Abstract
Background/Aim: Secure dose escalation is required to compensate avoidance of concurrent chemotherapy in radiotherapy for increasing elderly bladder cancer. We aimed to evaluate the efficacy of lipiodol submucosally injected as a fiducial marker during image-guided radiotherapy (Lip-IGRT) for muscle invasive bladder cancer (BC). Patients and Methods: Twenty-three patients with T2a-4aN0-1M0 BC underwent whole-bladder irradiation of 46 Gy and Lip-IGRT of 20 Gy, conventionally. The bladder volume exposed to 19 Gy (bV19:%) on Lip-IGRT was referred as an index predicting cystitis. Results: Lipiodol consistently highlighted the boundaries of 20 tumors (88%) on planning and portal verification images. Three of 4 patients under oral anticoagulant agents usage were complicated with grade ≥2 hematuria for 3 days (a patient with a bV19 of >50%) or more than a year (2 patients with bV19 of <50%) after the injection. The 3-year overall survival and disease-free survival rates were 70.4% and 71.1%, respectively. Conclusion: Lipiodol marking is an effective way of demarcating BC. However, it is necessary to address the comorbidities of elderly patients.
Cancer mainly affects the elderly, and Japan has an aging society (1). In addition, the annual incidence of bladder cancer (BC) has also increased in recent years (2). At the time of diagnosis, approximately 25% of BC patients present with muscle-invasive bladder cancer (MIBC) (3). Although cystectomy is the standard treatment for MIBC, elderly patients are less likely to undergo radical cystectomy (4). Bladder-sparing protocols, such as a combination of chemotherapy and external-beam radiotherapy (EBRT) after the transurethral resection (5, 6) or biopsying (7) of BC, have emerged as valid treatment options for MIBC patients who are unsuitable for, or unwilling to undergo radical surgery. However, chemotherapy is frequently contraindicated for elderly patients, which leaves radiotherapy as the only possible treatment (8, 9), but it has relatively unfavorable outcomes. Under these circumstances, dose escalation can be used to improve the efficacy of radiotherapy against BC.
Whole-bladder irradiation (WBI), involving fractions of 1.8-3 Gy up to a total dose of 40-50 Gy, was reported to result in a median survival period of 10 months and 1- and 3-year survival rates of 51.4% and 34.3%, respectively (10). As administering WBI at an excessive dose can induce radiation cystitis (11, 12), dose escalation should be limited to the dose delivered to the tumor-bearing region of the bladder alone (i.e., partial bladder irradiation [PBI]) in order to improve local control without increasing the risk/severity of toxicities (13). However, this was difficult to achieve until the introduction of image-guided radiotherapy (IGRT), which counteracts the inevitable daily shifts in the positions of bladder tumors using on-board cone beam computed tomography (CBCT). To spare the healthy bladder from radiation exposure as much as possible, attempts have been made to reduce the target volume by placing fiducial markers, such as lipiodol, around the tumor's borders (14, 15).
In cases involving extensive BC, PBI does not always reduce the radiation dose delivered to the healthy bladder enough to prevent late adverse events (AE). In two recent reports about definitive radiotherapy for BC, in which image-guided hypo-fractionated intensity-modulated radiotherapy was used to spare healthy bladder tissue from full-dose irradiation, grade ≥2 late urogenital (GU) AE occurred in 14% and 18% of cases, respectively (16, 17). The QUANTEC review suggested that the bladder volume exposed to ≥65 Gy should be <50%, in order to avoid late grade ≥3 toxicities after conformal radiotherapy (CRT) (18). Thus, the parameters obtained by dose-volume histogram (DVH) analyses might be useful for predicting the efficacy of PBI in terms of organ preservation. We conducted a prospective cohort study involving patients who were unfit for cystectomy or whose age prohibited definitive chemoradiotherapy in order to ascertain the safety and efficacy of lipiodol marking of MIBC during IGRT.
Materials and Methods
This prospective cohort study was approved by the institutional review board of Iwate Medical University Hospital in November 2011 (H23-031). All patients were greater than 20 years old and had European Cooperative Oncology Group (ECOG) performance statuses of 0-2 and MIBC. They were treated with definitive radiotherapy instead of cystectomy because of their age, medical comorbidities, or unwillingness to undergo surgery.
Initial radiotherapy. The EBRT system was composed of a CT scanner (Aquilion; Toshiba, Tokyo, Japan), a treatment planning system (Eclipse version 8.0; Varian Medical Systems, CA, USA), and a linear accelerator (Clinac 2100C; Varian Medical Systems, CA, USA). The patients were instructed to empty their bladders before the CRT, which was delivered to the whole bladder. The clinical target volume (CTV) was defined as the whole bladder, and the planning target volume (PTV) was defined by adding 1.5-cm margins to the CTV in all directions. For the patients with clinically positive or suspected lymph node metastases, the small pelvic lymph node area was also included. The CRT was delivered with 10-MV photons using a rectangular 4-field technique at a dose of 2.0 Gy per fraction, for 5 fractions per week, up to a total dose of 46 Gy.
Lipiodol injection. During the last week of the initial round of radiotherapy, the patients underwent cystoscopy with a 22 French rigid cystoscope. Using a 23-gauge Chiba-tip needle with a retractable, flexible sheath (a Williams cystoscopic injection needle; Cook Medical, Inc., Bloomington, IN, USA), which was inserted through the working canal into the tip of the cystoscope, the bladder mucosa was punctured, and lipiodol (Guerbet Japan LLC, Tokyo) was injected into the submucosal space. The lipiodol (0.25-0.5 ml per injection) was injected 2-3 mm from the tumor margins along the periphery of the tumor bed over 4-8 separate injections.
PBI. In the cases in which the bladder wall had been successfully circumscribed by lipiodol dots (the LP-guided group), the bladder wall formed the CTV on the second set of planning CT images, which were obtained with a full bladder. In the other cases; i.e., those in which the injections failed to produce lipiodol dots (the ST-guided group), the CTV was delineated by soft tissue demarcation. The CTV was expanded by 1 cm to produce the PTV. The IGRT boost was performed using a treatment system including a linear accelerator (Clinac iX; Varian Medical Systems, CA, USA) and an auto-positioning system (ExacTrac 6D; BrainLAB AG, Feldkirchen, Germany). After the patient set up, bony anatomy matching was conducted by registering the digitally reconstructed radiograph from the CT simulation image, and a radiograph was obtained with the positioning system in the translational (lateral, longitudinal, and vertical) and rotational (pitch, roll, and yaw) dimensions. Then, fiducial marker matching based on the lipiodol dots was conducted using CBCT with a resolution of 512×512 and a slice thickness of 2.0 mm. The portal outline was projected onto the CBCT images to ascertain whether it included the lipiodol dots along the bladder wall. Radiation was delivered in 10-MV photons (20 Gy over 10 fractions) through 3 or 4 portals, which were angled to spare the healthy bladder wall as much as possible.
DVH analysis. To quantify the ability of PBI to spare the healthy bladder from full-dose radiation exposure, a PBI DVH for the bladder was plotted for each patient. The percentage of the bladder volume that was exposed to 19 Gy (bV19) during the PBI was presumed to be equivalent to the percentage of the bladder volume that was exposed to a combined dose of 65 Gy during the WBI and PBI (the bV65), and a bV65 of ≥50% was previously reported to be useful for predicting late grade ≥2 bladder toxicities (18). The mean bV19 was compared between the LP- and ST-guided methodologies in order to quantify the utility of lipiodol marking for sparing the healthy bladder wall. The correlation between the size of the gross tumor volume (GTV) and bV19 was assessed to clarify the extent to which the sparing effect was influenced by tumor size.
Outcome assessment. The Common Terminology Criteria for Adverse Events, version 4.0, grading system was used to evaluate the severity of GU or gastrointestinal toxicities. Toxicities that occurred during or within the first 3 months after the radiotherapy were classified as acute AE, and those that occurred at ≥3 months after the radiotherapy were categorized as late AE. The initial effects of the radiotherapy on the bladder tumors were classified according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival (OS) and disease-free survival (DFS) rates were calculated based on the intervals between the initiation of radiotherapy and specific events using the Kaplan–Meier method. The statistical software SPSS, version 15.0J (SPSS Japan, Tokyo, Japan), was used for all statistical analyses. p-Values of <0.05 were regarded as significant.
Results
A total of 23 patients (21 males and 2 females) met the treatment protocol eligibility criteria. Their mean age was 78.8 years (range=62-88 years). Except in one case of adenocarcinoma, all of the patients had clinical T2a-4aN0-1M0 stage II-IV urothelial carcinoma. Metastasis was only found in the pelvic lymph nodes. The ECOG PS was 0, 1, and 2 in 10, 11, and 2 cases, respectively. More than half of the subjects (60.9%) had one or more comorbidities, such as diabetes mellitus (n=7), arrhythmia (n=5), cerebral infarction (n=2), myocardial infarction (n=1), or heart valve disease (n=1). Four of them were regularly taking oral anticoagulant agents (the OAC-pt). Six patients (26%) had a history of curative cancer treatment for prostate cancer (n=2), gastric cancer (n=2), renal cell carcinoma (n=1), or colon cancer (n=1). Chemotherapy was performed in 5 patients using a combination of cisplatin (CDDP) and docetaxel, either prior to radiotherapy (n=2) or concurrently (n=3).
Visibility of lipiodol dots on planning CT and delineation. The injection of lipiodol failed to provide fiducial markers on IGRT in 3 cases. This was due to a lack of any radiopaque dots on the bladder wall in 2 patients and the excessive spread of lipiodol into the region outside the bladder (far beyond the BC site) in another patient. These 3 failures occurred in the first half of the study. In the other 20 patients (87%), lipiodol dots were visible on the planning CT images (Figure 1A) and on CBCT (Figure 1B) throughout the course of the IGRT.
Planning target volume (PTV) outline of image-guided radiotherapy boost in a patient on simulation (A) and treatment (B). A: A planning CT image showed that PTV encompassed lipiodol dot-containing bladder wall. B: A cone-beam CT image at the level correspondent to A confirmed the area included within the superimposed PTV outline.
Toxicities. Half of the patients suffered grade 1 AE, such as pollakisuria with urgency or retention, or micturition pain. Grade ≥2 pollakisuria and micturition pain occurred in 3 and 2 patients, respectively. An OAC-pt who developed massive hematuria at 3 days after the injection of lipiodol required a blood transfusion and continuous irrigation of the bladder. During the follow-up period after radiotherapy (median duration: 37 (range=22-65) months), 3 patients developed grade 2 hematuria, and pelvic bone fractures and bloody stools occurred in one patient each. Two of the 3 patients that were complicated with ≥grade 2 hematuria were OAC-pt. None of the patients developed grade ≥4 AE.
DVH analysis. The mean cumulative bladder radiation dose gradually declined from 100% to 5% and then curved upward (Figure 2). The mean bV19 value of the LP-guided therapy group was slightly less than 50% (44.9±20.7%), although 12 patients had bV19 values of >50%. The mean bV19 value of the ST-guided therapy group was 60.7±6.2%, and there was no significant difference between the mean bV19 values of the two groups. The bV19 values of the two OAC-pt that experienced grade 2 hematuria were 26.6% and 29.0%, respectively, whereas that of the other patient that experienced grade 2 hematuria, who was not administered any OAC, was 59%. The bV19 value of the OAC-pt who developed hematuria immediately after the injection of lipiodol was 61.3% (Figure 3).
The mean bV19 (and 95% confidence intervals) during the IGRT boost according to the radiation dose on bladder DVH.
Response of BC. The initial response was evaluated as a complete response (CR: 4), partial response (PR: 17), or stable disease (SD: 4). BC recurred after a mean interval of 22.3 months after therapy as BC alone (n=6), BC with bone metastasis (n=1), pelvic lymph node and bone metastasis (n=1), or distant organ metastasis alone (n=1). The sites of BC recurrence were usually identical to the primary sites. During the follow-up period (mean duration: 30 months), 8 patients died due to BC, and 2 patients died of hepatocellular carcinoma and malignant lymphoma, respectively. The 3-year OS rate was 70.4%, and the DFS rate was 71.1%.
Distributions of the bV19 values of the OAC-pt and the other patients. The black circle indicates the patient with acute grade 3 hematuria, and the gray circle indicates those with late grade 2 hematuria.
Discussion
Among the 23 cases examined in this study, cystoscopic lipiodol injection failed to produce informative radiopaque dots around the bladder tumor in 3 of the first 11 cases, which is indicative of the learning curve for this technique. However, in the subsequent cases the accurate injection of a small amount of lipiodol into the submucosal space provided consistent information on the localization of BC during CRT planning and daily CBCT assurance throughout IGRT. Reliable tumor bed demarcation on planning CT without fiducial markers was challenging and tended to result in overestimates of the size of the bladder tumor, although this could not be statistically verified due to the small size of this study. Pos et al. (14) reported that the borders highlighted by lipiodol spots sometimes differed from the margins that radiation oncologists would have contoured based on cystoscopy reports and CT scans without lipiodol.
Three of the 4 OAC-pt included in this study were complicated with grade ≥2 hematuria (as an acute AE in a patient with a high bV19 value and as late AE in 2 patients with low bV19 values). This suggests that there is a close correlation between concomitant treatment with OAC and hematuria of moderate severity during IGRT. By the time it was punctured by the injection needle, the bladder mucosa had already been damaged by WBI involving nearly 40 Gy. At this point, the bladder mucosa might have been so fragile that wound healing to restore mucosal integrity and immediately achieving hemostasis after the injection were impossible. As 2 OAC-pt developed hematuria in spite of their low bV19 values, the temporary withdrawal of OAC before IGRT did not prevent the development of hematuria as a late AE. Conversely, the injection of lipiodol just before the PBI boost stabilized the lipiodol dots for a short period, whereas a 24% reduction in lipiodol visibility (15) or a gradual loss of lipiodol spot volume (“washout”) (14) were seen during 6-week courses of radiotherapy in previous studies. Another advantage of our technique is that it shows the tumor shrinkage induced by WBI, which allows the dose delivered to the healthy bladder wall to be reduced. Elderly patients frequently have cardiac comorbidities and so often need to take OAC, which can significantly affect the outcomes of radiotherapy. For patients that are taking OAC, the interval between lipiodol marking and WBI should be sufficient to allow an undisturbed healing process.
In cases involving large bladder tumors, PBI boosts after WBI do not necessarily reduce the radiation dose delivered to the bladder sufficiently to prevent late GU AE. Our treatment protocol had a limited sparing effect, as half of the patients were exposed to radiation levels above the bV19 <50% constraint, which might have contributed to the relatively high frequencies of late GU AE. Various studies have examined bladder motion and made recommendations regarding the tumor bed margins for PBI boost protocols. Several groups (19, 20) have suggested that a 20-25-mm margin should be added around the tumor bed for PBI boost treatment. In contrast, Sondergaard et al. (15) indicated that only a 10-15-mm tumor bed margin is required to accurately define the target for a PBI boost when lipiodol is used to help indicate the extent and location of the tumor bed. Furthermore, van Rooijen et al. (21) recommended that only a 5-mm tumor bed margin is necessary for PBI boost treatment when lipiodol is used. Therefore, it might be possible to reduce the PTV margins from 10 mm to 5 mm, in order to satisfy the abovementioned dose constraint.
As this study included a small number of patients with various backgrounds, it is difficult to compare the tumor control rates obtained in this study with those described in the literature. Although our OS and DFS rates were comparable with those reported by others, the CR rate was relatively low, and locoregional recurrence was predominant in this series. This suggests that there is room for further modification of our IGRT protocol in order to improve primary bladder tumor control. As PBI after WBI does not spare the healthy bladder enough to allow further dose escalation, another strategy should be introduced, such as shortening the overall treatment time or combining IGRT with tolerable chemotherapy.
Conclusion
Lipiodol marking is an effective way of facilitating the demarcation of BC. However, it is necessary to deal with elderly patients' comorbidities or alter the radiotherapy strategy to achieve better outcomes.
- Received May 18, 2018.
- Revision received June 9, 2018.
- Accepted June 14, 2018.
- Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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