| 1.Introduction.Source:Bladder cancer is the 9th most common cancer worldwide,with an annual incidence of 430,000 cases.It is ranked 13th in terms of cancer-related mortality and affects up to six times as many men as women.It is largely a disease of industrialized nations,and the age-standardized incidence is 3 times higher in developed countries compared to developing countries.Muscle-invasive bladder carcinoma(MIBC)accounts for 25%of all BCs.The most common bladder-preserving techniques are transurethral resection with AJ radiotherapy(RT),chemotherapy(CHT),and definitive chemoradiation.However,a challenge with RT is that it may endanger healthy tissue.In BC,RT is complicated by inter-and intrafraction target motion,which can vary up to 3 cm and is dependent on the location of the tumor in the bladder.Complete bladder treatment and large planning target volume margins,ranging from 15-20 mm,are used as a precaution for the target motion as the standard of care.Target visualization is critical in guided RT and is more challenging in partial bladder RT.Fiducial markers such as gold seeds and Lipiodol are used to improve visualization of the target area.However,both these markers may be lost or may move with time.For example,for Lipiodol this ranged from 5-24%of markers by the final RT session,and for the gold seeds this ranged up to 25%.Furthermore,one study reported that gold seeds are difficult to implant in the dome of the bladder,and another study found that Lipiodol was difficult to inject close to the bladder neck.This led to a new thought what if the target is clear and the area subjected to the RT is smaller which will result in lesser damage and would eventually even help in curing the cause.While the fiducial markers are not new in medicine,the use of fiducial markers in urology is not easy,so the thoughts were driven to a direction to find something which can help in the guidance of the precision RT,eventually,the voices named endoclip as the possible candidate for the use as a novel fiducial marker.The first use in urology was seen with great success and the follow-up presentation of the marker also encouraged its use,so the use was widened to include more patients.To assess the feasibility,cost-effectiveness,and reliability of endoclips as novel fiducial markers in precision RT,as part of a TMT bladder-preserving treatment of MIBC.Which will produce more reliable results?Theoretical significance:There are no reports on the use of endoclips as fiducial markers in precision RT of MIBC.In this retrospective study,we aimed to assess the feasibility and reliability of endoclips as novel fiducial markers for aid in precision RT after resection of MIBC.If the marker is applied successfully the visualization of the marker on the radio imaging will make it even clearer for the therapist to target the affected area,thus increasing the delivered dose to that area and improving the cure outcome.Because cure is the desired goal in cancer surgery,a complete resection of the tumor is crucial.Patients with positive or close tumor resection margins show a significantly poorersurgical outcome.It is becoming more and more common to send frozen section biopsies for analysis intraoperatively.The method of labeling these biopsies is language-dependent and individual to the surgeon.The processing pathologist receives a specimen and a label with a minimal idea of its orientation.From this,a simple response of "positive" or "negative" is sought.If a positive result is returned,it falls upon the memory of the surgeon to locate precisely where the sample was obtained,ultimately affecting the final resection margin.When collecting frozen sections,the site of the biopsy could be marked and mapped by the navigation probe,and this precise localization data stored.The labeled frozen sections and the dataset with coordinates could then be transmitted to the pathologist who can color code the positive and negative results on the virtual image.These can then be incorporated into the treatment software.This ultimately improves the communication between the surgeon and the pathologist.Also,the tumor resection margins could be marked with the navigation pointer to allow a precise delineation of the reconstruction volume.Application value:As with the currently used fiducial markers,the novel endoclip markers provided accurate target positioning.The application of the endoclips was achieved by using a rigid cystoscope.We have not yet been able to apply these markers by using a flexible cystoscope.To our knowledge,there are no contraindications for endoclip application after transurethral resection of bladder tumor.It can be used freely and the results are promising.It is readily available in hospitals and the cost is minimum.The required training process is minimal.Innovation:The use of fiducial markers is an innovative idea in the field of urology.By using the endoclip as a fiducial marker we were able to accurately target the tumor area and provide precision RT.The idea is very innovative and it can be used easily.As the gold seeds and Lipiodol are not readily available in some countries so having an alternative was always a question,by coming up with this idea it is very much beneficial that we can use a new innovative approach to create an opportunity for the radiation oncologists for precision in radiation delivery and increase the recurrence-free survival and overall survival rate in patients.The inadequacies of the dissertation:Our patient sample size is small,and we did not have a control group.One of our patients died from metastatic cancer of unknown origin possibly of the bladder.Larger studies of patients with a range of clinical stages are needed to compare endoclips with currently used fiducial markers for their help in oncologic outcomes.2.Background:BC is the seventh most common malignancy in the western world.It is about three to four times more common in men than in women.In the past decade,it was the fourth most common cancer in men and the thirteenth most common in women.The new number of cases diagnosed reached more than 400,000 with BC per year and the mortality was very high too.The vast majority of the cases were above 60 years of age.There are many risk factors in the development of the BC,while aging,smoking,and exposure to the industrial chemicals were the presumed major risks.BC is diagnosed when there is a systematic approach to hematuria,nonetheless,emergency presentation of the bladder problem is the common type,which unfortunately is often associated with the poor prognosis.While most of the BCs are non-Muscle invasive Bladder carcinomas(NMIBC)and are usually treated by the cystoscopic removal of cancer also known as the Transurethral Resection of the Bladder Tumor(TURBT),this represents about 75-8-%of the cases.This is followed by the instillation of the CHT or vaccine type treatment into the cyst.This is then followed by the regular cystoscopic follow-up to monitor the condition and response.While there are patients who are high risk,they are treated with radical cystectomy(RC).The patients with muscle-invasive bladder carcinoma(MIBC)are treated with the goal of a cure.The CHT,RT,and surgery are combined to achieve optimal outcomes.While the advanced stage cancer is dealt with palliatively using chemoRT.It is noteworthy that the involvement of the urogenital tract and the nature of the treatment gives this cancer a very strong psychological impact which is in addition to the physical impact of cancer and the therapies,often profound.The BC prevalence and the nature of the management make it a costly presentation.The diagnosis and the management of the BC are thought to be of considerable variation and provision of care among the people,who have it.The MIBC is offered a choice of RC or RT with a radiosensitizer to the patients with MIBC.The treatment is based on a full explanation to the patient and the suitable option which is agreed upon.The RC has long been the standard of care for the management of the MIBC.The results of modern RC have shown the results of 5-year overall survival around 56-66%.The literature has documented the morbidity and the mortality rates of RC.The organ-preserving therapies in the management of the cancer are on an increasing trend.there are suggestions from several studies that Tri-modality therapy(TMT)of BC generates favorable results,that in well-selected patients.The use of targeted RT has been the trend of AJ therapy.The use of fiducial markers for aid in targeted RT has shown good results.But those are not free of hurdles,the direction of our research was in the use of a novel fiducial marker.In Western countries,MIBC disease accounts for about one-fourth of newly diagnosed urothelial BC cases and approximately 10-30%of NMIBC that have progressed.Nearly half of patients with MIBC will relapse despite intensive therapies,eventually succumbing to their disease.Approximately,three-fourths of these patients relapse with distant failure,with the remaining one-fourth experiencing a local recurrence.Besides,somewhere between 5%and 15%of patients present with unresectable or metastatic disease at the time of diagnosis.When possible,for all patients with primary or secondary metastatic cancer,systemic platinum-based combination CHT is the standard treatment resulting in initial response rates of 40-70%,but the long-term survival of less than 15%within 5 yr In addition to the unfavorable response to systemic therapy,nearly half of patients are already unfit for this regimen due to renal and other comorbid conditions.Surgical extirpation of the primary or metastases is part of a multimodal approach in various malignancies yielding potentially better survival and/or quality of life.This concept is increasingly being considered in urology from accepted entities such as testis and kidney cancers to more recently,prostate cancer.Nevertheless,the role of surgery in metastatic urothelial carcinoma is not yet established with most of the experience being accrued from retrospective uncontrolled studies.No pertinent prospective randomized trials have been published on this topic.Therefore,there is a need to better delineate the evidence-based potential oncological benefit of surgical extirpation of the primary in the metastatic setting and of metastasectomy.Metastatic BC is still a lethal disease with little improvement in outcomes since the introduction of cisplatin-based combination.Cumulative but still limited evidence suggests a role for surgery and/or other consolidation therapies in managing a subgroup of patients with metastatic BC as an integral part of the sequenced multidisciplinary approach.Results are consistently pointing toward improved survival in patients with low volume disease after measurable response to targeted therapy in the lung,pelvic,and retroperitoneal lymph node(LN)metastases.Evidence shows that surgical resection is technically feasible with acceptable morbidity and can achieve long-term cancer control in well-selected patients.Further evidence is needed to identify the role of surgery in patients with metastatic BC,specifically in the era of immunotherapeutic that is upon us.3.Purpose:The use of the novel fiducial markers in the field of urology has seen good results,but those markers are associated with the problems.The fiducial markers in use are Gold seeds and Lipiodol.Whereas there are reported cases of the loss of gold seeds and the movement of the marker which are sometimes not seen on the imaging.While Lipiodol tends to move and form nonuniform borders which can be a hurdle in targeting the area for RT.Our purpose was to introduce a novel fiducial marker that is reliable,consistent,and increases the aimed success in targeted RT.The aim was to use a cost-effective method that would be easy to reproduce.The aim was to find a fiducial marker that would help guide the treatment and would be readily available.There won’t be side-effects and can be used with a simple setup to help the surgeons use it in any setup from basic to very advanced hospital setting.Whereas having the optimal visibility on the imaging modalities to help in guiding and planning the targeted RT.Keeping in mind that their use,application,reproduction,and the learning curve is simple.Image-guided RT is an essential tool in the accurate delivery of modern RT techniques.The RT positioned using skin marks or bony anatomy may be adequate for delivering a relatively homogeneous whole-pelvic RT dose,but these surrogates are not reliable when using reduced margins,dose-escalation,or hypofractionated stereotactic RT.Fiducial markers for image-guided radiotherapy have been in use since the 1990s.They require surgical implantation and provide a surrogate for the position for the target.A variety of fiducial markers are available and they can be used in several ways.This study aimed to establish the evidence for using novel fiducial markers in terms of feasibility,implantation procedures,types of fiducial markers used,fiducial marker migration,imaging modalities used,and the clinical impact of the fiducial marker.The evidence demonstrates that the fiducial marker provides a more accurate surrogate for the position of the RT.A combination of fiducial markers alignment and soft tissue analysis is currently the most effective and widely available approach to ensuring accuracy in image-guided RT.The fiducial marker implantation is safe and well-tolerated.The fiducial marker migration is possible but zero in our theory.Standardization of all techniques and procedures concerning the use of fiducial markers is required.4.Methods:This retrospective study was performed in our hospital.Between January 2015 to June 2018.15 patients underwent bladder preserving TMT TURBT of the MIBC.All the patients were diagnosed with MIBC after a comprehensive tumor study on computed tomography,magnetic resonance imaging,and electronic cystoscopy.The study was approved by the ethics committee of our hospital.Informed written consent was obtained from all patients or their guardians.Currently,there are two common preferred approach directions for T2N0M0 stage MIBC;RC or bladder preserving TMT approaches.Whereas the bladder preserving TMT approach is more common.In this study,we focused on the bladder preserving TMT approach.The patient was placed in supine,adjusted to a lithotomy position under spinal anesthesia.After preparation and draping the rigid cystoscope was inserted through the urethra to inspect the bladder.The location of the tumor was identified,the surrounding wall and related structures were carefully inspected and the resection was planned with standard healthy margins.After visual resection,the endoclip applicator was introduced through the operating channel of the cystoscope and the endoclips were applied 2-5 in number on the healthy margins of the bladder wall to delineate the target area for the targeted RT.After the successful application of the novel fiducial markers,the cystoscopy was performed to confirm the attachment of the novel fiducial markers to the wall of the bladder.Then cystoscope was removed and a three-way Foley’s catheter(18Fr)was placed for continuous saline flushing.Once there was no hematuria,the catheter was removed after bladder training and the patient was discharged.All patients underwent radio sensitizing CHT 3 weeks after the TURBT.The CHT regimen Gemcitabine lgram/m2 and Cisplatin 70miligrams/m2 was used in all patients.The image-guided RT was initiated one month after the TURBT.The protocol used was 5600～5800 centi-gray to the tumor site and 4500～5000 centi-gray to the whole bladder along with systemic CHT.The intravesical infusion of the CHT was initiated within 24 hours after surgery,then once a week for 8 consecutive weeks and then once a month for a total duration of 1 year.The follow-up was planned via electronic cystoscopy.This was performed once every 3 months for 4 consecutive times during the first year after the procedure.After completion of a yearlong AJ chemoRT,the endoclips were removed on the follow-up cystoscopy.Those who had recurrence during the follow-up were offered the salvage RC.Any procedure-related complications,such as loss or migration of the fiducial markers,recurrence of the tumor,and all-cause death were recorded and analyzed.5.Results:All patients underwent successful comprehensive resection of the tumor.It was completely resected in all patients.All the patients were in the clinical stage of T2N0M0.For all the patients a total of 49 fiducial markers were applied,ranging from 2-5 endoclips.There were no lost fiducial markers.There were no lost fiducial markers.There was no shift of the fiducial markers.The fiducial markers remained the same after the end of the last planned session of the targeted RT in all patients.All the fiducial markers were removed from the patients successfully.The mean number of follow-up months was 38.9±13.2.It ranged trom 11-52.The mean age was 67±10 and ranged from 46-79.There were 3 females and 12 males.The carcinoma in situ was in all patients.5 patients smoked.All the smokers were males.Two patients had recurrence at 10 months and 18 months post-surgery and salvage RC was performed in both patients.One patient died of cancer cachexia 9 months after completion of therapy,the CT showed retroperitoneal metastasis,but no new tumor in the bladder was seen.No autopsy was performed and the source of the tumor could not be determined but it is very much likely that the tumor was of bladder origin.At one year after surgery and completion of AJ treatment,the recurrence-free survival rate was 93.3%and the overall survival rate was 100%.6.Conclusions:Our data show that clinical stage T2 patients of MIBC show a low recurrence rate and high survival rate after TMT bladder preserving therapy.The use of novel fiducial markers is safe,cost-effective,and consistent,which makes the precision RT more effective and accurate.For selected patients of MIBC,the TMT bladder preserving therapy is an optimal choice with promising results. |
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