Monday, September 14, 2015

Blue Light Cystoscopy for Bladder Cancer

Bladder cancer is the fourth leading cause of cancer death in males and the most common site of cancer in the urinary system. An estimated 74,000 new cases of bladder cancer are expected to be diagnosed in the USA in 2015 and 16,000 deaths are estimated[1]. Non-muscle-invasive bladder cancer (NMIBC) has a high rate of recurrence and also a risk of progression that requires patients to undergo regular monitoring with cystoscopy after transurethral resection of the bladder tumor (TURBT). Current standard of care uses white-light cystoscopy (WLC) to map and resect all visible tumors. This blog will give an overview of the use of fluorescent cystoscopy in the management of NMIBC and review the evidence for its use.

Product Overview

Blue-light cystoscopy (BLC), also referred to as fluorescent cystoscopy or photodynamic diagnosis (PDD), is a procedure in which a photosensitizer medication is instilled in the bladder prior to cystoscopy. This photosensitizer is part of the heme biosynthesis pathway (that makes red blood cells) and causes an accumulation of photoactive porphyrins in neoplastic cells. These porphyrins preferentially accumulate in neoplastic cells due to the increased metabolic activity in these cells. When excited with blue-light in the 360-450 nm wavelength, the porphyrins emit a red light that can easily be seen during cystoscopy (Figure 1). There are two main photosensitizers that have been used in studies looking at fluorescent cystoscopy: 5-aminolevulinic acid (5-ALA) and hexaminolevulinate (HAL). HAL is the only photosensitizer that has been approved for use in the USA and Europe. In the USA it is marketed under the brand name Cysview, and in Europe under the brand name Hexvix.
Figure 1. 63 year old female with prior TURBT+BCG now with recurrence. (a) WLC of a prior resection site near a ureteral orifice. (b) Same site using BLC. Tumor was found to be high grade T1. (c) WLC showing an area of CIS that was missed upon repeat resection. (d) Same site using BLC.
From: Daneshmand, et al.[2]

Increased Tumor Detection

Most studies are in agreement that more tumors are found when using BLC compared to WLC alone. Perhaps the best evidence for this is a meta-analysis published in 2013 which looked at the raw data from 6 prospective studies including a total of over 800 patients[3]. This meta-analysis found that a significant proportion of tumors were missed by WLC alone. In fact, an additional 14.7% of Ta tumors were detected with BLC, 10.8% of T1 tumors, and 40.8% of CIS (carcinoma in situ or flat tumors) (Figure 2). Another meta-analysis by Shen et al4. failed to show a statistically significant difference in tumor detection rates between BLC and WLC, however this study was limited by the inclusion of a large number of studies which used the photosensitizer 5-ALA, which is not FDA approved and has been shown to have less fluorescent properties than HAL.

Figure 2. Increased detection of tumors using BLC alone when compared to WLC alone.
From: Burger, et al.[3]

Recurrence Free Survival

While the data on increased detection are consistent, data on recurrence-free survival (RFS) are less clear-cut. Cysview gained FDA approval following a study by Stenzl et al5. published in 2010. This study was a prospective, randomized, multi-center study that looked at 551 patients with suspected Ta or T1 disease and were randomized to either WLC or WLC+BLC. During the 9-month surveillance period, 47% of patients in the BLC group and 56% of patients in the WLC group had tumor recurrences for a relative reduction of 16%. Interestingly, the following year Stenzl published another paper which randomized patients to either 5-ALA or placebo which failed to show a difference in recurrence-free survival 12 months after tumor resection6. However, as previously mentioned, this study used 5-ALA which is not the FDA approved photosensitizer.

The study with the longest follow-up data is actually an extension to the original Stenzl study used for FDA approval. This study was published in 2012 by Grossman et al7. and showed that with a median follow-up for 53.0 months (WLC group) and 55.1 months (BLC group), 38% of the patients in the BLC group remained tumor free vs. 31.8% in the WLC group. The median time to recurrence was 16.4 months in the BLC group and 9.4 months in the WLC group. This study also looked at progression-free survival and cystectomy rates but was unable to show a statistical difference between the two groups, possibly due to the original study not being powered to look at differences in these outcomes.

Figure 3 summarizes additional studies that have looked at recurrence-free survival for BLC vs. WLC.

Figure 3. Summary of studies that have looked at recurrence-free survival for BLC vs. WLC.


Cost

Bladder cancer is one of the mostly costly cancers to treat on a per capita basis. Lifetime per capita costs have been estimated between $96,000 and $187,000 (2001 US dollars)8. Multiple analyses have looked at whether using BLC could reduce cost for bladder cancer treatments using the assumption that if a patient has a longer recurrence-free survival, they may require fewer or perhaps less frequent TURBTs. Garfield et al9. used a probabilistic decision-tree model and estimated that over 5 years, approximately $4,600 could be saved per patient by using BLC during diagnostic cystoscopy (excluding the cost of the equipment).

Indications

The current AUA guidelines for bladder cancer were written in 2007, 3 years before Cysview was approved for use in the USA and therefore do not have an official recommendation for the use of fluorescent cystoscopy in the management of NMIBC. The NCCN guidelines acknowledge that BLC has been shown to decrease recurrence in NMIBC but has not been shown to reduce progression. They suggest that “BLC may have the greatest advantage in detecting difficult-to-visualize tumors (eg, CIS tumors)” and “the limitations of BLC require judicious application of this additional diagnostic tool”10.

In 2013, an expert focus group convened in San Diego to create a consensus statement for appropriate use of BLC in the USA2. Based on the evidence reviewed, they recommend that BLC should be considered:
- At initial TURBT on suspicion of NMIBC
- In patients with positive urine cytology but negative WLC findings
- In patients with intermediate-risk NMIBC
- For assessment of disease recurrence

These recommendations are similar to consensus statements and guidelines from Europe.

Summary

Blue-light cystoscopy has been shown to increase detection of NMIBC during TURBT. Whether this increased detection leads to a difference in recurrence or progression is less clear. Most studies to date, especially those with longer follow-up times, have shown a decrease in recurrence in patients who undergo TURBT with BLC. No study to date has shown a difference in progression. It is likely that to show a statistically significant difference in progression, larger studies with longer follow-up will need to be conducted.

This blog was written by Kevin Curtiss, a medical student at Johns Hopkins School of Medicine. Kevin recently finished a four-week sub-internship at the Brady Urological Institute and gave a presentation to the department on "Blue Light Cystoscopy" from which this blog is inspired. Kevin is looking forward to a career in urology.





REFERENCES
1. Cancer of the Urinary Bladder - SEER Stat Fact Sheets. http://seer.cancer.gov/statfacts/html/urinb.html. Accessed September 2, 2015.
2. Daneshmand S, Schuckman AK, Bochner BH, et al. Hexaminolevulinate blue-light cystoscopy in non-muscle-invasive bladder cancer: review of the clinical evidence and consensus statement on appropriate use in the USA. Nat Rev Urol. 2014;11(10):589-596. doi:10.1038/nrurol.2014.245.
3. Burger M, Grossman HB, Droller M, et al. Photodynamic diagnosis of non-muscle-invasive bladder cancer with hexaminolevulinate cystoscopy: a meta-analysis of detection and recurrence based on raw data. Eur Urol. 2013;64(5):846-854. doi:10.1016/j.eururo.2013.03.059.
4. Shen P, Yang J, Wei W, et al. Effects of fluorescent light-guided transurethral resection on non-muscle-invasive bladder cancer: a systematic review and meta-analysis. BJU Int. 2012;110(6 Pt B):E209-E215. doi:10.1111/j.1464-410X.2011.10892.x.
5. Stenzl A, Burger M, Fradet Y, et al. Hexaminolevulinate guided fluorescence cystoscopy reduces recurrence in patients with nonmuscle invasive bladder cancer. J Urol. 2010;184(5):1907-1913. doi:10.1016/j.juro.2010.06.148.

6. Stenzl A, Penkoff H, Dajc-Sommerer E, et al. Detection and clinical outcome of urinary bladder cancer with 5-aminolevulinic acid-induced fluorescence cystoscopy : A multicenter randomized, double-blind, placebo-controlled trial. Cancer. 2011;117(5):938-947. doi:10.1002/cncr.25523.
7. Grossman HB, Stenzl A, Fradet Y, et al. Long-term decrease in bladder cancer recurrence with hexaminolevulinate enabled fluorescence cystoscopy. J Urol. 2012;188(1):58-62. doi:10.1016/j.juro.2012.03.007.
8. Botteman MF, Pashos CL, Redaelli A, Laskin B, Hauser R. The health economics of bladder cancer: a comprehensive review of the published literature. Pharmacoeconomics. 2003;21(18):1315-1330. http://www.ncbi.nlm.nih.gov/pubmed/14750899. Accessed September 2, 2015.
9. Garfield SS, Gavaghan MB, Armstrong SO, Jones JS. The cost-effectiveness of blue light cystoscopy in bladder cancer detection: United States projections based on clinical data showing 4.5 years of follow up after a single hexaminolevulinate hydrochloride instillation. Can J Urol. 2013;20(2):6682-6689. http://www.ncbi.nlm.nih.gov/pubmed/23587507. Accessed September 2, 2015.

10. NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer. 2015;http://www. http://www.nccn.org/professionals/physician_gls/PDF/bladder.pdf. Accessed September 2, 2015.

26 comments:

  1. This comment has been removed by the author.

    ReplyDelete
  2. This comment has been removed by the author.

    ReplyDelete
  3. Thank for Sharing about your cancer problem. I would like to also share about DCIS – Ductal Carcinoma In Situ Symptoms and Treatments

    ReplyDelete
  4. Treatment for bladder cancer in India is easy to arrange with top Oncologists. Cost i also affordable and the specialists assures for high success and better result with possibilities of least associated risks.

    ReplyDelete
  5. Nice Website...
    Hey JOIN now fblikesbot.com and Increase Facebook Likes your profile and websites.
    Increase Facebook Likes and check your website worth worth my websites
    FB Likes and check your website worth Website Value Calculator
    Hot Wallpapers seo tools website
    its may be very beneficial for you also really

    ReplyDelete
  6. Cancer patient is taking radiation to cure the cancer but the radiations are also very harmful for the human body it causes effects on the bones of the human and body faces muscular pain too. The Physiotherapy North Ryde is best for these pain of the patient as he also needs some side effect free therapy.

    ReplyDelete
  7. Nice post.. I attempted to write a simple worded article for women urology as a start point. Please take a look https://femaleaddablog.wordpress.com/2016/02/26/female-urology-find-a-urologist-in-your-area-today/

    ReplyDelete
  8. - Chứng bệnh tăng huyết áp hiện nay rất phổ biến tại Việt Nam, bệnh huyết áp chủ yếu xảy ra ở người lớn tuôi.
    - Hiện giờ số lượng người mắc bệnh tim tương đối lớn, con số đáng báo động kịp thời.
    - Điều trị bệnh máu nhiễm mỡ tại bệnh viện Thu Cúc uy tín và chất lượng tốt nhất.
    - cách chăm sóc người bị huyết áp thấp cũng đóng vai trò quan trọng giúp cải thiện nhanh chóng tình trạng sức khỏe.
    - Chứng bệnh rối loạn thần kinh thực vật có ảnh hưởng đến chức năng tự động cơ thể bao gồm nhịp tim, huyết áp, mồ hôi và tiêu hóa…
    - Bệnh lý huyết áp thường không bỏ qua ai, vì vậy việc theo dõi huyết áp bình thường là cần thiết để bảo vệ sức khỏe.
    - Chỉ số nhịp tim bình thường là bao nhiêu, các bạn nên tham khảo kỹ để biết cách chăm lo sức khỏe.
    - Tìm hiểu thông tin kiến thức về bệnh viện tim hà nội
    - Triệu chứng thiếu máu não là những căn bệnh rất nguy hiểm hiện nay.

    - Tìm hiểu cao huyết áp nên ăn gì để có những kiến thức cần thiaats cho các bạn.
    - Chỉ số huyết áp bình thường là bao nhiêu rất quan trọng cho mỗi chúng ta để biết tình hình sức khỏe của mình.
    - Tìm hiểu triệu chứng cao huyết áp để có biện pháp chữa trị hiệu quả nhất.
    - Cách giảm mỡ máu hiệu quả tốt nhất hiện nay là gì, mời các bạn tham khảo.
    - Căn bệnh mỡ máu cao ăn gì là tốt nhất và đảm bảo cho sức khỏe nhất hiện nay.
    - Cùng tìm hiểu nguyên nhân tăng huyết áp là gì và cách điều trị thế nào tốt.
    - biến chứng tăng huyết áp rất nguy hiểm cho người bệnh, các bạn không nên coi thường.

    ReplyDelete
  9. Gara Hà Thành cung cấp dịch vụ sơn xe ô tô giá rẻ.
    Sản xuất và lắp đặt cửa nhôm giá rẻ bảo hành lâu dài.

    ReplyDelete
  10. Wonderful post!!! Genuinely loved this kind of post. Although I want much more information on like precious subject matter. 
    Weight Loss management

    ReplyDelete
  11. Great article – Impressive: We think you might be interested to know more about our company. Techno Data Group helps you get your hands on world’s best class customized B2B Contact List, which can make your sales and marketing campaigns cost effective. Achieve Your Marketing Goals and Grow Your Business.Chief of Surgery Email List

    ReplyDelete
  12. Hello,
    Thank you for the Blog.Parana Impact help you reach the right target customers
    to advertise your products and services.
    Urology Users Email List

    ReplyDelete
  13. A fantastic blog with a lot of useful information. I would love to get updates from you. Keep blogging. All the best. Best Affordable Private hospital

    ReplyDelete
  14. I just want to share this personal story about how my husband survived the problem of NO ERECTIONS after prostate surgery.
    My husband undertook prostate surgery 3 years ago and before then i always looked forward to great sex with him and after the surgery he was unable to achieve any erections, we were bothered and we tried so many drugs, injections and pumps and rings but none could give him an erection to even penetrate. I searched for a cure and got to know about Dr. Hillary who is renowned for curing problems of this nature and he did encouraged me not to give up and he recommended his herbal medication which my hubby took for 3 weeks and today his sexual performance is optimum. You too can contact him for similar problems on hillaconn@gmail.com. A man who cannot satisfy his wife's sexual need is not a real man!

    ReplyDelete
  15. CURE YOUR SICKNESS AND DISEASE WITH HERBAL CURE FROM AFRICA.

    Are you in pains or can not find cure for your sickness or disease? Wipe your tears, we are here to cure you of whatever disease or sickness you are battling right now.

    We specialize in all kind of treatment and with the help of Almighty God you will be well again, hurry now and contact us via email: africanherbalcure@gmail.com

    HEALTH IS WEALTH.

    Dr Disu.

    ReplyDelete
  16. Thank you for your miracle Doctor Osemu Okpamen

    This article is dedicated to the Doctor Osemu Okpamen. I have been married with my wife for 5 years and recently she broke up with me and it hurt me deeply when she told me to leave her alone and that she does not love me anymore when i was always faithful and honest to her. I tried all the ways to get her back buying her what she wants like i always did and she still left me heart broken and she even has a new boyfriend which destroyed me even more until a friend of mine from high school directed me to this genuine spell Doctor called Osemu Okpamen. This man changed my life completely. I followed everything he told me to do and my wife came back begging for me back. I was stunned everything happened exactly like he told me. I had faith in everything he told me and everything was true. Also he was there every moment until i got my happiness back and he also provides spells that cures impotence, bareness, diseases such as HIV/AID E.T.C You can contact him via email at { Doctorokpamenspelltemple@yahoo.com } or visit his website http://www.doctorokpamenspells.com. He will help you in anything you need and quick to answer once you contact him.

    You can also call me for more info +1 (914)-517-3229.

    ReplyDelete
  17. Nice blog to read,Here drkvrprasad is a best urology doctor in hyderabad, visit for your urology doctor here.

    ReplyDelete
  18. This comment has been removed by the author.

    ReplyDelete
  19. Thank you for the effective information on treatment for bladder cancer. If you are looking forward for the bladder cancer treatment in Kerala, then please check in the best hospital in Ernakulam, Kochi, Cochin, Kerala.

    ReplyDelete
  20. Hi,
    Nice blog, Our database can help you to target prospects to get high response rates and guaranteed results. Now reach and engage with your targeted audience by Healthcare Email List and stay connected with Doctors in USA, Canada, UK, Australia and Europe.

    ReplyDelete
  21. We at MedisenseHealth, can help you by finding the top doctors specializing in urology. We have a group of 50 (?) hospitals on-board with us. Out of these hospitals, we have 10 (?) specialized urology centres. All you have to do is follow the links provided, or call our health care support and we will be able to schedule you for a second opinion with the best doctors in the field.
    More Details : Medisense Health

    ReplyDelete
  22. Nice article thanks for sharing.
    Dr. V. V. S. Chandrasekharam is a gold medallist in Pediatric Surgery from the All India Institute of Medical Sciences (AIIMS), New Delhi. He has presented over 15 clinical and research papers in various international and national conferences.

    For more info please visit: http://www.ankurahospital.com/doctor/dr-vvs-chandrasekha

    ReplyDelete