3D CRT and IMRT in the management of Cervical Cancers
Three dimensional conformal radiation therapy (3D CRT), and it's more recent modification Intensity Modulated Radiation Therapy, together represent one of the most significant developments in the delivery of external beam radiation therapy that have happened over the past one decade. Three dimensional conformal radiation therapy has been defined by Dr S. Webb as “A technique that aims to exploit the potential biological improvements consequent on better spatial localization of the high-dose irradiation volume”. Intensity Modulated radiotherapy (IMRT) is a special form of three dimensional conformal radiation therapy where the intensity (or rather the fluence) of the beam is modified across the beam with the use of some beam modifying device in order to give better conformality. Taken together, both the techniques rely heavily on the use of various volumetric imaging techniques and advanced planning systems, made possible practical, thanks to the rapid and universal availability of cheap computing power. Cervical cancer being the most common gynecological cancer, with it's unique position of being curable in a large proportion with radiation therapy, obviously forms a attractive target for these new techniques of external beam radiation therapy.
The basic principle behind the use of conformal radiation therapy is target delineation followed by planning to accommodate that target within a closely fitting (conforming) high dose envelope while at the same time using multiple individually designed beams to limit the surrounding dose spillage to the normal tissues. The nature of radiation beam itself is the most serious impediment to attainment of better conformality, with it's properties of entrance and exit dose and a continuously decreasing dose deposition across the length of the beam. The basic rationale behind the use of multiple beams is to divide the total dose to be delivered into smaller fractions directed at different angles at the target, so that the highest dose is localized to the area where the beams cross each other with a rapid dose falloff towards the periphery of the targeted volume. In IMRT the planning process is taken one step ahead with simultaneous modulation of the intensity of the beams to generate the most conformal dose distribution possible.
The target volume for external beam radiation therapy in carcinoma cervix includes the cervix uteri with it's gross disease extension, the soft tissue surrounding the uterus and the adenexa (parametrium) along with first echelon of the draining nodes. External beam radiation therapy is usually combined with brachytherapy so that a biologically equivalent dose of 55 - 60 Gy is delivered to the whole pelvis, with a higher dose to the cervical target volume (80 -85 Gy in early stage disease and a dose of 85 -90 Gy in advanced disease).
The role of these two techniques thus needs to be defined for two separate scenarios:
Where the target volume is being treated with external beam radiation therapy: This is the treatment of choice for many of the cervical cancers in our country. The radiation therapy in this situation is delivered with a combination of external whole pelvic radiation followed with a boost to the central disease with brachytherapy. Many other combinations of external beam radiation and brachytherapy are in use along a myriad of dose and fractionation schedules.
Where the target volume has been treated with the use of definitive surgery and the role of radiation therapy is to look after microscopic (or sometimes gross) residual disease.
In both of these scenarios the target volume for cervical cancer is bowl shaped, with the bowl walls following the pelvic walls and the base being formed by the central disease component. Through this “bowl” shaped target volume pass various structures like the rectum, bladder and sigmoid colon. The loops of the small intestine lie inside the bowl and in closer proximity to the base of the bowl in the postoperative patient. The conventional four field technique of external beam radiation therapy aims to encompass this bowl inside a large “box” shaped dose distribution. IMRT in this respect has the advantage that it allows dose sculpting so that the cumulative dose delivered is shaped to conform to this “bowl's” base and walls, containing the uterus, cervix and paracervical tissues, with maximal sparing of the “central contents” (ie. sigmoid colon, small intestines). Therein lies the true advantage and also the Achilles heel of the technique. Although the indications of IMRT are being defined, several potential applications of these techniques become readily apparent:
For irradiation of the whole pelvis: The advantage of the technique lies in better sparing of the pelvic contents from the high dose envelope. This indication is the one where the role of IMRT is being explored the most. The organs being spared include the bladder, sigmoid colon and small intestine along with the peripheral “organs” surrounding the target volume like the pelvic bone marrow and the femoral head.
For definitive of irradiation of the pelvic disease along with irradiation of the para-aortic nodes in patients with microscopic or gross disease in this area (Extended field radiation). The advantage of using IMRT in this scenario are two fold:
Delivery of a higher dose to the gross disease in the para-aortic nodal disease.
Significant sparing of the small bowel and the kidney during the process.
For irradiation of the residual disease in the pelvis after initial external beam radiation therapy especially when intracavitary brachytherapy is not feasible technically. The objective of IMRT in this scenario is to escalate the dose to the gross disease with a dose distribution mimicking that of brachytherapy.
As an alternative to brachytherapy using applicator guided IMRT, again the objective being to replicate the brachytherapy dose distribution.
For irradiation of recurrent disease with better confinement of the high dose region.
The planning of the patient for IMRT begins with volumetric image acquisition in the treatment position. Contrast enhanced CT (CECT) scans are the baseline imaging modality with additional bowel and rectal contrast being added as necessary. For better target delineation an MRI allows a better target delineation of the primary tumor, it's parametrial extensions and pelvic lymphadenopathy. The use of biological imaging modalities like Positron Emission Tomography (PET) registered to a CT scan may allow better definition of the volumetric target volume. The use of PET-CT also allows the treating physician to delineate areas of tumor which are suspected to harbor more radio-resistant cell populations like hypoxic cells (60Cu-ATSM PET) or proliferating cells (11C -Methyl Methionine), and target them with a higher dose of radiation.
The next step ie. target delineation is the most critical step which determines the success and failure of these advanced conformal techniques. Delineation of the gross disease volume (GTV) is enhanced by the use of MRI and PET scans but clinical examination forms a very vital part of the planning process with some features of the disease process like vaginal mucosal involvement being best defined by the clinician only. Two sets of GTV need to be defined – GTVT which includes the central disease component along with the parametrial, vaginal and uterine extensions, and the GTVN which includes the nodal disease. Noteworthy is the fact that the GTVT for patients being planned with definitive whole pelvic radiation forms the HR-CTV at the time of brachytherapy.
The CTV for the disease will depend on the indication for which IMRT is being delivered. Delineation of the nodal basin has been the subject of two well written reviews by Taylor and Chao and these guidelines give the treating physician guidelines for delineation of the nodal volume of CT images according to well defined vascular and bony landmarks. Separate guidelines for delineation of the para-aortic nodal volume also exist. The CTV for the patients being treated after an initial course of external radiation therapy includes the pretreatment gross cervical disease. Of note here is that IMRT can allow the treating physician to treat eccentric residual disease, parametrial disease and pelvic nodes also in this situation all of which are poorly treated using traditional intracavitary brachytherapy.
The PTV margins are a safety precaution for the setup inaccuracy inherent in delivery of fractionated external beam radiation therapy. Of note is the fact that the PTV is a composite of two broad types of uncertainties – the ITV (Internal Target Volume) which accounts for target (and normal tissue) motion and the SM (Setup margin) which accounts for the interfraction and intrafraction setup errors.
In addition to the target volume the normal organs like the bladder, rectum, sigmoid colon, urethra and the femoral heads are contoured. The small intestine being mobile needs to be contoured as a organ at risk volume which includes the entire peritoneal cavity. Normal organs need to be contoured at least 1 -2 cm above the delineated PTV. Separate PORV (Planning Organ at Risk Volumes) may need to be defined depending on the clinical setting.
The treatment prescription should not only include a statement for the dose, fractions and total time but also a statement regarding the desired quality of coverage. The modern day treatment planning systems limit us to description of a physical dose prescription but it is anticipated that in the near future prescriptions will include a statement on the biological dose coverage too. In addition to the desired target dose normal organ “constraints” need to be defined. These are usually based on the data of Emami et al but it is expected that with ubiquitous availability of CT based planning a better set of NTCP (Normal Tissue Complication Probability) against the volumetric dose volume parameters can be obtained. It is noteworthy that cervical cancers have the unique privilege of arising in a site where tumor bearing normal tissues have a significantly higher radiation tolerance than the surrounding organs.
Inverse or forward planning is done according to various algorithms based on these dose constraints. IMRT generally involves inverse planning to practically generate the complex intensity modulated field. The process of optimization of the plan using inverse planning is still iterative and time consuming at the present moment. However the use of multicriteria optimization may ease this process significantly in the near future. The calculation of the dose distribution is done using several algorithms and it is expected that in the coming years commercial Treatment Planning Systems will come with ability to calculate the dose distributions using Monte Carlo algorithms which have been shown to be consistently more accurate than the traditional methods.
Prior to the treatment verification of the dose distribution is mandatory especially if IMRT is being planned. Verification typically involves absolute and relative dosimetric checks in a phantom. Absolute dose variations of ≤ 3% and relative dose variations upto 5% are acceptable.
The actual treatment delivery can be done using several methods like compensator based IMRT, Jaw based IMRT etc. However modern day machines typically use Mutileaf collimators for ease of use and better reproducibility. It is important to understand the MLC configuration of the individual machine as that can influence and restrict the planning process significantly.
As the Achilles heel of conformal radiation therapy is the conformal dose distribution, regular checks on the setup accuracy are needed. In addition to minimize positional inaccuracies a consistent bladder and rectal filling pattern is desired. The most basic level of this check involves regular biweekly or even more frequent electronic portal images. However more recently widespread availability of sophisticated on board imaging facilities have allowed us to visualize, predict and control the setup uncertainties even more rigorously. Tomotherapy and Robotic IMRT will hopefully allow us to do this with greater precision, however the prohibitive cost limits their use in the developing countries.
Conformal radiation therapy holds a great promise in the management of cervical cancers. With proper use these modalities hold the potential to improve the control and reduce the normal tissue toxicity significantly. It is particularly so for cervical cancers where radiation therapy remains the main treatment for a significant majority. However practitioners must be aware that routine implementation of these techniques will require significant capital, education and manpower investments which may be beyond the reach of most of the developing nations at the present moment.