotherapy (24). Tumour specific T-cells (CTL) have been identified in metastases from melanomas and immune response against melanoma associated antigens have been identified in serum.
Interferon alfa has been tried for metastatic melanomas but the response rate was low (25). Immunostimulation with interleukin2 in combination with chemotherapy has also been tried, but the effect is not better than with DTIC alone and there are considerable side-effects (26).
Adjuvant treatment after lymph node dissection or given to patients with thick melanomas show prolonged diease-free interval in some patients, but with no benefit in survival. The treatment is long lasting, give rise to considerable side-effects and is not standard treatment (25).
Yervoy® (ipilimumab) is a human monoclonal antibody towards CTLA4 (cytotoxic T-lymphocyteantigen4). Ipilimumab enhances T-cell activation and thereby the immune response against cancer cells. Ipilimumab has shown an increased median survival of 2 months (15, 16). Some patients (15%) are long-term survivors. The treatment consists of 4 courses given with 3 weeks interval. The response often appears late, even after cessation of the treatment. A transient progression (pseudoprogression) is also commonly seen before the response. Ipilimumab should therefore not be applied in patients with rapidly progressing disease, debilitated general condition and/ or large tumour volume.
Yervoy® can cause serious side effects, the most common are autoimmune colitis, hepatitis, dermatitis and hypophysitis. It is very important that the patients report side-effects rapidly to departments experienced with such side-effects. The drug is accepted by FDA (US Food and Drug Administation) and EMA (European Medicine Agency) for treatment of melanomas with metastases. Ipilimumab is very expensive and Norwegian Hospitals are not approved to apply it without extra consession. In Norway (per September 2014) ipilimumab is given in a national phaseIV study (IPI-4 study).
Another naural inhibitor of T-cell activation is PD-1 (programmed death -1). Studies on antibodies against PD-1 are promising (26) and the antibody is expected to be accepted within a short time. A combination with ipilimumab and Nivolumab (PD-1 antistoff) is tested in a phse III study after promising results of a phase IV study (27).
The discovery of a mutation on the gene coding for serine-threonine protein kinase, BRAF V600E mutation, in many melanomas represents a possibility for “targeted therapy”(36). BRAF inhibitors (Zelboraf® and Tafinlar®) interferes with melanoma cells in around 50% of the patients with this mutation (37). BRAF inhibitors also have effect on brain metastases.
BRAF mutation can be identified in 50% of the patients with skin melanomas and in around 10% of the patients with mucosla melanomas. Both Zelboraf® and Tafinlar® are given as tabets twice a day. The effect will usually appear rapidly with a considerable shrinkage of the tumour and improvement of symptoms. The respons is not seldom of relatively brief duration, 6-8 months (38). After an interval retreatment may cause new improvement in some patients, The most common side-effects are diarrhea, dry skin, itching, exanthema, baldness, photosensitivity (which may be severe), fatigue, considerable joint- and muscle pain and development of keratoacanthoma and spinocellular carcinoma. Tafinlar® causes less photosensitivity but often give rise to fever and hyperkeratosis. The therapy sometimes have to be discontinued due to the side-effects. This will be in cases when symptomatic treatment, dose reduction or a pause in the treatment does not help. Dose reduction of more than 50% is not recommended.
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
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.
- 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.
- 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.
Maintain a clean LAF bench
Avoid contamination and preserve the sterility of the drug
Protect people and surroundings from exposure
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).
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
Syringes and cannulas
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
1 bed absorbent bed sheet
2 plastic bags with zippers (30 x 40 cm)
4 thin, white plastic bags (60 x 90 cm)
8 disposable wash cloths
Washing of LAF-bench
Gloves: either double vinyl gloves or special gloves
Bucket and soapy water
Waste container with plastic bag for chemotherapy waste (biohazardous waste)
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.
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.
Preparation of chemotherapy drugs outside of a pharmacy
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.
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.
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.
Replace the cannula bucket.
There should be a record for bench washing; the employee who washes should sign and date the record.
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.
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.
Sun exposure in connection with drug cancer treatment.
Prevent sun damage of the skin during and after cancer drug treatment.
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).
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.
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).
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) .
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 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).
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.
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
|See general precautions
|Redness in skin, tingling of the scalp and general unwellness
|Avoid sunlight completely the day of the treatment (9)
See general precautions
|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
||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)
|Treatment as with 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)
|See general precautions
||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)
|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)
(Cetuximab, panitumab, erlotinib, gefitinib, lapatinib, vandetanib)
|See general precautions
|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 .
- LOV-1999-07-02-63 Pasientrettighetsloven - pasrl. Lov om pasientrettigheter.
- Polovich M, White JM, Kelleher LO. Chemotherapy and biotherapy guidelines: recommendations for practice. Pittsburgh, PA: Oncology Nursing Society; 2005.
- González E, González S. Drug photosensitivity, idiopathic photodermatoses,and sunscreens. J Am Acad Dermatol 1996;35:871-85;quiz 886-7.
- Liffrig, JR. Phototrauma prevention. Wilderness Environ Med 2001;12:195-200.
- 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
- Gould JW, Mercurio MG, Elmets CA. Cutaneous photosensitivity diseases induced by exogenous agents. J Am Acad Dermatol 1995;33:551-73.
- Payne, AS & Bernandin, RM. Sunburn [topic last updated 2010 Oct 06]. I: BMJ Best Practice. Hentet 23. november 2010 fra http://bestpractice.bmj.com
- Zhang AY, Elmets CA. Drug-induced photosensitivity [updated 2010 Jan 15]. Hentet 1. desember 2010 fra: http://emedicine.medscape.com/article/1049648-overview
- Ulrich J, Hartmann JT, Dörr W, Ugurel S. Skin toxicity of anti-cancer therapy. J Dtsch Dermatol Ges 2008;6:959-77.
- 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
- Alley E, Green R, Schuchter L. Cutaneous toxicities of cancer therapy. Curr Opin Oncol 2002;14:212-6.
- 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.
- 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.
- 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
- Heidary N, Naik H, Burgin S. Chemotherapeutic agents and the skin: an update. J Am Acad Dermatol 2008;58:545-70.
- 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
- Hendrix JD Jr, Greer KE. Cutaneous hyperpigmentation caused by systemic drugs. Int J Dermatol 1992;31:458-66.
- Schmid-Wendtner MH, Wendtner CM, Volkenandt M, Heinemann V. Clinical picture: leopard-like vitiligo with capecitabine. Lancet 2001;358(9293):1575.
- 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.
Radiation therapy of malignant melanoma
Primary malignant melanoma
Radiation treatment does not play a great role in treatment of primary melanomas. In some cases of locally advanced melanoma, large lentigo melanoma in the face and melanoma in the eye, radiation therapy may be given. Radiation treatment of eye melanoma achieves similar results as enucleation but with some vision left. Enucleation is performed for large melanomas and / or involvement of the optic nerve.
As for skin melanomas, radiation sensitivity for melanomas in mucous membranes is variable, but they are not resistant. If the primary tumor is not too large and no distant metastases are present sugical treatment should be considered. For large melanomas where surgery will have to be extensive primary irradiation may be considered. Postoperative irradiation may also be an option. Fraction size is preferably > 2 Gy. Numerous regimens are mentioned in the literature. At Oslo University Hospital, commonly 2.5 Gy x 20 = 50 Gy is given postoperatively for mucosal melanomas.
Locoregional recurrence and distant metastases
Radiation treatment may provide palliation and local control of inoperable metastases which otherwise would have caused local problems.
Radiation treatment provides good palliation in up to 50% of patients (1).
Radiation treatment should be considered:
- Postoperatively, for example after resection of local relapse, and after bone and brain metastasis surgery where there is uncertainty of radicality, and where reoperation is not appropriate. For repeated locoregional relapse despite adequate surgery, or for repeated local relapse.
- For repeated locoregional relapse despite adequate surgery, or for repeated local relapse.
- In some cases after lymph node dissection. Studies suggest that patients operated for metastases in the neck may benefit from postoperative irradiation, especially after perinodal growth (39). When the resection margins are not free after lymph node dissection of the axilla or groin postoperative irradiation should also be considered.
- For painful, bleeding, or cosmetically problematic metastases, skin or subcutaneous, metastases where surgical or electrochemotherapy is not an option irradiation should be performed before the tumor volume is too large and before the tumor ulcerates. Cutaneous and subcutaneous metastases can be treated with electrons without any substantial problems for the patient. Such lesions respond often well to this kind of treatment.
- For bone metastases causing pain or possibility of fracture. Additional surgical treatment should also be considered when fracture is feared.
- For metastases which compromise or threaten vital structures such as the spinal cord, nerve roots, and central airways possibly combined with surgery.
- For brain metastases. In case of brain metastases (with other metastases under control) radiotherapy towards total brain should be considered, possibly supplied with a boost towards the tumor area. Stereotactic irradiation should be considered in case of 1-4 metastases. Transient control will be seen in 80-90 % of the patients (2).
- Stereotactic treatment may be given in some cases towards catastases in circumscribed areas in other organs like lung, liver, spleen and the adrenals, often with good result. Stereotactic irradiation can also be given towards 1-3 metastases in the vertebral column when these are not located imidiately near the spinal canal (30). Such treatment enhances the possibility of tumor control, rapid clinical response and a more prolonged effect. Reirradiation is possible due to a reduced dosage towards the spinal cord.
|Target volume definitions from ICRU
(International Commission on Radiation Units and Measurements)
GTV (= Gross Tumor Volume)
|Palpable or visible/identifiable area of malignant growth.
CTV (= Clinical Target Volume)
Clinical target volume
Tissue volume which contains GTV and/or subclinical microscopic malignant disease.
ITV (= Internal Target Volume)
Volume containing CTV and one inner margin taking into account inner movements and revisions of CTV.
PTV (= Planning Target Volume)
Geometric volume containing ITV and one set-up margin taking into account variation in patient movement, patient positioning, and field modeling.
A CT dosage plan is usually performed as a preparation for all radiation treatment. For stereotactic irradiation towards brain metastases MR of the brain is performed additionally. When cutaneous metastases is being treated with electrons, the field set-up is often marked directly on the patient`s skin.
During CT dose planning it is important that the patient is optimally treated for pain and is able to remain still in a supine position. Premedication may be given. Extra dose of opiated may also be necessary.
Before the first radiation treatment to the brain, a customized plastic mask is made for the head to immobilize the patient.
The radiation treatment can often be carried out on an outpatient basis with weekly doctor visits. Individual factors may suggest deviation from standard treatment. These factors may be:
- general status
- risk of bleeding
- the location of the lesion
- 3 Gy x 10, or 4 Gy x 5.
- 2.5 Gy up to 50 Gy, postoperative with a curative intention.
- 8 Gy x 1 to bone metastases.
- If the patient's other metastases are under control, 3 Gy x 10 to the entire brain can be administered.
Stereotactic irradiation (at Oslo University Hospital):
- Brain metastases: 18-25 Gy x 1 depending on the diameter of the tumor.
- Lung metastases: 15 Gy x 3 for peripherally located tumours, 7Gy x 8 for tumors at the Hilum/mediastinum.
- Metastases in the liver, spleen, adrenals: 3 fractions 10-15 Gy depending on size and location of the tumor.
- Vertebral column: 24 Gy x 1.
Many patients may require dexamethasone treatment during radiation treatment to the brain, or while waiting for the radiation treatment and possibly for some time after the treatment.
Irradiation combined with systemic treatment
- BRAF inhibitors: Patients treated with BRAF inhibitors (Zelboraf®, Tafinlar®) must discontinue the treatment for around 1 week before, during and 1 week after the irradiation to avoid serious side-effects, especially from the skin.
- Immunotherapy: Patients given Ipilimumab or PD-1 inhibitor may receive irradiation between 2 courses.
- Chemotherapy: Patiens on DTIC or other chemotherapy may receive irradiation between 2 courses.
All patients have their first follow-up at their local hospital or at Oslo University Hospital 4-8 weeks after end of treatment for evaluation of treatment result, side effects, and need for other treatment.
Subsequently, the patient attends a routine follow-up schedule.
Possible side effects may be:
- skin soreness
- soreness in the throat
- diarrhea, depending on area treated
The radiated area must be protected from sun exposure during the first years after treatment since the skin can be easily sunburned.
Complication treatment of malignant melanoma
Surgery, chemotherapy, and radiation therapy cause side effects to varying degrees.
It may be necessary to provide supportive care in order for the patient to complete and gain the full effect of planned treatment.
Supportive care can also be provided to reduce side effects and improve the patient's quality of life during and after treatment.
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.
- Nausea induced by chemotherapy drugs.
- Prevention and treatment of nausea and vomiting.
|Chemotherapies according to emetic potential
|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
|FEC-60 og FEC-100
(fluorouracil, epirubicin, cyklophosfamide)
| ENAP (etoposide, mitoxsantrone, cytarabine, prednisolone)
|ABVD (doxorubicin, bleomycin, vinblastine, dakarbazine
| FLv (fluorouracil)
| FuMi (fluorouracil, mitomycin)
|CHOP (cyclophosfamide, doxorubicin, vincristine, prednisolone)
|CHOEP (cyclophosfamide, doxorubicin, vincristine, etoposide, prednisolone)
|Methotrexate weekly dose
||ECO/ACO (epirubicin/doxorubicin, cyclophosfamide, vincristine)
||EOX (epirubicin, oxaliplatin, capecitabine)
||EPOCH-F (etoposide, prednisolone, vincristine, cyclofosfamide, doxorubicin, fludarabine)
||EPOCH-F (etoposide, prednisolone, vincristine, cyclophosfamide, doxorubicin, fludarabine)
||FLIRI (fluorouracil, irinotecan)
||FLOX (fluorouracil, oxaliplatin)
||IGEV (ifosfamide, gemcitabine, vinorelbine)
|| IME (ifosfamide, methotreksate, etoposide)
|| Vorphase (cyclophosfamide)
- 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.
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.
- 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.
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.
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.
In the event of conditional nausea, diazepam or other tranquilizers may be considered. Diversion or desensitization can be tried in more serious cases.
Ondansetron can have a constipating effect. Use of a laxative for several days should be considered.
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.
- Cancer treatment (chemotherapy, radiation, surgery).
- Maintain nutritional status in order for the patient to have the best possible conditions for implementing treatment.
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 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 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 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.
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.
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).
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.
ImplementationAll 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 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.
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.
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.
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.
The patient's nutrition status should be monitored at follow-up visits after the end of treatment.
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.
- Hemoglobin 13.4–17 g/dl
- Platelets 145–348 109/l
Assessment for a blood transfusion based on:
- 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
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.
- Complete the planned treatment
- Ensure hemostasis
- Ensure adequate oxygen transport to peripheral tissue.
- Maintain intravascular fluid volume for adequate circulations of vital organs
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%.
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.
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
Before the first blood transfusion, the following blood tests are performed:
Every three days, and as needed, pre-transfusion tests are taken.
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.
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
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:
- feeling of heat in the face
- breathing difficulty
- fall in blood pressure
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.
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 (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.
- 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
- Maintain treatment intensity
The patient should be adequately informed about the treatment.
- 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.
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.
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.
- A patient with neutropenia and simultaneously fever or clinical suspicion of systemic infection
- Avoid septicemia.
- The patient is able follow the planned scheme of treatment.
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.
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
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.
- 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.
- 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:
- 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.
Observe for symptoms of a new infection.
Intravenous extravasation occurs when there is an accidental leak of intravenous cytotoxic fluid (chemotherapy drug) from the vein to surrounding tissue.
If chemotherapy is given in a peripheral vein, a large vein should be used, which is preferably in the underarm. Before the infusion begins, the vein should be checked for leaks by injecting NaCl 9 mg/ml or glucose 50 mg/ml. Backflow should also be checked. The patient must be informed that pain or burning in the area is not normal and they must inform the doctor.
Cytotoxic chemotherapy drugs should always be given through a central vein catheter to reduce the risk of intravenous extravasation.
Risk factors for intravenous extravasation:
- Small veins (infants and children)
- Brittle veins (elderly patients)
- Reduced physical health (cancer patients)
- Sclerosizing veins
- Rolling veins
- Poor circulation (if the needle is placed in an arm with edema)
- Obstructed vena cava (raised venous pressure may cause leakage)
- Conditions such as diabetes and radiation damage
Chemotherapeutic drugs are separated into three groups according to the degree of toxicity:
- Tissue irritant
Cytotoxic drugs can cause blisters or ulcerations leading to skin necrosis if extravasation occurs. If intravenous extravasation is left untreated, it can lead to permanent tissue damage, necrosis, scar formation around ligaments, nerves and joints, infections, abscesses, contractures, and in the worst case, amputation.
- Intravenous extravasation of cytotoxic drugs.
- Limit damage of tissue from intravenous extravasation.
Non-cytotoxic drugs or non-irritants
Non-cytotoxic/non-irritant drugs normally do not cause skin necrosis.
Drugs that are tissue irritants can cause pain in and around the injection site and along the vein. They can also cause inflammation. Some tissue irritating drugs cause ulceration if a large amount leak extravasally.
Cytotoxic drugs are categorized into subgroups according to the mode of damage. This categorization is important for the choice of treatment.
DNA binders absorb locally into the cells, bind to DNA, and cause cell death. After cell death, the drug molecule can be liberated from the dead cell and start killing healthy cells. This group is divided into these subgroups:
- Alkylating drugs
For doxorubicin and mitomycin, progrediating tissue damage has been reported over weeks, and in some cases, months after intravenous extravasal injection.
This group of medications can lead to cell death through other mechanisms than DNA binding drugs. This group is divided into:
|Chemotherapy cytotoxicity (1)
Irritant, can cause flaking or inflammation
|Non-cytotoxic or non-irritant
* = Anthracycline
** = Alkylating agents
*** = Vinca alkaloids
**** = Taxanes
*****= Methylene blue is not a chemotherapy drug, but is used for ifosfamide-induced encephalopathy, and is therefore included on the list.
All chemotherapy drugs can damage tissue in high concentrations.
- Allwood M, Stanley A WP. The Cytotoxics Handbook. Ed. 4th ed. 2002. 2001
- Ekstravasation Guidelines Implementeringsværktøj [Online] 2007 [hentet 10. mars 2009]; Tilgjengelig fra URL: http://www.cancerworld.org/CancerWorld/getStaticModFile.aspx?id=2726
Identification of an extravasal injection
- A burning, stinging pain or other acute change of the puncture site.
- Local redness or inflammation of the skin around the puncture site.
- The infusion rate slows/stops.
- Swelling of the puncture site.
Extravasation has probably also occurred if blood cannot be aspirated, resistance is felt on the plunger when a syringe is used, and/or there is no current if the drug is infused.
Flow chart for treatment of intravenous extravasation of cytotoxic drugs:
- Stop the infusion immediately.
- Allow the needle to remain and aspirate with as much water as possible. Avoid applying direct pressure on the area of extravasation.
- The volume, type, and time of extravasation should be recorded.
- A doctor/plastic surgeon should be called for to examine the patient.
- The damaged area and skin manifestations should be marked/photographed.
- The affected area should be kept elevated.
- The remaining chemotherapy should not be discarded.
- The patient should be informed about what is happening and what must be done.
- The needle is removed while aspirating.
- Pain medication is administered if necessary.
Based on which medication has leaked extravasally, the doctor or plastic surgeon will decide whether conservative treatment or primary surgery is necessary.
Conservative treatment consists of two different treatment strategies to limit the damage by extravasation: localize/neutralize and spread/dilute (2).
Localize and neutralize:
- Place an ice pack on the area for 15-20 minutes, at least 4 times daily for multiple days. A coldpack is used to limit spreading of the drug. Studies have indicated that there is reduced cellular uptake of drugs at lower temperatures (2).
- The drug that has leaked extravasally is neutralized by a specific drug if the instructions are followed.
- The affected area of the body should be kept elevated.
Spread and dilute (applies to vincristine, vinorelbine, vindesine, and vinblastine):
- Warm compresses are placed on the area for 15–20 minutes, at least 4 times daily, for multiple days.
- To dilute the drug that has leaked extravasally, many subcutaneous injections are given with hyaluronidase diluted with sterile water.
If the patient has lasting pain or blisters, surgical treatment should be considered by excising the area with direct sutures, skin transplant, or flap reconstruction.
Another type of reconstruction may be necessary at a later time.
Dexrazoxan is an EDTA analong used to treat extravasation of anthracycline (doxorubicin, daunorubicin, epirubicin, idarubicin). The mechanism of action is not fully understood, but it is believed that it may work through two mechanisms. By chelating iron, the formation of the iron-doxorubicin complex and iron-mediated hydroxy radicals are hindered, which cause oxidative damage to cell membranes and proteins. Another possible mechanism is inhibition of topoisomerase II (3).
Treatment lasts for 3 days. In all cases of extravasation of anthracycline, this treatment should be assessed by an oncologist and surgeon/plastic surgeon.
- The first infusion should start as soon as possible and within 6 hours after extravasation.
- On the following two days, the infusions should occur at the same time as the previous infusion (+/- 3 hours).
- If possible, the infusion should be placed in a vein where there is no extravasation.
- An ice pack or cooling element used on the area must be removed at least 15 minutes before the infusion starts to ensure sufficient blood circulation.
A package costs about NOK 100,000.-. If the expiration date runs out, the drug is replaced by the pharmaceutical company free of cost.
DMSO (70–90% solution) quenches free radicals and prevents formation of sores. The solution can be used after extravasation of cytotoxic drugs (anthracycline, mitomycin C, doxorubicin, idarubicin, epirubicin andactinomycin D) together with cooling of the area when other treatment methods cannot be used (5, 6). DMSO cannot be used in combination with dexrazoxan (3, 4).
- An area twice as big as the affixed area is treated with the solution every 8 hours for one week.(6)
Hyaluronidase is an enzyme that breaks down hyaluronic acid found in connective tissue. This leads to permeability and increased diffusion of the drug that is leaking extravasally, and is used only to spread the drug out into the tissue (spread and dilute).
- Hyaluronidase is administered subcutaneously or intradermally in 5-10 locations on the border of the area where the drug has leaked extravasally (7).
The washing out technique can be used with chemotherapy drugs when tissue damage is likely. When used with anthracycline, it is important that this is performed before the chemotherapy drug goes intracellularly.
In most cases, this is a very successful method if it is performed within 6 hours after the extravasation.
- The patient receives regional anesthesia.
- Multiple small incisions must be made to ensure sifficient access to the damaged subcutaneous tissue.
- With an infiltration needle, which is usually used for liposuction, isotonic NaCl is flushed through the tissue and drains through the incisions.
- The infiltrated fluid is then carefully removed by suction through a small needle used for liposuction.
- The procedure is repeated until 300-500 ml fluid is used.
- Ekstravasation Guidelines Implementeringsværktøj [Online] 2007 [hentet 10. mars 2009]; Tilgjengelig fra URL: http://www.cancerworld.org/CancerWorld/getStaticModFile.aspx?id=2726
- Hasinoff BB. Dexrazoxane use in the prevention of anthracycline extravasation injury. Future Oncol 2008; 2006: 1–15.
- Statens legemiddelverk. Preparatomtale. 2008
- Langstein HN, Duman H, Seeling D, Butler CF, Evens GR. Retrospective study of the management of chemotherapeutic extravasation injury. Ann Plastic Surg 2002; 49: 369–74.
- Bertelli G, Gozza A, Forno GB, Vidili MG, Silvestro S, Venturini M et al. Topical dimethylsulfoxide for the prevention of soft tissue injury after extravasation of vesicant cytotoxic drugs: A prospective clinical study. J Clin Oncol 1995; 13: 2851–5.
- Clinical Pharmacology© 2008 database. Hyaluronidase. 2008.
For conservative treatment
The damaged tissue should be observed for multiple weeks (with mitomycin at least 13 weeks) since necrosis can occur after months.
For emergency surgical treatment
Patients treated by a plastic surgeon should receive follow-up care by the surgeon until the wound has healed.
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.
Weaning of nicotine in connection to cancer treatment.
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.
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.
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
|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.
- Headache, dizziness, nausea, flatulence and hiccup.
- Irritation in the mouth and esophagus using chewing gum/ lozenges/inhalator
- Skin irritations while using patches.
- 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%.
- Dry mouth, nausea, insomnia, hypersensitivity reactions and seizures (convulsions)
- 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.
- Nausea, sleep disturbances, headache, constipation, flatulence and vomiting
- 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
If the patient experiences a relapse, it is important to inform them that this is completely normal, and encourage them to continue. If the most common measures do not work,
consideration should be given both to increase the NRP and to provide closer follow-up by health care providers.
Guidance in smoking cessation is described in the literature as brief and clear advice and then further follow-up with a telephone helpline offering treatment for addiction and behavior change/issues. It is not necessary for the patient to have decided to quit smoking in order to be referred to a quitline. If the patient agrees to receive a call from quitline, he or she will be followed up by a supervisor. Supervisors are bound by confidentiality, are up-to-date professionally and offer free follow-up counseling calls for up to a year.
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- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Nagle CM, Bain CJ, Webb PM. Cigarette smoking and survival after ovarian cancer diagnosis. Cancer Epidemiol Biomarkers Prev. 2006;15(12):2557-60.
- 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.
- 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.
- 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.
- Arntzen A, Sandvold B. Hvordan veilede om røykeslutt? Sykepleien Forskning. 2010;5(3):182-90.
- Dresler CM. Is it more important to quit smoking than which chemotherapy is used? 2003. p. 119-24.
- 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.
- Richards J. Words as Therapy: Smoking Cessation. The journal of family practice. 1992;34(6):687-92.
- 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.
- 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.
- Waller LL, Weaver KE, Petty WJ, Miller AA. Effects of continued tobacco use during treatment of lung cancer. 2010. p. 1569-75.
- 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.
- 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.
- Krueger JK, Rohrich RJ, Mustoe TA. Clearing the smoke: The scientific rationale for tobacco abstention with plastic surgery. 2001. p. 1074-5.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Dresler CM, Gritz ER. Smoking, smoking cessation and the oncologist. 2001. p. 315-23.
- 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.
- 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.
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- Brunnhuber K, Cummings KM, Feit S, Sherman S, Woodcock J. Putting evidence into practice: Smoking cessation: BMJ Publishing Group; 2007.
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- 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 malignant melanoma
Goal of follow-up
- Diagnose local recurrence/distant metastases while the tumor volume is still small and easier treatable, preferably by surgery.
- Impart knowledge about self-exams and good sun habits
- Impart security
- Assess other pigmented lesions
Control frequency and content
- Malignant melanoma in situ - one simple check for information, scar inspection, as well as education for self-exams and sun habits.
- Malignant melanoma with Breslow thickness < 1 mm: check-up every 3 months for 3 years, thereafter as needed.
- Malignant melanoma with Breslow thickness > 1 mm: check-up every 3 months for 3 years, thereafter every 6 months for 2 years and further as necessary. This depends on the thickness of the primary tumor.
- Weight loss
- Other symptoms
- Inspection and palpation of operation scar
- Palpation of all lymph node regions
- Inspection of skin surface
- X-ray examinations depending on the thickness of the melanoma, disease stage, as part of evaluation of treatment and possible inclusion in studies.
- Blood test screening
In patients who do not participate in clinical studies and who are symptom-free, it is not necessary to perform supplementary examinations.
The patient should be checked every 2-3 months with naso/sinoscopy the first year after primary treatment, and every 3-4 months in the second year. Thereafter, biannually for at least 3 years for a total of 5 years.
According to etiology, there are two general classifications of lymphedema primary and secondary lymphedema. Primary lymphedema is caused by deficient or faulty development of the lymph system. Secondary lymphedema occur as a complication from trauma or diseases which damage the lymphatic vessels or lymph nodes. The primary cause of lymphedema in the western world, is impaired or disrupted flow of lymph fluid caused by cancer or cancer treatment (secondary lymphedema).
Lymphedema occurs when the transport capacity of the lymph system is reduced significantly.
The swelling is caused by an accumulation of fluid (rich in protein) in the tissue, due to reduced drainage of lymph fluid (1,2). The swelling is often chronic. A lymphedema can lead to pain/discomfort and changes in the soft tissues in the affected area (fibrosis) (3,4). Lymphedema occurs most often during the first 2-3 years after cancer treatment (5 6). Without treatment, lymphedema can lead to progressive swelling.
In some cancer treatment the lymph nodes and fatty tissue are removed, most often in the axilla, pelvis and the groin. This treatment causes damage to the lymphatic wessels and reduces the number of lymph nodes. The subsequent reduced capacity for drainage of lymph fluid in the arm and leg may result in lymphedema.
Radiation therapy may cause tissue scarring and fibrosis. The combination of surgery and radiation therapy to the axilla additionally increases the risk of developing lymphedema.
Cancer related lymphedema can also occur due to metastasis in areas where blocking the central lymph vessels in advanced disease.
Factors which may increase the risk for developing lymphedema are:
- infection in the area where lymphedema occurs
- trauma of the arm/leg on the operated side
Indications for treatment
Lymphedema in the arm/hand, breast, leg, groin, face and neck after treatment of:
- breast cancer where axillary dissection is performed
- gynecologic cancer where the lymph nodes in the pelvis or the groin are removed
- melanoma where the lymph nodes in the axilla or the groin are removed
- lymphoma and cancer of the head and neck region where lymph nodes in the neck region are removed
- prostate cancer where the lymph nodes in the pelvis or the groin are removed
- sarcoma where lymph nodes are removed
Without treatment the lymphedema can increase in size. This may cause skin changes (fibrosis), increased swelling and therefore more discomfort in the area (3).
- acute infections, local or general (erysipelas)
- arterial insufficiency with risk of necrosis
- thrombosis and embolism
Untreated cancer disease, heart failure, or kidney failure
- reduce lymphedema
- relieve tormenting side effects
- improve function
- prevent complications such as skin changes and inflammation in the area (erysipelas)
1. Rockson SG. Diagnosis and management of lymphatic vascular disease. J Am Coll Cardiol 2008;52:799-806.
2. Lawenda BD, Mondry TE, Johnstone PAS. Lymphedema: (Review) A primer on the identification and management of a chronic condition in oncologic treatment. CA Cancer J Clin 2009;59:8-24.
3. Mortimer PC. The patophysiology of lymphedema. Cancer 1998;83(12 Suppl American): 2798-802.
4. Erickson VS, Pearson ML, Ganz PA, Adams J, Kahn KL. Review: Arm edema in breast cancer patients. J Natl Cancer Inst 2001;93:96-111.
5. Nesvold IL, Dahl AA, Løkkevik E, Mengshoel AM, Fosså SD. Arm and shoulder morbidity in breast cancer patients after breast-conserving therapy versus mastectomy. Acta Oncol 2008;47:835-842.
6. Norman SA, Russel Locario A, Potashnik SL, et al (2009) Lymphedema in breast cancer survivors: incidence, degree, time course, treatment, and symptoms. J Clin Oncol 2009;27:390-397.
7. Johansen J, Overgaard J, Blichert Toft M, Overgaard M. Treatment morbidity associated with the management of the axilla in breast-conserving therapy. Acta Oncol 2000;39:349-54
Complete psysical therapy treatment of lymphedema
Consists of manual lymph drainage, compression therapy, skin care and instruction in exercises and self-treatment (1). The treatment is performed by physical therapists with special expertise.
The treatment may be extensive at the start. In cases of severe swelling one usually start with manual lymph drainage followed by bandaging of the arm/leg (1).
Manual Lymph Drainage
This is a kind of massage which requires guided training to perform optimally. The goal is to encourage the drainage of lymph fluid and thereby reduce the swelling of the tissue (2). It is quite different from other kinds of massage applied within physiotherapy. The anatomical conditions of the lymph system is the basis for manual lymph drainage. These are: the course of the large lymph veins, the borders of different lymphatic functional regions (watershed), natural anastomoses crossing these lines, and the lack of valves in the lymphatic vessels .
Bandaging is used mostly at the start of a treatment to reduce swelling. When the swelling is reduced a compression stocking is adjusted.
Clinical experience and research show that compression is the most important treatment. (3;4) Accordingly it is of great importance to adjust a compression stocking for the arm or leg. If there is swelling of the hand, a compression glove might help.
A compression stocking is used to increase tissue tension. The pressure from the stocking increases absorption of tissue fluid. The stocking provides a graded pressure highest distally and lowest proximally. To adjust the stocking, the circumference of the arm or leg is measured at several defined points. There are several compression classes, but the most commonly used are class 1 and 2. The stocking should provide a constant pressure without causing discomfort. It may take some time to get used to the compression stocking. Some choose to use the stocking occasionally, while others wear it daily.
A facemask at night is recommended to treat lymphedema in the neck and face region (5). Patiens with lymphedema in the groin can be helped by using a bike pant or a panty. Bandaging, tubigrip or bike pants may benefit if there is swelling of the penis and scrotum .
Intermittent pressure massage with pulsation
Treatment is carried out with an electronically powered apparatus which blows air in a double-walled cuff. The cuff, covering the whole arm or leg, has multiple channels and creates a peristaltic pressure wave in proximal direction. The treatment encourages the lymph drainage and thereby reduces the swelling (4).
1. The diagnosis and treatment of peripheral lymphedema. Consensus document of the International Society of Lymphology Executive Committee. Lymphology 2003;36:84-91.
2. McNeely ML, Peddle CJ, Yurick JL, Dayes IS, Mackey JR. Conservative and dietary interventions for cancer-related lymphedema: A systematic review and meta-analysis. Cancer 2010.
3. Badger C, Preston N, Seers K, Mortimer P. Physical therapies for reducing and controlling lymphedema of the limbs. Cochrane Database Syst Rev 2004;CD003141.
4. Johansson K, Albertsson M, Ingvar C, Ekdahl C. Effects of compression bandaging with or without manual lymph draining treatment in patients with postoperative arm lymphedema. Lymphology 1999;32:103-110.
5. Deng J, Ridner SH, Murphy BA. Lymphedema in patients with head and neck cancer. 2011;38:1-10.
Main points of information
Information should be given to patients who have received surgery only or combined with radiotherapy with increased risk of getting lymphedema. The patient usually gets information about lymphedema after the surgery. Sufficient information and guidance is important and crucial for both avoiding getting lymphedema and being able to identify lymphedema at the very beginning.
- The function and purpose of the lymphatic system
- Causes of lymphedema
- Symptoms of lymphedema
- Different treatment options
- Complications/side effects caused by the disease and treatment
- The importance of maintaining mobility in the arm or leg
Symptoms of lymphedema
- A feeling of uncomfortable change
- A feeling of heaviness
- Bursting pain
- Changes of consistency (visible or palpable) in the soft tissues
- Suspicion of increased circumference
- Swelling may disappear overnight, but usually returns during daytime
- Some have swelling sporadically
The dominating symptom is lasting swelling in the involved area. Other symptoms will to a large extent depend on the amount, duration, and localization of the edema.
Moderate swelling after cancer surgery, can be a reaction which often spontaneously disappears.
Lymphedema is usually measured using a clinical method. There are multiple methods to measure the extent of lymphedema. The gold standard is the water displacement method, which measures and compares the volumes of both arms/legs. But a method of comparing volume by using several circumferential measurements of the arms/legs is often used in research and sometimes in the clinical setting. The most widely used method is measurement of circumference at multiple anatomic points on the arm/leg with comparison with the contralateral arm/leg. A difference in circumference of ≥2cm is often defined as lymphedema. Stemmer sign is also used.
With development of lymphedema, it is important to take precautionary measures as soon as possible. Treatment with compression is the component which seems to be most effective in reducing the swelling. Manual lymph drainage is often used in combination with bandaging in the first 1-2 weeks of the treatment. This complete decongestive therapy is a composite treatment including multiple techniques which are performed by a specially trained physical therapist.
The intensive phase
- Compression treatment – possibly with bandaging and thereafter adjustment of an elastic stocking
- Manual lymph drainage
- Circulation and drainage inducing exercises
- Skin care
During the intensive phase, the patient is usually treated 5 days a week with continuously bandaging until the desired volume reduction is achieved. This usually takes one to two weeks.
After stimulating the lymphatic flow by manual lymph drainage, a compression stocking is used or the whole arm is bandaged for one to two weeks. The bandages should be worn as long as they are not too uncomfortable. Correct bandaging with short, elastic bandages provide the tissue with high pressure under activity and low pressure while resting.
- An ointment with a low pH (5.5) should be applied to the skin.
- A light tube gauze should be worn.
- The padding is then applied.
- The bandaging starts distally to the lymphedema.
- The bandages are laid evenly, circularly, and in multiple layers.
- The pressure should decrease gradually from distal to proximal.
- The pressure is regulated partially with the bandaging technique and mainly by the number of layers of bandages.
- The stocking may be removed at night.
- At night an ointment is preferably applied to the skin.
- With incipient lymph edema, wear the stocking during activity.
- In moderate and extensive lymph edema, the stocking is usually worn all day.
- The stocking should be washed at least every third day.
A poorly customized stocking may create faulty compression. The most frequent error is that the compression stocking is used after it has lost its elasticity (worn out) and therefore has less effect.
Manual Lymph Drainage
The massage strokes should be performed in the direction of the lymphatic drainage with light pressure and with slow motions. The treatment should not be painful.
Manual lymph drainage has four main movements: standing circles, pumping grip, turning grip, and corkscrew grip.
Pressure massage with pulsator
Pulsation is never a first choice for treatment of lymphedema, but could be a measure over time when monitoring has shown that the treatment is effective. At the start, the patient should be informed about possibly complications. Sometimes, an increase in edema is seen proximal to the cuff. Further pulsation treatment should then be postponed until manual lymph drainage and exercises have improved the condition. If the pressure is too high, the lymphatic vessels may be damaged and the amount of interstitial fluid may increase.
The pressure should be moderate and the patient should experience the treatment as comfortable. It is not the amount of pressure that is important, but uniform rhythmic pressure wave. Tuning of rate and pressure are adjusted for each patient.
Usually, the treatment should last for twenty minutes at the start increasing gradually to thirty to forty minutes. Can be used daily or when needed. Pulsation treatment may also be performed by the patient at home.
Regardless of whether the patient has lymphedema or not, it is important to hinder the occurrence of scratches, sores, and unnecessary skin irritation. Use of gloves is appropriate in some situations. The patient should also be cautious of overheating and sunburn. The main goal of skin care is to prevent infections, because this can trigger an eruption of lymph edema.
Regular use of bandages and compression stockings dries out the skin. Use of skin care products and cleansers with a low pH (5.5) are recommended. Good skin care keeps the skin soft and supple and maintains the skins natural ability to fight infection.
Disinfecting ointment and adhesive tape should be used in the event of an ulcer or scratch or if there is danger of infection.
- Use of elastic stocking and/or glove as needed
- Skin care
- Regular exercises to facilitate the muscle-joint pump
- Possible intermittent pressure massage with pulsator
The patient obtains some treatment during the maintenance phase and may have treatment by a physical therapist if necessary. In the short term, the treatment is almost always satisfactory. In the long run, the result depends on the patient practicing the measures recommended. The pulsator may usually be borrowed from a health care center.
Exercises to improve mobility and lymph flow of the shoulder/arm
Dynamic exercises with a relaxation phase are optimal. "Throwing" movements may feel uncomfortable. Many experience that it is better to walk with poles, but it is important to maintain a loose grip of the pole.
Correctly adjusted movement exercises:
- induce circulation without straining the reduced lymphatic system
- provide adequate joint movements
- stimulate dynamic change between tension and relaxation, preferably in conjunction with respiration
Movement therapy in a heated pool may be favorable for some lymphedema patients. Water pressure stimulates lymphatic drainage and simultaneously activates circulation and movement.
If necessary, the patient may obtain a referral for physical therapy in their home area for further follow-up. Follow-up and guidance by a physical therapist with the necessary skills is important. Some with serious lymphedema will need frequent treatment for the rest of their life. But others will be able to manage the treatment themselves by adhering to the guidelines that they have learned. Compression with stockings and skincare are often sufficient treatment. So many patients do not need physical therapy as treatment, but rather information and functional guidance.
Moderate physical activity improves joint movement, circulation, and well-being, as well as stimulation of lymph drainage. Blood pressure should not be measured and vaccinations should not be given in the treated arm. Gloves are recommended for gardening.
Fibrosis of the dermis and epidermis with affects some persons with lymphedema. The skin loses its elasticity and is more easily traumatized than normal skin.
The immune system is weakened in the edematous area. This may be for multiple reasons, among others, weakened transport of dendritic cells, lymphocytes, and proteins. If the area’s regional lymph nodes are removed, this will also weaken the local immune system.
In some edema patients, especially secondary lymphedema, a distinctive reaction (erysipelas) may occur in the skin of the affected area. This will usually start acutely with a strong feeling of malaise with high fever, hyperemia with flushing, and increased swelling of the skin. The area of skin involvement is often limited. The symptoms are usually improved after four to six days but it is not uncommon for the edema to deteriorate. The condition should be treated with antibiotics (penicilin) as quickly as possible.
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.
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.
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.
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.
- 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.
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.
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.
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.
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.
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.
- 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