21 Urinary Bladder Cancer

SECOND EDITION

The GEC ESTRO Handbook of Brachytherapy

PART II: CLINICAL PRACTICE Urogenital Tract 21 Urinary Bladder Cancer Bradley Pieters, Elzbieta van der Steen- Banasik, Erik Van Limbergen

Editors Erik Van Limbergen Richard Pötter

Peter Hoskin Dimos Baltas

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THE GEC ESTRO HANDBOOK OF BRACHYTHERAPY | Part II: Clinical Practice Version 1 - 21/04/2015

21 Urinary Bladder Cancer

Bradley Pieters, Elzbieta van der Steen-Banasik, Erik Van Limbergen

1. Summary 2. Introduction

3 3 4 4 4 5 5 5

9. Treatment planning

8 9 9

10. Dose, Dose rate and Fractionation

3. Anatomical Topography

11. Monitoring

4. Pathology 5. Work Up

12. Results

10 10 11 12

13. Adverse Side Effects

6. Indications and Contraindications

14. Key messages 15. References

7. Target volume 8. Techniques

1. SUMMARY

Brachytherapy for bladder cancer was introduced several decades ago as a treatment to preserve bladder function. The original technique and one that is still used is the suprapubic approach. With this technique it is necessary to perform a suprapubic or Pfannenstiel incision to do a cystotomy. This technique has never gained worldwide acceptance despite the good clinical outcome. Local control rates of 70-80% have been reported. The bladder conservation rate is 85%-90%. A new and evolving technique is by performing the implant with laparoscopy or robot-assistance. In the majority of cases, the bladder does not need to be opened with this technique. There is extensive experience with LDR and PDR. The experience with HDR is less, but it seems that fractionated therapy with doses less than 2.5 Gy per fraction will result in a similar outcome as with LDR/PDR.

2. INTRODUCTION

Urology) guidelines provide an extensive description of the man- agement of non-muscle invasive bladder cancer (1). In case of muscle invasion (pT2 and greater) cystectomy (partial or total) and/or radiotherapy is the treatment of choice. Radi- cal cystectomy with lymph node dissection is considered as the standard treatment (2). However, new developments in the field of radiotherapy provide the possibility of bladder preservation. Better tumour delineation with lipiodol markers and position verification on the treatment machines for external beam radio- therapy have increased the accuracy of treatment. Randomized studies have shown better local control and overall survival with the addition of chemotherapy to radiotherapy (3, 4). James et al found after a median follow-up of 69.9 months a 67% lo- coregional disease free survival at 2 years with the addition of concomitant 5-FU and mitomycin compared with 54% without chemotherapy (4). The overall survival at 5 years was 48% vs. 35%, respectively. Only 11% of the patients in the chemoradia- tion group needed salvage cystectomy because of a relapse. Another modality for bladder sparing is the combination of lim- ited surgery with external beam radiotherapy and brachytherapy as mentioned in the Dutch and French national guidelines (5, 6).

Bladder cancer occurs after the fourth decade with a peak inci- dence at 75 years. It is more frequent in men than in women (3- 4:1). It has been associated mainly with use of tobacco, but also with occupational exposure to carcinogens such as aniline dyes, phenacetin-containing analgesics, artificial sweeteners, and chronic irritation of the bladder mucosa due to bladder stones, or schistosomiasis. The main symptoms are painless haematuria, urinary frequency, urgency, dysuria, and recurrent urinary tract infections, particularly in men. Other less common symptoms are suprapubic pain or pain in the flank and a palpable suprapu- bic mass. The tumour originates as non-muscle invasive confined to the mucosa or submucosa (pTa) of the bladder wall. These are usual- ly papillary tumours on cystoscopy. Erythematous coloured areas can also be distinguished which are compatible with carcinoma in situ (pTis). The next step in the evolution of bladder cancer is invasion of the muscularis mucosae (pT1). Non-muscle invasive bladder tumours are treated with excision and bladder instillations with chemotherapeutical agents or immunotherapy with Bacillus Calmette-Guérin (BCG). The EAU (European Association of

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3. ANATOMICAL TOPOGRAPHY

T2a Tumour invades superficial muscle (inner half) T2b Tumour invades deep muscle (outer half) T3 Tumour invades perivesical tissue: T3a Microscopically T3b Macroscopically (extravesical mass) T4 Tumour invades any of the following: prostate stroma, semi- nal vesicles, uterus, vagina, pelvic wall, abdominal wall T4a Tumour invades prostate stroma, seminal vesicles, uterus, or vagina T4b Tumour invades pelvic wall or abdominal wall There is an abundant network of lymph channels originating from the submucosa entering the muscle layers and ending at the outer surface of the bladder. From there the drainage goes to the external iliac nodes. The posterior wall of the bladder drains into the external and internal iliac lymph nodes. The inferior part can drain to the presacral nodes and common iliac lymph nodes. The obturator, external iliac, internal iliac, common iliac, and presacral nodes are considered as the regional lymph nodes for the bladder. Most bladder cancers are urothelial carcinoma (UC). About 75% of cases present with non-muscle invasive bladder cancer (NMIBC). NMIBC is usually papillary in appearance. They are histopathologically graded as low- or high-grade according to the World Health Organization classification and the Interna- tional Society of Urologic Pathologists (8). Carcinoma in situ (CIS) has a flat erythematous appearance and tends to spread diffusely through the bladder mucosa. Muscle-invasive bladder cancer (MIBC) usually has a solid appearance. Invasive tumours are always high-grade. Squamous cell carcinoma is more often seen in patients with a history of local bladder irritation. Ade- nocarcinoma arising from residual urachus is rare. Other his- tologies that may arise are sarcomas, lymphomas, carcinoid tu- mours, and small cell cancers. Depth of invasion, lymph node status, and blood vessel invasion are the most important prognostic factors for local control, dis- ease-free survival and overall survival (9). Substaging into pT2a and pT2b appears to be associated with prognosis (10, 11). The indications for brachytherapy depend on the size of the tu- mour, its location (bladder neck versus upper trigone and dome), the depth of invasion, and the presence or absence of multifocal disease elsewhere in the bladder mucosa. 4. PATHOLOGY

The bladder is roughly pyramidal in shape when empty and be- comes ovoid when filled. When full, the bladder dome extends out of the pelvis into the abdomen. The trigone, at the bladder base, is triangular and is situated deeply in the true pelvis, be- hind the pubis, so that it is less accessible to implantation pro- cedures. The ureters enter the bladder at the superolateral angles of the trigone, and the urethra leaves the bladder at the inferior angle. The wall consists of mucosa, submucosa and the muscle layers of the detrusor. The mucosa is smooth at the trigone, but is thrown into folds at the dome when the bladder is empty. The bladder wall endoluminally is covered by urothelial cells of the mucosal membrane. Beyond the mucosa there is a thin layer of submucosa. The outer layer of the bladder wall is formed of three smooth muscle layers that contract during voiding. The three muscle layers are arranged as the inner longitudinal, outer spi- ral, and outer longitudinal layer. The outer longitudinal layer is covered by adventitia containing arteries, veins and lymphatic vessels. The bladder on itself is surrounded by perivesical fat at its fixed inferior part, while the dome is covered by abdominal peritoneum. The rectum or rectovaginal septum is at the poste- rior side of the bladder. Anteriorly and laterally the bladder is bounded by the pubic bone. Laterally the bladder is supported by the obturator internus muscle and inferiorly by the levator ani muscle as part of the urogenital diaphragm. In men the prostate lies between the bladder and the urogenital diaphragm. The tumour originates from the epithelial lining of the bladder wall. Invasion of the tumour takes place through the bladder wall layers and ultimately into the perivesical fatty tissue or adjacent organs. This extension of tumour invasion is reflected in the TNM classification (7).

5. WORK UP

Fig 22.1: T classification UICC 2009.

After recording the patient’s history and a full clinical examina- tion, fresh urine is sampled for cytological examination and a cystoscopy is carried out for diagnosis and biopsy. Positive cytol- ogy raises the suspicion of the presence of urothelial tumours, in particular high-grade tumours or carcinoma in situ.

T stage according to TNM staging system (fig 22.1) Tx Primary tumour cannot be assessed T0 No evidence of primary tumour Ta Non-invasive papillary carcinoma Tis Carcinoma in situ: “flat tumour” T1 Tumour invades subepithelial connective tissue T2 Tumour invades muscle

For staging, the primary tumour should be assessed by biman-

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ual suprapubic and transrectal palpation during anaesthesia for cystoscopy. Ultrasonography, CT or MRI may be helpful in as- sessing the depth of invasion. CT often underestimates the depth of tumour extension into the bladder wall (12). With MR, bet- ter distinction between the bladder wall layers and invasion in neighbouring organs can be appreciated, which can help in bet- ter tumour staging (13). If possible, a complete transurethral re- section of the tumour is performed (TUR), and random biopsies are taken of the remaining bladder mucosa. An accurate draw- ing of the tumour and its relation to the ureteral ostia should be made. The pathologist should carefully assess grade and depth of invasion. For the primary work up blood chemistry, and a CT scan of the whole abdomen and thorax are necessary. For assessment of lo- cal extent and of abdominal pathology, an MRI scan may also be recommended. To complete the investigation of the upper urinary tract, an excretory-phase CT urography is done. A bone- scan and CT-brain are only indicated in case of suspicious symp- toms. Currently there is no convincing evidence for routine use of PET-scan in the primary diagnostic work up. The multidisciplinary committee should take the final therapeu- tic decision. The indication for brachytherapy of bladder cancer is a solitary tumour of maximal 5 cm in diameter. The most common stage is pT2 after transurethral resection of the bladder (TURB). pT1 tumours can also be treated with brachytherapy, but these tu- mours are nowadays usually treated by TURB with or without bladder instillations. Limited pT3 tumours can also be implant- ed provided that there is enough dose coverage at the periphery of the tumour. Implantations of pT3 tumours should be reserved for brachytherapists with considerable experience. Multifocality is considered as not suitable for brachytherapy, although small multifocal papillary tumours within a limited area of less than 3-5 cm have been implanted with success (14). Tumours located in the bladder neck are difficult to implant by the open suprapubic approach and this is therefore considered as a relative contraindication. In this area, access to the bladder wall is hampered by the pubic bone. However, this area can more easily be implanted with the robotic technique. 6. INDICATIONS AND CONTRAINDICATIONS

Fig 22.2: Tweezers pointing at TURB scar area at cystotomy.

Fig 22.3: TURB scar area with 5 mm margin for CTV.

8. TECHNIQUES

Brachytherapy for bladder cancer is performed by an afterload- ing technique. Extensive experience has been gained with con- tinuous low-dose rate (cLDR) with Caesium needles and Iridium wires (15-21). Nowadays cLDR has been replaced by pulsed- dose rate (14, 22, 23) or HDR stepping source afterloaders. For brachytherapy for bladder cancer flexible catheters are placed within the bladder wall. There are two techniques to place the catheters. The original technique is by performing a cystostomy to insert the catheters, the so-called suprapubic approach. The second technique is with laparoscopy and/or robot-assistance. In the latter case the bladder is not opened. The catheters used are either double-leader catheters or specially designed catheters for laparoscopic use. When performing the suprapubic approach, a median suprapubic or Pfannenstiel incision is performed. For the laparoscopic techniques, four 1 cm incisions are used for the insertion of instruments. Catheters are placed at the position of a visible tumour or TURB scar tissue (Fig 22.2). If a partial cystectomy has been performed, two catheters are placed at either side of the bladder slice plane. All the techniques have in common that the catheters will exit through the abdominal wall.

7. TARGET VOLUME

The clinical target volume (CTV) for brachytherapy includes the gross disease (GTV) or the bladder scar after TURB (Fig. 22.2) or partial cystectomy cutting edge, and a circular security mar- gin of 5 mm (Fig 22.3). The full thickness of the bladder wall should be in the CTV with mucosa, submucosa and muscle lay- ers. The localisation and size of the CTV is indicated by direct visualisation either with cystotomy or cystoscopy and measured by the circular calliper. Because the catheters are located within the bladder wall no PTV margin is used, although no studies have been done up till now to investigate the positional accuracy.

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8.1 Treatment of pelvic lymph nodes There are two policies towards the pelvic lymph nodes. Either the pelvic lymph nodes are treated with external beam radiotherapy prior to brachytherapy or the lymph nodes are surgically treat- ed. The standard pelvic area to treat is up to the common iliac bifurcation, and including the internal iliac, presacral, obturator fossa, and external iliac nodes, although there is debate on the extension of pelvic lymph node treatment (2). If the lymph nodes are treated with radiotherapy, a dose of 40 Gy in 2 Gy daily frac- tions is usually applied. During surgery lymph nodes areas are palpated to exclude or remove lymph node metastases. A lymph node dissection is only performed when suspicious lymph nodes are present. If the policy is to treat the lymph nodes surgically, a formal lymph node dissection should be performed. 8.2 Partial cystectomy For thick tumours in which a single plane implantation is not possible, partial cystectomy by removing the tumour should be done. A location at the dome can also be excised as these loca- tions are easily removed. Other indications to perform a partial cystectomy are a tumour located within a diverticulum, distal ureter, or in the urachus. 8.3 The classical suprapubic approach When performing the suprapubic approach, a median suprapu- bic or Pfannenstiel incision is performed. The bladder is opened at some distance from the tumour site, usually with a parame- dian incision opposite to the tumour side, to make the implan- tation easier. After inspection and palpation of the tumour site, the urologist and radiation oncologist make the final decision whether to perform a partial cystectomy or not. In difficult cases, biopsies and frozen section examination may guide the decision. The bladder wall is then implanted with curved hollow needles, or by commercially available Reverdin needles (22). Some of these needles need to be manoeuvered with a special holder for- ceps, others have a handle. The length and curvature of the nee- dles (Fig 22.4) are chosen depending on the site of the tumour in the bladder. Needles are implanted from the inner side of the bladder muco- sa, through the muscular bladder wall, reappearing back at the

mucosal surface. After that the catheters must be guided to leave the inner bladder surfacel through the bladder wall. The same hollow needle is used to bring the catheters through the blad- der wall (Fig 22.5). The catheters used are double-leader cath- eters. These are hollow closed flexible catheters with thin flexi- ble leader tubes at both ends as are also used in head-and-neck brachytherapy. The catheters can be pulled into the bladder wall by the flexible leaders. To implant deep localisations close to the bladder neck, it may be helpful to use a boomerang device (Fig 22.6), which helps to make a tight bend behind the pubic bone. Because curved catheters with a curved source track result in an asymmetrical dose distribution towards the concave side, the needles should be placed in the outer 2/3 of the bladder wall, so that the reference isodose will cover the entire thickness of the bladder wall. Usually 2 catheters parallel with the surgical scar will be suffi- cient to cover the target after partial cystectomy, while 2-4 cath- eters may be required in other cases when a larger surface must be covered (fig 22.7).

Fig 22.5: Catheters in the bladder wall and intravesical spacers

Fig 22.6: A “boomerang” device, used for endoscopical prostate resections, with a curved steel bladder implantation needle welded to it. Pressure on the button advances the needle in a semi-circular movement forwards and permits implantation deeply into the small pelvis.

Fig 22.7: Diagram showing the plastic tube technique for interstitial bladder implantation. A two catheter implant for small target volumes or after partial cystectomy (right picture). A three catheter implant for a larger implant (left and middle picture).

Fig 22.4: Bladder implantation needles of different curvature. Upper needle has a 40 degree curve and the lower needle has a 10 degree curve.

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Twisting of catheters over each other preventing parallelism can be avoided by placing intravesical Teflon spacers (24) (fig 22.8). Before the catheters exit the inner part of the bladder, the cathe- ters first pass through the spacers. The spacers are attached with a cord to the Foley-balloon catheter and can be removed as soon as the irradiation catheters have been removed after the treat- ment. The spacers are removed together with the Foley-balloon catheter. The spacers are not only necessary to prevent twisting of the catheters, but can also be used to define the length of the target length. If no spacers are used, the target length is marked by metal mark- ers, implanted in the bladder wall at both ends of the target area. To prevent stone formation, the markers should not be clipped to the mucosa surface, but implanted into the muscle. For sites very low in the trigone, it may be better to make a loop than two parallel lines, to be able to cover the target adequately.

localised by the light from the cystoscope that can be observed from the outer wall view. By slightly pressing from the outside on the bladder with laparoscopic instruments, the position of the tumour area can be checked from the cystoscopic view (Fig 22.9). By verifying the position of the tumour area from both sides proper placement of the catheters is guaranteed.

Fig 22.9: Upper panel: Light emission from cystoscope, visible outside the bladder. Three catheters placed with the robotic arm. Lower panel: Cystoscopic view of the TURB scar. Manip- ulation outside the bladder is visible cystoscopically Picture kindly provided by Dr. G. Smits, Rijnstate Hospital, Arnhem, The Netherlands

Fig 22.8 : Intravesical spacers to maintain source separation of the implanted bladder brachytherapy catheters.

Afterloading catheters of sufficient length (50 cm) are needed to bridge the distance from skin to bladder and back outside the patient and still to have enough length to allow for connecting to the afterloader. The catheters should be guided preferentially through the ab- dominal wall, including the abdominal wall fascia, and not through the laparotomy scar. To reduce the risk of kinking when the fascia is sutured together, the catheters should not leave the abdomen too close to a median incision. Finally the catheters are fixed on the skin with buttons and the catheter is cut open. Another method to fix the catheters is by using perforated gas- tric tubes at both extra-abdominal ends of the loop. To prevent kinking in the course of treatment it is advisable to place a syn- thetic or metallic guide wire in the catheters. 8.4 The minimal invasive laparoscopic technique In 2009 the Arnhem group developed an implantation technique using laparoscopy. Later this technique was developed toward a robot-assisted approach. This allows minimal invasive surgery with four 1 cm incisions in the abdominal wall for the inser- tion of instruments. By using a cystoscope introduced through the urethra into the bladder, an endoscopic view of the location and extension of the residual tumour (or the scar) is obtained. Minimal manipulation is sometimes necessary to reach the out- er bladder wall, while a light emitted by the cystoscope exposes the affected part of the bladder. This provides a full view of the bladder wall from both sides. The position of the tumour area is

Needles with catheters attached to them are implanted through the skin into the abdominal cave where they are taken over by the instruments operated by the urologist. The catheters have a needle attached at one side of the catheter to be controlled by the laparoscopic instruments (Fig 22.10). The needles are inserted from the outer side of the bladder, through the muscular bladder wall, reappearing again at the surface beyond the tumour area (Fig 22.9). The cystoscopic view ensures that the needle followed by the catheter remains intramural and does not enter intravesi- cally. As with the suprapubic approach, usually 2- 4 catheters are needed to cover the target area completely. If a partial cystecto- my is performed, 2 catheters are placed along the vesical scar. After that the catheters are guided to pass through the abdom- inal wall to be fixed on the skin with buttons. Finally titanium surgical clips are fixed next to the catheter insertion points on the bladder outer surface to mark the CTV area properly.

Fig 22.10: Specially designed catheter with needle for laparoscopic use.

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After the procedure, a Foley catheter is introduced to remain in place during the irradiation period. Because of the straight path between the bladder wall and the abdominal wall, kinking of the catheters seldom occurs with this technique (Fig 22.11). However, even with the laparoscopic technique it is advisable to place a synthetic or metal wire in the catheter to prevent kinking during the course of the treatment. A further development of the Arnhem technique is the robot-as- sisted laparoscopic implantation technique, which facilitates ac- cess to difficult bladder locations such as the bladder neck. Fur- thermore the console makes it possible to look at the endoscopic intravesical and laparoscopic views simultaneously.

report 58 recommendations, the ratio prescription isodose over the Mean Central Dose (85% in a non-dwell time optimized Par- is system implant) should always be recorded and reported (26). One to two days after the suprapubic approach or a few hours postoperatively after a laparoscopic procedure, a CT-scan is done for treatment planning. Catheters can be reconstructed from the CT-scan. The markers or spacers indicate the target volume length. Marking the target volume length is necessary to decide on the position of dwell sources that are activated. Contouring of the CTV can be done by delineating the full blad- der wall in between the spacers or titanium markers.

Fig 22.11: Orthogonal x ray of a laparoscopic interstitial bladder implant. The nearly straight plastic tubes leave the abdomen laterally in the abdominal walls, avoiding any risk of kinking of the tubes.

Fig 22.12: Bladder wall implant with stepping source afterloading catheters. Intravesical spacers assure equidistant parallelism of the implanted source carriers.

9. TREATMENT PLANNING

For optimal dosimetry, catheters should be placed parallel and equidistantly (Fig 22.12). One method is by implanting accord- ing to the rules of the Paris system (See chapter 7). Source spacing at the time of implantation is chosen so that the full thickness of the bladder wall is treated (Fig 22.13). The thick- ness of the bladder wall is measured with a circular calliper (Fig 22.14) or any other measuring device. If the area is difficult to reach, then the thickness can be estimated between finger and thumb or measured on a recent CT/MR image. CT or MR imaging should be performed before the TURB or at least 4 weeks after TURB. Catheter spacing of 10 to 20 mm will result in a treated volume of 5 to 12 mm thick. Provisional dosimetry can be done according to the Paris-system implanta- tion rules by calculating the proper catheter spacing (see chapter 7) to guarantee adequate coverage of the target thickness (Fig 22.15). For 3D dosimetry on CT-scan, geometrical optimization and slight dwell time adaptations can be done for optimisation of the dose distribution to correct for inaccuracies of implantation. Another method of dosimetry is by prescribing to dose points (25). With this method, the dose points are 5-7 mm from the sources, depending on the bladder wall thickness. It is impor- tant to verify the coverage of the target volume on the planning CT-scan and to evaluate the high-dose volumes. For example the 150% isodose volumes around the individual catheters (source tracks) should not merge with each other and preferably not be larger than 7-8 mm in transverse diameter to avoid necrosis. Whatever the prescription isodose chosen, following the ICRU

Fig 22.13: CT-scan overview of a bladder implant in the left dorsal wall just cranial to the trigonum.

Fig 22.14: Circular calliper to measure tumour size and bladder wall thickness.

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Fig 22.15: Three equidistant and parallel catheters in the dorsal bladder wall with the corresponding isodose lines.

10. DOSE, DOSE RATE AND FRACTIONATION

the dose prescription was done on a tumour encompassing iso- dose, without reporting the basal dose points as recommended by ICRU 58. After a short median follow-up time of 14 months, local control was 72% and less than the LDR experience. Five patients developed severe late bladder toxicity. This result was explained by a wrong choice of α/β-ratio when designing HDR schedules from LDR schedules. Radiobiology modelling of clini- cal data proposes a schedule of 40 Gy in 28 fractions of 1.4 Gy in 7 days as the best equivalence between LDR and HDR if the T½ is 1 hour and the α/β−ratio 10-15 Gy (30). Otherwise 56 frac- tions of 0.7 Gy are necessary if the T½ is 0.5 hours. Alternatively, a schedule with a 40 Gy external beam dose followed by 10 frac- tions of 2.5 Gy in three fractions a day has been proposed (25). However, no long-term experience has yet been published with this alternative schedule. After the operation the patient stays for one or two days in the urology department to receive adequate post surgical care. For PDR treatments the patient is transported to the radiotherapy department. If the treatment is by HDR, the patient can stay on the urology ward and be taken to the HDR-unit for each frac- tion. Since the implanted material is very soft and flexible, it is well tolerated by the patient. Urine leakage and wound infections are much less frequent with plastic tube implants than reported after radium or caesium needle implants (23).Patients should re- ceive adequate prophylaxis for venous thrombosis. Urinary an- tiseptics, and if needed appropriate antibiotics, are prescribed as well as analgesics and spasmolytics. Particularly implants close to the bladder neck can cause painful spasms that need to be controlled by spasmolytics. Pre-operatively epidural anaesthesia can also be helpful. After 1-2 days, the patient is admitted to the brachytherapy de- partment for simulation and loading of the plastic tubes. After laparoscopic or robotic surgery treatment can start on the op- eration day. 11. MONITORING

Brachytherapy is usually given as a boost to external beam radio- therapy. External beam radiotherapy of the whole pelvis is given to a dose of 40 Gy in 2 Gy fractions. Subsequently a brachyther- apy dose of 25-30 Gy in continuous LDR or PDR technique with Iridium-192 is given to a total dose of 65-70 Gy EQD2 calculated for an α/β−ratio of 10-15 Gy and T1⁄2 of 0.5-1 hour. It is rec- ommended to report the prescribed dose according to ICRU 58. PDR treatments are used most often nowadays. Recommended PDR schedules are 60 pulses of 0.5 Gy with a time period of 1 hour, 30 pulses of 1 Gy with a time period of 2-3 hours or the office hour schedule of 28 pulses of 1 Gy with 10 pulses per day (27). If a partial cystectomy has been performed, the brachytherapy dose can be lowered with 15-20 Gy EQD2 (14). Alternatively for some patients elective pelvic irradiation can be omitted. This is the case if the pelvic lymph nodes have been surgically dissected or for example in the rare case of a bladder treatment after previous pelvic irradiation. In these cases the whole bladder is irradiated to 3 fractions of 3.5 Gy followed by a brachytherapy dose of 55-60 Gy EQD2. Low dose external beam radiotherapy to the whole bladder is given to prevent implanta- tion of urothelial tumour cells in the surgical wound (28). There is less experience with HDR brachytherapy in the inter- stitial treatment of bladder cancer than with LDR and PDR. The first publication on HDR by Soete et al. describes 15 patients with T1-T3 tumours (29). All patients except one were treated with a fraction size of 3 Gy. In total 15 brachytherapy fractions were given preceded by 3 external beam fractions of 3.5 Gy re- sulting in an EQD2 of 60 Gy. The median follow-up in this small feasibility study was only 23 months. Of the 15 treated patients, 2 experienced a local relapse. Two patients had severe persistent radiation cystitis. The experience with HDR brachytherapy at The Netherlands Cancer Institute was disappointing. The external beam dose to 40 patients was 30 Gy or 29.25 Gy in 2.0 Gy or 2.25 Gy frac- tions. The brachytherapy dose was 10 fractions of 3.2 Gy (Total EQD2 =65 Gy). Exact dose reporting cannot be given, because

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Depending on the dose prescribed, treatment times vary from 2.5 to 5 days. The output of urine and from the wound drain is monitored daily. The Foley catheter can be removed when the bladder incisions are completely healed. For the ssuprapubic ap- proach this is after 1-2 weeks. If laparoscopic or robot-assisted surgery has been performed, the Foley catheter is removed di- rectly at the end of brachytherapy. Removal of the brachytherapy catheters and intravesical spacers can easily be done without sedation or anaesthesia. Only very exceptionally is it necessary to resort to cystoscopy to remove the tubes.

patients who had undergone cystectomy but retrospectively were also candidates for brachytherapy on clinical staging. The 5-year disease specific survival (71% and 60%) and 5-year overall survival (57% and 52%) were similar with no statistically signif- icant difference’. Aluwini published the results of the single-centre study with the longest follow-up (33). Only patients with clinical T2 and T3 tu- mours were analysed with a mean follow-up of 106 months. The 10-year local relapse-free survival was 73%. Overall survival at 5 and 10 years was 65% and 46%, respectively. Fifty percent of the relapses were non-muscle invasive. All the studies show that for selected cases of patients with T2, limited T3 solitary and maximum of 5 cm tumours, oncolog- ical outcome with brachytherapy is not inferior to radical cys- tectomy. A direct comparison with concomitant external beam radiotherapy and chemotherapy is hampered by lack of studies. In the recent randomized study of chemoradiation, a 2-year re- currence-free rate of 67% and 5-year overall survival of 48% was found (4). The main advantage of brachytherapy over external beam radiotherapy is that the irradiated volume of bladder and bowel is probably smaller. James et al found a 38% rate of grade 3-4 toxicity with chemoradiation, which is higher than in other chemoradiation series (34). Brachytherapy side effects will be discussed in the next paragraph. Follow-up data with the emerging laparoscopic technique is lim- ited. At a median follow-up period of 1 year, a 2-year local con- trol of 77% was found (35). Table 22.1 summarises the results of recent publications. Acute adverse effects that can be expected in 5-10% after brachytherapy are urinary tract infection, wound dehiscence, postoperative ileus, hydronephrosis due to obstruction at the distal ureter, bladder bleeding, and pulmonary embolism (14, 23, 37). In about 10% of patients, urgency requiring more than 6 months anticholinergic use, can occur. With the introduction of the laparoscopic technique, hospitalisation time was reduced from average 16 days to 7 days (25). Severe late effects that have been reported are: vesico-cutaneous or vesico-vaginal fistula, stricture of the urethra and ureters, ne- crosis, and persisting urine leakage, (23, 33). The reported rate of grade 3 and 4 bladder toxicity is 5.8% and for grade 3 and 4 in- testinal toxicity 1% (33). External beam dose was found to be as- sociated with late toxicity in the Dutch cohort series (22). In The Netherlands two external beam schedules were commonly used: low dose external beam therapy of 10.5 Gy or a higher external beam dose of 40 Gy. The higher the dose the more late effects, such as fistula formation, ulceration and necrosis, were seen. Aluwini in their series with a mean follow-up time of 106 months found a cystectomy-free survival rate of 93% at 5 years and 85% at 10 years. In this analysis both cystectomy due to bladder re- lapse and severe toxicity and functional loss of bladder function were considered together. Others also reported a bladder preser- vation rate of more than 89% (14, 37, 38). Ulceration at the implantation site is regularly seen. Aluwini found these ulcerations in about 25% of cases (33). Usually these ulcerations are asymptomatic, occurring due to the high mucosal dose of brachytherapy. These ulcerations should be dis- 13. ADVERSE SIDE EFFECTS

12. RESULTS

12.1 Local Control and Survival Van der Werf-Messing from Rotterdam was the first to report extensively on clinical outcome (18-21). The local control after interstitial radium was 91% for T1 lesions, 84% for T2a (current classification), and 72% for T2b (current classification). These historical results were confirmed in a recent analysis of Blank et al. (14). The 5-year local relapse-free rate for pT1-pT3 tumours was 76%. Overall survival in this series was 73% at 5 years and 49% at 10 years. The rather low overall survival at 10 years reflects the advanced age at which patients were treated (median age 65 years). The ten-year local and distant relapse-free survival was 66%. The main goal in performing brachytherapy apart from good local control, is to preserve the bladder. In their experience, more than 90% of surviving patients maintained bladder function. The largest reported series on brachytherapy for bladder cancer is that of Koning et al (22). In this Dutch cohort study, 1040 pa- tients were retrospectively analysed. Both LDR and PDR were used for treatment delivery. The local recurrence-free proba- bility, metastasis-free probability, disease-free probability, and overall survival at 5 years were 75%, 74%, 61%, and 62%, re- spectively. In this analysis 41% of the bladder relapses occurred in non-muscle invasive tumours. The majority of these patients could be salvaged with tumour resection and possibly bladder instillations. Only 6% of all patients underwent salvage cystecto- my because of invasive tumour recurrence. There is no randomized study comparing bladder-preserving therapy for muscle-invasive bladder cancer with brachytherapy with cystectomy. These two modalities were compared with each other in a systematic review with metaregression analysis for studies published in the period 1981-2012 (31). Overall surviv- al was found to be very similar for the two modalities (10-year 40%-45%). Nieuwenhuijzen et al. retrospectively compared patients treated with brachytherapy with patients treated with cystectomy (32). The two groups were not completely comparable. There were more T2 tumours in the brachytherapy group and on the other hand more multifocal tumours in the cystectomy group. Infor- mation on tumour size was lacking for the majority of cystec- tomy patients. Nevertheless the 5-year disease specific survival (73% and 72%) and 5-year overall survival (62% and 67%) rates were similar. A similar comparative study was performed in the East-Nether- lands region (23). Brachytherapy patients were compared with

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Table 22.1: Five-year local control, cause-specific survival, and overall survival.

NUMBEROF PATIENTS

YEAR

5-YEAR

AUTHOR

Cause-specific survival

Local control

Overall survival

T1 T2 T3

100% 65% 62%

100% 70% 38%

69% 60% 38% 65% 73% 70% 57% 62% 65%

De Crevoisier (36)

2004

58

Nieuwenhuijzen (32)

2005 2007 2008 2009 2012 2013

108 122 111

T1-T2 T1-T3 T1-T2 T1-T2 T1-T3 T2-T3

-

75%

Blank (14) Onna (34)

76%

- -

82% 71%

van der Steen-Banasik (23)

89

Koning (21) Aluwini (31)

1040

75% 80%

-

192

75%

tinguished from a local relapse and unnecessary biopsies must be prevented. If biopsy is performed, the probability of fistula formation will increase. Bladder function is poorly evaluated in the majority of studies. Blank evaluated bladder function in a subset of patients (14). In 11% of cases they observed a deterioration of bladder capacity at follow-up. About 25% of patients reported increased urinary frequency.

Only preliminary results are available on late effects from the laparoscopic technique. Of 30 patients treated with laparoscopy, only 1 late effect was noted (35).

14. KEY MESSAGES

• Bladder brachytherapy is indicated for a selected group of patients with muscle-invasive bladder cancer

• Local control and overall survival rates with brachytherapy are in the same range as with cystectomy

• With brachytherapy a high rate of bladder sparing is obtained

• The toxicity profile with PDR is favourable, as it was in the past with LDR

• Experience with HDR is still limited

• Laparoscopic and robot-assisted implantation is an emerging technique and will replace the classical suprapubic approach

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15. REFERENCES

22. Koning CCE, Blank LECM, Koedooder C, et al. Brachytherapy after external beam radiotherapy and limited surgery preserves bladders for patients with solitary pT1-pT3 bladder tumours. Ann Oncol 2012;23:2948-2953. 23. van der Steen-Banasik EM, Ploeg M, Witjes JA, et al. Brachytherapy versus cystectomy in solitary bladder cancer: A case control, multicentre, East-Neth- erlands study. Radiother Oncol 2009;93:352-357. 24. van ‘t Riet A, Mak ACA, Moerland MA, et al. A conformation number to quan- tify the degree of conformality in brachytherapy and external beam irradiation: application to the prostate. Int J Radiat Oncol Biol Phys 1997;37:731-736. 25. Nap-van Klinken A, Bus SJEA, Janssen TG, et al. Interstitial brachythera- py for bladder cancer with the aid of laparoscopy. J Contemp Brachytherapy 2014;6:313-317. 26. ICRU. Dose and volume specifcation for reporting interstitial therapy, ICRU report, 58. Bethesda, MD: ICRU; 1997. 27. van der Steen-Banasik EM, Visser AG, Reinders JG, et al. From continuous LDR to office-hours PDR in bladder brachytherapy. Radiother Oncol 2007;83:S56. 28. van der Werf-Messing B. Carcinoma of the bladder treated by suprapubi- cradium implants. The value of additional external irradiation. Eur J cancer 1969;5:277-285. 29. Soete G, Coen V, Verellen D, et al. A feasibility of high dose rate brachytherapy in solitary urinary bladder cancer. Int J Radiat Oncol Biol Phys 1997;38:743-747. 30. Pos FJ, Horenblas S, Lebesque J, et al. Low-dose-rate brachytherapy is superior to high-dose-rate brachytherapy for bladder cancer. Int J Radiat Oncol Biol Phys 2004;59:696-705. 31. Bos M, Ordoñez Marmolejo R, Rasch CRN, et al. Bladder preservation with brachytherapy compared to cystectomy for T1-T3 muscle-invasive bladder cancer: a systematic review. J Contemp Brachytherapy 2014;6:191-199. 32. Nieuwenhuijzen JA, Pos F, Moonen LM, et al. Survival after bladder-preserva- tion with brachytherapy versus radical cystectomy: a single institution experi- ence. Eur Urol 2005;48:239-245. 33. Aluwini S, van Rooij PH, Kirkels WJ, et al. Bladder function preservation with brachytherapy, external beam radiation therapy, and limited surgery in bladder cancer patients: Long-term results. Int J Radiat Oncol Biol Phys 2014;88:611- 617. 34. Kaufman DS, Winter KA, Shipley WU, et al. Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral sur- gery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy. Urolo- gy 2009;73:833-837. 35. van der Steen-Banasik E, Smits G. Laparoscopic bladder implantations in solitary bladder cancer: Inevitable evolution? Int J Radiat Oncol Biol Phys 2013;87:S398. 36. de Crevoisier R, Ammor A, Court B, et al. Bladder-conserving surgery and in- terstitial brachytherapy for lymph node negative transitional cell carcinoma of the urinary bladder: results of a 28-year single insitution experience. Radiother Oncol 2004;72:147-157. 37. van Onna IEW, Oddens JR, Kok ET, et al. External beam radiation therapy followed by interstitial radiotherapy with iridium-192 for solitary bladder tu- mours: results of 111 treated patients. Eur Urol 2009;56:113-122. 38. Pos F, Moonen L. Brachytherapy in the treatment of invasive bladder cancer. Semin Radiat Oncol 2005;15:49-54.

1. Babjuk M, Böhle A, Burger M, et al. Guidelines on non-muscle-invasive blad- der cancer (Ta, T1 and CIS). http://www.uroweb.org/gls/pdf/05 Non-muscle Invasive BC_TaT1_LR.pdf 2014. 2. Witjes JA, Compérat E, Cowan NC, et al. Guidelines on Muscle-invasive and metastatic bladder cancer. http://www.uroweb.org/gls/pdf/07 Muscle Invasive BC_LR LV2 May 14th.pdf 2014. 3. Coppin CM, Gospodarowicz MK, James K, et al. Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1996;14:2901-2907. 4. James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemother- apy in muscle-invasive bladder cancer. N Engl J Med 2012;366:1477-1488. 5. Dutch guidelines bladder carcinoma. http://www.oncoline.nl/bladdercarcino- ma 2013. 6. Pfister C, Roupert M, Neuzillet Y, et al. Recommandations en onco-urolo- gie 2013 du CCAFU: tumeurs de la vessie. Progrès en Urologie 2013;Suppl 2:S105-S125. 7. TNM classification of malignant tumours, 7th edition. Oxford: Wiley-Black- well; 2009. 8. Epstein JI, Amin MB, Reuter VR, et al. The World Health Organization/Inter- national Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Con- ference Committee. Am J Surg Pathol 1998;22:1430-14311. 9. Leissner J, Koeppen C, Wolf HK. Prognostic significance of vascular and peri- neural invasion in urothelial bladder cancer treated with radical cystectomy. J Urol 2003;169:955-960. 10. Tiki D, Reich O, Karakiewicz PI. Validation of the AJCC TNM substaging of pT2 bladder cancer: deep muscle invasion is associated with significantly worse outcome. Eur Urol 2010;58:112-117. 11. Ghoneim MA, Abdel-Latif M, el-Mekresh M. Radical cystectomy for carcino- ma of the bladder: 2720 consecutive cases 5 years later. J Urol 2008;180:121- 127. 12. Paik ML, Scolieri MJ, Brown SL, et al. Limitations of computerized tomog- raphy in staging invasive bladder cancer before radical cystectomy. J urol 2000;163:1693-1696. 13. NG CS. Radiologic diagnosis and staging of renal and bladder cancer. Semin Roentgenol 2006;41:121-138. 14. Blank LECM, Koedooder K, van Os R, et al. Results of bladder-conserving treatment, consisting of brachytherapy combined with limited surgery and ex- ternal beam radiotherapy, for patients with solitary T1-T3 bladder tumours less than 5 cm in diameter. Int J Radiat Oncol Biol Phys 2007;69:454-458. 15. Battermann JJ, Tierie AH. Results of implantation for T1 and T2 bladder tu- mours. Radiother Oncol 1986;5:85-90. 16. Mazeron JJ, Crook J, Chopin D, et al. Conservative treatment of bladder carci- noma by partial cystectomy and interstitial iridium 192. Int J Radiat Oncol Biol Phys 1988;15:1323-1330. 17. Rozan R, E. A, Donnarieix D, et al. Interstitial iridium-192 for bladder cancer (a multicentric survey: 205 patients). Int J Radiat Oncol Biol Phys 1992;24:469- 477. 18. van der Werf-Messing B, van Putten W. Carcinoma of the urinary bladder cate- gory T2,3NxM0 treated by 40Gy external irradiation followed by Caesium 137 implant at reduced dose (50%). Int J Radiat Oncol Biol Phys 1989;16:369-371. 19. van der Werf-Messing B, Menon RS, Hop WC. Carcinoma of the urinary blad- der category T2, T3 (NxM0) treated by the combination of radium implant and external irradiation: Second report. Int J Radiat Oncol Biol Phys 1983;9:481- 485. 20. van der Werf-Messing B, Menon RS, Hop WC. Carcinoma of the urinary blad- der category T3NxM0 treated by the combination of radium implant and ex- ternal irradiation: second report . Int J Radiat Oncol Biol Phys 1983;9:177-180. 21. van der Werf-Messing B, Hop WC. Carcinoma of the urinary bladder (category T1NxM0) treated either by radium implant or by transurethral resection only. Int J Radiat Oncol Biol Phys 1981;7:299-303.

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ACKNOWLEDGEMENTS The authors of this chapter are much indebted to the authors of the original version of the chapter on Urinary Bladder Cancer in the first edition of the GEC-ESTRO Handbook on Brachytherapy Jean Jacques Mazeron and Erik Van Limbergen. Dr. G. Smits is acknowledged for providing images of ro- bot-assisted implantations.

AUTHORS Bradley Pieters

Academic Medical Center University of Amsterdam The Netherlands Elzbieta van der Steen-Banasik Radiotherapy Group

Location Arnhem The Netherlands

Erik Van Limbergen Department of Radiation Oncology University Hospital Gasthuisberg Leuven Belgium