Cancer of the Ovary - Radiotherapy

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This guide summarises some of the basic concepts of radiation physics and radiobiology to assist in the understanding of the use of radiation as a form of treatment. Different radiotherapy techniques are reviewed including brachytherapy and external beam radiotherapy. Radiotherapy planning and how radiation treatment is delivered are explained. The different ways in which radiotherapy can be combined with surgery and chemotherapy are also discussed. The common side effects of radiotherapy as used for gynaecological cancers are summarised as well as some recommendations for the care of some of these side effects.

Radiation Physics

Radiation therapy (or radiotherapy) is the use of ionising radiation as a treatment modality. Ionising radiation is radiation which, when absorbed, can eject an orbital electron from the atoms that make up the absorbing matter. This process requires a great deal of energy and so ionising radiation is also high-energy radiation.

Ionising radiation can be electromagnetic radiation that includes x-rays and gamma rays or particulate radiation that includes electron beams and beta rays. Usually electrical machines produce x-rays and electron beams whereas gamma rays and beta rays are produced by an intranuclear reaction in a radioactive substance (radioactive decay).

X-rays and electron beams can be of variable energies depending on the generating machine but gamma rays and beta rays produced by the decay of a radioactive isotope are of a fixed and unalterable energy.

The absorbed dose is the amount of energy that is absorbed per unit mass by the matter that receives the radiation. The term for the dose of radiation given is the Gray (Gy) which is 1 joule/kg. Previously, the term used for dose was the rad and 1 Gray is equal to 100 rads. In radiotherapy, the different ranges of electromagnetic radiation used are:

	superficial radiation (10 to 125 kilovolt)
	orthovoltage radiation (125 to 400 kilovolt)
	megavoltage radiation (4 to 20+ megavolt)

The greater the energy of the electromagnetic radiation, the greater the penetration of the radiation into the matter irradiated before ionisation occurs. Megavoltage radiation is skin sparing because the maximum dose is delivered not at the skin surface (which occurs with superficial and orthovoltage radiation) but at some distance below the surface. The dose continues to be delivered beyond this maximum dose delivery level for many centimetres below the skin surface.

Particulate radiation is more readily absorbed by matter and therefore does not penetrate as deeply as electromagnetic radiation. The greater the energy of the electron beam or beta rays, the greater the penetration into matter but there is also a very rapid fall off in dose with depth once the maximum dose is delivered unlike electromagnetic radiation. This means that particulate radiation is useful for treating superficial structures and for protecting deeper structures from unnecessary radiation dose compared with megavoltage radiation.

Radiobiology

Ionising radiation can produce high-energy electrons in the irradiated matter either directly such as with particulate radiation or indirectly by causing the ejection of orbital electrons, which occurs with x-rays (photons) or gamma rays. In biological tissue, these electrons can interact with DNA directly or more commonly with water which makes up 80% of the cell. The interaction with water produces free radicals that are very unstable and therefore very short-lived. Free radicals are able to interact with biologically important material (eg DNA or cell membranes) to produce detrimental effects or can revert back to their former stable state. All these effects occur randomly.

A cell that is damaged by radiation may lose its reproductive capacity due to DNA damage. Some cells die immediately (apoptosis) while most cells only die when they attempt to divide. Some cells may remain viable but unable to divide.

In rapidly dividing tissue (such as skin, mucous membranes, marrow, tumours), radiation induced cell kill is manifest sooner compared to more slowly dividing tissue (such as skeletal muscle, vasculature).

Not all radiation induced damage results in cell death or permanent damage. Some damage can be repaired (sublethal damage and potentially lethal damage). Malignant cells are less able to repair this damage compared to normal cells. The majority of such sublethal damage is repaired within six hours of being exposed to radiation.

The presence of oxygen during radiation is essential for cell kill. Hypoxia provides cells with a radioprotective effect. Thus anaemia may reduce the effectiveness of radiation therapy. Cells can also respond to radiation damage by cell proliferation with shortening of the cell cycle. There is a difference in this response between normal cells and tumour cells.

Radiotherapy Dose

In general, radiation is given as a course of treatment. The total dose to be given is divided into a number of small daily treatments or fractions. This is to improve the therapeutic ratio of the treatment by maximising the tumour cell kill and minimising the permanent damage to the irradiated normal tissues. The total dose delivered and the fractionation used depends on a number of factors including:

	Tumour type
	Tumour size
	Intent of treatment (curative or palliative)
	Part of body treated
	Volume of body treated
	Critical structures included in radiation fields
	Age and health of patient
	Chemotherapy (pre-XRT, concurrent, post-XRT)
	Surgery (pre-op or post-op radiotherapy)

The dose of radiation given is most influenced by the intent of treatment, i.e. cure or palliation.

When cure is intended, the dose given is the maximum that can be given, allowing for normal tissue within the radiation fields to remain functional. The higher the dose that can be given, the greater the chance of eradicating all malignant cells but there is an increased risk of excessive death of normal cells which could then result in irreversible damage to normal tissues and potential serious long-term (or late) side-effects from treatment.

If palliation is the intention of treatment, then the aim is not to eradicate every malignant cell but rather to kill off a sufficient proportion of cells to cause a reduction in the volume of the tumour to relieve symptoms caused by the tumour. This lower dose will have fewer side effects on normal tissues and can be given in a shorter time period.

The radioresponsiveness of the tumour is also important. The greater the sensitivity of the tumour cells to radiation induced damage, the greater the chance of curing the tumour with irradiation using tolerable doses of radiation.

The size of the daily fractions used is also important. The smaller the fraction size above a minimum dose, the more sparing of the more slowly dividing tissues and therefore the greater the sparing of late side-effects from treatment. In curative treatments, the fraction size ranges from 1.6 to 2.0 Gy per fraction whereas with palliative treatments where late side effects are not so important larger doses per fraction are commonly used such as 3 to 4 Gy per fraction.

For example, a typical dose/fractionation schedule for treating a post-operative pelvis with radical (ie curative) intent would be 52.5 Gy in 30 fractions over 6 weeks, with five fractions per week (Monday to Friday). By contrast, a palliative treatment to the pelvis could be 20 Gy to the pelvis in 5 fractions given over one week or 30 Gy in 10 fractions given over two weeks.

Radiotherapy Techniques

Two types of radiotherapy are used in treating gynaecological malignancies - internal radiation or brachytherapy and external beam radiation.

Brachytherapy involves the placement of radiation sources into or close to a tumour. The dose delivered to the tumour can be very high with this type of radiotherapy, as there is a rapid fall-off in dose away from the source sparing surrounding normal tissues from the high dose radiation. The volume that can be treated with brachytherapy techniques, however, is very limited and has to be both accurately defined and able to be encompassed by the brachytherapy implant. Brachytherapy is ideal for treating uterine and vaginal tumours as the uterus and the vagina can readily be implanted with radioactive sources. Commonly, afterloaded intracavitary or interstitial applicators are used. A high dose of radiation can be delivered to the cervix, uterus, parametrium and vagina while limiting the dose to the bladder and rectum.

Megavoltage external beam radiation is typically produced by a linear accelerator (LA). Electrons produced by heating a wire filament are accelerated in a linear fashion to high speeds, sometimes approaching the speed of light. These very energetic electrons then strike a heavy metal target that causes a rapid deceleration. The acquired kinetic energy is then converted into heat and x-rays. This beam of x-rays of varying energies (up to a maximum dependant on the speed of acceleration) can then be used for treatment. In Queensland, Australia, the usual range of megavoltage beam energies is from 4MV to 10 MV.

The beam of x-rays so produced can then be defined and shaped using collimators in the treatment head of the machine and customised lead shielding. Beams can be modified to adjust the intensity of the radiation across the beam. The beam is focused to deliver the maximum dose of radiation at a fixed point called the isocentre. Linear accelerators are able to rotate the treatment head and the treatment couch all around this isocentre.

High-energy electron beams can also be produced by linear accelerators by using the accelerated electrons directly and can be modified in similar ways to the x-ray beams.

Linear accelerators are very complex machines and most radiotherapy departments rely on a team of physicists and engineers to ensure that the machines are in working order and producing beams of an assured quality that can be precisely targeted to the isocentre. Regular maintenance of the machinery is essential.

Radiotherapy Planning

Planning is essential to the delivery of radiation therapy. The tumour volume and the target volume must be decided upon and accurately localised. The critical normal tissues that are likely to be traversed by the radiation beams must also be defined and accurately localised. This requires physical examination; information from surgery (e.g. clips at sites of known disease); and imaging (e.g. diagnostic x-rays, ultrasounds, CT scans and MRI scans). A knowledge of the tumour and its natural history and patterns of spread is vital to deciding on the target volumes.

The patient then needs to be positioned into a comfortable and stable position for the proposed treatment that can be easily reproduced. Immobilisation devices and other positioning devices to try and reduce normal tissue included in the treatment field are frequently used. In pelvic treatments for example, a "belly-board" can be used to try and move the small bowel out of the pelvic radiation field by positioning the patient prone with the upper abdomen placed into a "hole" in the treatment table.

Once the patient has been positioned satisfactorily and the target volume localised, then how the radiation treatment is to be delivered is decided upon. Varying arrangements of the radiation beams coming from different directions are trialed and different plans for the distributions of delivered radiation dose are reviewed and modified so that the best distribution is chosen. The aim is to achieve a uniform and adequate dose across the tumour whilst keeping the critical normal structures to minimal doses.

A radiation simulator is used to check that the planned treatment is achievable. A simulator has the ability to mimic the movements of a treatment unit but has a diagnostic x-ray head and an image intensifier to accurately define the radiation beam location using bony landmarks. These simulator x-rays can then be used for comparing images taken on the actual linear accelerator of the treatment beams to verify correct positioning.

Markings need to be placed onto the skin of the patient to indicate the entrance sites of the radiation beams. These marks may be temporary using vegetable dyes and inks or permanent in the form of tiny tattoos. These marks are needed to ensure that treatment is given to the same volume every day.

Radiation Treatment

Patients attend for radiotherapy on a daily basis. They are positioned according to the planned position on the treatment couch by the radiation therapists who work on the linear accelerators. A light beam, which indicates the position of the actual treatment beam, is used to position the treatment field. Small laser dots and lines are used to position the patient correctly. For this the room is usually dark to see the laser lights and light beam clearly. It takes approximately 15 minutes for a straightforward four field pelvic treatment to be given and most of that time is spent positioning the patient. Once this is done, the treating radiation therapists will turn the room lights on and leave the treatment room so that the patient is alone in the room for treatment. Treatments usually take only a matter of minutes to be delivered.

Radiotherapy and Surgery

Radiation and surgery can be combined in many complementary ways.

Radiation can be given before surgery to sterilise possible malignant cells at the edges of the surgical resection and possibly reduce the risk of malignant cells being dislodged and spread at the time of surgery. Radiation can sometimes make an inoperable tumour more amenable to surgery.

Radiation can be given post-operatively in cases that are identified by the surgical and pathological findings as being at risk for recurrence in the region of the surgery, although adequate wound healing must occur before this can be given. Planned post-operative radiotherapy may allow for a lesser amount of surgery to be performed with preservation of organ function, improved cosmesis and possibly lesser side effects.

Radiotherapy and Chemotherapy

Chemotherapy and radiotherapy are often combined together to improve the therapeutic index of both because of the differing modes of action and side effect profiles.

Chemotherapy can make cells more sensitive to the damaging effects of radiation for example by synchronising cells in the cell cycle and arresting them at the more radiosensitive parts of that cell cycle or by sensitising hypoxic cells to radiation. Chemotherapy may also have a purely additive or independent effect to radiotherapy.

As a systemic treatment, chemotherapy may be able to treat occult micrometastases outside of the radiation field and thus improve on the outcome of the combined treatment.

Chemotherapy can be given before radiotherapy (neo-adjuvant), after radiotherapy or concurrently with radiation. For cervix cancer, there has been at last 5 recently published randomised series that have demonstrated a benefit for the use of concurrent chemotherapy and radiotherapy with respect to improved local control and overall survival.

Radiation Side Effects

Acute side effects and tumour damage develop after the cumulative dose reaches a certain level during a fractionated course of treatment. For most radical treatments, this will commence approximately halfway into a course of treatment. For palliative treatments, the side effects and benefits may not become obvious until after the treatment course is completed.

Clinically, the first indicator may be an inflammatory reaction in the irradiated area followed by signs of a lack of regeneration eg skin and mucosal ulceration followed by subsequent healing which may commence several weeks after treatment is completed. This occurs as the surviving normal tissue stem cells proliferate and usually the treated tissue recovers to continue normal function. If there is excess stem cell injury then tissue atrophy or even necrosis could occur.

Late effects of treatment occur after six months through to many years later. They are due to reduced stem cell numbers and changes in the supportive connective and vascular tissue with increased fibrosis, arteriole wall hyalinisation and subsequent reduced blood flow. These effects may be compounded by production of cell cytokines produced by the damaged cells that may perpetuate the injury chronically. Larger doses per fraction of radiotherapy will tend to produce greater late effects.

The severity of the side effects naturally depends on the total dose given and the dose per fraction. The effects on the health of the patient depend on the volume treated, the site of the treatment and the sensitivity of the structures within the volume.

There is the risk of induction of a second malignancy by radiation that may occur after a 5 to 15+ year latent period. These can include other carcinomas, sarcomas or haematogenous malignancies.

Care of Acute Side Effects

The commonly seen acute side effects with pelvic treatments are:

	Skin and perineal reaction - mild reactions include an erythematous, dry desquamating, mildly oedematous skin
	Skin and perineum - severe reactions include a moistly desquamating, ulcerated and painful skin
	Bowel-mild reactions include enteritis, colicky abdominal pains, nausea, diarrhoea
	Rectum and anus-reactions include proctitis, tenesmus, aggravation of haemorrhoids, anal fissures
	Bladder-reactions include cystitis (infective or sterile) with urinary urgency, frequency, mild dysuria, minor incontinence

Mild skin and perineal reactions can be managed by measures such as:

	Keeping the treatment area cool
	Avoiding irritants, hot water, sunlight, friction by clothes
	Using gentle moisturisers eg aqueous cream, sorbolene cream
	Using other soothing agents eg aloe vera
	Using weak salt water baths
	Using topical intrasite gel and local anaesthetic

Severe skin and perineal reactions can be managed by measures such as:

	Using appropriate analgesics including narcotics
	Treating any infection
	Using SSD cream, zinc and castor oil dressings after XRT completed

Bowel reactions of mild degree can be managed by measures such as:

	Dietary modification, e.g. modified fibre diet
	Dietary supplements, e.g. sustagen, ensure
	Using antidiarrhoea agents, e.g. lomotil, imodium, codeine
	Using oral sucralfate during radiotherapy may be helpful for diarrhoea

More severe bowel reactions may require:

	Bowel rest
	Intravenous fluid replacement
	An interruption in the treatment

Reactions involving the rectum and anus can be managed by measures such as:

	Using local anaesthetics eg rectinol cream suppositories
	Using corticosteroid suppositories, e.g. predsol
	Topical formalin applications or laser therapy may be required for problem bleeding and mucous discharge

Bladder reactions can be managed by measures such as:

	Ensuring that there is no urinary tract infection
	Having an adequate fluid intake
	Using urinary akalinizers

Late Side Effects

Potential late side effects from treating the pelvis include:

	Skin - atrophy, telangiectasia, alopecia in hair-bearing areas
	Subcutaneous - lymphoedema of lower limbs and pubic/suprapubic tissues, fibrosis
	Ovaries-atrophy, early menopause
	Vagina- narrowing, fibrosis, reduced lubrication
	Bowel- strictures, perforation, fistulae
	Rectum and anus- telangiectasia that can bleed, fibrosis, atrophy, incontinence
	Bladder- telangiectasia that can bleed, fibrosis and reduced capacity, incontinence from fibrosed sphincters, fistulae
	Second malignancy (Note: severe side effects listed are very uncommon with a less than 1% incidence)