23 Bladder Cancer –
Technical Basis of Radiation Therapy
Alan R. Schulsinger, Ron R. Allison, Walter H. Choi, and Marvin Rotman
A. R. Schulsinger, MD, Associate Professor of Radiation Oncology, Department of Radiation Oncology, State Uni versity of New York, Health Science Center at Brooklyn, 450 Clarkson Avenue, Box 1211, Brooklyn, NY 11203-2098, USA and Director of Radiation Oncology at the Long Island College Hospital M. Rotman, MD, Distinguished Service Professor and Chair- man, Department of Radiation Oncology, State University of New York, Health Science Center at Brooklyn, 450 Clarkson Avenue, Box 1211, Brooklyn, NY 11203-2098, USA
R. R. Allison, MD, Professor and Chairman, Department of Radiation Oncology, Leo Jenkins Cancer Center, Brody School of Medicine, Greenville, NC 27834, USA
W. H. Choi, MD, Department of Radiation Oncology, SUNY Downstate at Brooklyn, 450 Clarkson Avenue, Box 1211, Brooklyn, NY 11203, USA
23.1
Natural History of the Disease (Patterns of Spread)
Bladder cancer is the sixth most common cancer in the United States (Cancer Statistics 2004).
It accounts for approximately 4% of all cancers, which translates into 60,000 new cases a year. The 12,000 deaths per year attributable to bladder malig- nancies are comparable to the yearly mortality rates of brain, stomach, and esophageal cancers.
Over the past 25 years, we have witnessed a nearly twofold increase in the incidence of bladder cancer, but overall survival rates have remained essentially unchanged.
Risk factors for transitional cell cancer of the bladder include exposure to chemical carcinogens (i.e., aniline dyes), tobacco (estimated to account for half of all cases that occur in men in the United States and one-third of all cases that occur in women), coffee, artificial sweeteners, and phenac- etin-containing analgesics (Whitmore et al. 1977).
Chronic irritation by foreign bodies (i.e., indwelling Foley catheters, calculi, and Schistosoma hemato- bium in endemic areas) are risk factors for squa- mous cell cancers. Exstrophy of the bladder is the main risk factor for adenocarcinoma (Morison and Cole 1976).
Some of the more common clinical presentations of bladder cancer include (1) painless hematuria, which occurs in up to 80% of patients; (2) bladder irritability, such as urinary frequency, urgency, and dysuria (all of which are suggestive of muscle-inva- sive disease); and (3) recurrent urinary tract infec- tions, particularly in men. Some of the less common clinical presentations include (1) flank pain or anemia associated with a pelvic mass; (2) pelvic mass associated with lower extremity weakness, weight loss, abdominal pain, or bone pain; and (3) suprapubic pain.
Anatomically, the bladder is a hollow muscu- lar organ that lies in the anterior half of the pelvis.
When full, it contains about 0.5 l of urine. It occu- pies a triangular space bound anteriorly and later- ally by the symphysis pubis and the diverging walls of the pelvis, respectively. The posterior border is the rectum/rectovaginal septum. The lateral and inferior portions of the bladder are supported by the obturator internus and levator ani muscles, respec- tively. In males, the prostate lies between the leva- tor ani and the bladder. The superior surface of the bladder is covered by peritoneum.
The interior inferior surface of the bladder is lined by a loosely attached mucus membrane, except
CONTENTS
23.1 Natural History of the Disease (Patterns of Spread) 561 23.2 Work-Up and Staging 562
23.3 Prognostic and Predictive Factors 563 23.4 General Management 564
23.5 Radiation Therapy Techniques (General Description) 568 23.6 Simulation 569
23.7 Target Volume and Organs at Risk (Critical Structures)
−Specifications (Including Tolerance Doses) 569 23.8 Dose Prescription Beam Selection/Design Isodoses Plan Evaluation/Implementation 570
23.8.1 Simulation/CT Simulation Procedures 570 23.9 Future Directions 573
References 575
in the trigone region where the mucus membrane is firmly attached. The urinary epithelium lining the bladder is thrown into many folds in the relaxed state. This allows the bladder to expand with the fill- ing of urine. Deep to the epithelium, the wall of the bladder consists of three loosely arranged smooth muscle and elastic fiber layers which contract during micturition. These are the inner longitudinal, outer spiral, and outer longitudinal layers. The outer lon- gitudinal layer is surrounded by the outer adven- titial coat. This coat contains arteries veins and lymphatic channels. Because these lymphovascular channels reside most abundantly in the outer layer of the bladder, depth of penetration of tumor cells is correlated with the incidence of locoregional lymph node metastasis. The trigone region that leads into the bladder neck is defined by the ureteral orifices posterolaterally and by the urethral aperture at the inferior/anterior angle. Transitional cell epithelium lines the bladder and is contiguous into the ureters (urothelium).
The bladder contains submucosal plexus of lym- phatics that are most abundant in the region of the trigone. These lymphatics usually drain into chan- nels that pierce the muscular layers and then orga- nize from the superior and inferolateral surfaces of the bladder to ultimately drain into the external iliac lymph nodes. From the posterior surface of the bladder, lymphatic channels drain to both the external iliac and internal iliac lymph node chains.
Lymphatic vessels from the bladder neck may com- bine with some prostatic lymphatic vessels in males, which can ultimately drain to the presacral and common iliac lymph nodes.
The most common histology in the United States is transitional cell carcinoma, which makes up approximately 90% of cases, followed by squa- mous cell (7%), and adenocarcinoma (less than 1%) (Pearse 1994). Sarcomas, lymphomas, carcinoid, and small cell tumors are rarely seen. About 30% of bladder cancers present as multiple lesions. Adja- cent carcinoma in-situ (CIS) is also common.
Tumors of the bladder may be papillary in appear- ance – which are generally not deeply invasive – or solid in appearance – which are generally deeply invasive. Most transitional cell tumors are found at the trigone, followed in frequency by the lateral and posterior walls and then the bladder neck (Mostofi et al. 1988). Adenocarcinoma also most frequently arises at the trigone (Johnson et al. 1972).
Tumors progress by further muscle invasion and by lymphatic involvement to the external iliac lymph nodes. About 40% of patients with muscle-invasive
cancers have involved lymph nodes at presentation (Skinner et al. 1982). Almost all of these patients will ultimately die of distant metastasis (Skinner et al. 1982). Of note is that metastases is rarely seen in squamous cell histology.
The most common sites of spread are lung, bone, and liver.
23.2
Work-Up and Staging
The basis of the work-up in bladder cancer is to determine whether the disease is a superficial non- invasive cancer, a locally invasive lesion, or meta- static disease. In addition to evaluating the blad- der, the ureters and kidneys are also examined for lesions, since multiple tumors are not uncommon.
Perhaps this is related to common carcinogen expo- sure or embryology.
Cystoscopy and urethroscopy allow for excel- lent visualization and biopsy of lesions. A bladder diagram should be completed at the time of cystos- copy to record pertinent findings (Fig. 23.1). This information can be quite valuable to the radiation oncologist for treatment planning, as a precise knowledge of the tumor location is critical. In addi- tion, computed tomography (CT) and/or magnetic resonance imaging (MRI) can be used to evaluate for bladder wall thickening and invasion as well as for lymphadenopathy. It should be kept in mind that edema and hemorrhage seen on MRI and CT scan obtained shortly after transurethral bladder resection (TURBT) may easily be confused with tumor ( Barentsz et al. 1996, 2000). For this reason, we advise imaging studies be performed prior to TURBT. All patients should also have blood taken for a complete blood count and serum chemistries, including liver functions tests, as this may offer clues to systemic spread (Table 23.1). Chest and abdomi- nal CTs are also recommended for invasive disease.
Positron emission tomography (PET) scanning may also help delineate disease spread.
Bimanual examination under anesthesia should
be performed both before and after transurethral
bladder resection of the visualized lesion to get a
better appreciation of the size, consistency, and
location of the tumor. This allows for estimation of
the extent of local infiltration into the surround-
ing tissue by assessing whether the mass is freely
mobile, tethered, or fixed, before and after maximal
transurethral bladder resection.
Determination of muscular wall invasion is the most important aspect of staging. It is often not pos- sible for the pathologist examining TURBT speci- mens to determine whether the tumor is confined to the superficial muscle layers of the muscularis propria, which is the first muscle layer reached after tumor cells have already invaded the connective tissue of the lamina propria, or whether the tumor has penetrated further to involve the deeper muscles layers. This inability to distinguish deep from super- ficial muscle invasion leads to both understaging
and, less frequently, overstaging. These limitations to accurate staging have undoubtedly compounded the difficulty of showing the benefit of effective bladder-sparing treatments.
A further difficulty to accurate staging is the use of both clinical and pathological staging systems in clinical trials. Caution is therefore required in the interpretation and comparisons of trial results. The two most widely used staging systems are presented in Table 23.2. In the American Joint Committee on Cancer (AJCC) staging system, if staging is based on evaluation of the cystectomy specimen, the stages are preceded by the lower case letter p.
23.3
Prognostic and Predictive Factors
Approximately 70% of patients have Tis, Ta, or T1 disease at presentation. Approximately 20% have stage T2T4 disease and another 10% present with metastatic disease. Although the majority of tumors are superficial, they can behave aggressively and locally they recur repeatedly, often with further and deeper invasion. Eventually, penetration of the blad- der muscular layers occur. Once muscle is involved, lymphatic and blood vessel invasion is common. It is generally reported that pathological T2 disease has a 30% risk of nodal involvement, as does early T3 dis- ease. Patients with advanced T3 or T4 tumors have a 5080% risk of nodal involvement (Shipley et al.
Posterior Hemisphere Anterior Hemisphere
Posterior Wall
Posterior Neck Trigone Right Ureteral Orifice
Right Wall
Left Anterior Wall
Air Bubble
Left Ureteral Orifice
Prostatic Urethra Prostatic Substance
Anterior Neck Dome
Right Anterior Wall Left Wall
Table 23.1. Diagnostic Work-Up for Bladder Cancer Routine
History and physical examination Pelvic/rectal examination Laboratory studies
Complete blood cell count Live function tests and chemistries Urinalysis and Urine Cytology Imaging
Computed tomography or magnetic resonance scan of pelvis and abdomen
Intravenous pyelography Chest radiograph Radioisotope bone scan Cystourethroscopy
Bimanual pelvic/rectal examination under anesthesia Biopsies of bladder and urethra
Transurethral resection, if indicated
Fig. 23.1. A bladder diagram is completed at the time of cystoscopy and used to record the cystoscopy fi ndings, biopsy, information, and tumor characteristics
1985). As nodal metastasis is in part an indicator of potential for systemic spread, a similar frequency of distant metastasis is eventually noted for these patients also.
Poor prognostic factors at presentation include deeply invasive tumors (there is an increasing prob- ability of perivesicular and pelvic nodal metastasis as the depth of invasion increases), associated CIS, vascular invasion, positive lymph nodes, tumors greater than 6 cm in size, urethral obstruction/
obstructive uropathy, solid tumor morphology, a palpable mass present on bimanual examination, visible tumor following TURBT, solid/flat surface tumor histology as opposed to papillary histology which is a more favorable characteristic, high-grade (poorly differentiated) tumors, hemoglobin of less than 12 gm/dl, stage T3b or T4 tumors, and multiple tumors (Shipley et al. 1985).
23.4
General Management
Optimal therapeutic options for bladder cancer depend on histology and stage of disease. Patients with squamous cell cancer tend to experience failure locally. Management of these individuals should be with a course of preoperative radiation therapy to the pelvis followed by radical cystectomy. This approach yields an approximate 50% 5-year survival rate and is generally considered to offer the best chance for cure (Awwad et al. 1979; Ghoneim et al. 1985). The management of transitional cell cancers should be based on whether the patient has non-muscle- or muscle-invading disease. For non-muscle-invading disease [stage 0 (Tis), and stage A (T1)], acceptable local control rates and 5-year survival rates have been obtained with a variety of interventions includ-
Table 23.2. Comparsion of Marshall and AJC Staying System for Bladder Cancer
Marshall modifi cation of Jewett-Strong classifi cation
AJCC
Tumor Extent
Confi ned to Mucosa 0
• nonpapillary, noninvasive TIS
• papillary, noninvasive Ta
Not Beyone Lamina Propria (no mass palpable after complete TUR) A T1 Invasion of superfi cial muscle (inner half) (no duration after complete TUR) B1 T2a Invasion of deep muscle (outer half) (induration after complete TUR) B2 T2b Invasion into perivesical fat (mobile mass after TUR)–microscopic C T3a –macroscopic T3b Invasion of neighboring structures: Muscle invasion present
Substance of prostate, vagina, uterus D1a T4a
Pelvic sidewall fi xation or invading abdominal wall D1a T4b
Nodal involvement (N)
Minimum requirements to assess the regional nodes cannot be met Nx
No involvement of regional lymph nodes No
Involvement of a single lymph node, 2 cm or less in size N1
Involvement of a single lymph node >2 cm or less but <5 cm or multiple lymph nodes measuring <5 cm
N2
Lymph node mestastasis >5 cm in diameter N3
Distant metastasis (M)
Minimum requirements to assess the presence of distant metastasis cannot be met Mx
No distant metastasis Mo
Distant metastasis M1
a In the Marshall modifi cation of the Jewett-Strong staging system, D1 disease may involve lymph nodes below the sacral promontory (bifurcation of the common iliac artery). D2 implies distant metastases or more exten- sive lymph node metastases.
TUR, transurethral resection
ing transurethral resection and fulguration of the bladder, partial cystectomy, interstitial implants, intraoperative irradiation, intravesicular chemo- therapy, and Bacillus Calmette Guerin (BCG) fol- lowing TUR. Early-stage patients (Tis, Ta, T1) with non-muscle-invasive disease are generally managed by maximal TURBT followed by intravesicular BCG instillation. For muscle-invasive bladder cancers, survival results and morbidity remain poor with cystectomy. This surgery usually includes perma- nent ileal conduit with loss of sexual potency and is considered “standard treatment” in the United States for muscle-invasive disease. Although pre- operative external beam irradiation may improve outcome (Silverman et al. 1992), and the combina- tion of chemotherapy with irradiation may allow for organ preservation, only a fraction of patients are offered these options.
Transurethral resection in the management of non-muscle-invasive disease is often an outpatient procedure in which transurethral visualization of the lesion(s) in question is obtained and a biopsy, if not a resection, is accomplished. Tumor removal may be by scalpel, heat, or laser source. The goal is to remove tumor down to uninvolved tissue. TURBT is a well-tolerated procedure; however, after multiple TURBTs have been performed, the bladder is typi- cally fibrotic and contracted. Perforations are rare, although at times they do occur and may require surgical repair. Most of these patients undergo one or more TURBT, generally followed by intravesicu- lar BCG. Local control rates of 6080% are obtained (Herr et al. 1995). A significant minority of patients will go on to develop invasive bladder cancer or a second urethral malignancy. For this reason, close follow-up with cystoscopy performed at 3- to 4- month intervals is recommended.
Interstitial and intraoperative radiation treatment of non-muscle-invasive bladder cancer has excellent outcome for selected patients, but is rarely employed in the United States. Matsumoto, using intraopera- tive radiation therapy delivered by an electron beam, achieved an impressive 95% local control rate for early-stage solitary lesions ( Matsumoto et al. 1981).
Van der Werf-Messing et al. (1981) implanted the bladder by brachytherapy and reported 8085%
local control rates. Given that understaging is such a significant problem after TURBT, it is possible that intravesicular therapy may be undertreating some of these patients with “non-muscle-invasive” dis- ease. Patients receiving some form of radiation are adequately treated, as the not-infrequent muscle- invasive component is responsive to radiation but
not chemotherapy or immunotherapy, neither of which penetrates into the full thickness of the blad- der as completely as radiation does. To date there are no randomized trials comparing intravesicular therapies to radiation. There is, however, prospec- tive, nonrandomized data from the Dutch South Eastern Bladder cancer study “that suggests that if radiotherapy is used routinely and not restricted to unfavorable subgroups, the results are prob- ably better than with adjuvant intravesical therapy”
(Rodel et al. 2005).
Perhaps due to the inherent inadequacies of clini- cal staging, the optimal management for muscle- invasive disease remains unclear. For these patients, however, TUR alone is usually unacceptable due to high local failure rates. The exception to this is in selected patients with single, small, superficially muscle-invasive tumors (T2a) not associated with CIS (Herr 1987; Solsona et al. 1992). Treatment options for the remaining patients include cys- tectomy (partial in selected cases) and combined modality therapy with a view to bladder preserva- tion (i.e., maximal TUR followed by irradiation with chemotherapy). In patients with T2 disease, most commonly, cystectomy alone is employed and offers a 60% survival in pathologically staged patients (Resnick and O’Connor 1972; Brannan et al. 1978).
The role of radiation in this stage of disease in not yet well defined; however, van der Werf- Messing reported that selected T2 patients implanted with radium needles achieved an 80% disease-free sur- vival at 5 years (van der Werf-Messing et al. 1983).
These results were replicated by Batterman and Denue (1986). External beam radiation series for T2 disease is composed mainly of clinically staged patients. Clinical staging is inherently inaccurate and often includes individuals with pathologically more advanced tumors. Further, these outcomes are generally based on medically inoperable or elderly and frail patients. Despite these shortcomings, good local control and survival rates are possible as sum- marized in Table 23.3.
Table 23.3. Outcomes of trials of radiation alone to treat bladder cancer
Series (ref) No. of Patients
Complete Response T2 (%) T3 (%)
Blandy et al. (47) 704 48 42
Duncan et al. (48) 889 49 41
Smaaland (49) 146 69 36
Greven et al. (50) 116 36 18
Vale et al. (51) 60 79 46
For most patients with T2 disease, “surgical option” means radical cystectomy combined with pelvic lymphadenectomy. Radical cystectomy includes resection of the bladder, distal ureters, perivesicular fat, and the regional peritoneum.
In men, the prostate, seminal vesicles, vas defer- ens, and proximal urethra are also removed. Up to 40% of men undergoing radical cystectomy for bladder cancer have been found to have pros- tate cancer (Nixon et al. 2002; Wood et al. 1989).
It has been suggested that men not at high risk of either bladder cancer involvement of the pros- tatic urethra or a second primary prostate cancer should be considered for prostate sparing cystec- tomy with a view toward improved urinary control and sexual potency (Cookson 2005). In women, the uterus, fallopian tubes, ovaries, anterior vagi- nal wall, and urethra are resected. Urinary diver- sion may be by ileal conduit with external appli- ance or an internal stoma reservoir that may even maintain continence. Regarding the extent and completeness of the lymphadenectomy, there has been a renewed interest in extending the resection above the “traditional” level of the bifurcation of the iliac arteries, as this may impact on the disease specific survival even in patients without appar- ent lymph node involvement, up to the level of the inferior mesenteric artery (Cookson 2005). It must be remembered, however, that there is an increased risk of lymphedema in extending the level of resec- tion. Results of developing multi-institutional randomized studies comparing “traditional” with extended lymphadenectomy will hopefully resolve this issue.
Operative mortality is still about 1−2%, mainly due to pulmonary emboli, myocardial infarction and stroke. There is also significant blood loss associ- ated with the procedure, and overall 30% of patients require transfusion with a median requirement of two units of packed red blood cells (Cookson 2005).
Additionally, there are major lifestyle changes brought about by this procedure, including vaginal dryness, incontinence (depending on the method of reconstruction), and the loss of sexual function.
A small minority of patients may be eligible for partial cystectomy. These are individuals with soli- tary well-defined tumors that allow at least 2 cm of margin all around the resection plane. Preopera- tive pelvic irradiation should be considered when there is a significant likelihood of microscopically involved pelvic lymph nodes.
Radical cystectomy is also the most widely selected therapy for patients in the United States
with stage T3 disease. Cystectomy alone offers a 20 40% 5-year survival and similar local con- trol rates (Greven et al. 1992; Montie et al. 1984;
Morabito et al. 1979; Drago and Rohner 1983;
Marshall and McCarron 1977). In an attempt to improve results, several randomized studies involv- ing preoperative external beam radiation therapy have been employed. In general, 4500 centigray (cGy) are delivered (Bloom et al. 1982; Batata et al. 1981;
Timmer et al. 1985; Woehere et al. 1993). Despite the fact that these studies have shown improved local control and survival rates, in the United States, most patients undergoing radical cystectomy do not receive preoperative radiation therapy.
Radiation therapy alone is usually unsuccess- ful in patients with T3 disease, with 5-year surviv- als reported in the 20% range (Bloom et al. 1982;
Goffinet et al. 1975; Quilty and Duncan 1986;
Pollack et al. 1994; Edsmyr et al. 1985; DeWeerd and Colby 1973). This may be due, in part, to the fact that many of the patients who are chosen for
“definitive radiation therapy” are often patients who initially failed multiple TURBTs with BCG and either refused salvage cystectomies or were deemed medically inoperable. These patients typically have scarred, contracted bladders to begin with, and per- haps have biologically more aggressive tumors as evidenced by their history of recurrences. It should also be kept in mind that a significant number of patients undergoing cystectomy for clinical stage T3 lesions are found to have T4 lesions on pathological analysis (Marshall 1952; Richie et al. 1975; Whit- more et al. 1977). A significant minority are also downstaged (Marshall 1952; Richie et al. 1975;
Whitmore et al. 1977). For this reason, comparing results from clinically staged series to pathologically staged series is difficult. Some radiation series do reveal fair pelvic local control rates (Table 23.3) but often it is based on salvage cystectomy in patients able to undergo this procedure.
Various clinical trials suggest that bladder cancer is a chemoresponsive tumor. Recent reports of che- motherapy integrated with radiation therapy sug- gest that results can be improved over radiation therapy alone and may obviate the need for radical cystectomy with its resultant compromised quality of life.
Chemotherapy has been successful in improving
outcome for both early and advanced patients. Com-
pared with TURBT alone, single agents instilled into
the bladder – or BCG employment for early-stage
patients following maximal transurethral bladder
resection – clearly increase local control. For patients
with muscle-invasive disease, chemotherapy plays an important role in enhancing the effects of radia- tion therapy. Numerous trials demonstrate that the addition of radiosensitizing doses of chemotherapy [i.e., 5-fluorouracil (5-FU), cisplatin, etc.] improve complete response rates by more that 50% when compared with radiation therapy alone (Rotman et al. 1987; Reibischung et al. 1992; Tester et al. 1993;
Cervak et al. 1993; Dunst et al. 1994).
Incorporation of chemotherapy into the manage- ment paradigm of muscle-invasive bladder cancer offers the theoretical advantage of “spatial coopera- tion”, where the primary role of chemotherapy is to control micrometastasis at distant sites, while either surgery, irradiation, or irradiation with radiosensi- tizing doses of chemotherapy are used to address the localized primary tumor.
The major side effect of chemotherapy is gener- ally hematological toxicity. Also, many patients who were referred for radiation therapy with chemother- apy are often sent because they are medically inoper- able. Frequently, these patients have coronary artery disease, and certain chemotherapeutic agents may cause coronary artery spasm (i.e., 5-FU) (Devita et al. 1989). Although it is unclear whether or not the addition of chemotherapy will ultimately increase the rate of long-term complications, this has not yet been reported in any prospective randomized stud- ies. There may be increased frequency of diarrhea in patients who are treated with concomitant 5-FU, but these side effects are frequently prevented by pro- phylactically placing patients on a combination of Metamucil and Pepto-Bismol prior to initiation of treatment.
As distant metastases remain the most common cause of treatment failures for patients with muscle- invasive bladder carcinoma, it seems reasonable to try to incorporate a systemic component into the treatment regimen in an attempt to control micro- metastases at distant sites.
Results of the South West Oncology Group trial 8710 (INT-00800) – a phase-III trial of neoadjuvant methotrexate, vinblastine, doxorubicin, cisplatin (MVAC) plus cystectomy versus cystectomy alone in patients with locally advanced bladder cancer – have shown improved 5-year survival figures for patients treated with the neoadjuvant chemotherapy (Natale et al. 2001). Two other recently published randomized trials including the Medical Research Council/European Organization for Research and Treatment of Cancer (MRC/EORTC) and US Inter- group studies have also suggested both improve- ment in locoregional control and metastatic relapse
(Hussain and James 2005). These studies suggest that neoadjuvant chemotherapy does in fact have an impact on the control of micrometastases.
Despite numerous trials by groups utilizing cis- platin, it is becoming increasingly clear that cispla- tin may not be the ideal drug of choice for chemo- radiotherapy in the treatment of bladder cancer. As pointed out by James and Hussain (2005; Hussain and James 2005), “… a significant proportion of patients (with bladder cancer) have impaired renal function, and administration would require inpa- tient stay and hydration. Only about 50% of patients were fit to receive cisplatin at their institution at the doses used in the Canadian study.” In studies reported by Rotman et al., patients with clinically staged bladder cancer underwent high doses of exter- nal beam radiation therapy in combination with sen- sitizing doses of 5-FU chemotherapy (Rotman et al.
1990). The majority of patients retained functioning bladders, and minimal toxicities were noted. More importantly, survival rates were excellent. This and other studies provide evidence that chemotherapy also improves local tumor complete response rates.
Table 23.3 summarizes the complete response rates for various studies employing the use of radia- tion therapy alone (Blandy et al. 1980; Duncan and Quilty 1986; Smaaland et al. 1991; Greven et al.
1990; Vale et al. 1993). Table 23.4 summarizes the results of studies combining aggressive TURBT fol- lowed by combining concomitant chemotherapy and radiation therapy (Saver et al. 1990; Rotman et al.
1987; Jakse et al. 1985; Tester et al. 1993; Richards et al. 1983; Cervak et al. 1993). Comparison of these results strongly suggests that the addition of chemo- therapy improves results over standard radiation therapy alone.
In patients treated with nonsurgical bladder- sparing approaches, maximal TURBT is usually the initial step and is followed by radiation therapy combined with chemotherapy. When such strategies have been employed, response rates of 70% or greater have been obtained (Devita et al. 1989; Dunst et al.
1994; Eapen et al. 1989; Housset et al. 1993).
Hyperfractionated trials draw from the encour- aging results from the Royal Marsden Hospital where local control for muscle-invading bladder cancer was enhanced by accelerated multiple daily treatments (Cole D Durant et al. 1992; Horwich et al. 1995). Incorporating this benefit into com- bined modality therapy with maximal TURBT and chemotherapy has resulted in impressive results in both French and Italian trials (Housset et al. 1993;
Danesi et al. 2004).
Danesi and Arcangeli recently reported long- term results on a phase I/II trial in which a series of invasive bladder carcinomas were treated with or without an initial two cycles of methotrexate, cis- platin, vinblastine (MCV) followed by concomitant continuous infusion of 5-FU and continuous infu- sion of cisplatin and irradiation (Danesi et al. 2004).
Treatment consisted of three 100-cGy fractions per day of radiation, 5 days per week, for a total dose of 5000 cGy in 3.5 weeks. If required, due to resid- ual disease, a consolidative dose of 2000 cGy was given in 1 week. A complete response rate of 90%
(65 patients) was obtained in a series of 77 patients.
High-grade toxicity was uncommon. With a median follow-up of 82.2 months, 44 of 65 patients who had an initial complete response were still alive, and 33 (57.1%) of these patients remain with a tumor-free bladder (61.5). The 5-year overall, bladder-intact, tumor-specific, disease-free, and cystectomy-free survival rates for all 77 patients were 58.5%, 46.6%, 75%, 53.5%, and 76.1% respectively.
Patients with T4 disease have poor survival no matter what treatment is employed. Radical surgery has few 5-year survivals, and preoperative irradia- tion delivered prior to radical cystectomy has not
improved on this. Some investigators have exam- ined multi-agent chemotherapy for these patients.
However, long-term results are not yet available.
Possibly, organ preservation chemoradiation proto- cols may be an option (Table 23.4)
23.5
Radiation Therapy Techniques (General Description)
A wide variety of planning, dosing, and actual therapy techniques are available in the treatment of bladder cancer. The ultimate goal for each of these is to optimally define the tumor volume, while at the same time minimizing dose to normal tissues.
This requires accurate definition of the critical normal structures in relation to the tumor volume so that uninvolved organs can be maximally shielded during treatment to minimize morbidity.
Precise knowledge of tumor location on a daily basis is critical information for the radiation oncol- ogist treating patients with bladder tumors. Cys- togram, CT, and MRI have all been relied on for
Table 23.4 Outcomes of trials of chemotherapy and radiation to treat bladder cancer. CR complete response, conc concomi- tant, neo neoadjuvant
Reference No. Stage Chemotherapy Radiation dose Sequence Median F/U CR(%) Survival (%) Rotman
et al. (1990)
19 T24 5-FUrMMC 6065 Gy Conc 38 months 7489 53.6
Russell et al. (1990)
34 5-FUx2 40 Gy Conc 18 months 81 64
Housset et al. (1993)
54 T24 CDDP+5-FUx2 24 Gy/8Fx/
4 days+20 Gy boost
Conc 27 months 74 59 (3 years)
Tester et al. (1996)
91 T24A MCVCDDPx2 39.6 Gy Neo+Conc 75 62 (4 years)
Sauer et al. (1998)
115 T14 CDDP or Carbo x2 45 Gy Conc 7.5 years 7085 57-69 (5 years)
Birkenhake et al. (1999)
25 T34 CDDP+5-FUx2 59.4 Gy Conc 38 months 88 80
Radosevic-Jelic et al. (1999)
67 T34 Carbo weekly 65 Gy Conc 92.5 55 (5 years)
Hussain et al. (2004)
41 T34 5-FU+MMCx2 55 Gy in 20Fx Conc 51 months 71 36 (5 years)
Rodel et al. (2002)
45 T14 5-FUx2 5459.4 Gy Conc 31 months 87 67
Sauer et al. (1998)
67 T14 CDDPx2 50.4 Gy Conc 75 66 (3 years)
Danesi et al. (2004)
77 T24A MCVCDDP+5-FU PVI 69 Gy 3Fx/day Neo+Conc 82 months 90.3 58.5 (5 years)
obtaining this information. PET/CT can also be very helpful in this regard. Rothwell et al. (1983) have demonstrated that CT localization is superior to cystogram localization and additionally points out that when cystogram is used alone, up to 85% geo- graphic miss occurred. Graham et al. (2003) com- pared MRI with CT planning and concluded that CT was sufficient if the whole bladder is to be treated.
However, they advocate the use of MRI information in treating partial bladder volumes. It should again be reiterated that edema and hemorrhage seen on MRI obtained shortly after TURBT may easily be confused with tumor. For this reason, we advise on relying on MRI obtained prior to TURBT in addition to utilizing bladder-mapping information obtained at the time of the initial cystoscopy.
Treatment volume used during planning must be the same during daily treatment set-ups. There are advantages and disadvantages to treating with an empty as opposed to full bladder. The advantage is that patients are more comfortable with an empty bladder and the bladder location is more certain. The disadvantage is that less of the small bowel is pushed out of the field of treatment (potentially resulting in increased treatment morbidity), and it is also pos- sible to spare more normal bladder mucosa when the bladder is full and the tumor volume maximally displaced from uninvolved bladder mucosa.
23.6 Simulation
One must always remember that patient comfort is a priority when setting up a treatment (i.e., simula- tion). One half-hour prior to simulation, the patient may be given an oral contrast to drink so that the small bowel can be adequately visualized during the simulation process. Patients may be treated supine or prone. When the regional lymph nodes are to be covered for the initial 4500 cGy of treatment, we recommend that the patient be treated prone on a belly board, with the bladder fully distended. If this pushes the small bowel out of the lateral treatment portals, small bowel toxicity may be minimized;
otherwise, supine treatment may be more comfort- able to the patient. During simulation, an alpha cradle is fashioned, or landmarks are identified, for each patient so that the individual can be optimally and accurately repositioned for the precise daily treatment setup. Once positioned, a Foley catheter is inserted into the bladder with a sterile technique,
and 7 cc of Hypaque is used to inflate the Foley catheter balloon.
The Foley catheter is pulled down to ensure that the balloon is at the base of the bladder. This critical step is required to ensure identification of the location of the bladder base. A solution of Hypaque mixed with saline in a one to two ratio is then instilled into the bladder. Generally, 25 cc of this mixture is instilled.
Subsequent to this, approximately 25 cc of air is also injected into the bladder and the Foley catheter is clamped. Patients should be informed that a small quantity of air will be injected into the bladder so that they will not become alarmed when, after the proce- dure is over, they note that air is being passed from their bladder. The information obtained from this air contrast cystogram is combined with informa- tion previously obtained from examination, bladder mapping obtained at the time of initial cystoscopy, CT scan, and possibly cystogram, if previously per- formed, to optimally define the bladder location and the tumor and target volume for treatment. At some institutions, a rectal tube is placed at the distal end of the anal canal to identify this anatomy (a rectal balloon may also limit rectal movement but if it is used for this purpose it must be used on a daily basis during the course of treatment). The rectal tube is then connected to a Twomey syringe that has been previously filled with 25 cc of barium paste mixed with 25 cc of water. Please note that the rectal tube should be inserted into the rectum empty; No barium should be inserted into the rectum until later during the procedure when the lateral fields are simulated.
The barium may obscure the outline of the blad- der on anterior posterior simulation films. An anal canal marker should be placed at the distal end of the anal canal.
At this point, patient positioning should be re- verified by fluoroscopy as these manipulations may have induced misalignment.
23.7
Target Volume and Organs at Risk (Critical Structures)−Specifications (Including Tolerance Doses)
Morbidity should be analyzed by envisioning the tissue that will be traversed by the treatment beams. Consider the consequences of the beam as it passes through skin, small bowel, rectum, bone, and bladder.
The target volume in the treatment of bladder
cancer includes the bladder and regional lymphat-
ics up to the level of the common iliac lymph nodes.
It should be mentioned that there are institutions that treat the bladder only to 4500 cGy and then either continue on to 6500 cGy or cone down to the tumor only. The primary critical structures of major concern include the femoral heads (tolerance dose 4500 cGy), small bowel (tolerance dose of 4500 cGy), and rectum (tolerance dose of 6000 cGy) (Emami et al. 1991). These tolerances are for patients treated using standard fractionation schemes in which the bladder is treated with a 2-cm margin. Institutions utilizing hypofractionation schemes typically use smaller margins of 1 cm to compensate for the larger fraction sizes in terms of side effects (Murren et al. 2004).
The radiation oncologist, when considering mor- bidity related to treatment, should think in terms of both acute and chronic morbidity. With optimal treatment planning, acute morbidity can be mini- mized to less that 10%, and long-term morbidity to the normal surrounding structures can be brought down to less than 5%.
23.8
Dose Prescription Beam Selection/Design Isodoses Plan Evaluation/Implementation
23.8.1
Simulation/CT Simulation Procedures
External beam therapy is most commonly deliv- ered by means of a four-field box technique (Figs. 23.223.4); however, multiple conformal fields outlining the bladder can also be employed. In a four- field treatment plan, matched anterior/posterior and lateral portals are employed. The anteroposterior/
posteroanterior (AP/PA) field encompasses the blad- der as outlined by information obtained from both diagnostic studies and during simulation, and may be expanded to cover the regional lymph nodes if needed. When the regional lymph nodes are cov- ered for the initial 4500 cGy of treatment, the patient should be treated prone on the belly board with the bladder full to push the small bowel out of the field, minimizing small-bowel toxicity. In general, these fields are defined superiorly by the S1/S2 interspace (midsacroiliac joint) to cover pelvic nodes up to the level of the common iliac lymph nodes.
If this volume should encompass a significant amount of small bowel despite the patient being prone and on a belly board, then the upper border
should be lowered accordingly to minimize the volume of small bowel in the treatment field. This generally requires the upper border to be placed at the lower sacroiliac joints. However, it must be kept in mind that to adequately cover the bladder, the upper border should extend approximately 2 cm above the dome of the bladder as visualized by the air contrast cystogram. The inferior border of the AP/PA field is placed at the lower border of the obturator foramen, which allows for good nodal and bladder coverage. The lower border of the field should be placed at the lower border of the obturator foramen only when there is no clinical suspicion or cystoscopic evidence of involvement at the base of the bladder or proximal urethra.
AP - PA : Lateral 20 : 8
10 MV X-Rays 25 MV X-Rays
2000 3000
5040 5040
3000 2000
Minimum Tumor Dose - 1800 7cm Lateral Fields
10 MV X-Rays 25 MV X-Rays
2400 2200 2000 2000 2050
1800 900
1800 900
1800 900
900 1800
Fig. 23.2. Composite isodose curves for whole pelvic irradia- tion (isocentric four fi eld) to 50.4 Gy. Compares 10-MV with 25-MV photons
Fig. 23.3. Isodose distributions for boost portion of treatment delivered through opposed lateral fi elds. These do not refl ect effects of beam width improving device. Compares 10-MV with 25-MV photons
In cases where the tumor is at the bladder neck or disease is noted near or involving the proximal urethra, the border should be extended inferiorly, generally to the level of the ischial tuberosity, to adequately cover disease in this region. If there is any suspicion of urethral involvement, the entire length of the proximal urethra should be covered.
Frequently in this situation, the lower border will be at the bottom of the ischial tuberosities.
Laterally, the anterior field borders of the AP/PA fields are placed 1.52 cm lateral to the bony pelvis to allow coverage of the iliac lymph nodes. Custom blocking is employed to shield the femoral heads and prepubertal soft tissues. If the lymphatics are not to be included, these fields should be dimin- ished to outline the bladder with a 2-cm margin. In this clinical situation, the patient should be treated with an empty bladder to minimize the treatment volume.
The lateral fields, superior and inferior borders are set at the same anatomical levels of the AP/PA fields, hence the term four-field box technique. The anterior border on the lateral field should be placed 2 cm above the bladder as outlined on the air con- trast cystogram and also include the external iliac lymph nodes on the lateral fields. The only way to accurately locate the external iliac lymph nodes is to perform a bipedal lymphangiogram prior to simula- tion. This technique is not frequently employed, but we have found that the external iliac lymph nodes are adequately covered if the anterior border on the lateral field is defined by a line extending from the tip of the pubic symphysis to a point 2.5 cm ante- rior to the bony sacral promontory. After 4500 cGy
of radiation has been delivered, an attempt to shield a portion of the pubic symphysis on the lateral films should be made to prevent osteoradionecrosis or fracture from developing. The posterior border of the lateral field is also determined by the air con- trast cystogram and places 2 cm beyond where the bladder is outlined. During lateral simulation, the barium paste mixed with saline should be injected into the rectum so that it can be accurately defined on the lateral simulation field and optimally blocked by custom blocking. Also note that the small bowel, which is opacified by the oral contrast given to the patient prior to simulation, should be shielded as outlined on the lateral field. The entire anal canal as well as the soft tissue anterior/inferior to the pubic symphysis should also be shielded. During design of these custom blockings to shield both the rectum and the small bowel, care should be taken so that the tumor is not inadvertently blocked. After the AP/PA and lateral radiographs have been obtained and reviewed to the satisfaction of the attending radia- tion oncologist, the field borders and field centers of the AP and lateral fields are marked on the patient.
If available, we recommend obtaining a com- puter treatment plan to optimize dose homogene- ity. To accomplish this, generally a treatment posi- tion CT scan cut is obtained at the isocenters of the field. A physicist will use the CT scan to optimally select appropriate wedges and field weighting to minimize dose inhomogeneity to less than 510%
around the target volume while also minimizing the dose to the normal surrounding critical organs. A typical four-field box technique isodose is shown in Fig. 23.2. In general, these large fields are treated
a
b
Anterior and Posterior Lateral
W 5 cm V
Bladder tumor
volume Bladder
tumor volume 1 cm V
S1 L5
Fig. 23.4a,b. Radiation fi elds for initial whole pelvic treatment. a Anterior/posterior; b laterals
to 4500 5040 cGy at 180 cGy per day. If the patient is being treated by chemoradiation and any small bowel is present in the treatment fields, we routinely reduce the fields by employing custom blocking to shield the small bowel after 4000 cGy had been deliv- ered. This minimizes the chance of small-bowel tox- icity even if it means potentially blocking the exter- nal iliac lymph nodes. Further, if chemotherapy is used during treatment, we generally limit our treat- ment to the bladder and lymphatics to 4500 cGy in 5 weeks. After this dose has been delivered, a boost field is constructed to encompass regions at risk such as residual disease or the premaximal TURBT tumor volume.
Information obtained from pre-TURBT CT scan, examination under anesthesia, and cystoscopy find- ings are used to define the boost volume for treat- ment planning optimally (Fig. 23.5). This volume is taken to be the tumor bed with margin. In some institutions, boost is delivered with bilateral 120q arc rotations as seen in Figure 23.6. Several com- posite examples of radiation treatment technique are provided in Figure 23.7 and Figure 23.8. The boost fields are generally treated to a total dose of 6500 cGy.
It is of utmost importance that the normal tissue tolerances of critical organs such as the rectum, small bowel, and femoral heads are respected. We regard the tolerance of the entire rectum to be 6000 cGy (1/2 of 6.5 weeks) and try to limit our dose to the rectum to no more than 5500 cGy, especially when chemotherapy is employed. We also keep the dose to the femoral heads and small bowel below 4500 cGy. As previously mentioned, we limit the
dose to the small bowel to 4000 cGy when chemo- therapy is employed.
As part of the entire radiation treatment or as part of the boost field, conformal three-dimen- sional (3D) radiation therapy is an option if it is available. Figure 23.9 is an example of a 3D Beam’s eye view treatment plan for fields conformally out- lining the bladder. Normal tissues such as bowel, rectum, prostate and femoral bones are outlined, as is the bladder. With the resultant anatomical information and localization, a treatment plan can be created that offers high precision and dosing to the bladder while constructing appropriate and precise blocks to shield as much normal anatomy as possible. Since this anatomical information is readily available in all dimensions, not just AP/PA
Bladder tumor volume
1 cm V
L5
S1
Fig. 23.5. Lateral boost fi eld
6cm 120q Lateral Arcs
10 MV X-Rays 4 MV X-Rays
7cm Lateral Fields
2400 2200 2000 1800
900
900 900
1800
1800
Fig. 23.6. Isodose distribution for boost portion of treatment compares 120° arc rotation using 4-MV photons with opposed lateral fi elds using 10-MV photons
8cm 45q Wedge Pair
10 MV X-Rays
7cm Lateral Pair
Minimum Tumor Dose - 1800
900
900 1800
2000 2200 2400 1800
900 1800
1600
Fig. 23.7. Isodose distribution for boost portion of treatment using 10-MV photons delivered through opposed laterals or an anterior wedged pair
and lateral as is the usual case for a box field simu- lation, the flexibility to create an improved course of therapy using multiple noncoplanar portals is at hand.
In summary, multiple CT scan slices are obtained from the pelvis in the treatment position.
The bladder is outlined on each slice and digitized into an appropriate 3D conformal treatment plan- ning computer. At that point, custom blocks are created based on the reconstructed digitized blad- der anatomy so that four, six and possibly eight or more fields can be employed to treat the bladder and spare a maximal amount of normal surround- ing tissues. Many linear accelerators are directly linked to the 3D treatment planning device and
create the blocking necessary using multi-leaf col- limators.
23.9
Future Directions
The goal of the radiation oncologist in any treat- ment is to deliver an adequate dose of radiation to destroy tumor cells within a given target volume while avoiding injury to the surrounding normal tissue. A high enough dose of radiation can eradicate just about any cancerous mass. The cost, however, is injury to the surrounding normal tissue which limits the delivery of high doses of radiation. Inten-
Fig. 23.9a,b. a Conformal 3D treatment plan contours bladder and surrounding anatomy in sagittal, coronal, and transverse views. b The single perspective view reveals superb isodose lines contouring the bladder and sparing normal anatomy. (Courtesy of RAHD oncology products, St. Louis, MO)
Fig. 23.8.a,b Composite isodose distributions for whole pelvic irradiation through four-fi eld technique (50.4 Gy) plus various boost methods (18 Gy) in defi nitive plan for T2-T3 bladder carcinoma
25 MV X-Rays
Whole Pelvis - 5040 AP - PA : Lateral
20 : 8 Lat. Tumor Boost - 1800
7000 68406000
5000 4000
3500
6cm 120q Arc Boost 7cm Lateral Boost
10 MV X-Rays
Whole Pelvis - 5040 AP - PA : Lateral
20 : 8 Tumor Boost - 1800
4 MV X-Rays
4300
7050
5040 5040
6840 6840
6000
4000
a 4000 b
a b
sity modulated radiation therapy (IMRT) can poten- tially allow for dose escalation in the treatment of bladder cancer without an increase in morbidity, while resulting in improvement in local control.
It potentially offers the possibility of further improvements in bladder preservation. IMRT is a computer-generated plan that employs the use of multiple beams of varying intensity coming from different angles to deliver maximal radiation to the tumor target while minimizing the irradiation of healthy tissue and organs at risk. In many cases, IMRT is an improvement over conformal CT plan- ning. This is particularly true in cases in which the tumors are concave in physical nature and not well separated from the surrounding normal organs at risk (i.e., tumor wraps itself around an organ).
In these cases IMRT delivers a greater dose to the tumor while limiting the radiation dose to the adja- cent healthy tissue. This is accomplished by the delivery of hundreds of tiny radiation beams of varying intensity delivered through many angles rather than delivery of radiation by larger beams of uniform intensity through more limited angles.
IMRT utilizes more numerous beams with
“inverse” planning. Inverse planning is a method that begins with the required dose distribution and works “backward” through a computer algorithm to produce the necessary beam profiles to accomplish the desired dose prescriptions and constraints.
For IMRT to be worthwhile, it is critical for the tumor/target to be defined as precisely as possible and for the dose of radiation to be delivered with greater accuracy to a more precisely defined target volume. Patient and organ motion can easily negate the benefits of IMRT. Therefore, rigid immobiliza- tion and real time target verification with on line portal imaging are highly desirable when treating organs, such as the bladder, which move consider- ably. In addition to the greater sensitivity of IMRT over other radiation techniques to patient and organ motion, other potential disadvantages include higher integral dose of normal tissues (higher aggregate volume of normal tissue exposure); prolonged treat- ment delivery time; possibility that close delineation of the radiation field to the tumor leaves parts of the tumor untreated; greater vulnerability to the physi- cal uncertainties in defining the tumor volume; and greater risk of error due to the increased complex- ity of planning, delivery, quality assurance, and portal verification. Patients selected as candidates for IMRT should therefore clearly benefit more from this modality than from conventional techniques.
The best way to be certain of this is to compare IMRT
plans with conventional plans on a given patient prior to treatment.
Special markers such as small ball bearings, rods, cross hatches, etc., known as “fiducial markers,” are placed on the patient and/or the patient’s immobili- zation device. This enables the planning computer to localize any point within the patient on a 3D grid.
Target volumes and normal tissue are then outlined on CT images for treatment planning. For gross tumor, the clinician outlines this gross tumor volume (GTV). When warranted, microscopic targets can be added to the GTV (i.e., to include draining lymphat- ics at high risk for harboring micrometastatic dis- ease). This combination of GTV with microscopic targets is referred to as the clinical target volume (CTV). If there is no gross tumor present (e.g., after
Fig. 23.11. Multi-segment intensity modulated (IMRT) treat- ment. Note dramatic dose fall off of dose (red to green) to sur- rounding structures and homogeneous dose distribution (red volume) to the bladder. (Courtesy of East Carolina University Department of Radiation Oncology)
Fig. 23.10. Five-fi eld 3D conformal treatment plan. Excellent bladder coverage with minimal rectal dosing. (Courtesy of East Carolina University Department of Radiation Oncology)
complete TURBT), previously obtained tumor map- ping obtained prior to TURBT should be consulted.
In cases with no gross tumor present, only a CTV may be applicable. An advantage of IMRT is that multiple GTVs and subclinical target volumes can be out- lined. This allows the clinician to treat each volume with a different daily dose. For the actual treatment, an additional margin may be added to the CTV to allow for variations in organ motion [the internal target volume (ITV)] and in patient set-up [the plan- ning target volume (PTV)]. The next step is to spec- ify the desired dose to the targets and dose limiting normal tissues and organs. There are several meth- ods to accomplish this. One method is to specify a maximal dose limit to the tumor and normal critical structures. Each structure is then assigned a relative weighting that identifies to the planning system the relative importance of the structure. Typically, the tumor volume receives the highest weighting, but a critical structure may supersede this if the toxicity to that organ would be inadmissible, such as bowel perforation or myelopathy. At the State University of New York, Health Science at Brooklyn (SUNY- HSCB), a typical weighting would be rectum/colon 6000 cGy maximal dose with a weighting of 0.8–1.0, small bowel 4500 cGy maximal dose with a weight- ing of 1–1.2, and GTV 6500 cGy minimal dose with a weighting of 2.
Another method of defining dose criteria is to incorporate dose–volume constraints to each struc- ture. The idea here is that structure injury in most organs is a function of dose received by a certain volume of the structure. These numbers are being defined empirically based on experience of observed side effects and tumor complete response rates in treated patients.
Planned treatment volumes should take into account organ motion in the ITV. This can be accom- plished by ultrasound-guided target volume identifi- cation or portal image guided set-up with implanted fiducial insertions. Newer linacs may combine kilo and/or megavoltage CT scanners to allow for image- guided radiation therapy (IGRT). This will allow for treatment modification in real time with improved targeting accuracy as well as conformal avoidance of normal tissue.
Given the above considerations, particularly those of organ motion and the need for image-guided ther- apy during actual treatment, it will likely be several more years before IMRT is used as the standard in the treatment of bladder cancer. At the time of this writing, there is only one report in the literature on IMRT being used in the treatment of bladder cancer
(Budgell et al. 2001). In this series, a standard field arrangement and set-up were employed to achieve a somewhat homogeneous dose within the same treatment volume, with some additional sparing of normal tissue compared with that expected with 3- D conformal CT planning.
We also expect advances to be made with the suc- cessful incorporation of newer chemotherapeutic radiosensitizers into bladder preservation paradigms.
As pointed out by Rodel et al. (2005) gemcitabine and paclitaxel are both potent radiosensitizers that have shown significant activity against urothelial tumors.
The Radiation Therapy Oncology Group (RTOG 99- 06) is conducting a trial using twice-daily radiation therapy with concomitant paclitaxel and cisplatin followed by either selective bladder preservation or radical cystectomy and adjuvant chemotherapy with gemcitabine and cisplatin. Mention is also made that the “future aspects of radiosensitization” may “relate to the potential inhibition of oncogene products frequently activated and overexpressed in bladder cancer, such as H-ras and c-erbB-1.” “Inhibition of EGF receptor activity with small molecule tyrosine kinase inhibitors or antibodies against receptors may also increase tumor radiosensitization in blad- der cancer” (Rodel et al. 2005).
Finally, proper use of molecular markers are likely to be of more help in the future as bladder cancer is one malignancy with “extensive informa- tion regarding molecular pathogenesis and genetic predictors of natural history as well as response to various modalities of treatment based on molecu- lar profiles” (from Rodel et al. 2005; Hussain and James 2005). In these reviews the authors stress the need to investigate the use of these molecular prog- nostic markers, such as p53, bcl-2, bax, Rb, and p21, to predict sensitivity to chemotherapy, radiotherapy, and overall survival in randomized trials, pointing out that it may ultimately become possible to per- form chemo/radiosensitivity testing similar to that used for antibiotics (Rodel et al. 2005).
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