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Radiation therapy in the modern era has come a long way in the last 100 years, since its efficacy was shown to treat malignant lesions in the Radium era. The perception of the clinicians to be able to volumetrically encompass the tumour within the limits of 4 lines, circumscribing a square or a rectangular surface field, has also undergone a sea change with the understanding of the patterns of tumour spread, better diagnostic tools and radiobiological implications of the parameters, that have a bearing not only on the tumour control, but also on the morbidity of the adjacent normal structures.

Coupled with these, is the gradual recognition of the need of organ preservation, both in terms of its anatomy and function, thereby ensuring an event free long-term survival, along with a better quality of life. Radiation therapy is thus steadily assuming the fulcrum of multimodality approach, in the management of most cancer patients.
Fig 1: Depicting the volumes covered by various radiotherapy techniques. Cancer by its nature of spread is not a square or round shape, but is highly irregular in shape (red). The disadvantage of square shaped conventional treatment areas (green) enclosing the vital organs (organ 2 in yellow) is overcome by conformal shape of the 3DCRT (maroon). The sophisticated IMRT/SRT etc is capable of enclosing the tumour only (white line enclosing the tumour), even excluding the deep-seated vital organ as well (organ 1 in blue).

To know what the IGRT is all about it is necessary to understand the evolution of modern day radiotherapy in four phases.

In the first phase of conventional radiotherapy, 2 sets of jaws having a square field (collimator) were used to treat the tumour. To enclose all the extensions of the tumour, liberal margins were given all around, which invariably results in the inclusion of large volumes of normal tissues in the treated areas as well. In view of this, normal tissue tolerance was the major issue and the dose of radiation is planned with consideration of tolerance of the normal tissue rather than the requirement of delivering as high dose as a possible with sole purpose of getting the maximum cure. (Yet, in the modern day radiotherapy department, complex fields with irregular treatment areas are used, even for the simplest of treatments as a rub-off of the technological developments described below).

Since tumours come in different shapes and sizes there was a need to produce irregular shaped beams of radiation. To fulfil this requirement, came the second phase of the development of 3-dimensional approach with a devise that can create irregular treatment fields called multi-leaf collimator (MLC). The MLC is a device with a series of computer-controlled leaf-like plates. Simultaneously, there was a rapid development in the imaging and computer technology. The three-Dimensional Conformal Radiation Therapy (3DCRT) thus became an advanced form of external beam radiation therapy that has used computers to create a three-dimensional (3D) picture of the tumour using high definition software. Computer Assisted Tomography (CT or CAT scans), Magnetic Resonance Imaging (MR or MRI scans) and/or Positron Emission Tomography (PET scans) are used, individually or by fusion, to create detailed, three-dimensional representations of the tumour and the surrounding organs. To enclose this tumour, multiple irregularly shaped radiation beams conforming to the general shape of the tumour are possible. As the radiation beams are very precisely directed, adjacent normal tissues receive less radiation and are able to heal quickly. Hence, this treatment is superior to the conventional 2D treatment. Going by the high standards prevalent today, 3D-CRT, without MLC, networking and portal (treatment area) imaging is not complete.

Precision radiotherapy with IGRT involves imaging at the time of treatment to track the tumour (see Fig 2).
In the third phase Intensity-Modulated Radiation Therapy (IMRT) came into existence. 3DCRT has a limitation - it can only fit into the general shape of the tumour and not exactly fit into the undulating surface and finger like extensions of the tumours (see figure). IMRT incorporates two distinct features over 3DCRT; 1) inverse treatment planning i.e. feed the dosage to be delivered to a particular area and let the computer to plan the treatment, and 2) computer-controlled intensity modulation of the radiation beam i.e., vary the intensity across the treatment beam so as to include tumour areas and to exclude normal tissue areas.

In IMRT, the intensity of the radiation beam is non-uniform (i.e., modulated) across the treatment field, rather than producing a single, uniform, intensity beam. This was achieved by using MLCs to subdivide (modulate) radiation beams into many beamlets aimed at the tumour, from various directions. Also, intensity of each of these beamlets can be adjusted individually.
This high-precision radiotherapy utilizes computer-controlled x-ray accelerators to deliver precise radiation doses that conform to the highly irregular shape of the tumour. This results in sparing surrounding normal tissues accurately, which in turn limit the side effects. With IMRT, a higher dose can be given to the tumour when the specified area is required to be targeted more accurately. IMRT spares the normal tissues in or around a tumour where even 3DCRT cannot do. In many situations, this allows a relatively higher dose of radiation to be delivered to the tumour, increasing the chance of cure. As this method of treatment delivery is very accurate, proper positioning of the patient becomes crucial. Without a good computer based inverse planning methodology and rigorous QA, IMRT cannot be complete.

There are some specialised treatment situations, which are spin-off of IMRT, especially in brain tumours. Here, a smaller version of MLC is used, with more precision, named as Micro-MLC (MMLC) to treat small tumours. The techniques are Stereotactic Radiotherapy (SRT), used as multiple sessions or stereotactic radiosurgery (SRS) as a single session (see the box item for the SRS procedure). The speciality of this technique is, it is also used in treating non malignant conditions of the brain. This technique is used in conditions like pituitary adenomas, meningiomas, schwanommas, AVMs, metastatic brain tumours etc. In this technique, a double layered mask system is prepared, which has a reproducible accuracy of +/- 1 mm. The patient undergoes imaging with localizer box. Precise marking of the lesion is done subsequently and SRT planning is done using software. Intensity modulation can also be done using MMLC in highly irregular shaped AVMs and other brain lesions and that technique is known as Intensity Modulated SRS (IMSRS). In SRS, when Cobolt-60 source is used, instead of Linear Accelerator, it is known as Gamma-knife. This is especially useful in treating very small tumours of the brain.

The fourth phase is the development of IGRT. Tumours can move between treatment sessions due to changes in organ-filling or while breathing. There could also be variations in patients’ position during day to day treatment session set up. Since, the radiation dose was more and more confined to the tumour, naturally, there developed a need to see the location of the tumour during the delivery treatment sessions. Until now the Radiation Oncologists have been treating patients with external beam radiation therapy in a mathematically precise way but unable to see what is being treated. Now, a new technology has arrived to overcome this defect. The change in the position of tumour can be tracked with a CT image (called Cone Beam CT), just before the treatment delivery and the appropriate corrections are made online. The imaging information from the “planned CT” scan done earlier is overlapped on this Cone Beam CT. This is called IGRT (image guided radiotherapy). IGRT further helps to better the delivery of radiation. In some cases, tiny gold markers are implanted in or near the tumour to pinpoint it for IGRT. The technique of tracking the tumour during respiration and treating at a particular phase of breathing is called Gated or Breath Synchronized (BSRT) IGRT. This is also known as 4D IGRT (fourth dimension is time.

If IMRT improves the radiation delivery precision and IGRT improves the radiation delivery accuracy. Hence, IGRT is by far the most advanced form of radiotherapy today.

Cone beam CT is of two types and both are approved by FDA –
  1. Megavoltage (MVCBCT): Here, CT picture is taken using the treating source of radiation. It has certain technical and operational advantages.
  2. Kilo-voltage (KVCBCT): Here, the CT picture is taken using separate attachment to the machine. The attachment is a kilo-voltage x-ray equipment, similar to the routine CT scan machine and has the advantage of better image quality.
The important development that is happening now is the use of IGRT along with Targeted Drug Therapy. Presently, there are several relatively safe drug molecules, compared to the conventional chemotherapy, which can more specifically target the cancer cells. As of now the disadvantage of these molecules lies in their ability to block only selected pathways in the complex multi-pathway of cell function. Along with IGRT, which by itself is a targeted therapy, these molecules are getting increasing importance in the routine use of the considered strategy of homing in on the cancer cells avoiding the normal cells. Both together, are expected to give the maximum cure rate that is possible.

Uses of IGRT: IGRT can be used whenever precision radiotherapy is planned i.e. 3DCRT or IMRT or SRT. It is especially useful in deep seated tumours of chest, abdomen and pelvis or when vital organs are close by the tumour e.g. eyes, brain structures, spinal cord, heart, kidney or when the tumours change in position day to day e.g. prostate cancer, pancreas cancer.

Following are the concepts in the various stages of implementation in clinical practice.

Dose Painting IGRT: The functional images (the images that show the function of cells, rather than the anatomical structure of the organ) such as PET scan and the upcoming genetic-molecular imaging of the cell are fused with existing anatomical imaging such as MRI and CT scan. The functional images show which areas are more malignant and which are benign and the dose of radiation can be “painted” fitting to these areas which is expected to improve the cure rate dramatically, especially along with simultaneous use of drugs acting at the genetic and molecular levels.

SBRT: Delivery of high dose of radiation treatment to a smaller volume in 3 to 5 sittings, instead of 5-6 weeks of conventional radiotherapy (which is possible in selected patients) using precision delivery is Stereotactic Body Radiotherapy (SBRT).

Dose Guided Radiotherapy (DGRT): It is still at the conceptual stage and at its initial experimental stage of implementation. Conceptually, the device (FLAT PANEL) that takes the images in the IGRT also forms the image of the dose distribution within the body of the patient. This is matched with the dose distribution image done before the treatment and the position of the patient is changed to fit into the planned dose distribution, online, if variation is found.

Fig 2: Tracking the tumour during the treatment sessions. Tumour (red) and the vital organ (blue) may move or position of the patient may vary during the treatment sessions. If the radiation treatment is delivered without knowing the position of tumour on that day, the area of IMRT (outlined in white) may miss the tumour and irradiate the vital organ as well (Fig 2 A). With IGRT, tumour position is localized, patient moved to correct position and IMRT fits to the tumour and the vital organ spared (Fig 2 B).

Results with IGRT:
There are reports of improved survival and reduced recurrence with modern day radiotherapy. It is moving in complimentary with the concurrent and targeted therapy using chemotherapy drugs. Depending upon the site and stage of the disease, the IGRT is expected to give significant decrease in the severe side effects of radiation and tangible improvement in the survival and more importantly in the quality–of-life.

IGRT and the survival
The equivalent uniform dose to the tumour rose with IGRT guidance, with a fall in variability in the dose delivered. The target dose could be augmented by an average of 13% with online guidance, for the same dose limit. Benefits varied for individual patients, with little advantage in 27% of patients and substantial dose escalation (by 15% to 41%) possible in 32%. Assuming an estimated 3% rise in tumour-control probability with every increase in one Gray (unit of dose), a 13% boost in dose (to 79 Gray) in carcinoma prostate should enhance the probability of tumour control by 33% and of 5-year survival by 10%.

Limitations of IGRT:
  1. Work load: The workload on radiotherapy planning, delivery, and review processes increases.
  2. Cost: Additional cost of image-guidance technologies include initial financial investment and costs attributable to greater requirements for human resources, teaching, data storage, maintenance of equipment, and potential for reduced throughput because of increased time needed at the treatment unit for imaging decision-making. Enhanced storage of imaging data and better archiving and retrieving systems are indirect but, necessary costs.
  3. Support strategies: The upsurge in information obtained at the treatment unit might require delegation of responsibilities, with image assessment and decision-making being allocated to therapists at the treatment console, rather than attending doctors. Better decision-support strategies and efficient correction algorithms are needed to avoid time delays and errors at the time of treatment.
  4. The extra radiation dose administered to the patient is very low compared to treatment doses and probably clinically unimportant for most patients. However, long-term follow-up of people treated in the modern era of image-guided and intensity-modulated radiotherapy is needed before the actual risk for side effects from low-dose irradiation—such as second malignant diseases—can be known, especially in young patients.
  5. Final limitation of image-guided treatment is the potential for the false reassurance it can provide if used inappropriately, leading to unsuitable margin reduction and overconfidence. Quality-assurance procedures and education programmes need to be formalized with broad community input to avoid incorrect use of image guidance as it is rapidly disseminating into clinical practice. With enhanced precision of treatment, other uncertainties, such as target delineation errors, become important.

IGRT Machines
  1. Linear Accelerator Based IGRT
    The most of the descriptions given above are of that of Linear Accelerator (LA) based IGRT. LA is the machine where electrons travel in a linear wave-guide, gets accelerated and hits a target to produce the x-rays required for the treatment. Major advantage of this machine is its versatility. It can be used to treat any size of tumour in any location, except for very minute tumours.
    The CyberKnife is a frameless image-guided robotic radio¬surgery system. Cyberknife is a robotic system that delivers automated, high-precision treatments to the tumor anywhere in the body and adjusts for patient and tumor motion throughout the entire treatment, once the tumor is “marked” by a x-ray opaque material. Treatment, is typically delivered in 1 to 3 sessions.
    Tomotherapy, literally translated, means “slice therapy". The first implementation of this concept was performed by NOMOS Corporation and was provided as an add-on accessory to existing linear accelerators. The add-on feature consists of a set of multileaf collimators that provide a narrow “fan” beam shape projecting a maximum width at the patient of about 20 cm. Tomotherapy is a new modality of radiation treatment that combines the use of very sophisticated computer-controlled radiation beam collimation with an on-board computed tomography (CT) scanner to image the treatment site.

    The system employs a unique approach to radiation therapy delivery designed around a CT scanner. Prior to each administration of radiation a CT scan is performed to precisely target the tumor and avoid nearby critical normal tissues by adjusting the patients position based on anatomical changes in tumor position, shape, or size. Once this adjustment takes place, radiation is administered in a helical fashion (360 degree arcs) where tens of thousands of tiny "beamlets" of radiation are directed at the target from all angles while attempting to minimize the dose to healthy tissue. The CT scan and treatment take about 20 minutes per day.

    The ability of the system to acquire daily fan beam CT scans allows for accurate recalculation of dose and periodic evaluation of the patient's treatment. Should changes to the patient occur during the course of treatment (weight loss or tumor shrinkage) adjustment of the radiation delivery can be performed via adaptive radiotherapy.
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