BLADDER RADIOTHERAPY PLANNING DOCUMENT

A 2X2 FACTORIAL RANDOMISED PHASE III STUDY COMPARING STANDARD VERSUS REDUCED VOLUME RADIOTHERAPY WITH AND WITHOUT SYNCHRONOUS CHEMOTHERAPY IN MUSCLE INVASIVE BLADDER CANCER (ISRCTN 68324339) BLADDER RADIOTHERAPY PLANNING DOCUMENT An NCRI trial supported by Cancer Research UK www.bc2001.org.uk Version 1.2, 15/05/2002 1

Contents 1. INTRODUCTION 3 2 ISUES RELATED TO REDUCED VOLUME TREATMENT IN BLADDER CANCER 3-4 3 CT SCANNING PROTOCOL 4 4.O 4.1 4.2 5 5.1 5.2 RADIOTHERAPY PLANNING PROTOCOLS RADIOTHERAPY PLANNING FOR ARM 1 (WHOLE BLADDER AND EXTRAVESICAL TUMOUR) RADIOTHERAPY PLANNING FOR ARM 2 (REDUCED VOLUME RADIOTHERAPY) HOW TO ACHIEVE THE DOSES DEFINED IN ARM 2 METHOD 1 TWO PHASE TECHNIQUE IMRT / CONCOMITANT BOOST PLAN - ONE PHASE TECHNIQUE LEGENDS FIGURE 1 &2 FIGURE 3 FIGURE 4 FIGURE 5 4-5 5 7 8 14 Version 1.2, 15/05/2002 2

Planning bladder radiotherapy for BC2001 1.Introduction One aim of the BC2001 study is to investigate whether reducing the portion of the bladder receiving the full dose of radiotherapy can affect the toxicity of the treatment without affecting tumour control. This is being investigated by comparing a standard whole bladder radiotherapy technique with a novel technique which aims to treat wherever possible the unaffected bladder to 80% of maximum dose and the tumour and margin to 100% of the dose. The potential of dose sparing effect are shown in the table below (Note this study investigated with 2cm added to CTV/GTV). STRUCTURE NON-TARGET BLADDER RECTUM BOWEL DOSE > 55 Gy > 60 Gy > 50 Gy > 45 Gy Conventional plan: 100.0 100.0 35.3 54.9 Whole bladder Conformal plan: 100.0 100.0 14.9+ 41.6 Whole bladder Conventional plan: 88.7 86.0 26.7 53.3 2 phase partial bladder conformal plan: 88.4 82.4 11.1 37.9 2 phase partial bladder Conventional plan 85.0 81.7 37.5 53.8 1phase partial bladder Conformal plan: 85.3 78.3 12.3 38.7 1 Phase Partial bladder 9 Field intensity modulated radiotherapy 84.9 73.0 13.7 37.7 Data courtesy of Dr J Staffurth; Presented at British Cancer Meeting, Leeds, July 2001 All figures refer to average percentage of the organ at risk treated to the specified dose in a series of 6 patients with bladder cancer. 2. Issues related to Reduced volume treatment in bladder cancer Aiming to specifically target the tumour in bladder cancer radiotherapy is unfamiliar to most radiotherapists and raises some problems which are not normally encountered. Commonly raised issues are: How do I localise the tumour? How do I deliver a boost treatment? How can I be sure that I am treating the cancer during my radiotherapy treatment? This guide aims to help answer these questions and help clinicians in their planning of radiotherapy for this study. The first 2 points are addressed in section 4.2. Treatment accuracy is always a concern in bladder radiotherapy due to the muscular nature of the organ. Standard radiotherapy practice accounts for this by adding1.5-2cm margin to the gross tumour volume (GTV) (perhaps more correctly the clinical target volume (CTV) if treating the whole bladder) to form the PTV and similar margins are used in this study. A study of UK patients by Turner et al (1997) documents some significant movements (>1.5cm) in 60% of patients, movement being more common in patients with larger residual bladder volumes and larger rectums. A recently reported Dutch study (Meijer et al) found that 1cm margins would be sufficient for lateral and anterior bladder Version 1.2, 15/05/2002 3

walls, 1.3cm for inferior and posterior portions. Large movements were seen predominantly in the bladder dome which required larger 2 cm margins. In the Turner study, large movements that compromised margins occurred in 30% of patients in one or more scans but in only 2 patients were consistent movements seen which required. The rest of the large movements being of a contraction type (i.e. to the centre of the bladder). Experience of planning volumes aimed at the bladder tumour alone at the Royal Marsden Hospital suggests that most all circumstances the PTV crosses the midline so this sort of movement should not compromise treatment. The effect of outward movements should be no different to standard radiotherapy. 3. CT Scanning protocol Patients will be scanned with an empty bladder which should be emptied approximately 15-30 minutes before the scan according to a consistent protocol to be used throughout treatment. Patients should be scanned from the bottom of the ischial tuberosities to 3 cm above the bladder dome or the bottom of L5 whichever is higher. A scan interval of 5mm with a scan thickness of 4-5 mm should be used to enable accurate target delineation in the reduced volume arm. 4.0 Radiotherapy planning protocols 4.1 Radiotherapy planning for Arm 1 (whole bladder and extravesical tumour) Patients in this arm will receive standard radiotherapy to the whole bladder. Accordingly the clinical target volume (CTV) will be bladder plus any extravesical tumour extension. The bladder and tumour extensions should be outlined according to standard local practice. A 1.5 cm margin is added to the CTV to form the PTV around the bladder and tumour. Treatment fields are designed to cover the PTV with the PTV receiving +/- 5% of the reference dose* i.e. the PTV should be encompassed by the 95% isodose 1. Usually this can be achieved satisfactorily by using 2 lateral wedged and a single anterior field though 4 field treatments or other arrangements can be used if appropriate. Treatment should be planned so the posterior rectal wall receives less than 80% of the reference dose. The use of conformal shielding is optional but a consistent policy should be used for patients in both arms of the trial. *Reference dose = 64Gy/32f or 55Gy/20f which is to be chosen by each centre prior to randomisation and to be used in all patients. 4.2 Radiotherapy planning for Arm 2 (reduced volume radiotherapy) The key aspect of this treatment arm is to attempt to reduce the volume of the bladder receiving the full radiation dose. This raises two problems in the planning process which are not usually encountered in bladder radiotherapy. Firstly precise localisation of the primary tumour and secondly delivery of a dose differential across the bladder The target volume for this arm of the trial is as follows GTV 1 = Bladder tumour PTV 1 = GTV 1 +1.5 cm margin CTV 2 = Bladder (not including PTV 1 ) PTV 2 = CTV 2 +1.5 cm margin 1 93% is allowable in the superior/inferior dimension Version 1.2, 15/05/2002 4

The aim is to deliver the following doses: To PTV 1 : reference dose +/- 5% To PTV 2 : 80% of reference dose +/- 5% *Maximum rectal dose, on central slice should be, <-80% of the reference dose Approximately 80% of reference dose equates to 44Gy/16fractions in the 55Gy/20f dose schedule and 50Gy/25 fractions for the 64Gy/32f dose schedule 2. 4.2.1 Tumour Localisation The localisation of CTV 2 (the whole bladder and extravesical tumour) is identical to that described above. When defining the tumour in the bladder you should have available: Diagnostic images of the bladder (CT or MRI) The surgical bladder map The planning CT scans. The ability to localise the tumour can vary. The tumour may be obvious on the planning CT scan and as such the localisation is likely to be straightforward. The gross visible tumour as well as surrounding bladder wall thickening should normally be included unless the latter is extensive and is clearly not tumour related. The suggested approach is to localise the GTV (GTV 2 ) and then add a symmetrical margin. Two situations can cause difficulty. Firstly if there has been extreme bladder emptying. Then it can be difficult to visualise the tumour (and it may be difficult to spare any bladder). To try to make this less likely the protocol suggests a 15-30 minute interval between emptying the bladder and undertaking the CT scan. In such circumstances reference to the diagnostic images are crucial. Comparison of the diagnostic scans and the therapy scans should be made and information from both the diagnostic scans and the bladder map should be used to define the volume on the planning CT scan. The second difficult circumstance is either when the patients has had a complete TURBT and/or neoadjuvant chemotherapy has been used and no tumour is visible. In these patients information from a good surgical bladder map is essential. Any residual thickening should be used as a guide, but if there is no radiological indication of the tumour site then the portion of the bladder described to be involved on the bladder map should be included in the GTV/CTV. Where there is real doubt a pragmatic approach may be to cover the half of the bladder thought to contain the tumour. Examples of some outlining are shown in figure 1 and 2. 5. How to achieve the doses defined in arm 2 To achieve the doses of radiotherapy defined in the protocol a method of delivering a higher dose to the bladder tumour than to the un-involved bladder needs to be utilised. In this section are described two methods for achieving this objective. These methods are provided as a guide and do not exclude the use of alternative methodology which conforms to dose/volume guidelines. 2 50Gy in 25F is actually 78.1% but is considered a standard dose in this setting. Version 1.2, 15/05/2002 5

5.1 Method 1 The conventional way to deliver the planned radiotherapy dose is to use a conventional 2 phase technique. Hence 5.1.1 Phase I whole bladder and extravesical tumour (PTV 1 and PTV 2 ) use 3-4 coplanar fields to encompass PTV 1 and PTV 2 within the 95% isodose as described for arm 1 Dose 44gy/16f or 50Gy/25f 5.1.2 Phase II to cover PTV 1 For this plan 3-4 coplanar fields are arranged to exclude as much non target bladder as possible without exceeding rectal dose limits (sum of dose of phase I and II to posterior rectal wall should be less than 80% of reference dose) Dose to phase 2 11 Gy/4f or 14Gy/7f 5.1.3 Notes on dose delivery The doses delivered to phase I and II are given as a guide only. As the dose delivered to the boost volume will contribute some additional dose to the bladder volume adjustment of the relative dose contribution may be made to account for this. It is aimed to give a total dose to bladder wall outside PTV 1 of 80% of the reference dose (+/- 5%). In patients with small bladders and/or large tumours the amount of bladder sparing may be limited in which case a higher dose to the uninvolved bladder wall has to be accepted (figure 3). The ordering of the boost and whole bladder treatment is not defined. In the pilot work at the Royal Marsden the boost was treated first, before any radiation reaction develops. It may be advisable to plan both treatments at the same time so the relative balance of treatments can be defined. 5.2 IMRT / concomitant boost 1 phase plan 5.2.1 Background At the Royal Marsden Hospital we have recently devised a second technique for delivering this radiotherapy plan. Essentially it is a form of concomitant boost treatment or it could be described as a simple step and shoot intensity modulated treatment. It aims to deliver 80% of dose to the bladder and 100% to the tumour in a single phase. It thus has the advantage of the treatment being deliverable with 1 set of planning, simulation and checking. It also means that contributions from each field are taken into account without the need for juggling applied doses. Disadvantages are that the treatment planning is a little more complex and each day 6 fields may be required. The radiobiological dose to the bladder is fractionally lower as essentially 50 Gy is given over 32 fractions (if 64Gy in 32fractions are delivered). However modelling suggests the effect on tumours with high α/β ratios is low and less than the benefits for long term normal tissue effects. Details of how to plan this technique are given below. 5.2.2 Technique for single phase reduced high dose volume treatment The target doses are the same as for method 1.i.e. To PTV 1 : reference dose +/- 5% (55Gy/20f or 64Gy/32f) To PTV 2 : 80% of reference dose +/- 5% (44Gy/16f or 50Gy/25f) Maximum rectal dose 80% of the reference dose Version 1.2, 15/05/2002 6

A three-field technique will be used. The primary aim is to limit the dose to the whole bladder from the fields that give the concomitant boost to PTV 1. Define Isocentre The isocentre is set to the geometric centre of PTV 1 Step 1 defining gantry angles (GAs) The GAs used to treat the whole bladder are chosen for their geometrical ability to treat PTV 1 with maximal sparing of CTV 2 (residual bladder). This is done by comparing the axis of PTV 1 with the residual bladder. Generally opposed fields with a third beam more or less at right angles to these beams is chosen (figure 4) Step 2 defining field sizes, beams weights and wedges Using beam s-eye-view (BEV) information the appropriate field sizes are set using independent diaphragms. Wedges and weights are applied to these fields to create acceptably homogenous PTV 2 coverage. This may require wedges in the superior-inferior plane. Step 3 defining the smaller fields Second fields are then added from each gantry angle, with field sizes set to cover PTV 1 only (from BEV). The wedges are likely to be the same (or similar) to those for the larger fields needed to treat PTV 2. Step 4 defining the weighting relationship of the smaller fields to themselves. The relative weights of the smaller fields TO EACH OTHER will be in the same (or similar) proportion as the larger fields TO EACH OTHER. This will be governed mainly by the GAs and patient outline. Step 5 defining the relative weights of the smaller fields compared to the larger fields. The dose prescribed from the large fields is 50 Gy in addition the dose prescribed from the boost fields are 14 Gy. The relative weight of the fields are set so that the smaller fields give the maximum possible contribution to the overall treatment. This is limited by the coverage of the peripheral part of PTV 2 as this only receives radiation from the larger fields. PTV 2 must be covered by the relevant isodose. For example, as these patients are planned conformally (100% volume within 95% isodose 3 ), if 50 Gy is prescribed for the larger volume and 64 Gy for the smaller, then all of PTV 2 must be within the following isodose: 50 Gy * 95/100 * 100% = 74% isodose. 64 Gy An example isodose is given in figure 5. 3 93% is allowable in the superior / inferior direction Version 1.2, 15/05/2002 7

Legends Figure 1 & 2 Examples of patient tumour outlining. Paired slides show the thickening of the bladder wall and the area (marked in red) outlined as tumour. Figure 3 Target definition for two patients Figure 4 Example of field arrangements selected to treat the tumour for anterolateral bladder tumour. Figure 5 Final isodose distribution (for the patient in figure 4) treated according to BC2001 protocol by concomitant boost technique. Please refer to the BC2001 website www.bc2001.org.uk for clearer images of the above figures. Version 1.2, 15/05/2002 8

Figures 1 & 2 Examples of patient tumour outlining. Paired slides show the thickening of the bladder wall and the area (marked in red) outlined as tumour. Figure 1a Figure 1b Version 1.2, 15/05/2002 9

Figure 1c Version 1.2, 15/05/2002 10

Figure 2a Figure 2b Version 1.2, 15/05/2002 11

Figure 2c Figure 2d Version 1.2, 15/05/2002 12

Figure 3 Figure 4 Example of field arrangements selected to treat the tumour for anterolateral bladder tumour. Version 1.2, 15/05/2002 13

Figure 5 - Final dose distribution (for patient in figure 4) treated according to BC2001 protocol by concomitant boost technique. Version 1.2, 15/05/2002 14