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Brachytherapy

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Brachytherapy (from the Greek word brachy, meaning "short-distance"), also known as internal radiotherapy, sealed source radiotherapy, curietherapy or endocurietherapy, is a form of radiotherapy where a radiation source is placed inside or next to the area requiring treatment. Brachytherapy is commonly used as an effective treatment for cervical,[1] prostate,[2] breast,[3] and skin cancer[4] and can also be used to treat tumours in many other body sites.[5] Brachytherapy can be used alone or in combination with other therapies such as surgery, External Beam Radiotherapy (EBRT) and chemotherapy.

In contrast to EBRT in which high-energy x-rays are directed at the tumour from outside the body, brachytherapy involves the precise placement of radiation sources directly at the site of the cancerous tumour.[5][6] A key feature of brachytherapy is that the irradiation only affects a very localised area around the radiation sources. Exposure to radiation of healthy tissues further away from the sources is therefore reduced. In addition, if the patient moves or if there is any movement of the tumour within the body during treatment, the radiation sources retain their correct position in relation to the tumour. These characteristics of brachytherapy provide advantages over EBRT - the tumour can be treated with very high doses of localised radiation, whilst reducing the probability of unnecessary damage to surrounding healthy tissues.[5][6]

A course of brachytherapy can be completed in less time than other radiotherapy techniques. This can help reduce the chance of surviving cancer cells dividing and growing in the intervals between each radiotherapy dose.[6] Patients typically have to make fewer visits to the radiotherapy clinic compared with EBRT, and the treatment is often performed on an outpatient basis. This makes treatment accessible and convenient for many patients.[7][8] These features of brachytherapy reflect that most patients are able to tolerate the brachytherapy procedure very well.

Brachytherapy represents an effective treatment option for many types of cancer. Treatment results have demonstrated that the cancer cure rates of brachytherapy are either comparable to surgery and EBRT, or are improved when used in combination with these techniques.[9][10][11][12][13][14][15][16] In addition, brachytherapy is associated with a low risk of serious adverse side effects.[17][18]


History

Brachytherapy dates back to 1901 (shortly after the discovery of radioactivity by Becquerel in 1896) when Pierre Curie suggested to Henri-Alexandre Danlos that a radioactive source could be inserted into a tumour.[19][20] It was found that the radiation caused the tumour to shrink.[20] Independently, Alexander Graham Bell also suggested the use of radiation in this way.[20] In the early twentieth century, techniques for the application of brachytherapy were pioneered at the Curie institute in Paris by Danlos and at St Luke's and Memorial Hospital in New York by Robert Abbe.[5][20]

Following initial interest in brachytherapy in Europe and the US, its use declined in the middle of the twentieth century due to the problem of radiation exposure to operators from the manual application of the radioactive sources.[20][21]

However, the development of remote afterloading systems and the use of new radioactive sources in the 1950s and 1960s, reduced the risk of unnecessary radiation exposure to the operator and patients.[19] This, together with more recent advancements in three dimensional imaging modalities, computerised treatment planning systems and delivery equipment has made brachytherapy a safe and effective treatment for many types of cancer today.[5]


Types

Different types of brachytherapy can be defined according to (1) the placement of the radiation sources in the target treatment area, (2) the rate or ‘intensity’ of the irradiation dose delivered to the tumour, and (3) the duration of dose delivery.


Source placement

The two main types of brachytherapy treatment in terms of the placement of the radioactive source are interstitial and contact.

  • In the case of interstitial brachytherapy, the sources are placed directly in the target tissue of the affected site, such as the prostate or breast.
  • Contact brachytherapy involves placement of the radiation source in a space next to the target tissue. This space may be a body cavity (intracavitary brachytherapy) such as the cervix, uterus or vagina; a body lumen (intraluminal brachytherapy) such as the trachea or oesophagus; or externally (surface brachytherapy) such as the skin. A radiation source can also be placed in blood vessels (intravascular brachytherapy) for the treatment of coronary in-stent restenosis.


Dose rate

The dose rate of brachytherapy refers to the level or ‘intensity’ with which the radiation is delivered to the surrounding medium and is expressed in Grays per hour (Gy/h).

  • Medium-dose rate (MDR) brachytherapy is characterized by a medium rate of dose delivery, ranging between 2 Gy.hr-1 to 12 Gy.hr-1.[22]
  • High-dose rate (HDR) brachytherapy is when the rate of dose delivery exceeds 12 Gy.hr-1.[22] The most common applications of HDR brachytherapy are in tumours of the cervix,[1] oesophagus,[26] lungs,[27] breasts[3] and prostate.[2] Most HDR treatments are performed on an outpatient basis, but this is dependent on the treatment site.[28]
  • Pulsed-dose rate (PDR) brachytherapy involves short pulses of radiation, typically once an hour, to simulate the overall rate and effectiveness of LDR treatment. Typical tumour sites treated by PDR brachytherapy are gynaecological[1] and head and neck cancers.[23]


Duration of dose delivery

File:Brachytherapy.jpeg
Permanent brachytherapy is often performed for prostate cancer using "seeds" - small radioactive rods implanted directly into the tumour.

The placement of radiation sources in the target area can be temporary or permanent.

  • Temporary brachytherapy involves placement of radiation sources for a set duration (usually a number of minutes or hours) before being withdrawn.[5] The specific treatment duration will depend on many different factors, including the required rate of dose delivery and the type, size and location of the cancer. In LDR and PDR brachytherapy, the source typically stays in place up to 24 hours before being removed, while in HDR brachytherapy this time is typically a few minutes.[29]
  • Permanent brachytherapy, also known as seed implantation, involves placing small LDR radioactive seeds or pellets (about the size of a grain of rice) in the tumour or treatment site and leaving them there permanently to gradually decay. Over a period of weeks or months, the level of radiation emitted by the sources will decline to almost zero. The inactive seeds then remain in the treatment site with no lasting effect.[30] Permanent brachytherapy is most commonly used in the treatment of prostate cancer.[25]

Clinical applications

Body sites in which brachytherapy can be used to treat cancer

Brachytherapy is commonly used to treat cancers of the cervix,[1] prostate,[2] breast,[3] and skin.[4]

Brachytherapy can also be used in the treatment of tumours of the brain,[31] eye,[32] head and neck region (lip, floor of mouth, tongue, nasopharynx and oropharynx),[23] respiratory tract (trachea and bronchi),[27] digestive tract (oesophagus, gall bladder, bile-ducts, rectum, anus),[26][33][34][35] urinary tract (bladder, urethra, penis),[36][37][38] female reproductive tract (uterus, vagina, vulva),[39][40] and soft tissues.[24]

As the radiation sources can be precisely positioned at the tumour treatment site, brachytherapy enables a high dose of radiation to be applied to a small area. Furthermore, because the radiation sources are placed in or next to the target tumour, the sources maintain their position in relation to the tumour when the patient moves of if there is any movement of the tumour within the body. Therefore, the radiation sources remain accurately targeted. This enables clinicians to achieve a high level of dose conformity – i.e. ensuring the whole of the tumour receives an optimal level of radiation. It also reduces the risk of damage to healthy tissue, organs or structures around the tumour,[28] thus enhancing the chance of cure and preservation of organ function.

The use of HDR brachytherapy enables overall treatment times to be reduced compared with EBRT.[41][42] Patients receiving brachytherapy generally have to make fewer visits for radiotherapy compared with EBRT, and overall radiotherapy treatment plans can be completed in less time.[43] Many brachytherapy procedures are performed on an outpatient basis. This convenience may be particularly relevant for patients who have to work, older patients, or patients who live some distance from treatment centres, to ensure that they have access to radiotherapy treatment and adhere to treatment plans. Shorter treatment times and outpatient procedures can also help improve the efficiency of radiotherapy clinics.[44][45]

Brachytherapy can be used with the aim of curing the cancer in cases of small or locally advanced tumours, provided the cancer has not metastasized (spread to other parts of the body). In appropriately selected cases, brachytherapy for primary tumours often represents a comparable approach to surgery, achieving the same probability of cure and with similar side effects.[46][47] However, in locally advanced tumours, surgery may not routinely provide the best chance of cure and is often not technically feasible to perform. In these cases radiotherapy, including brachytherapy, offers the only chance of cure.[48][49] In more advanced disease stages, brachytherapy can be used as palliative treatment for symptom relief from pain and bleeding.

In cases where the tumour is not easily accessible or is too large to ensure an optimal distribution of irradiation to the treatment area, brachytherapy can be combined with other treatments, such as EBRT and/or surgery. Combination therapy of brachytherapy exclusively with chemotherapy is rare.


Cervical cancer

Brachytherapy is commonly used in the treatment of early or locally confined cervical cancer and is a standard of care in many countries.[1][50][51][52][53] Cervical cancer can be treated with either LDR, PDR or HDR brachytherapy.[11][52][54] Used in combination with EBRT, brachytherapy can provide better outcomes than EBRT alone.[9] The precision of brachytherapy enables a high dose of targeted radiation to be delivered to the cervix, while minimising radiation exposure to adjacent tissues and organs.[51][52][55][56]

The chances of staying free of disease (disease-free survival) and of staying alive (overall survival) are similar for LDR, PDR and HDR treatments.[49][57] However, a key advantage of HDR treatment is that each dose can be delivered on an outpatient basis with a short administration time[9] providing greater convenience for many patients.

Prostate cancer

Brachytherapy to treat prostate cancer can be given either as permanent LDR seed implantation or as temporary HDR brachytherapy.[2][58][59]

Permanent seed implantation is suitable for patients with a localised tumour and good prognosis [12][58][60][61] and has been shown to be a highly effective treatment to prevent the cancer from returning.[10][12] The survival rate is similar to that found with EBRT or surgery (radical prostatectomy), but with fewer side effects such as impotence and incontinence.[18] The procedure can be completed quickly and patients are usually able to go home on the same day of treatment and return to normal activities after 1 to 2 days.[7] Permanent seed implantation is often a less invasive treatment option compared to the surgical removal of the prostate.[7]

Temporary HDR brachytherapy is a newer approach to treating prostate cancer, but is currently less common than seed implantation. It is predominately used as to provide an extra dose in addition to EBRT (known as ‘”boost” therapy) as it offers an alternative method to deliver a high dose of radiation therapy that conforms to the shape of the tumour within the prostate, while sparing radiation exposure to surrounding tissues.[13][14][59][60][62][63] HDR brachytherapy as a boost for prostate cancer also means that the EBRT course can be shorter than when EBRT is used alone.[13][14][63][64]


Breast cancer

Radiation therapy is standard of care for women who have undergone lumpectomy or mastectomy surgery, and is an integral component of breast-conserving therapy.[3][65] Brachytherapy can be used after surgery, before chemotherapy or palliatively in the case of advanced disease.[66] Brachytherapy to treat breast cancer is usually performed with HDR temporary brachytherapy. Post surgery, breast brachytherapy can be used as a “boost” following irradiation of the whole breast using EBRT.[65][67] More recently, brachytherapy alone is applied in a technique called APBI (accelerated partial breast irradiation), involving delivery of radiation to only the immediate region surrounding the original tumour.[16][65][67]

The main benefit of breast brachytherapy compared to EBRT is that a high dose of radiation can be precisely applied to the tumour while sparing radiation to healthy breast tissues and underlying structures such as the ribs and lungs.[66] APBI can typically be completed over the course of a week.[16] The option of brachytherapy may be particularly important in ensuring that working women, the elderly or women without easy access to a treatment centre, are able to benefit from breast-conserving therapy due to the short treatment course compared with EBRT (which often requires more visits over the course of 1-2 months).[8] Brachytherapy has demonstrated excellent local control of breast cancer at follow-up of up to 6 years post treatment.[16][68][69]

With breast brachytherapy, radiation oncologists place flexible plastic tubes called catheters or a balloon into the breast. Twice a day for a determined number of days, the catheters or the balloon will be connected to a brachytherapy machine, also called a high-dose-rate afterloader to safely and effectively deliver the radiation to the lumpectomy site under computer guidance. The radiation is only left in place for a few minutes at a time. At the end of the course of treatment, the catheter or balloon is removed.[70] This treatment is still being studied to see if it is as effective as three to eight weeks of external beam radiation therapy.[citation needed]

Skin cancer

HDR brachytherapy for nonmelanomatous skin cancer, such as basal cell carcinoma and squamous cell carcinoma, provides an alternative treatment option to surgery. This is especially relevant for cancers on the nose, ears, eyelids or lips, where surgery may cause disfigurement or require extensive reconstruction.[4] Various applicators can be used to ensure close contact between the radiation source(s) and the skin, which conform to the curvature of the skin and help ensure precision delivery of the optimal irradiation dose.[4]

Brachytherapy for skin cancer provides good cosmetic results and clinical efficacy; studies with up to 5 years follow-up have shown that brachytherapy is highly effective in terms local control, and is comparable to EBRT.[71][72][73] Treatment times are typically short, providing convenience for patients.[74] It has been suggested that brachytherapy may become a standard of treatment for skin cancer in the near future.[74]


Other applications

Brachytherapy can be used in the treatment of coronary in-stent restenosis, in which a catheter is placed inside blood vessels, through which sources are inserted and removed.[75] The therapy has also been investigated for use in the treatment of peripheral vasculature stenosis[76] and considered for the treatment of atrial fibrillation.[77]


Side effects

The likelihood and nature of potential acute, sub-acute or long-term side-effects associated with brachytherapy depends on the location of the tumour being treated and the type of brachytherapy being used.


Acute

Acute side effects associated with brachytherapy include localised bruising, swelling, bleeding, discharge or discomfort within the implanted region. These usually resolve within a few days following completion of treatment.[78] Patients may also feel fatigued for a short period following treatment.[78][79]

Brachytherapy treatment for cervical or prostate cancer can cause acute and transient urinary symptoms such as urinary retention, urinary incontinence or painful urination (dysuria).[18][80][81] Transient increased bowel frequency, diarrhoea, constipation or minor rectal bleeding, may also occur.[18][80][81] Acute and subacute side effects usually resolve over a matter of days or a few weeks. In the case of permanent (seed) brachytherapy for prostate cancer, there is a small chance that some seeds may migrate out of the treatment region into the bladder or urethra and be passed in the urine.

Brachytherapy for skin cancer may result in a shedding of the outer layers of skin (desquamation) around the area of treatment in the weeks following therapy, which typically heals in 5-8 weeks.[4] If the cancer is located on the lip, ulceration may occur as a result of brachytherapy, but usually resolves after 4-6 weeks.[82]

Most of the acute side effects associated with brachytherapy can be treated with medication or through dietary changes, and usually disappear over time (typically a matter of weeks), once the treatment is completed. The acute side effects of HDR brachytherapy are broadly similar to EBRT.[79]


Long-term

In a small number of people, brachytherapy may cause long-term side effects due to damage or disruption of adjacent tissues or organs. Long-term side effects are usually mild or moderate in nature. For example, urinary and digestive problems may persist as a result of brachytherapy for cervical or prostate cancer, and may require ongoing management.[18][80][81]

Brachytherapy for prostate cancer may cause erectile dysfunction in approximately 15-30% of patients.[2][30] However, the risk of erectile dysfunction is related to age (older men are at a greater risk than younger men) and also the level of erectile function prior to receiving brachytherapy. In patients who do experience erectile dysfunction, the majority of cases can successfully be treated with drugs such as Viagra.[2] Importantly, the risk of erectile dysfunction after brachytherapy is less than after radical prostatectomy.[46][80]

Brachytherapy for breast or skin cancer may cause scar tissue to form around the treatment area. In the case of breast brachytherapy, fat necrosis may occur as a result of fatty acids entering the breast tissues. This can cause the breast tissue to become swollen and tender. Fat necrosis is a benign condition and typically occurs 4-12 months after treatment and affects about 2% of patients.[83][84]


Safety around others

Patients often ask if they need to have special safety precautions around family and friends after receiving brachytherapy. If temporary brachytherapy is used, no radioactive sources remain in the body after treatment. Therefore, there is no radiation risk to friends or family from being in close proximity with them.[85]

If permanent brachytherapy is used, low dose radioactive sources (seeds) are left in the body after treatment - the radiation levels are very low and decrease over time. In addition, the irradiation only affects tissues within a few millimeters of the radioactive sources (i.e. the tumour being treated). As a precaution, some people receiving permanent brachytherapy may be advised to not hold any small children or be too close to pregnant women for a short time after treatment. Radiation oncologists or nurses can provide specific instructions to patients and advise for how long they need to be careful.[85]

Procedure

Typical stages of a brachytherapy procedure.

Initial planning

In order to accurately plan the brachytherapy procedure, a thorough clinical examination is performed to understand the characteristics of the tumour. In addition, a range of imaging modalities can be used to visualise the shape and size of the tumour and its relation to surrounding tissues and organs. These include x-ray radiography, ultrasound, computed axial tomography (CT or CAT) scans and magnetic resonance imaging (MRI). The data from many of these sources can be used to create a 3D visualisation of the tumour and the surrounding tissues.

Using this information, a plan of the optimal distribution of the radiation sources can be developed. This includes consideration of how the source carriers (applicators), which are used to deliver the radiation to the treatment site, should be placed and positioned. Applicators are non-radioactive and are typically needles or plastic catheters. The specific type of applicator used will depend on the type of cancer being treated and the characteristics of the target tumour.

This initial planning helps to ensure that ‘cold spots’ (too little irradiation) and ‘hot spots’ (too much irradiation) are avoided during treatment, as these can respectively result in treatment failure and side-effects.


Insertion and imaging of the applicator(s)

Before radioactive sources can be delivered to the tumour site, the applicators have to be inserted and correctly positioned in line with the initial planning.

Imaging techniques, such as x-ray, fluoroscopy and ultrasound are typically used to help guide the placement of the applicators to their correct positions and to further refine the treatment plan. CAT scans and MRI can also be used. Once the applicators are inserted, they are held in place against the skin using sutures or adhesive tape to prevent them from moving. Once the applicators are confirmed as being in the correct position, further imaging can be performed to guide detailed treatment planning.


Creation of the ‘virtual’ patient to plan the delivery of brachytherapy.

Creation of a virtual patient

The images of the patient with the applicators in situ are imported into treatment planning software and the patient is brought into a dedicated shielded room for treatment. The treatment planning software enables multiple 2D images of the treatment site to be translated into a 3D ‘virtual patient’, within which the position of the applicators can be defined. The spatial relationships between the applicators, the treatment site and the surrounding healthy tissues within this ‘virtual patient’ are a copy of the relationships in the actual patient.


Optimizing the irradiation plan

Refinement of the treatment plan during the brachytherapy procedure.

To identify the optimal spatial and temporal distribution of radiation sources within the applicators of the implanted tissue or cavity, the treatment planning software allows virtual radiation sources to be placed within the virtual patient. The software shows a graphical representation of the distribution of the irradiation. This serves as a guide for the brachytherapy team to refine the distribution of the sources and provide a treatment plan that is optimally tailored to the anatomy of each patient before actual delivery of the irradiation begins.[86] This approach is sometimes called ‘dose-painting’.

Treatment delivery

The radiation sources used for brachytherapy are always enclosed within a non-radioactive capsule. The sources can be delivered manually, but are more commonly delivered through a technique known as ‘afterloading’.

Manual delivery of brachytherapy is limited to a few LDR applications, due to risk of radiation exposure to clinical staff.[29]

In contrast, afterloading involves the accurate positioning of non-radioactive applicators in the treatment site, which are subsequently loaded with the radiation sources. In manual afterloading, the source is delivered into the applicator by the operator.

Remote afterloading systems provide protection from radiation exposure to healthcare professionals by securing the radiation source in a shielded safe. Once the applicators are correctly positioned in the patient, they are connected to an ‘afterloader’ machine (containing the radioactive sources) through a series of connecting guide tubes. The treatment plan is sent to the afterloader, which then controls the delivery of the sources along the guide tubes into the pre-specified positions within the applicator. This process is only engaged once staff are removed from the treatment room. The sources remain in place for a pre-specified length of time, again following the treatment plan, following which they are returned along the tubes to the afterloader.

On completion of delivery of the radioactive sources, the applicators are carefully removed from the body. Patients typically recover quickly from the brachytherapy procedure, enabling it to often be performed on an outpatient basis.[28]

Radiation sources

Commonly used radiation sources (radionuclides) for brachytherapy

Radionuclide Type Half-life Energy
Caesium-137 (137Cs) γ-ray 30.17 years 0.662 MeV
Cobalt-60 (60Co) γ-rays 5.26 years 1.17, 1.33 MeV
Iridium-192 (192Ir) γ-ray 74.0 days 0.38 MeV (mean)
Iodine-125 (125I) X-rays 59.6 days 27.4, 31.4 and 35.5 keV
Palladium-103 (103Pd) X-ray 17.0 days 21 keV (mean)
Ruthenium-106 (106Ru) β-particles 1.02 years 3.54 MeV


Electronic brachytherapy

Electronic brachytherapy involves placement of miniature low energy x-ray tube sources into a pre-positioned applicator within body/tumour cavities to rapidly deliver high doses to target tissues while maintaining low doses to distant non-target tissues.

See also

References

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  34. ^ Ash D; et al. (2005). "Bile duct cancer". In Gerbaulet A, Pötter R, Mazeron J, Limbergen EV (ed.). The GEC ESTRO handbook of brachytherapy. Belgium: ACCO. {{cite book}}: Cite has empty unknown parameter: |coauthors= (help); Explicit use of et al. in: |last= (help)CS1 maint: multiple names: editors list (link)
  35. ^ Mazeron JJ; et al. (2005). "Anorectal cancer". In Gerbaulet A, Pötter R, Mazeron J, Limbergen EV (ed.). The GEC ESTRO handbook of brachytherapy. Belgium: ACCO. {{cite book}}: Cite has empty unknown parameter: |coauthors= (help); Explicit use of et al. in: |last= (help)CS1 maint: multiple names: editors list (link)
  36. ^ Van Limbergen E; et al. (2005). "Urinary bladder cancer". In Gerbaulet A, Pötter R, Mazeron J, Limbergen EV (ed.). The GEC ESTRO handbook of brachytherapy. Belgium: ACCO. {{cite book}}: Cite has empty unknown parameter: |coauthors= (help); Explicit use of et al. in: |last= (help)CS1 maint: multiple names: editors list (link)
  37. ^ Gerbaulet A; et al. (2005). "Urethral cancer". In Gerbaulet A, Pötter R, Mazeron J, Limbergen EV (ed.). The GEC ESTRO handbook of brachytherapy. Belgium: ACCO. {{cite book}}: Cite has empty unknown parameter: |coauthors= (help); Explicit use of et al. in: |last= (help)CS1 maint: multiple names: editors list (link)
  38. ^ Gerbaulet A; et al. (2005). "Penis cancer". In Gerbaulet A, Pötter R, Mazeron J, Limbergen EV (ed.). The GEC ESTRO handbook of brachytherapy. Belgium: ACCO. {{cite book}}: Cite has empty unknown parameter: |coauthors= (help); Explicit use of et al. in: |last= (help)CS1 maint: multiple names: editors list (link)
  39. ^ Pötter R; et al. (2005). "Endometrial cancer". In Gerbaulet A, Pötter R, Mazeron J, Limbergen EV (ed.). The GEC ESTRO handbook of brachytherapy. Belgium: ACCO. {{cite book}}: Cite has empty unknown parameter: |coauthors= (help); Explicit use of et al. in: |last= (help)CS1 maint: multiple names: editors list (link)
  40. ^ Gerbaulet A; et al. (2005). "Primary vaginal cancer". In Gerbaulet A, Pötter R, Mazeron J, Limbergen EV (ed.). The GEC ESTRO handbook of brachytherapy. Belgium: ACCO. {{cite book}}: Cite has empty unknown parameter: |coauthors= (help); Explicit use of et al. in: |last= (help)CS1 maint: multiple names: editors list (link)
  41. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 18627617, please use {{cite journal}} with |pmid=18627617 instead.
  42. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 11089712, please use {{cite journal}} with |pmid=11089712 instead.
  43. ^ Hoskin P, Coyle C, ed. (2005). Radiotherapy in practice: brachytherapy. New York: Oxford University Press. {{cite book}}: Cite has empty unknown parameter: |coauthors= (help)
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  45. ^ Quang TS; et al. (2007). "Technological evolution in the treatment of prostate cancer". Oncology. 21. {{cite journal}}: Cite has empty unknown parameters: |month= and |coauthors= (help); Explicit use of et al. in: |author= (help)
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  47. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 17455209, please use {{cite journal}} with |pmid=17455209 instead.
  48. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 19734106, please use {{cite journal}} with |pmid=19734106 instead.
  49. ^ a b Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 15275728, please use {{cite journal}} with |pmid=15275728 instead.
  50. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 17336465, please use {{cite journal}} with |pmid=17336465 instead.
  51. ^ a b National Institute for Health and Clinical Excellence (2006). "High dose rate brachytherapy for carcinoma of the cervix". NICE. Retrieved 25th September, 2009. {{cite web}}: Check date values in: |accessdate= (help); Unknown parameter |month= ignored (help)
  52. ^ a b c Viswanathan AN; et al. "American Brachytherapy Society cervical cancer brachytherapy task group" (PDF). American Brachytherapy Society. Retrieved 25th September, 2009. {{cite web}}: Check date values in: |accessdate= (help); Cite has empty unknown parameter: |month= (help); Explicit use of et al. in: |author= (help)
  53. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 19619956, please use {{cite journal}} with |pmid=19619956 instead.
  54. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 19409728, please use {{cite journal}} with |pmid=19409728 instead.
  55. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 18661430, please use {{cite journal}} with |pmid=18661430 instead.
  56. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 16403584, please use {{cite journal}} with |pmid=16403584 instead.
  57. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 11815967, please use {{cite journal}} with |pmid=11815967 instead.
  58. ^ a b Merrick GS; et al. "American Brachytherapy Society prostate low-dose rate task group" (PDF). American Brachytherapy Society. Retrieved 25th September, 2009. {{cite web}}: Check date values in: |accessdate= (help); Cite has empty unknown parameter: |month= (help); Explicit use of et al. in: |author= (help)
  59. ^ a b Hsu I-C; et al. "American Brachytherapy Society prostate high-dose rate task group" (PDF). American Brachytherapy Society. Retrieved 25th September, 2009. {{cite web}}: Check date values in: |accessdate= (help); Cite has empty unknown parameter: |month= (help); Explicit use of et al. in: |author= (help)
  60. ^ a b Ash D; et al. (2005). "Prostate Cancer". In Hoskin P, Coyle C (ed.). Radiotherpay in practice: brachytherapy. New York: Oxford University Press. {{cite book}}: Cite has empty unknown parameter: |coauthors= (help); Explicit use of et al. in: |last= (help)
  61. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 19036530, please use {{cite journal}} with |pmid=19036530 instead.
  62. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 19748692, please use {{cite journal}} with |pmid=19748692 instead.
  63. ^ a b Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 19046556, please use {{cite journal}} with |pmid=19046556 instead.
  64. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 19734106, please use {{cite journal}} with |pmid=19734106 instead.
  65. ^ a b c Keisch; et al. (2007). "American Brachytherapy Society breast brachytherapy task group" (PDF). American Brachytherapy Society. Retrieved 25th September, 2009. {{cite web}}: Check date values in: |accessdate= (help); Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)
  66. ^ a b Hoskin P; et al. (2005). "Breast Brachytherapy". In Hoskin P, Coyle C (ed.). Radiotherapy in practice: brachytherapy. New York: Oxford University Press. {{cite book}}: Cite has empty unknown parameter: |coauthors= (help); Explicit use of et al. in: |last= (help)
  67. ^ a b Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 19225919, please use {{cite journal}} with |pmid=19225919 instead.
  68. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 11113440, please use {{cite journal}} with |pmid=11113440 instead.
  69. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 18778971, please use {{cite journal}} with |pmid=18778971 instead.
  70. ^ http://www.rtanswers.com/treatmentinformation/cancertypes/breast/accelerated.aspx
  71. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 10758310, please use {{cite journal}} with |pmid=10758310 instead.
  72. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 18681873, please use {{cite journal}} with |pmid=18681873 instead.
  73. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 15927410, please use {{cite journal}} with |pmid=15927410 instead.
  74. ^ a b Musmacher J; et al. (2006). "High dose rate brachytherapy with surface applicators: Treatment for nonmelanomatous skin cancer". Journal of Clinical Oncology. 24: 15543. {{cite journal}}: Cite has empty unknown parameters: |month= and |coauthors= (help); Explicit use of et al. in: |author= (help)
  75. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 15769784, please use {{cite journal}} with |pmid=15769784 instead.
  76. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 12021726, please use {{cite journal}} with |pmid=12021726 instead.
  77. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 16836719, please use {{cite journal}} with |pmid=16836719 instead.
  78. ^ a b Macmillan Cancer Support. "Brachytherapy". Retrieved 25th September, 2009. {{cite web}}: Check date values in: |accessdate= (help); Cite has empty unknown parameter: |month= (help)
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  80. ^ a b c d Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 15301172, please use {{cite journal}} with |pmid=15301172 instead.
  81. ^ a b c Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 18954913, please use {{cite journal}} with |pmid=18954913 instead.
  82. ^ Casino AR; et al. (2006). "Brachytherapy in lip cancer". Medicina Oral. 11: E223-9. {{cite journal}}: Cite has empty unknown parameters: |month= and |coauthors= (help); Explicit use of et al. in: |author= (help)
  83. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 18181095, please use {{cite journal}} with |pmid=18181095 instead.
  84. ^ Department of Human Oncology, University of Wisconsin School of Medicine and Public Health. "Breast brachytherapy". Retrieved 25th September, 2009. {{cite web}}: Check date values in: |accessdate= (help); Cite has empty unknown parameter: |month= (help)
  85. ^ a b http://www.rtanswers.com/treatmentinformation/treatmenttypes/brachytherapy.aspx
  86. ^ Trnková P. (2009). "New inverse planning technology for image-guided cervical cancer brachytherapy: Description and evaluation within a clinical frame" (PDF). Radiotherapy and Oncology. 93 (2): 331–340. {{cite journal}}: Cite has empty unknown parameter: |month= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
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