Background
Urothelial cancer is the sixth most common type of cancer in the European Union and is responsible for 40,000 cancer-related deaths every year [
1]. It is estimated that approximately 27,000 new cases of urothelial bladder cancer are diagnosed every year in Italy [
2]. Muscle-invasive disease is among the most aggressive epithelial cancers. Radical cystectomy after neoadjuvant cisplatin-based chemotherapy as well as bilateral extended pelvic lymphadenectomy is the standard of care. However, about 50% of patients will relapse following surgery; the 5-year survival rate is approximately 60%, and 25–35% in high-risk patients (stages T3–4 and/or N+) [
3,
4].
At present, a platinum-based chemotherapy is the standard front-line treatment in the metastatic setting. The combinations gemcitabine/cisplatin or methotrexate, vinblastine, adriamycin, and cisplatin (M-VAC) are used in patients able to tolerate cisplatin, while a carboplatin-based regimen or a single agent are the choice for the about 50% of patients unfit for a cisplatin-containing regimen. Although response rates are initially high, with about 50% reported in phase III trials, the majority of responding patients develop progressive disease within 8 months [
5‐
7].
In small single-arm phase II trials, multiple traditional agents and novel targets have been studied in the second-line setting after a platinum-based regimen showing different overall response rates and median survivals [
8,
9]. Due to limited therapeutic benefit, none of these treatments have been investigated in phase III trials.
Thus far, vinflunine is the only chemotherapeutic agent to have been studied in a randomized phase III trial [
10] for the treatment of advanced or metastatic transitional cell carcinoma of the urothelium (TCCU) after failure of platinum-based chemotherapy. Vinflunine is a microtubule-targeting agent that induces mitotic arrest with subsequent cell death [
11]; at non-cytotoxic concentrations, vinflunine also exerts antiangiogenic and antivascular activity [
12]. The randomized phase III trial [
10] demonstrated that after failure of a platinum-containing therapy in patients with metastatic disease, chemotherapy with vinflunine prolonged median overall survival (OS) by 2.6 months as compared to best supportive care (6.9 vs 4.3 months) with a 22% reduction in the risk of death, a statistically significant improvement, which was maintained in the eligible population in long-term (>3.5 years) follow-up, and manageable side effects [
13].
Due to the favorable phase III results, vinflunine has been the only chemotherapeutic agent registered in Europe since 2009 for the treatment of advanced or metastatic TCCU after failure of platinum-based chemotherapy. An analysis of the data from the pivotal phase III study with vinflunine [
14] and a retrospective analysis of pooled prospective phase II trials [
15] produced interesting additional data; the main adverse prognostic factors for OS in patients who have failed a platinum-based regimen were hemoglobin <10 g/dL, the presence of liver metastases, performance status (PS) >0 and the time from prior chemotherapy (TFPC) <3 months; patients harboring a combination of all risk factors had a worse OS compared with those who had none.
After vinflunine entered the market, its effectiveness and good tolerability were confirmed in clinical practice by several observational studies performed in different European countries [
16‐
22]; these studies reported a disease control rate (DCR) ranging from 30% to 65% and a median OS from 8 to 12 months.
In Italy, vinflunine has been marketed since February 2011; however, no data are available on its use in real-world clinical practice. The aim of this study was to investigate whether the results from a large cohort of unselected Italian patients treated with vinflunine were consistent with those of the phase III registration study [
10] in terms of clinical outcome and safety.
Discussion
With 217 patients enrolled from 28 Italian centers, the MOVIE study represents the largest-ever reported observational study evaluating vinflunine in nationwide clinical practice for the treatment of metastatic TCCU. The principal limitation of the present study is that, by design, the cohort was selected by receipt of vinflunine, and this may introduce a bias in comparison with a prospective randomized trial. However, in this study all patients consecutively followed in the participating centers were included over a well-defined period of time.
The characteristics of this population show that patients had mostly ECOG PS 0 and 1, but 7% had ECOG PS of 2. Vinflunine was used as third-line chemotherapy in 23% of patients as the study also included patients treated just after marketing authorization of vinflunine in Italy. Two thirds of the patients were ≥65 years old as opposed to less than half of the population enrolled in the registration study [
10].
Overall, vinflunine resulted in an OS of 8.1 months, which is similar to OS reported in other published observational studies [
16‐
22] (Table
5) and longer than the OS observed in the registration study (6.9 months) [
10]. Compared to other published postmarketing observational studies, this study has some substantive differences: the sample size is larger and was calculated from the beginning on the basis of a solid statistical hypothesis, and we chose to include only patients treated during a well-defined time span and only in centers that had treated at least 4 patients, according to the AIFA register. These aspects reinforce the value of the results achieved.
Table 5
Observational retrospective real word multicenter studies
| 102 | 92% | NR | 17% | 25% | 3.9 | 10.0 |
| 100 | 80% | 39% | 25% | 23% | 2.8 | 6.3 |
| 134 | 71% | 24% | 28% | 22% | 4.2 | 8.2 |
| 71 | 77% | 22% | 30% | 13% | 6.2 | 11.9 |
| 77 | 100% | 17% | 22% | 23% | NR | 7.7 |
Present study | 217 | 93% | 12% | 22% | 13% | 3.2 | 8.1 |
In line with the registration study, the present study confirms the role of ECOG PS ≥1; the number of disease sites and liver metastases as unfavorable prognostic factors for survival, whilst the same correlation was not observed for hemoglobin level < 10 g/dL and TFPC <3 months. We could postulate that the difference is probably related only to the sample size. In our population, only 12% of patients had Hb <10 g/dL whereas in the registration trial the basal value of Hb was not reported. Moreover, in our population, the median survival of this group was poor and was about half that of patients with basal Hb value > 10 g/dL (4.8 vs 8.5 months, respectively).
The 40% DCR is comparable with that of the registration study; however, a higher response rate was observed (13% vs. 9%), including CR in 3% of patients.
As reported in previous European observational studies [
16‐
22], vinflunine had a manageable toxicity profile. In fact, the rates of grade 3–4 hematological and non-hematological adverse events were considerably lower than those reported in the registration study with about five times fewer cases of neutropenia and three times fewer cases of constipation. This difference could have been a result of some patients receiving prophylactic treatment for neutropenia and constipation. Indeed, treatment was better tolerated in the real-world setting, probably due to dose adaptation. Concerning drug exposure, the present real-world study shows that 64% of starting doses were 320 or 280 mg/m
2, while 36% of initial treatments where started at 250 or 200 mg/m
2. The median number of cycles was 4, higher than that reported in the phase III study.
The landscape for urothelial carcinoma treatment is rapidly changing with the introduction of immunotherapy and in particular checkpoint inhibitors targeting the programmed cell death protein (PD-1) pathway. Different agents targeting the PD-1 pathway have shown promising results in patients with metastatic urothelial cancer [
23,
24]. The majority of these agents are currently under investigation in phase II or III clinical trials in the second- and first-line treatment of TCCU and recently the USA Food and Drug Administration (FDA) approved the first of such agents, atezolizumab, in patients with urothelial cancer progressing after a platinum-based chemotherapy. The efficacy of immunotherapy seems to be correlated with the ligand expression pattern on tumor cells and tumor-infiltrating immune cells assessed by immunohistochemistry, suggesting that treatments need to be tailored to patient subgroups with specific immunochemistry profiles [
23]. Overall, median survival observed with immuno-checkpoint inhibitors is comparable to that observed with vinflunine in our study. The real impact of these treatments on OS and the best ways of integrating immunotherapy with existing chemotherapy treatments remain to be determined.
Acknowledgements
Medical writing assistance in drafting the outline and preparing the final draft for submission of this manuscript was provided by Dr. Cécile Duchesnes, PhD, of Springer Healthcare Communications.
Authors thank:
Dr. Renata Todeschini (GOIRC secretary).
Bruno Perrucci, ASST- Istituti Ospitalieri Cremona, Cremona, Italy.
Roberto Sabbatini, Oncologia Policlinico di Modena, Modena, Italy.
Sara Testoni (data manager), IRST Meldola-Presidio Ospedaliero Forlì, Meldola (FC), Italy.
Alessandra Russo (data manager), Farmacologia Clinica UO Oncologia Medica e Ematologia Humanitas Cancer Center, Rozzano, Milan, Italy.
Elena Verri and Serena Detti (data manager), Oncologia Medica Urogenitale e Cervico Facciale, IEO Milan, Italy.
Pasquale Mighali (data manager) and Elisa Pettorelli (data manager), SSD DH Oncologico, AOU Policlinico di Modena, Italy.
Domenico Amoroso and Cheti Puccetti (data manager), UOC Oncologia Medica, Ospedale Versilia, Lido di Camaiore, Lucca, Italy.
Claudia Mucciarini, Giorgia Razzini (data manager) and Antonella Pasqualini (data manager), UO Medicina Oncologica, Ospedale di Carpi Modena, Italy.
Angela Maria Trujillo (data manager), UOC Oncologia Medica Istituto Tumori, Napoli, Italy.
Barbara Melotti and Stefania Giaquinta (data manager), Oncologia Medica, Policlinico Sant’Orsola Malpighi, Bologna, Italy.
Teresa Grassani (data manager), Oncologia Medica Policlinico Universitario Campus Bio-Medico di Roma, Rome, Italy.
Antonio Bernardo, Luca Licata, Unità Dipartimentale di Oncologia Medica, Istituti Clinici Maugeri, IRCCS, Pavia, Italy.
Luca Galli and Elena Onori (data manager), Oncologia Medica, Ospedale Santa Chiara AOU Pisana, Pisa, Italy.
Giovanni Lo Re, Oncologia Ospedale Santa Maria degli Angeli, Pordenone, Italy.
Luca Gianni and Paola Sannicolo (data manager), Oncologia Medica IRCSS Ospedale San Raffaele, Milan, Italy.
Paola Maggioni (data manager), Oncologia Medica, Cliniche Humanitas Gavazzeni, Bergamo, Italy.
Evaristo Maiello and Giovanna Capuano (data manager), UOC Oncologia, Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo Foggia, Italy.
Donatello Gasparro and Elena Rapacchi (data manager), Oncologia Medica Azienda Ospedaliero-Universitaria, Parma, Italy.
Francesco Di Costanzo and Emanuele Cilia (data Manager), Oncologia, Azienda Ospedaliera Universitaria Careggi, Firenze, Italy.
Giampiero Candeloro and Giovanna Vittoria Amiconi, UOSD Oncologia, Ospedale Civile di Avezzano, L’Aquila, Italy.
Luigi Endrizzi, Oncologia, Ospedale ULSS, Bassano del Grappa, Vicenza, Italy.
Susanne Baier and Alessandra Marabese (data manager), Oncologia Medica, Ospedale Regionale Bolzano, Italy.
Carmelo Bengala and Maria Giulia Martellucci, UOC Oncologia Medica, Ospedale Misericordia, Azienda USL9, Grosseto, Italy.
Roberta Gnoni (data manager) and Giovanna Stridi (data manager),Oncologia Medica IRCCS Arcispedale Santa Maria Nuova, IRCCS, Reggio Emilia, Italy.
Massimo Boccalon, UOC Oncologia ULSS 10 Veneto Orientale, San Donà di Piave, Venice, Italy.
Rodolfo Mattioli and Susanna Vitali (data manager), UO Oncologia Medica Ospedale Santa Croce, Fano, Italy.
Luigi Cavanna and Camilla Di Nunzio (data manager), Dipartimento di Oncologia, AUSL Piacenza, Italy.
Maria Cristina Locatelli, Alessandro Rodriquez and Giada Pagani (data manager), UOC Oncologia Medica, Azienda Ospedaliera San Carlo, Milan, Italy.
Rita Cengarle and Patrizia Morselli (data manager), Oncologia, AO Carlo Poma, Mantova, Italy.