First line therapies:
During this period the everyday practice was the use of cytotoxic drugs for Stage IIIB/IV patients as following: bevacizumab+paclitaxel (42), gemcitabin+cisplatin (68), gemcitabin+carboplatin (26), paclitaxel+carboplatin (21), pemetrexed+cisplatin (31), docetaxel+ cisplatin (23), gemcitabin (13). The first line therapy was used for all 224 patients, in case of 116 men and 108 women. From this result we have concluded that, all 224 patients were in good general condition, ECOG: 0-2.
Second line therapies:
The second line therapy was used for 85 patients (38%), in case of 36 men and 49 women. It is very important message that for the second line therapy less than 40% of all patients were eligible. Behind this reason there are different things: disease progression, death, decrease of performance status (ECOG =2), and sometimes the patients decisions. As I mentioned before during this period we could use EGFR TKI erlotinib in second line, and only for those patients who were KRAS wilde type for 38 patients (17%). The second more frequent therapy was pemetrexed. Docetaxel monoterapy was used in case of 10 patients and paclitaxel+ carboplatin treatment was used in case of 3 patients.
Third line therapies:
The patient number is low, as only 18% of patients were eligible. The reasons are similar like in case of second line was: disease progression, death, decrease of performance status (ECOG =2), and sometimes the patients decisions. From the treated 41 patients more were women (23), and less 18 were men. In this group 19 patients were treated with erlotinib, and 14 patients with pemetrexed and for more than 8 patients docetaxel was the therapeutic choice.
Lung cancer symptoms are very poor this is the one of reasons why more than 60% of lung cancer have distant metastases at the time of diagnosis. From the analysed total 224 patients in case of 174 patients (78%) distant metastases were verified. Most of patients, 72 (42%) had at least one bone lesion detected, in case of 42 patients (24%) brain metastases and in case of 28 patients (16%) liver metastases were found. Both brain and bone metastases were verified in case of 32 patients. When the brain metastasis appears we can use complex oncotherapy but the death is coming so fast. The progression time of bone metastases is much longer but the appearance of strong pain and SRE decrease the Quality of Life (Table 1).
Ratio of Bone metastases within EGFR mutant patients:
Bone lesions are detected by Bone Scintigraphy-75%, Computer Tomograph (CT) : 23%, X-Ray: 2%. We could realize in case of 174 patients distant metastases out of 224 patients. Bone metastases are the most frequent 42% followed by brain metastases as: 24%. Syncron bone and brain metastases were verified as 18-%. Liver metastases were less only 16% were detected. Quality of life decreased rapidly with the prevalence of bone metastases because of strong bone pain as well as with life-threatening SRE. There are complex oncotherapy possibilities what we can use step by step. Giving Bisphosphonate to the patient to turn back the bone remodeling is the most frequent therapeutic process; this was used at 36%. Radiotherapy is very important because not only stabilises the bone structure but decrease the bone pain. This method was used at 20%. Best Supportive Care (BSC) therapy was done for 32% of the patients. Considering the EGFR mutation status is a well-known prognostic and predictive factor in case of lung adenocarcinoma as well we have tried try to find some correlations between the prevalence of bone metastases and EGFR mutations status. From the 72 patients with verified bone metastases we could detect EGFR mutation in case of 38 patients, and in other 34 patients EGFR mutation was not detected. Surprisingly the ratio was similar within those patients who have not suffered from bone metastases. In this group, from 152 patients the ratio was: 78 patients were EGFR mutant, and 74 patients were wild type (Table 2)
I. Statement: We can conclude that there is no significant correlation between appearance of bone metastases and EGFR mutation status. (p=0.59).
Bone and Brain Metastases appearance within KRAS mutant patients:
Carcinogenesis of lung cancer has a long pathway. During this process lots of genetics and epigenetics abnormalities are accumulated in the normal lung tissue, which leads to the malignant disease. KRAS mutations are one of the most important and very early mutation which correlates with smoking habits [20
]. The other very important signal transduction pathway is the activation of EGFR mutations. Those patients who are heavy smokers the KRAS mutation status is very high and they will not respond for EGFR TK inhibitors therapy. This analysis is based on these correlations. In this study, from 72 patients who were suffering from bone metastases in case of 44 patients KRAS mutation (62%) was detected and in case of 28 patients (38%) there were no mutations (Wt). In case of those 85 patients (56%) who have no verified bone metastases there were no KRAS mutations detected. In this study we have found syncron bone and brain metastases in case of 32 patients. Duplex metastases were documented at 60% in case of 19 patients and they were verified as KRAS mutant patients, opposite the 40% who were KRAS Wilde type. The prevalence of duplex metastases decreased rapidly the Quality of life and Survival time also.
The results of this analysis showed that there is a higher ratio, (60%) of bone metastases within patients where KRAS mutation was detected. These patients are mostly heavy smokers, and they are not eligible for EGFR TK inhibitors therapy according to Hungarian Health Insurance rules.
In other hand, ratio of bone metastases was lower within non-smokers (40%) and mostly (56%) for those patients who are not representing KRAS mutation, so they were KRAS wild type. According to the Hungarian Health Insurance Rules these patients are eligible for the treatment with EGFR TK inhibitors. In the scientific literature a complex therapeutically effect is mentioned. In this case the targeted agents, like EGFR TK inhibitors are influencing the bone remodeling system, changing the osteolytic metastases into osteoblastic metastases, and there is a pain killer effect as well (Table 3)
The survival results of the three years analysis which was done from 01.Jan.2008 to 31.Dec. 2010 are the following. Closing time of survival data collection was at 31.12.2013. Survival times were calculated using Kaplan-Meier method. At that time from the total of 224 patients only 42 patients (18%) were alive, most of the patients - 182 patients (82%) have died. The gender ratio of between 42 survivors was: 24 women and 18 men. Out of 182 patients who had died, 98 patients (54%) were man and 84 patients (46%) were women. The therapeutic decision making KRAS mutation status was the following: From those patient who had died, 60 % detected KRAS mutation, so they were not treated by EGFR TK inhibitors. The rest of patients who had died 40% where KRAS wild type. From the 42 survivors 31 patients were KRAS mutant and 71 (58%) were wild type. In this study according to the Hungarian Health Insurance Policy we could use erlotinib only for 2nd and 3rd lines, for KRAS Wt patients. The smokers were not eligible for this EGFR TK inhibitor therapy because of higher presence of KRAS mutation. Cytotoxic chemotherapy was given to all these patients as a 1st line therapy, so there is some overlap in these two types of therapy. Chemotherapy was given for 167 patients because of KRAS mutant status they were not eligible for EGFR TKI therapy. In conclusion we have realized that the EGFR TKI treatment possibilities give longer life for the selected populations. This is clear that these good results are coming from the very strict eligible criteria (For 2nd
line, for ECOG 0-2 patients).
Those patients lived longer who were never smokers, who were KRAS wild type and who were treated with EGFR TK inhibitors. Good performance status (ECOG 0-2) which was a selection criterion by Hungarian Health Insurance has a great influence on these results.