Wednesday, April 23, 2014

Upper Tract Urothelial Cancer Chemotherapy: When? For Whom?

Urothelial cancer refers to cancer of the lining of the urinary tract and was previously known as transitional cell carcinoma.  Urothelial cancers can occur in the bladder or the upper tract of the urinary system which includes the lining of the kidney (otherwise known as the renal pelvis) and the ureter.  Biologically, upper tract urothelial cancers (UTUC) are similar to urothelial cancers of bladder.  However, they have several important distinctions:

  • UTUC is rare, accounting for only 5% of all urothelial cancers. [1]
  • UTUC are more difficult to visualize and treat endoscopically.
  • UTUC are morphologically similar to bladder cancers but have different embryologic origins and genetic characteristics.  
  • Like urothelial cancer of the bladder, stage (i.e. depth of invasion) is the most important predictor of prognosis.  However, unlike the bladder, grade is highly correlated to stage:
    • 91% of high-grade tumors in the renal pelvis are invasive
    • 64% of high-grade tumors in the ureter are invasive [2] 
  • Prognosis is different for UTUC compared to urothelial cancer of the bladder.
    • Upwards of 19% of patients with UTUC present with metastases.[3]
    • However, in matched cohorts with less aggressive disease, progression and death occurred with equal frequency among patients with UTUC and bladder cancers.[4] 
  • The role of neoadjuvant and adjuvant chemotherapy is not well-established in UTUC (see below).
The last important distinction is that chemotherapy is almost considered "standard-of-care" either before or after removal of the bladder in certain circumstances.  Adjuvant chemotherapy (AC or chemotherapy immediately after surgery without any evidence of metastases) has an established niche for patients with adverse pathological features at the time of radical cystectomy for urothelial cancer of the bladder.
Similarly, neoadjuvant chemotherapy (NAC or chemotherapy before surgery) has a growing role in the treatment of muscle-invasive urothelial cancer of the bladder (please see prior blog entry Neoadjuvant Chemotherapy for Bladder Cancer: What Does It All Mean?). 

The role of NAC prior to nephroureterectomy (NU or removal of the kidney and ureter) or AC following surgery is less well-understood.  The lack of data supporting the use of either NAC or AC is based mostly on the poor overall survival rate for patients with high-grade and high-stage UTUC regardless of treatment and the subsequent lack of overall response rate to chemotherapy.  

However, there are a number of reasons that chemotherapy surrounding surgery makes sense.  First, patients with locally advanced disease experience a 50% or greater risk of progression and less than a 2-year median survival duration.[5-8]  Therefore surgery alone is not curative and the addition of a systemic therapy may improve cancer outcomes.   

Here we review the limited data regarding AC and NAC in the treatment of UTUC.

Adjuvant Chemotherapy (AC) Following Nephroureterectomy (NU)

A recent, systematic review of AC following NU examined one prospective study and nine retrospective studies (no randomized trials were available) comparing 482 patients receiving AC after NU and 1300 patients undergoing NU alone.  This analysis demonstrated a 50% reduction in disease recurrence and 60% reduction in overall death in favor of those patients receiving AC.[9]  Importantly, this was a heterogeneous group of patients with pT2-4, node-negative and node-positive disease; and all patients receiving AC had adequate renal function.         

Neoadjuvant Chemotherapy (NAC) Prior to Nephroureterectomy (NU)

There are a number of specific reasons why NAC before NU makes sense:
  • NAC works for the bladder.
    • Survival is improved 5-10% with chemotherapy before surgical removal of the bladder.
    • UTUC is biologically similar to urothelial cancer of the bladder.
  • NAC effectively down-stages urothelial cancer (discussed below)
  • Many patients who undergo NU are not eligible for chemotherapy after surgery because they are older and/or have baseline chronic kidney disease.
    • The best chemotherapies for urothelial cancer are filtered by the kidneys.
    • Reduced filtering ability of the kidneys can cause:
      • decreased efficacy of chemotherapy
      • increased toxicities including worsening renal function
In two retrospective series of patients receiving NAC compared to historical patients undergoing NU alone, there was a significant proportion of down staging in the NAC group with a 14% complete response rate.[10]  The follow-up study demonstrated a 90% cancer-specific survival rate at 5-years compared to 57% in the NU alone group.[11]  A meta-analysis of NAC data demonstrated a disease-specific survival improvement of nearly 60% for NAC in retrospective studies; and favorable pathologic downstaging rates and survival rates upwards of 90% in two, prospective phase 2 NAC trials.[9]

Summary

Chemotherapy should play a role in the treatment of UTUC, should be considered in the time period surrounding NU and should be discussed as an option with patients.
  
Adjuvant Chemotherapy (AC) can improve cancer-recurrence rates and overall survival.  AC should be considered following NU in patients with:
  • adequate renal function
  • high-risk pathological features (pT3 or pT4, N1 or positive surgical margins)
Neoadjuvant Chemotherapy (NAC) effectively downstages tumors and may improve survival in limited studies.  NAC should be considered prior to NU in patients:
  • invasive high-grade UTUC
  • high-volume, high-grade UTUC with clinical suspicion of invasive disease
  • baseline renal dysfunction that may preclude chemotherapy following surgery
More data and well-designed prospective studies are needed to define the exact role and benefits of AC and NAC in UTUC.

This entry was written by Phillip M. Pierorazio, MD, Assistant Professor of Urology and Oncology at the Brady Urological Institute at Johns Hopkins.










[1] Melamed MR, Reuter VE: Pathology and staging of urothelial tumors of the kidney and ureter. Urol Clin North Am 1993; 20: 333
[2] McCarron JP Jr, Mills C, Vaughn ED Jr. Tumors of the renal pelvis and ureter: current concepts and management. Semin Urol 1983;1:75–81.
[3] Akaza H, Koiso K, Niijima T,et al: Clinical evaluation of urothelial tumors of the renal pelvis and ureter based on a new classification system. Cancer 1970; 26: 58
[4] Catto JW, Yates DR, Rehman AR,et al: Behavior of urothelial carcinoma with respect to anatomic location. J Urol 2007; 177: 1715-1720
[5] Brown GA, Busby JE, Wood CG, et al. Nephroureterectomy for treating upper urinary tract transitional cell carcinoma: time to change the treatment paradigm? BJU Int. 2006; 98: 1176-1180.
[6] Hall MC, Womack S, Sagalowsky AI, Carmody T, Erickstad MD, Roehrborn CG. Prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: a 30-year experience in 252 patients. Urology. 1998; 52: 594-601.
[7] Lehmann J, Suttmann H, Kovac I, et al. Transitional cell carcinoma of the ureter: prognostic factors influencing progression and survival. Eur Urol. 2007; 51: 1281-1288.
[8] Ozsahin M, Zouhair A, Villa S, et al. Prognostic factors in urothelial renal pelvis and ureter tumours: a multicentre Rare Cancer Network study. Eur J Cancer. 1999; 35: 738-743.
[9] Jeffrey J. Leow, William Martin-Doyle, André P. Fay, Toni K. Choueiri, Steven L. Chang, Joaquim Bellmunt, A Systematic Review and Meta-analysis of Adjuvant and Neoadjuvant Chemotherapy for Upper Tract Urothelial Carcinoma, European Urology, Available online 16 March 2014, ISSN 0302-2838, http://dx.doi.org/10.1016/j.eururo.2014.03.003.
[10] S.F. Matin, V. Margulis, A. Kamat et al.  Incidence of downstaging and complete remission after neoadjuvant chemotherapy for high-risk upper tract transitional cell carcinoma.  Cancer, 116 (2010), pp. 3127–3134
[11] S. Porten, A. Siefker-Radtke, A. Kamat, C. Dinney, S. Matin.  Survival outcomes in patients undergoing neoadjuvant chemotherapy for upper tract urothelial cell carcinoma [abstract].  J Clin Oncol (Suppl 6) (2013), p. 311

5 comments:

  1. Dr. Miracle Herbal Medicine Is A Good Remedy For Herpes, I Was A carrier of Herpes and I saw a testimony on how Dr. Miracle, cure Herpes, I decided to contact him, I contacted him and he guided me. I asked him for solutions and he started the remedies for my health. After he finish casting the spell, he told me to go for check up, could you believe that i was confirm herpes negative after the test, and i went to a different hospital and it was also negative, i am so happy today because i'm free from herpes disease with the help of Dr. Miracle. Thank God, now everything is fine, I'm cured by Dr.Miracle,herbal medicine, I'm very thankful to Dr. Miracle, Reach Him On (MiracleSpellHome@yahoo.com) Or WhatApp Him Or Call: +39(349)549- 4143,,, DOCTOR MIRACLE CAN AS WELL CURE THE FOLLOWING DISEASE:- (1). HERPES( 2). HIV/AIDS (3). CANCER ALL KINDS (4). Hepatitis A,B,C (5)Pregnant (6) Penis Enlargement ,,,,

    ReplyDelete
  2. Most prostate cancers are adenocarcinomas, cancers that arise in glandular cells of the prostate’s epithelial tissue. Prostate cancers usually progress slowly and produce no symptoms in the initial stages. Eventually, the tumor may enlarge like mine use too, the prostate gland, pressing on the urethra and causing painful or frequent urination and blood in the urine. So I was so uncomfortable with this prostate cancer diseases then I decided to do online search on how to cure cancer because I well have read a lot about herbal medicine,I came across a lot of testimony how Dr Itua cure HIV/herpes then Cancer was listed below the comment.with courage I contacted Dr Itua and he sent me his herbal medicine through Courier service then I was asked to pick it up at my post office which i quickly did. I contacted Dr Itua that i have received my herbal medicine so he instructs me on how to drink it for three weeks and that is how Dr Itua Herbal Medicine cure my prostate Cancer, The treatment takes three weeks and I was cured completely. Dr Itua is a god sent and I thank him every day of my life. Contact him now On:Email:drituaherbalcenter@gmail.com/ info@drituahebalcenter.com. Whatsapp:+2348149277967.
    He listed to that he can as well cure the following diseases below.... Cerebral Amides. Lung Cancer, Alzheimer's disease, Adrenocortical carcinoma. Alma, Uterine Cancer, Breast Cancer, Allergic diseases. Kidney cancer, Love Spell, Colo rectal cancer, Lottery Spell, Bladder Cancer, Skin Cancer,Ovarian Cancer,Pancreatic Cancer, HIV /Aids, Herpes, Non-Hodgkin lymphoma, Inflammatory bowel disease, Copd, Diabetes, Hepatitis

    ReplyDelete
  3. WHAT A GREAT MIRACLE THAT I HAVE EVER SEE IN MY LIFE. My names are Clara David I’m a citizen of USA, My younger sister was sicking of
    breast cancer and her name is Sandra David I and my family have taking her
    to all kind of hospital in USA still yet no good result. I decided to go to
    the internet and search for cancer cure so that was how I find a lady
    called peter Lizzy she was testifies to the world about the goodness of a
    herbal man who has the roots and herbs to cure all kind of disease and the
    herbal man email was there. So I decided to contact the herbal man @herbalist_sakura for my younger sister help to cure her breast cancer. I contacted him and told him
    my problem he told me that I should not worry that my sister cancer will be
    cure, he told me that there is a medicine that he is going to give me that
    I will cook it and give it to my sister to drink for one week, so I ask how
    can I receive the cure that I am in USA, he told me
    That I will pay for the delivery service. The courier service can
    transport it to me so he told me the amount I will pay, so my dad paid for
    the delivery fee. two days later I receive the cure from the courier
    service so I used it as the herbal man instructed me to, before the week
    complete my sister cancer was healed and it was like a dream to me not
    knowing that it was physical I and my family were very happy about the
    miracle of Doctor so my dad wanted to pay him 5 million us dollars the
    herbal man did not accept the offer from my dad, but I don't know why he
    didn't accept the offer, he only say that I should tell the world about him
    and his miracle he perform so am now here to tell the world about him if
    you or your relative is having any kind of disease that you can't get from
    the hospital please contact dr.sakuraspellalter@gmail.com or whats app him
    +2348110114739  you can follow him up on Instagram @herbalist_sakura for the cure, he will help you out with the
    problem. And if you need more information about the doctor you can mail me
    davidclara223@gmail.com 

    ReplyDelete
  4. I'm 40 years old female I tested genital herpes (HSV1-2) positive in 2002. I was having bad outbreaks. EXTREMELY PAINFUL. I have try different kinds of drugs and treatment by the medical doctors all to know was avail. Six months ago I was desperately online searching for a helpful remedies for genital herpes (HSV1-2) cure, which i come across some helpful remedies on how Dr OYAGU have help so many people in curing genital herpes (HSV1-2) with the help of herbal treatment because I too believe there is someone somewhere in the world who can cure herpes completely. At of the past 2 months, however, I've been following his herpes protocol Via oyaguherbalhome@gmail.com or +2348101755322 and it stopped all outbreaks completely! To my greatest surprise I was cured completely by following the protocol of his herbal medicine . Don't be discouraged by the medical doctors. There is a cure for HSV with the help of herbs and roots by a herbalist Dr call Dr OYAGU he is so kind and truthful with his herbal treatment, kindly contact him for more information Via oyaguherbalhome@gmail.com or WhatsApp DR on +2348101755322 you will be lucky as i am today

    ReplyDelete
  5. I was diagnosed as HEPATITIS B carrier in 2013 with fibrosis of the
    liver already present. I started on antiviral medications which
    reduced the viral load initially. After a couple of years the virus
    became resistant. I started on HEPATITIS B Herbal treatment from
    ULTIMATE LIFE CLINIC (www.ultimatelifeclinic.com) in March, 2020. Their
    treatment totally reversed the virus. I did another blood test after
    the 6 months long treatment and tested negative to the virus. Amazing
    treatment! This treatment is a breakthrough for all HBV carriers.

    ReplyDelete