Non-small cell lung cancer: from targeted therapy to tailored therapy

Keywords::

• bevacizumab
• lung cancer
• tailored therapy
• targeted therapy

Since large, randomized controlled trials showed a positive effect of chemotherapy on survival in patients with advanced non-small cell lung cancer (NSCLC) over two decades ago [1,2], a considerable number of Phase III trials have been carried out, defining current clinical recommendations for the management of the disease [3]. As platinum compounds quickly emerged as the mainstay of treatment of NSCLC in the first-line setting, cisplatin and carboplatin have been combined in a wide variety of regimens, with a 1-year survival rate increasing from 10 to 15% with first-generation agents (e.g., mitomycin, ifosfamide) to 20 – 25% associated with second-generation agents such as etoposide [2]. A plateau, with a 1-year survival rate around 30 – 35% and a median overall survival around 8 – 10 months, has been achieved with a number of third-generation regimens [3], including cisplatin and gemcitabine, cisplatin and docetaxel, carboplatin and paclitaxel, and cisplatin and vinorelbine [4,5]. In spite of comparable results in terms of survival and progression-free survival, third-generation agents present a remarkably heterogeneous toxicity profile, which should be wisely incorporated in the decision-making process for the choice of first-line treatment. In fact, as exemplified by Scagliotti et al. [4], grade 3 – 4 neutropenia and nausea/vomiting were prominent side effects of vinorelbine/cisplatin, while grade 3 – 4 thrombocytopenia was most frequent with gemcitabine/cisplatin, and grade 3/4 alopecia and peripheral neurotoxicity were most common with carboplatin paclitaxel. Taking such data into account, the treating physician should regard patients with diabetic neuropathy to be unsuitable to receive carboplatin/paclitaxel, which may represent the treatment of choice in patients unable to tolerate hydration required for or expected nephotoxic effects of cisplatin. Similarly, cisplatin and gemcitabine may be inappropriate in patients with bleeding disorders or history of hemoptysis. With the advent of targeted therapy for treatment of NSCLC, the choice of the chemotherapy agents to be employed has become even more critical, as our efforts to increase treatment efficacy by combining chemotherapy with targeted agents may be vain if overlapping side effects cause unacceptable toxicity. In fact, unlike small molecules such as gefitinib, erlotinib and crizotinib, which are employed as single agents [3], monoclonal antibodies cetuximab and bevacizumab, respectively, directed at EGFR and VEGF, showed to be effective when combined with chemotherapy [6-8]. While rash is the main side effect associated with cetuximab [8], bevacizumab causes a variety of toxic effects such as hypertension, bleeding, fatigue and thrombosis/embolism both when employed in combination with chemotherapy as in NSCLC [6,7] and as single agent as in kidney cancer [9]. In particular, in a meta-analysis involving 14,277 patients with solid tumors treated with bevacizumab, the addition of bevacizumab to chemotherapy increased the risk of severe bleeding by 60%, with a greater than threefold increase in patients with non-small cell lung cancer (RR 3.41, 95% CI 1.68 – 6.91), with a possible dose-dependent increase in risk [10]. In a meta-analysis involving a total of 10,217 patients with a variety of advanced solid tumors, the addition of bevacizumab to chemotherapy was associated with a 46% increase in the risk of fatal adverse events (RR 1.46; 95% CI 1.09 – 1.94; p = 0.01; incidence, 2.5 vs 1.7%), with hemorrhage being the most common cause of drug-related death (23.5% of cases) [11]. This represents the reason why bevacizumab is contraindicated in NSCLC with history of hemoptysis, untreated brain metastasis, and tumors with squamous cell histology [3]. In the randomized, placebo-controlled three-arm Avail trial, cisplatin plus gemcitabine was administered with either placebo or bevacizumab at 7.5 mg/kg three-weekly or bevacizumab at 15 mg/kg three-weekly to patients with non-squamous NSCLC, with a benefit in progression-free survival in both the low-dose group (median PFS, 6.7 for bevacizumab vs 6.1 months for placebo; p = 0.003) and in the high-dose group (median PFS, 6.5 for bevacizumab vs 6.1 months for placebo; p = 0.03), but no advantage in overall survival. The overall rate of grade 3 – 4 thrombocytopenia was 23 – 27%, with a overall rate of severe bleeding of 4% in the bevacizumab arms (vs 2% in the placebo arm). Interestingly, in the Phase III trial by Sandler et al. [6], a statistically significant benefit in both progression-free survival (6.2 vs 4.5 months), and overall survival (12.3 vs 10.3 months) was achieved with the addition of bevacizumab to carboplatin and paclitaxel with respect to placebo in patients with non-squamous NSCLC. The incidence of severe hemorrhage was similar to that reported in the AVAIL trial, despite carboplatin–paclitaxel–becavizumab yielded grade 3 – 4 thrombocytopenia in less than 2% of patients. Although this is consistent with the data that only 1 out of 10 episodes of bleeding were related to any grade of thyombocytopenia in the AVAIL trial, we believe that the increased risk of bleeding related to thrombocytopenia maybe more relevant in a population of less selected patients such as those treated in common clinical practice. Furthermore, it is important to note that cisplatin and gemcitabine has ceased to be the standard regimen for patients with non-squamous histology NSCLC, as cisplatin pemetrexed yielded better results in terms of survival prolongation and tolerance in this subset of patients [3]. The use of bevacizumab has also been explored in combination with cisplatin and low-dose daily etoposide with interesting results [12,13]. Although cisplatin and etoposide present a less favorable toxicity profile than third-generation cisplatin-based regimens, metronomic administration of etoposide has the biological potential to enhance the anti-angiogenetic activity of bevacizumab, with positive immunosuppressive and epigenetic effects [12]. Nevertheless, the high activity of cisplatin, bevacizumab and metronomic etoposide must be balanced against its increased toxicity (e.g., neutropenia) [13].

In this context, we hold in great consideration the results shown by Leon et al. [14], who report about 49 patients with non-squamous NSCLC treated with the combination of vinorelbine, cisplatin, and bevacizumab. Importantly, this Phase II trial scheduled vinorelbine on days 1 and 8 and employed a cisplatin dosage of 80 mg/m² every 3 weeks which showed to be better tolerated than the weekly schedule for vinorelbine administration in combination with CDDP administered at 100 mg/m² monthly [15]. A progression-free survival and an overall survival of 6.0 months (95% CI 4.5 – 7.5) and 14.7 months (95% CI 8.4 – 21), respectively, were obtained with no event of toxicity-related death or grade 3 – 4 thrombocytopenia and a single event of severe bleeding during maintenance. Even if the absence of severe thrombocytopenia events here reported with this schedule may not necessarily translate into a lower incidence of severe hemoptysis, further investigation of this schedule in the context of a Phase III trial appears of utmost importance for a number of reasons. First, we have explained how important it is for the clinician to be able to choose among the different third-generation agents available because of their different toxicity profile. Presently, this possibility is limited to cisplatin–gemcitabine or paclitaxel–carboplatin by the number of Phase III trials carried out, if patient is to be treated with bevacizumab. Second, the optimal dosage of bevacizumab is to be defined. Third, it would be extremely useful to compare cisplatin–vinorelbine–bevacizumab to cisplatin–pemetrexed or carboplatin–pemetrexed–bevacizumab, for the reasons discussed above.

In conclusion, we believe that, taken into account all of these considerations, it is time to embrace the concept of “tailored therapy” in oncology and especially NSCLC, which is wider than that of “targeted therapy” and better describes the exciting possibilities of diversified treatment associated with the growing number of therapeutic options effective or potentially effective in NSCLC, such as cisplatin–vinorelbine–bevacizumab. Such concept encompasses and refers to all variables, not only of biological nature, useful in the extremely complex decision-making process regarding the choice of medical treatment of NSCLC.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.