Neoadjuvant use of Tyrosine Kinase Inhibitors

Patients with clinical stage IIIA-N2 non-small cell lung cancer (NSCLC) have a 5-year overall survival (OS) of only 10%-15%, and it decreases to 2-5% in patients with mediastina N2 bulky disease. The efficacy of surgery in this stage is limited and remains controversial. In 4 different studies with a total of 1180 patients who underwent surgical resection, 5-year survival was 14-30% [1-4]. To improve this rate and supported by the introduction of new chemotherapeutic agents, induction chemotherapy (CT) has been added to the treatment approach in this stage. The theoretical advantages of induction CT include: in vivo assessment of response to CT, which would help identify patients who might benefit from adjuvant CT; early treatment of micro metastasis to increase control of distant metastases; reduction of drug resistance due to early exposure to chemotherapeutic agents and increased surgical resect ability, due to enhance of response rates that also allows preservation of healthy lung parenchyma.


Introduction
Patients with clinical stage IIIA-N2 non-small cell lung cancer (NSCLC) have a 5-year overall survival (OS) of only 10%-15%, and it decreases to 2-5% in patients with mediastina N2 bulky disease. The efficacy of surgery in this stage is limited and remains controversial. In 4 different studies with a total of 1180 patients who underwent surgical resection, 5-year survival was 14-30% [1][2][3][4]. To improve this rate and supported by the introduction of new chemotherapeutic agents, induction chemotherapy (CT) has been added to the treatment approach in this stage. The theoretical advantages of induction CT include: in vivo assessment of response to CT, which would help identify patients who might benefit from adjuvant CT; early treatment of micro metastasis to increase control of distant metastases; reduction of drug resistance due to early exposure to chemotherapeutic agents and increased surgical resect ability, due to enhance of response rates that also allows preservation of healthy lung parenchyma.
Induction CT is a standard treatment accepted in IIIA stage which has shown survival increase in patients with inoperable stage III NSCLC; however, response and survival rates remain very unsatisfactory.
Selection of treatment for stage IV patients has evolved rapidly in recent years, as we can see in the identification of activating mutations and response to EGFR inhibitors [5]. ALK translocation for selecting crizotinib and treatment with pemetrexed in patients with nonsquamous histology [6]. They have shown a change in prognosis and an increase in survival. However, these new options of treatments have not been transferred to patients with stage III NSCLC, who are still receiving platinum-based doublets CT, without further treatment selection [7].
In this small series we present our experience and review the use of new treatments in stage III disease.

Case Report
We present 3 cases of patients diagnosed with stage IIIA non-small cell lung cancer, non-resect able at the moment of diagnosis. See Table  I   After 30 days of treatment, a PET/CT was performed in to assess the clinical response (Figure 1).

Figure 1: Tumor CT response
Down staging was achieved pathologically in 2 patients (patient 1 and 3) and clinically in one of them (patient 2), so they underwent surgery, and it was on the surgical specimen where the response to treatment with TKIs was assessed. Patient 1 passed from stage IIIA at diagnosis to stage IIA, and patient 2 passed from stage IIIB at diagnosis to stage IIIA. At the restaging moment, patient 3 had stable disease on the PET/CT but pathologically negative mediastina lymph nodes when bronchoscopy was made. He received 30days of erlotinib and underwent surgery. Although there was no down staging when surgical specimen was analysed, the piece had over 50% of necrosis.
After surgery, all of three patients received adjuvance: patient 1 was treated with erlotinib for 2 months, and suspended it because of grade 2 toxicity. She relapsed locally and with brain metastasis in March 2014 after 14 months of disease free survival. She is being treated with afatinib with good response. Patient 2 received 4 cycles of carboplatin AUC5 and paclitaxel, and was disease free for 15 months, when she relapsed with brain metastasis and is receiving treatment with gefitinib, with good control of the disease since May 2012. Patient 3 received adjuvant radiotherapy with 54Gy because the surgical specimen showed pleural involvement, and initiated erlotinib for 2 months. Erlotinib was suspended in November 2013 because of grade 2 asthenia, anorexia and diarrhoea. He remains disease free until today.

Discussion
Neo adjuvant treatment has gained acceptance in stage IIIAN2 NSCLC because of the results of several clinical trials suggesting that it increases the OS of these patients [8][9][10][11]. As distant metastases remain the most common form of relapse, it is likely that more active cytotoxic drugs or other anticancer agents may be necessary to increase the response rate and survival. All studies of patients with EGFR mutations show a double response rate with TKI when compared to chemotherapy. This is the main point of interest of neo adjuvant treatments where complete surgical resection [12][13]. Tumor down staging and pathological complete response is predictive factors for long-term survival. Pathologic complete response after induction chemotherapy varies between 0 and 9.5%. A phase II study of preoperative gefitinib in clinical stage I NSCLC, in EGFR mutant patients showed extensive fibrotic changes (mean: 32.8% of tumor area), and significantly lower cellularity (mean:24.2% of tumor area) and Ki-67 proliferative index(mean:4.6%)compared to wild type EGFR adenocarcinoma (cellularity 58.6%,p=0.01,Ki-67:31.4%,p=0.002) and non-adenocarcinoma tumors (cellularit 55%,p=0.026, Ki-67:49.8%,p=0.001) [14]. Similar information showed in another study in resected disease from an enriched population (never-smoker, female sex, non-squamous histology, or Asian ethnicity). Pathologic examination showed more than 50% necrosis in 14 patients (23%), three (5%) of whom had more than 95% tumor necrosis. The response rate in the enriched population was 34% (10 of 29 patients).
Another theoretical benefit of using neo adjuvant TKI in selected patients with EGFR mutation would be the possibility of an early evaluation. In our 3 cases, the response was obtained within 30 days of treatment. Other aspect to consider is the tolerability of these treatments. Patients older than 70 years may have problems with treatment tolerance (platinum-doublet chemotherapy) [15]. One of our patients was older than 70 year old, and he could receive sequential treatment with TKI after stabilization with chemotherapy. As he did not have toxicity after induction treatment, surgical resection was performed, also without complications. We would like to underline that none of the patients interrupted the treatment in the first 20 days, when the response evaluation must be done, so we think that a short course of TKIs is feasible, safe and does not lead to treatment interruption. The maintained treatment in adjuvant or metastatic setting is associated to toxicities that can lead to the interruption of the TKIs treatment as happened after several months with two of our patients.
Neo adjuvant use of EGFR-TKIs in mutated patients has been reported only anecdotally so far [16][17][18][19][20]. In 2 of our cases, there is a special feature that makes it much more informative and not previously described. They were treated with chemotherapy doublets, one with cisplatin and pemetrexed, to obtain greater response optimization. In both, a short course of 20 days of TKI treatment was used. Because of the short duration is did not interfered in the patient treatment, if there had been no progression or response to treatment with definitive chemo radiotherapy. It remains questionable whether to apply adjuvant treatment with these compounds might be relevant. The NCIC Clinical Trials Group BR.19 study randomized 503 patients with resected stage IB-IIIA NSCLC to oral gefitinib 250 mg daily for 2 years or to placebo [21]. Overall survival trended in favour of placebo (hazard ratio:1.23; p=0.136), and patients with EGFR wild-type (hazard ratio:1.21;p=0.301) and EGFR mutation (hazard ratio:1.58; p=0.16) experienced non significantly worse survival on gefitinib, however this is not a large number of patients.
New studies should be done in selected populations to explore this approach, but it seems logical that in selected populations with EGFR mutation the results of advanced stages should be reproduced.