Should Patients with Upper Tract Urothelial Cancer Receive Neoajuvant and Adjuvant Chemotherapy? A Physician’s Dilemma.

Upper tract urothelial cancer (UTUC), or cancer of the lining of the kidney or ureter, is a rare disease, accounting for only 5% of all urothelial cancers and 5-10% of renal tumors [1,12,19,20]. The annual incidence is approximately 2/100,000 people with around 3000 new cases per year in the U.S. [2,11]. Because the incidence of UTUC is so low and survival is generally poor, it is a difficult disease to study. It has been suggested that systemic therapy may be beneficial in improving the survival of UTUC patients with high-risk disease, but there is a lack of good evidence and no randomized control trials investigating the role of adjuvant (AC) or neoadjuvant chemotherapy (NAC) therapy. This lack of evidence can make it difficult for physicians to decide whether individual patients presenting with UTUC would benefit from NAC, AC or would do better with radical nephroureterectomy (RNU) alone.  

A Case

The case of a recently seen 55-year old male illustrates the challenges in making this decision. This otherwise healthy gentleman presented with gross hematuria and a large, amorphous renal mass involving the parenchyma of the kidney. The mass was biopsied and proven high-grade urothelial carcinoma in the left renal pelvis prior to our consultation. NAC was considered given that his disease was high-grade, the mass was known to be large on imaging (8cm), and he had adequate renal function to receive platinum based chemotherapy. However, he was experiencing flank pain so he elected to undergo RNU as soon as possible without chemotherapy prior.



Robot-assisted laparoscopic nephroureterectomy and lymph node dissection revealed a 9cm urothelial carcinoma invading the pelvic and perinephric fat and replacing a large part of the renal parenchyma. There was no involvement of the (ten) lymph nodes from the hilar dissection and surgical margins were negative, giving him a final stage of T4N0M0. Given his high stage disease the patient was started on dose-dense MVAC six weeks post-operatively. Unfortunately, he was found to have metastatic disease not long after and his renal function also deteriorated to the point where he could no longer tolerate cisplatin-based chemotherapy.

This case highlights many of the difficulties in selecting treatment for high-risk UTUC, including:

• Could the patient have completed NAC and surgery or would he have progressed before RNU could be done? 
• Would NAC prior to surgery would have prevented or delayed recurrence?
• Deteriorating renal function after RNU made administration of AC difficult
• Would renal function prior to surgery have been better & allowed a full NAC regimen to be administered? 
• Did chemotherapy have any benefit for this patient or would his outcomes have been the same with RNU alone? 

    
This blog will review the rationale and current evidence for both NAC and AC in the treatment of UTUC.

 

The Need for Systemic Therapy

Despite the lack of definitive evidence, there is a clear need for systemic treatment to improve survival of UTUC patients. 5-year disease specific survival (DSS) is 75% for all UTUC patients, however, it is only 35% for patients with locally advanced (pT2 or greater) or node positive disease [11,19,20,23]. Two large series have shown that relapse in UTUC patients following RNU is primarily distant as opposed to local [11,20]. This suggests that RNU provides UTUC patients with good local disease control, but that additional systemic therapy is necessary in many patients, particularly those with high-risk or stage disease. Based on similarities to urothelial cell carcinoma of the bladder, NAC and AC, primarily cisplatin-based regimens, have been suggested as being potentially beneficial in the treatment of UTUC.

 

Neoadjuvant Chemotherapy

One of the primary arguments for NAC as opposed to AC in the treatment of high-risk UTUC is that renal function inevitably decreases following RNU. Cisplatin based chemotherapy is thought to be most effective in the treatment of UTUC but it requires adequate renal function (the standard cutoff is eGFR>60ml/min) and is also nephrotoxic making its administration problematic in UTUC patients particularly post-operatively. GFR has been found to decrease by an average of 24% or 13.9ml/min following RNU [24,25]. Even prior to surgery only about 50% of UTUC patients are eligible for full dose cisplatin using the standard cut-off, and patients over 70 years and those with pT3 or greater disease are even more likely to have poor pre-operative renal function [24].
While many UTUC patients have poor renal function pre-operatively, RNU can only decrease after surgery making NAC a logical choice in this regard. Another argument for the use of NAC is the potential to downstage high-grade tumors and control clinically unapparent metastases prior to surgery. This may help prevent early recurrence after surgery in patients like the one in the case above.
Leow and colleagues recently reviewed all of the available literature regarding the use of NAC and AC in the treatment of UTUC [15]. There are five existing retrospective cohort studies that looked at the benefit of NAC and these included a total of 123 patients treated with NAC compared to 1724 patients who underwent primary RNU. Combining the data from two of these studies that looked a DSS survival, NAC showed a 60% survival benefit as compared to primary RNU [15]. One of these individual studies also showed significant benefits in overall survival (OS) after NAC in addition to benefit in DSS [14]. Additionally, four studies showed a complete pathologic response (T0N0 at time of surgery) in 13-28% of patients who received NAC as compared to none who were treated with primary RNU [3- 5, 17]. Radiographic response of tumor was also investigated in one of the studies and patients who underwent NAC showed an average 2cm or 50% decrease in size pre-operatively [3].
It is important to keep in mind that all of these studies had small treatment groups (43 was the largest) and selection criteria varied in terms of whether patients with clinically node positive disease were included and also how high-risk patients to receive NAC were chosen. Chemotherapy regimen was also variable with MVAC being the most common. Despite these shortcomings, there seems to be a benefit from NAC prior to RNU for patients who have high-risk disease and can tolerate chemotherapy.

 

Adjuvant Chemotherapy

The primary benefit of AC over NAC is that deferring chemotherapy until post-operatively allows definitive pathological staging prior to treatment and thus avoids potential overtreatment. UTUC is very difficult to stage preoperatively. Compared to urothelial carcinoma of the bladder, full thickness biopsy of the collecting system is more difficult to obtain without perforation and therefore staging is less accurate. Also, unlike the bladder, exam under anesthesia is not possible and imaging with CT and MRI has been found to understage UTUC [2,3]. Since it's difficult to stage patients pre-operatively, risk stratification for NAC becomes difficult leading to the possibility of unnecessary treatment and chemotherapy toxicity; this makes AC an attractive option.
An additional argument for AC is that NAC may prevent some patients from ever getting RNU or make RNU more difficult [2,3]. Primary RNU verses after NAC have been compared with the only significant difference being operative time, with no differences in complications, EBL, or hospital stay [17]. However, the number of patients who are unable to undergo surgery after NAC has not been investigated and remains a potential concern. Similar to NAC, the goal of AC is to eradicate subclinical metastases and there by minimize recurrence and maximize survival.
Leow and colleagues review identified nine retrospective and one prospective cohort study of AC in the treatment of UTUC. These studies looked at a total of 482 patients treated with AC compared to 1300 who underwent RNU only [15]. Of these studies only three showed statistically significant benefits of AC, however, a meta-analysis particularly of the five studies where all patients received cisplatin-based therapy suggests a benefit. There was a 57% OS benefit and 51% disease free survival (DFS) benefit in patients who received AC based on studies in which all patients received cisplatin. DSS was not significant, and including the studies that used AC regimens other than exclusively cisplatin based showed no significant benefit [15].
The only prospective study of AC for UTUC looked at 36 patients with T3 or greater or node positive UTUC who received paclitaxel and carboplatin following RNU and found their 5 year OS to be 52% and DFS to be 40.2% [10]. This data is difficult to interpret since there is no control group for comparison and the sample size is small. Additionally, this study did not use cisplatin, which is believed to be the most effective therapy for these patients.
Again, these studies all had small cohorts (140 or less) who received AC and criteria varied in terms whether node positive and T2 patients were included. Chemotherapy regimens were also varied with significant benefit seen in patients who all received cisplatin based therapy, most commonly MVAC (15). However, there does seem to be a benefit of AC with cisplatin-based therapy in those patients whose renal function is sufficient to tolerate chemotherapy and whose surgical pathology shows locally advanced or node positive disease.

 

Conclusions

• No Level 1 Evidence exists regarding the use of NAC or AC for locally advance or node positive disease making treatment selection difficult
  • Only evidence comes from small, heterogeneous retrospective cohort studies
• The existing evidence suggests a benefit for both NAC and AC over RNU alone in properly selected patients
  • High risk features preoperatively or locally advance or node positive disease post-operatively
  • Renal function able to tolerate cisplatin based therapy
  • Good enough overall health to tolerate chemotherapy and desires treatment with chemotherapy despite risk of side effects
• There is no evidence for the selection of NAC verses AC so this has to be made taking into account the individual patient and their preferences
• The POUT trial is a randomized control trial of AC verses primary RNU for invasive or node positive UTUC that is currently underway and will hopefully provide better evidence in the near feature (estimated completion March 2017) (9)

 

This blog was written by Katherine Fischer, a medical student at SUNY Downstate Medical School in Brooklyn, New York. Katherine recently finished a four-week sub-internship at the Brady Urological Institute and gave a presentation to the department on "Neoadjuvant and Adjuvant Chemotherapy for Upper Urinary Tract Urothelial Cancer" from which this blog is inspired. Katherine is looking forward to a career in urology.

 

 

 
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