Contemporary best practice in the management of urothelial carcinomas of the renal pelvis and ureter

Tumour grade

The 1973 World Health Organization (WHO) classification was the international standard for UC grading. It distinguishes grades G1–G3. ⁷ The 2004 WHO classification ⁸ (currently also known as the 2016 WHO classification) distinguishes in the noninvasive papillary tumours, papillary urothelial neoplasia of low malignant potential, and low- and high-grade carcinoma (low grade versus high grade for the invasive forms). The current guidelines are based on the 2016 WHO classifications. ⁹

Tumour node metastasis staging

The 8th AJCC and UICC edition of the tumour, node, metastasis (TNM) classification is identical to the previous 7th edition. ¹⁰ Concerning the correlation between biopsy tumour stage and resection tumour stage, staging upper urinary tract tumours is fraught with difficulties, mainly due to the small size of the biopsy material submitted for diagnosis. The muscularis propria is rarely seen in the biopsies of the upper tract. Some biopsies may be so small and superficial that only the epithelium is present, thus precluding assessment of invasion entirely. A study by Vashistha and colleagues reported a pT stage concordance of 60% for biopsies. A pT classification was not feasible in 10.6% of cases. ¹¹ Patients with an advanced clinical stage (cT3–4) or with clinically enlarged lymph nodes (cN+) are potential candidates for neoadjuvant chemotherapy (NAC), even though the influence of NAC on OS showed no statistically significant benefit. ¹²

Lymph node dissection performed at the time of renal nephroureterectomy (RNU) allows for optimal tumour staging. Its curative role is debated. The regional lymph nodes are the hilar and retroperitoneal nodes, and for the mid and distal ureter, the intrapelvine nodes. The only difference between the 7th and the 8th editions is that, since there are no data to substantiate the three N categories in the 7th edition, the previous category of N3 metastasis in a lymph node greater than 5 cm is now collapsed with N2 in the 8th edition. Lymph node metastases and extranodal extension are predictors of survival outcomes in UTUC. ¹³

Lymphovascular invasion (LVI) is seen in about 20% of the UTUCs. Since it is an independent predictor of survival, LVI should be specifically included in the pathology reports of all UTUC specimens. ¹⁴

Positive soft tissue surgical margin (R) after RNU is a factor for disease recurrence. Uropathologists should look for surgical margins and report positive margins at the level of ureteral transection, bladder cuff, and around the tumour if the T stage >2. ¹⁵

Since tumour stage is difficult to assess clinically in UTUC, it is useful to ‘risk stratify’ UTUC into low- and high-risk neoplasms to identify those patients who are more suitable for renal sparing treatment versus radical extirpative surgery ¹⁶ (Figure 1).

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Figure 1.

Whole mount section of the kidney with urothelial papillary carcinoma involving the pelvis and calyces.

Additional pathological features

The architecture is a strong prognosticator with sessile growth pattern being associated with worse outcome. Concomitant CIS in organ-confined UTUC and a history of bladder CIS are associated with a higher risk for recurrence and cancer-specific mortality. ¹⁷

Tumour necrosis (i.e. >10% of the tumour area) is present in approximately 20% of the patients. Its prevalence increases with advancing pathological stage, from 7% and 10.6% to 50% in T1, T2 and T3–4, respectively. In addition, tumour necrosis is associated with features of aggressiveness in UTUC, including a high grade, lymph node metastasis, LVI, a sessile architecture of the tumour and concomitant CIS. Tumour necrosis is not an independent predictor of clinical outcomes. ¹⁸

Predictive tools

Several predictive tools have been proposed in UTUC, both in the preoperative and postoperative settings. At present, the Yates’ model remains the only one to have been validated in a different population. ¹⁹ As the current staging system is not useful in the neoplasms of the UTUC prior to RNU, new prognostic factors and tools are needed in the decision-making process. This will help clinicians in the identification of high-risk patients who will benefit from certain types of therapy and those who could be spared from the side effects of an unnecessary therapeutic intervention. In order to select such patients, highly accurate tools estimating individual prognosis are needed. As for the variants, as recently stated by Moschini and colleagues for the urinary bladder, their clinical relevance can manifest at three different levels: ‘diagnostic, as identification is challenging and misinterpretation is not uncommon; prognostic, for patient risk stratification and outcome estimation; and therapeutic, as particular variants could be responsive to specific treatment strategies’. ²⁰ The same applies to UTUC and its variants.

Molecular and genetic markers

Several studies have investigated the prognostic impact of markers related to cell adhesion, cell differentiation, angiogenesis, cell proliferation (Ki-67), epithelial-mesenchymal transition, mitosis, apoptosis, and vascular invasion, and c-met protein. ²¹ Microsatellite instability (MSI) can help detect germline mutations and hereditary cancers. It is an independent molecular prognostic marker. ²² Several molecular markers have been associated with worse outcomes of UTUC. Because of the rarity of UTUC, the main limitations of such studies are their retrospective design and small sample size. None of the markers have fulfilled the criteria necessary to support their introduction in daily clinical decision making. Ki-67 is the only one that has been prospectively evaluated. ²³

Targeted next-generation sequencing of 300 cancer-associated genes has been performed in order to define the genomic landscape of UTUC and to compare its results with BUC. The spectrum of genes mutated in UTUC and BUC is similar. However, differences in the prevalence of alterations in several recurrently mutated genes, including FGFR3, HRAS, TP53, and RB1 were seen.^24,25 Such data can provide an important reference for the development of multimodal strategies in the management of UTUC. The high prevalence of potentially actionable genetic events in UTUC suggests that routine genomic profiling may speed up the process of developing novel drug targets. In particular, the ‘association of variant histology with specific mutation patterns promises to be helpful in discovering targeted therapeutic approaches based on specific molecular pathways’. ²⁰

First-line therapy

Currently, a cisplatin-containing combination chemotherapy regimen is considered the ‘gold-standard’ upfront treatment for patients with advanced BUC and urinary tract who are suitable for cisplatin. In this regard it is crucial to stratify the patients into medically ‘fit’ and ‘frail’ populations by using international criteria ²⁹ which can help to define medical frailty. They include the WHO/Eastern Cooperative Oncology Group (ECOG) performance status of 2 or greater or a Karnofsky performance status of 60–70% or less; creatinine clearance less than 60 ml/min, a hearing loss (measured at audiometry) of 25 dB at two contiguous frequencies, grade 2 or greater peripheral neuropathy (i.e. sensory alteration or paresthesia, including tingling, but not interfering with activities of daily living), New York Heart Association class III or greater heart failure. ²⁹

For medically fit patients with advanced UC, several cisplatin-based chemotherapy regimens have been proposed. The most commonly used regimens include MVAC [methotrexate (30 mg/m² on days 1, 15, 22), vinblastine (3 mg/m² on days 2, 15, 22), doxorubicin (30 mg/m² on day 2), and cisplatin (70 mg/m²), repeated every 28 days for six cycles]; ³⁰ GC [gemcitabine (1000 mg/m² on days 1, 8, 15) plus cisplatin (70 mg/m² on day 2), repeated every 28 days for a maximum of six cycles], and PCG [paclitaxel (80 mg/m² before GC on days 1 and 8), gemcitabine (1000 mg/m² on days 1 and 8), and cisplatin (70 mg/m² on day 1)], repeated every 21 days for a maximum of six cycles. ³¹

MVAC is the first combination regimen which demonstrated, based on the results of randomized clinical trials, a clear superiority compared with single-agent cisplatin.^32–34 MVAC showed a significant improvement in the overall response rate (OR; 39% versus 12%) and progression-free survival (PFS; 10 versus 4 months; OS, 13 versus 8 months). Toxicity is a major concern with the MVAC regimen, particularly since many patients with advanced UC are elderly or have multiple comorbidities and in the case of UTUCs patients often show impaired renal function after radical surgery.^32–34 Myelosuppression, neutropenic fever, sepsis, mucositis, and nausea and vomiting are common. The use of hematopoietic growth factor support may reduce the rate, grade and length of some of these toxicities, especially myelosuppression and mucositis. ³³

In a phase III randomized trial, MVAC was compared with the combination of GC. In terms of OR (49 versus 36%) and 5-year survival (PFS of both arms, 7 months, OS 14 versus 15 months) the two regimens appeared equivalent. However, toxicity was significantly less in the GC arm with less serious (grade 3/4) neutropenia (71 versus 82%), neutropenic sepsis (2 versus 14%), and mucositis (1 versus 22%). ³¹ This trial was designed to assess whether GC was superior and was not powered to demonstrate equivalency between the two regimens, but given the similar efficacy and lesser toxicity, GC is widely considered the standard first-line regimen for patients with advanced BUC and upper urinary tract.

In an effort to improve outcomes and lower toxicity with MVAC therapy, the European Organisation for Research and Treatment of Cancer (EORTC) investigated the potential role of high-dose MVAC (hd-MVAC), which consisted of rapid 2-week cycles (instead of the standard 4 weeks). A total of 246 patients were randomized to receive either standard MVAC or hd-MVAC. Although the OR and OS rates were similar, PFS was significantly improved (9.5 months versus 8.1 months, p = 0.037) and toxicity was decreased in patients treated with hd-MVAC. ³⁵

In order to improve the outcome obtained with the dual therapy, attempts were made to incorporate a third agent to the doublet of GC. The triplet combination of paclitaxel, gemcitabine, plus cisplatin (PGC) was demonstrated in the EORTC 30987 phase III study, which enrolled 626 patients with advanced UC (81% with primary bladder cancer) and randomly assigned them to treatment with GC or PGC for a maximum of six cycles. Final results after a median follow up of 4.6 years have been reported. ³⁶ Compared with GC, PGC resulted in an increase in the OR (56 versus 44%, p = 0.003). A trend towards an improvement in PFS (median 8.3 versus 7.6 months, HR for progression 0.87, 95% CI 0.74–1.03), longer OS (median 16 versus 13 months, HR for death 0.85, 95% CI 0.72–1.02) was observed. The trial showed an increased incidence of serious toxicities, including neutropenia (65 versus 51%), fatigue (15 versus 11%), and infections (18 versus 14%), but a lower incidence of serious thrombocytopenia (35 versus 52%). The PGC regimen even if more toxic than the GC regimen may be considered as an alternative option in patients with excellent performance status without relevant comorbidities.

Second-line chemotherapy

For patients with advanced UC who progress to first-line treatment, there is no standardized therapy. Most available data come from phase II studies which have too small numbers of patients for carrying out head to head comparisons between different agents or regimens. Patients with advanced bladder cancer who have failed an initial chemotherapy regimen should be encouraged to participate in clinical trials whenever possible.

Currently, the only product licensed for second-line chemotherapy in Europe is vinflunine, a third-generation, semisynthetic, vinca alkaloid. A phase III study comparing vinflunine with best supportive care showed a significant survival benefit in eligible patients (6.9 versus 4.3 months), with an objective response rate (ORR) of 8.6%. ⁴⁸

The choice of second-line chemotherapy is complex and depends on performance status, first-line treatment used, prior chemosensitivity in terms of duration of response, and the presence of visceral metastases. The most important predictors of poor outcome in the second-line setting are hemoglobin level, presence of liver metastasis, poor performance status and time from prior chemotherapy.^49,50 For selected patients who progress on first-line cisplatin-based chemotherapy and are still eligible for cisplatin treatment, rechallenge with cisplatin-containing chemotherapy is feasible, depending on their initial response.^51,52 Several other single-agent chemotherapies including paclitaxel, docetaxel, gemcitabine, ifosfamide, oxaliplatin, pemetrexed and nab-paclitaxel^53–57 have been tested in second-line therapies with response rates ranging from 5% to 33%, short times to progression and no improvement in OS. Better response rates (15–60%), with higher toxicity rates and no OS benefit, are generally achieved in multidrug combinations, which often include taxanes and gemcitabine.^58–61

Antiangiogenic agents

Angiogenic agents have been tested in UC in different clinical studies, with discordant results.

Bevacizumab, a monoclonal antibody directed against the vascular endothelial growth factor (VEGF), showed promising results. In a phase II trial in which bevacizumab was combined with GC as a first-line treatment of metastatic UC, a 72% OR and a median OS of 19.1 months, was reported. ⁷¹ In another phase II study chemo-naïve patients with metastatic disease, whose expected survival was approximately 9 months, bevacizumab combined with gemcitabine and carboplatin led to a 63% response rate and OS of 13.9 months. ⁷² In both trials an advantage against historical controls was observed. In the neoadjuvant setting, in a phase II trial, bevacizumab was combined with MVAC, resulting in an increased pathologic response, to less than stage T2. ⁷³

More disappointing were results with tyrosine kinase inhibitors that target VEGF receptors (VEGFRs). Sunitinib, a multikinase inhibitor, that targets VEGFRs and also c-kit, platelet-derived growth factor receptor (PDGFR)-a and -b, Fms-related tyrosine kinase 3 and RET, was studied as second-line therapy using two different schedules. A partial response was seen in 5% of patients, with OS reported as 6.9 months. The treatment was not well tolerated, 74% of the patients experienced grade 3 and 4 toxicities, most common adverse events were lymphopenia, thrombocytopenia, anemia, fatigue and nausea. ⁷⁴ In another study, sunitinib was given as first-line treatment in patents ineligible for cisplatin, due to renal impairment. An 8% response rate and 8.1-month OS were reported. Although the incidence of grade 3 and 4 toxicities was less, 2 of 38 patients died (1 of myocardial infarction and 1 of stroke), possibly related to treatment. ⁷⁵

Finally, sunitinib given as maintenance therapy in a phase II trial to patients who had achieved stable disease, partial or complete response after 4–6 cycles of chemotherapy did not improve 6-month PFS compared with placebo. ⁷⁶ Because of these disappointing results, no trials of sunitinib for metastatic UC are ongoing.

Other antiangiogenic agents have been investigated for efficacy against UC.

Sorafenib, which targets VEGFR-2 and -3 and B-Raf, c-Raf, and PDGFR-a and -b, achieved no response as either first-line treatment for cisplatin-ineligible patients or single-agent second-line treatment.^77,78 These studies led researchers to conclude that sorafenib has little or no activity against UC. Similarly, in a trial of pazopanib, an antiangiogenic agent that targets VEGFR-1, -2, and -3, PDGFR-a and -b, and c-kit, the drug effected no response when given as a single agent in second-line treatment ⁷⁹ and led to a 17% response rate in another trial, with a median OS of only 4.7 months. ⁸⁰ A trial of pazopanib combined with GC as first-line treatment for cisplatin-ineligible patients (NCT01622660) closed because of hepatotoxicity. A trial of pazopanib combined with vinflunine as second-line treatment was discontinued at the first dose level for safety reasons. ⁸¹

Although small molecule inhibitors of VEGFR have so far shown limited efficacy, a three-arm randomized phase II study of recently developed monoclonal antibodies targeting VEGFR-1 (icrucumab) and VEGFR-2 (ramucirumab) combined with docetaxel in patients with disease progression after first-line therapy has been recently published. It showed how a combination of docetaxel and ramucirumab improved PFS than docetaxel alone (5.4 versus 2.8 months); icrucumab instead did not experience any PFS improvement. ⁸²

Anti-epidermal growth factor receptor therapy

Progression of muscle-invasive UC has been linked to epidermal growth factor receptor (EGFR) overexpression.^83,84 When 20 patients with muscle-invasive disease were treated with erlotinib before cystectomy, 60% were downstaged to pT1 or less, suggesting single-agent activity with EGFR inhibitors. ⁸⁵ However, gefitinib administered as a single agent in second-line treatment produced only a 3% response rate and a 3-month OS. ⁸⁶ Moreover, gefitinib combined with GC, given either as a standard dose ⁸⁷ or at a fixed-dose rate, ⁸⁸ did not improve either the response rate or OS for patients with untreated metastatic UC.

Furthermore, the combination of GC chemotherapy and cetuximab, a monoclonal antibody targeting EGFR, was intolerable, and both PFS and median OS proved detrimental. ⁸⁹ A randomized phase II trial of another EGFR-specific monoclonal antibody, panitumumab, combined with GC compared with chemotherapy alone as first-line treatment was terminated early because of insufficient recruitment (NCT01374789). Another randomized phase II trial of patients with previously treated metastatic disease reported a 25% response rate for cetuximab combined with paclitaxel, but no activity for cetuximab as a single agent. ⁹⁰ These data support preclinical data showing synergism between anti-EGFR monoclonal antibodies and taxanes. ⁹¹ Overall, it appears that in unselected patients, targeting EGFR has limited efficacy. Therefore, it is imperative to identify biologic markers, most likely to identify patients responding to anti-EGFR treatment. The oral tyrosine kinase inhibitor vandetanib, was studied in the second-line setting combined with docetaxel in a phase II double-blind trial that reported no significantly improved OR, PFS, or OS in patients with advanced UC. ⁹² A single-arm phase II study tested the safety and efficacy of the antihuman EGFR-2 (HER2) antibody trastuzumab combined with GC, carboplatin, and paclitaxel in patients with HER2 overexpression found by immunohistochemistry, gene amplification, or elevated serum HER2 levels. ⁹³

The patient outcomes exceeded expectations, with an ORR of 70% and an OS of 14.1 months. ⁹³ Although the incidence of grade 1–3 cardiac toxicity (22.7%) was more frequent than anticipated, these unexpected results prompted additional studies. A randomized phase II trial compared trastuzumab (NCT01828736) with GC or GC and carboplatin versus GC or GC and carboplatin alone in HER2-expressing bladder cancer. ⁹⁴ That study screened 563 patients with advanced UC over 5 years and found only 75 patients (13.3%) with HER2-positive (HER2+) tumours. No difference was observed in the ORR, PFS, or OS between the chemotherapy-alone arm and the chemotherapy-plus-trastuzumab arm. The investigators did find that the HER2 levels were predictive of PFS regardless of treatment. A study investigating trastuzumab combined with standard GC chemotherapy in the first-line setting closed enrolment early (NCT02006667). Another study investigating trastuzumab as a single agent in the second-line setting (NCT02013765) closed early because of recruitment difficulties.

Lapatinib, an agent that has selective activity against both EGFR and HER2, was hypothesized to have significant clinical activity. Although lapatinib had only a 1.7% response rate as a single agent in unselected patients with platinum-refractory metastatic UC, it led to a marked difference in OS in those with low EGFR/HER2 compared with patients with high EGFR or high HER2. ⁹⁵ This subgroup analysis reinforces the concept of selecting appropriate patients for targeted therapies. In a recently completed trial that combined lapatinib with GC (GCL), four cycles of GCL were administered as neoadjuvant therapy for patients with muscle-invasive UC. Although initially designed as a phase II efficacy study with a primary endpoint of pathologic complete response at the time of radical cystectomy, the dose selected for investigation proved excessively toxic. ⁹⁶ A completed phase II/III trial comparing maintenance lapatinib with placebo after first-line chemotherapy [LAMB (maintenance lapatinib versus placebo after first-line chemotherapy in patients with locally advanced or metastatic bladder cancer) trial, ClinicalTrials.gov identifier: NCT00949455] in patients expressing either EGFR or HER2 will shed more light on the role of dual-targeting these growth pathways in UC. Results are awaited.

A phase II trial testing the oral, irreversible inhibitor of the ErbB family, afatinib is currently ongoing (NCT02122172). Preliminary results showed that patients with HER2 or ERBB3 alterations achieved a 3-month PFS versus none of patients without alterations. The median time to progression/discontinuation was 1.4 months in patients without alteration compared with 6.6 months in patients with HER2 amplifications or ERBB3 mutations. ⁹⁷

PI3K/AKT/mTOR pathway

Early phase clinical trials of PI3K pathway inhibitors are currently underway in UC. A phase II clinical trial testing buparlisib, a pan-class I selective PI3K inhibitor, in UC is ongoing (NCT01551030). The trial is enrolling metastatic transitional cell UC patients with alterations in the PI3K pathway. ⁹⁸ Preliminary results from another phase I study of a PI3K inhibitor GSK2126458 in 170 patients with advanced solid cancer have shown objective responses (1 of 3 UC patients bearing PIK3CA mutations), although responses were also observed in wild-type patients (2 of 15 UC patients). ⁹⁹ Further work is required to characterize the relationship between PIK3CA mutation and response to PI3-kinase inhibition in UC.

mTOR plays a central role in metabolism, cell proliferation and growth, and inhibiting this protein is an important target for therapeutic intervention. ¹⁰⁰ However, the results of two phase II clinical trials of mTOR inhibitors as a single-agent therapy in UC patients have not been promising in unselected patients.^101,102 In a phase II single-arm, nonrandomized study with everolimus in 45 UC patients who had progressed on cytotoxic agents, 1 patient had near complete response, 1 had a partial response, and several had minor responses. The primary end point of 2-month PFS in more than 70% of patients was not achieved. ¹⁰¹ Subsequent whole genome sequencing of the patient who showed near complete response to everolimus in the study had nonsynonymous mutations in the tuberous sclerosis complex, lending biomarker credibility to this regulator of mTOR. ¹⁰³ Analysis of another phase II study of everolimus in platinum-resistant patients led to the conclusion that intact PTEN activity was required for mTOR inhibitor sensitivity due to feedback through AKT.^103,104 Recently, a phase I study of an mTOR inhibitor in combination with pazopanib has been reported in which a patient who showed a 14 month complete response to therapy had two activating mutations in mTOR. ¹⁰⁵ Another phase II study of the dual PI3K and mTOR inhibitor BEZ235 in patients with locally advanced or metastatic transitional cell carcinoma showed modest clinical activity and an unfavourable toxicity profile; however, a minority of patients experienced a clinical benefit, suggesting that a complete blockade of the PI3K/mTOR axis could improve the outcome in some specific patients. ¹⁰⁶ These findings highlight the importance of biomarker-enriched trial designs in UC-targeted therapy trials.