bladder cancer is a significant cause of morbidity and mortality in the uk with ~10,000 new cases diagnosed and 5,000 deaths registered each year ( 1 ) .
the most common pathological subtype is transitional cell carcinoma ( tccu ) ( 90% of cases ) ( 2 ) with ~50% of all cases being stage ii or beyond at the time of diagnosis ( 1 ) .
standard of care for localized , muscle invasive tccu is radical cystectomy , which historically , i.e. , without modern neoadjuvant combination chemotherapy , leads to 5-year overall survival in the approximate range of 5060% ( 3 ) . a meta - analysis including 11 trials and 3,005 patients confirmed the value of preoperative cisplatin based combination chemotherapy which was shown to reduce the risk of relapsing disease and conferring a 5-year absolute overall survival advantage of 5% ( 4 ) .
a recent meta - analysis comprising 945 patients and nine clinical trials similarly demonstrated the benefits of postoperative cisplatin based combination chemotherapy ( 5 ) .
however , not all patients are eligible for curative - intent multimodal therapy , and about one in five patients present with stage iv disease ( i.e. , locally extending to other organs , to the pelvic or abdominal wall , and/or with evidence of distant metastases ) at the time of diagnosis ( 1 ) . patients with relapse following primary treatment , or with advanced disease at presentation , confer a significant challenge , and even among those fit for optimal platinum - based combination chemotherapy the median overall survival does not exceed the range of 1215 months ( 6,7 ) . the recommended first line chemotherapy for these patients are cisplatin based combinations and either mvac ( methotrexate , vinblastine , doxorubicin , and cisplatin ) or gc ( gemcitabine and cisplatin ) ( 6,7 ) although the gc regimen is often preferred due to a milder toxicity profile ( 7 ) . for patients with acceptable performance status and preserved organ functions , and where the relapse occurs later than 12 months following neoadjuvant / adjuvant cisplatin - based combination chemotherapy , change of platinum based regimen may be a feasible option ( 8) . in selected cases the addition of paclitaxel to gemcitabine and cisplatin may be considered ( 9 ) . for patients unfit for cisplatin combinations alternative although potentially less efficient combination regimens have been proposed , either with alternative platinum agents [ oxaliplatin ( 10 ) or carboplatin ( 11 ) ] or a platinum - free combination of paclitaxel and gemcitabine ( 12 ) . in patients deemed ineligible for standard cisplatin based treatment , combination treatment with split dose cisplatin and gemcitabine has reported encouraging results ( 13 ) . following failure of first line chemotherapy ,
be it early relapse following platinum based neoadjuvant / adjuvant chemotherapy , or progressive disease during palliative first - line chemotherapy , treatment options have so far been limited .
studies , mostly phase ii and retrospective series , have reported activity with taxanes and pemetrexed ( 14 ) . until recently there were no randomized studies to confirm the benefit of second line chemotherapy for patients with metastatic tccu .
vinflunine ( javlor ) , a microtubule inhibitor of the vinca - alkaloid family of anticancer agents ( 15 ) , is the first drug to obtain european medicine agency ( ema ) approval for use in tccu ( 2009 ) due to evidence of efficacy from phase ii ( 16,17 ) and phase iii trials ( 18,19 ) .
considering the multiple challenges in the second - line setting , with declining performance status due to progressive disease , persistent side effects or complications from earlier treatments , and primary or acquired chemo resistance after primary chemotherapy , the safety profile and efficacy data from the recent vinflunine reports are encouraging . in the phase iii trial ( 18,19 )
median overall survival was 6.9 months in the vinflunine plus best supportive care compared to 4.3 months in the best supportive care only population .
further empirical studies have confirmed vinflunine to be a safe and effective second line approach in spain [ n=66 ( 20 ) ] , france [ n=134 ( 21 ) ] and germany [ n=77 , hegele ( 22 ) ] with reported overall survival of 7.710.4 months .
based on the accumulating evidence , the esmo guidelines now suggest vinflunine as the recommended second - line therapy in advanced bladder cancer ( 23 ) .
vinflunine as a second line therapy is not currently recommended for uk practice , nor is it available to the nhs patients through the approved list of drugs on cancer drug fund .
it has however been made available through the free of charge program ( focp ) sponsored by pierre fabre .
here we evaluate the outcome of patients treated with vinflunine as a second line therapy in this program .
data were collected retrospectively on patients with advanced metastatic tccu diagnosed between 6th june 1999 and 20th june 2013 .
data were collected via a pre - defined crf adopted for the study and sent to local investigators for population .
all patients who received vinflunine as a second line therapy following failure of first line therapy were eligible for inclusion .
all patients received vinflunine as a second - line therapy through the free of charge program ( focp ) and received at least one dose of vinflunine .
all patients were included in the analysis , irrespective of any dose reductions or toxicities .
the dose of vinflunine was 320/280/250 mg / m every 3 weeks as per the spc .
the aim was to document the toxicity , radiological rr and os for patients treated with vinflunine in real life setting within the focp .
demographic data were collected on patient gender , age , height , weight and performance status as well as the site of the disease recurrence and their hemoglobin level at the time that the decision to prescribe vinflunine was made .
details on the type of first - line therapy were requested as was whether this was in the neo - adjuvant or adjuvant setting .
continuous data are presented as medians ( iqr ) and categorical data are expressed as frequencies of counts .
the primary outcome measure of interest is overall survival ( os ) which is measured as the time from intention to treat with vinflunine until death by any cause .
progression - free survival ( pfs ) is measured as the time from first vinflunine administration until progression or death by any cause .
objective response rate is defined using recist criteria ( version 1.1 ) and determined at each local site .
univariate analyses are carried out to assess patient demographics as prognostic factors for overall survival using cox proportional hazards models .
hazard ratios ( hr ) are presented with associated 95% confidence intervals ( ci ) .
reported toxicities are defined using ctcae ( version 4 ) and are reported based on being either grade 12 or 34 , respectively .
data are provided on 49 patients from nine contributing sites throughout the uk and ireland ( ccc 15 ; christie 5 ; cork 6 ; glasgow 9 ; st .
george 's 1 ; royal free london 2 ; royal marsden 6 ; northampton 1 ; newcastle 4 ) diagnosed with advanced metastatic tccu between 6th june 1999 and 20th june 2013 .
patient demographics are provided in table i. the patient group consists of 67% ( 33/49 ) males and have a median ( iqr ) age of 64 ( 5770 ) . as per the summary of product characteristics ( spc ) for vinflunine , patients with a 0/1 performance status ( ecog ) or a hemoglobin ( hb ) level > 10 g / dl were targeted .
thirteen patients ( 27% ) had an ecog performance status of 2 or a hemoglobin level < 10 .
two patients ( 4% ) had chronic constipation at presentation and two patients ( 4% ) had coronary artery disease .
information on first - line therapy is available for 48/49 ( 98% ) of all participating patients .
first line neo - adjuvant chemotherapy was given to 60% ( 27/48 ) and consisted of gemcitabine / cisplatin ( 74% ; 20/27 ) , gemcitabine / carboplatin ( 22% , 6/27 ) , or gemcitabine / cisplatin switched to carboplatin in view of worsening renal functions ( 4% , 1/27 ) .
in the metastatic setting patients received platinum regimens consisting of either gemcitabine / cisplatin ( 30% , 13/43 ) , gemcitabine / carboplatin ( 37% , 16/43 ) , gemcitabine / cisplatin switched to carboplatin ( 2% , 1/43 ) , or some other combination ( 30% , 13/43 ) .
following first - line therapy , patient best response rates were complete response 15% ( 7/48 ) , partial response 48% ( 23/48 ) , stable disease 17% ( 8/48 ) and progressive disease 19% ( 9/48 ) .
the overall response rate for first - line therapy was 63% ( 30/48 ) and 98% ( 43/44 ) of patients demonstrated disease progression with 77% ( 34/44 ) demonstrating bone , liver , or lung metastases .
the starting dose was 250 mg / m ( 4% , 2/49 ) , 280 mg / m ( 76% , 37/49 ) or 320 mg / m
three patients ( 6% ) had a dose escalation and 10 ( 21% ) had dose reduction .
eight patients ( 17% ) had only a single cycle , while the maximum number of cycles at the time of analysis was 18 .
toxicities are reported by sites as being either grade 1/2 or grade 3/4 hematological or non - hematological .
overall 31% ( 15/49 ) of patients reported at least one grade 3/4 adverse event .
the most common grade 3/4 toxicities are constipation reported by 8% ( 4/49 ) and asthenia / fatigue reported by 6% ( 3/49 ) of patients .
patients were followed up for a median of 9.1 months . at the time of analysis , 41 ( 84% )
1 ) give a median ( 95% confidence interval ) of 9.1 months ( 6.012.7 ) .
ecog performance measures were investigated further as a key prognostic indicator of interest ( fig .
median survival estimates of 13.1 ( 6.0 , na ) months and 7.6 ( 5.9810.5 ) months were observed for ecog performance measures of 0 and 12 , respectively .
this was not significant statistically [ hr ( 95% ci ) : 1.62 ( 0.74 , 3.55 ) ; p=0.23 ] . a total of 45 ( 92% ) of patients had disease progression at the time of analysis .
sensitivity analyses report the result only on patients who meet the spc ( ecog < 2 , hb > 10 ) . here
35 patients gave an estimated os of 9.9 months ( 7.616.4 ) with an estimated pfs of 6.0 months ( 4.812.1 ) and a partial response rate of 30% .
toxicities are reported by sites as being either grade 1/2 or grade 3/4 hematological or non - hematological .
overall 31% ( 15/49 ) of patients reported at least one grade 3/4 adverse event .
the most common grade 3/4 toxicities are constipation reported by 8% ( 4/49 ) and asthenia / fatigue reported by 6% ( 3/49 ) of patients .
patients were followed up for a median of 9.1 months . at the time of analysis , 41 ( 84% )
1 ) give a median ( 95% confidence interval ) of 9.1 months ( 6.012.7 ) .
ecog performance measures were investigated further as a key prognostic indicator of interest ( fig .
median survival estimates of 13.1 ( 6.0 , na ) months and 7.6 ( 5.9810.5 ) months were observed for ecog performance measures of 0 and 12 , respectively .
this was not significant statistically [ hr ( 95% ci ) : 1.62 ( 0.74 , 3.55 ) ; p=0.23 ] .
a total of 45 ( 92% ) of patients had disease progression at the time of analysis .
sensitivity analyses report the result only on patients who meet the spc ( ecog < 2 , hb > 10 ) . here
35 patients gave an estimated os of 9.9 months ( 7.616.4 ) with an estimated pfs of 6.0 months ( 4.812.1 ) and a partial response rate of 30% .
the prognosis for patients with advanced metastatic tccu who have progressed after first - line therapy remains dismal , and whilst previously published randomised trials and empirical evidence have favoured the use of vinflunine in this patient group , the results have not been clear enough to favour its wide spread use in the uk . as a consequence , many patients will end antitumour therapy or proceed onto palliative care once the first - line regimen has failed .
we performed a retrospective observational study in this clinical setting to assess the effects of vinflunine in terms of both efficacy and toxicity .
data on 49 patients from sites across the uk and ireland were collected and analysed .
the dose of and number of cycles were consistent with previous studies , with a median of 3.5 cycles being similar to the number recorded in the phase iii trial ( 18,19 ) .
the most common starting dose was 280 g / m ( 75% ) and the dose was relatively well tolerated with only 10 ( 29% ) patients requiring a reduction .
further to this , the present median overall survival of 9.1 months ( 6.012.7 ) is consistent with or even slightly better than the 6.9 months of the vinflunine treated arm of the bellmunt phase iii study ( 18,19 ) .
further , the present numbers compare favourably with the empirical ' real life ' results obtained from spain ( 16 ) germany ( 22 ) and france ( 21 ) which all report median survivals between 7.710.4 months in similar patient populations .
toxicity rates observed in our study also show little cause for concern with 39% ( 19/49 ) patients reporting a grade 3 + adverse event , the most common being constipation ( 4 patients ) and fatigue ( 3 patients ) .
toxicity can be further improved with the use of prophylactic laxative and oral antibiotics and should provide little concern in the prescribing of vinflunine .
further inspection of study efficacy shows that patients with a baseline ecog ps of 0 display a median os of 13.1 ( 6.0 , na ) months , while patients of ps 12 have a poorer prognosis of 7.6 ( 6.010.5 ) months .
20 reporting survival estimates of 13.2 and 6.7 months , respectively , for the same patient groups and emphasise baseline ps as a key prognostic predictor although not ruling out the potential benefits even in the ps 12 population .
this study is limited by the retrospective nature of the data collection and the lack of a randomised comparative arm against which to compare the efficacy , which ultimately open the study results to possible bias . in saying that , however , the study analysis includes patients who did not meet the spc for vinflunine as well as patients who only received a single dose .
coupled with the high rate of ecog > 0 and the distribution of metastases this suggests a patient population which is representative of general clinical practice rather than a narrowly selected clinical trial population .
recently there has been much interest in the role of immune checkpoint inhibitors in urothelial cancer with durable responses have been noted with pd1 [ e.g. , pembrolizumab ( 24 ) and pdl1 atezolizumab ( 25 ) ] .
the results of recently completed trials comparing anti - pd1/pdl1 antibodies , with standard of care chemotherapy of institution 's choice that includes vinflunine in the 2nd line setting ( nct 02256436 ) are awaited with interest . in conclusion ,
the empirical results obtained from uk and ireland practice reflect what has been observed in randomised trials of vinflunine as well as other retrospective studies throughout the european union .
the accumulating evidence puts forward vinflunine single drug therapy as an efficient , safe and reasonably tolerable second - line therapy in patients with advanced tccu .
 there is no standard of care in the uk or ireland for second - line chemotherapy for patients with advanced transitional cell carcinoma ( tccu ) . 
 vinflunine is approved for tccu patients who have failed a platinum - based regimen , and is standard of care in europe but is not routinely available in the uk . 
 data were collected retrospectively on patients who received vinfluine as a second - line treatment . 
 the aims were to document the toxicity and efficacy in a real life setting . 
 data were collected on 49 patients from 9 sites across the uk and ireland [ median age , 64 ( iqr , 5770 ) years , 33 males ] . 
 all patients had advanced metastatic tccu . 
 thirteen patients had bone or liver metastases , 4 patients had ps 2 and 11 patients had hb < 10 . 
 median vinflunine administration was 3.5 cycles ( range 118 ) . 
 most common grade 34 toxicities were constipation ( 4 patients ) and fatigue ( 3 patients ) . 
 partial response rate was 29% ( 14 pr , 11 sd , 19 pd , 4 ne , 1 not available ) . 
 median os was 9.1 ( 6.0 , 12.7 ) months . 
 results are consistent with real life data from europe . 
 toxicity is further reduced with prophylactic laxative and oral antibiotics . 
 vinflunine is an efficient and tolerable second line treatment in advanced tccu . 
Introduction
Patients and methods
Results
Toxicity
Overall survival
Disease progression
Patient response
Discussion