Beyond Cisplatin – I

Roughly 25% of patients at diagnosis of urothelial cancer (UC) have at least muscle invasive disease [1] and about half of these have extravesical extension or more advanced disease at that time. Additionally 10–15% of patients who initially have non-muscle invasive UC will subsequently develop muscle invasive or more advanced cancer. The outlook for patients with advanced or metastatic UC, particularly those who do not respond to Cisplatin-based combination chemotherapy regimens is very poor. Moreover, except in adjuvant and neoadjuvant settings, despite objective response rates to Cisplatin based combination therapies of about 50% [2] median survival is only about 15 months and time to progression far briefer, with 5 year survival only being about 15% [3]. Additionally, because of comorbidities and frailty, many patients with advanced UC cannot receive these Cisplatin containing regimens. Relapsing patients respond poorly to additional treatments with median survival of usually 10 months in patients heavily pretreated with cisplatin chemotherapy [11]. Moreover, neither of these studies used biomarkers to select participants; since if they had, a higher proportion of responses may have been seen. Interestingly, in other studies, inhibitors of VEGF-R1 and VEGF-R3 were not effective [7]. In a separate report [12], Afatinib, an oral irreversible inhibitor of the ErbB receptor family was used as a single agent in 23 patients with metastatic UC, and while only 22% (N = 5) of patients had responses, 5 of the 6 patients with HER2 or ErbB3 alterations accounted for all of these, while none of the 15 without either of these alterations responded. Moreover the one patient with both HER2 amplification and ErbB3 mutations achieved the longest response (10.3 months), actually never progressing while on therapy (stopped because of reduced cardiac ejection fraction which may or may not have been related to the drug). While ErbB3 does not have intrinsic receptor tyrosine kinase activity, it is thought to dimerize with HER2, increasing activity of HER2 akin to amplification of HER2. These alterations in HER2 and ErbB3 were determined by genetic analyses, which did not correlate with immunhistochemical (IHC) expression of the proteins – and, as opposed to the genetic analyses, IHC did not correlated with clinical response. Diarrhea, fatigue and rash were major side effects but only 2 patients experienced grade 3 toxicity. The papers reviewed here illustrate both the promise and complexities of studying targeted agents in advanced UC. While there’s much work still to do, we now have begun to have means to help patients who are refractory to, or unsuitable for cisplatin therapy.