Treatment Outcome in Patients with Metastatic Non-Small Cell Lung Cancer at Presentation (Retrospective Study) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Al-Azhar International Medical Journal | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Article 10, Volume 1, Issue 1, January 2020, Page 53-60 PDF (415.75 K) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Document Type: Original Article | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
DOI: 10.21608/aimj.2020.22738.1093 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Author | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Abd Elmonaem Mohamed Abd Elmonaem | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
clinical oncology department ,Faculty of medicine, Al-Azhar University | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Abstract | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Background: Worldwide, lung cancer representing 13% of all new cancer cases And has the highest mortality rate . In Egypt, lung cancer incidence is about 4.6% of all cancers . recent trials reporting that immune therapy (anti PDL1) showed a significant superior progression-free survival (PFS) and overall survival (OS) if compared with standard chemotherapy Objectives: To assess outcome of treatment in patients with metastatic non-small cell lung cancer at presentation, in term of response to treatment, progression free survival and, overall survival, treatment related toxicity. Patients and Methods: patient related data: Age, sex, special habits, and performance status. Disease related data: date of diagnosis, extent of disease, histopathology details and sites of metastasis , Treatment related data:- Chemotherapy (regimen ,cycles , response related toxicity ), Radiotherapy (site , related toxicity ) ,Response to treatment according to RECIST criteria .Progression free survival, Overall survival . Results: our study among 56 patients, 29 patients received chemotherapy. radiotherapy used for palliation of symptoms , patients who received chemotherapy showed improvement of progression free survival and overall survival when compared with those who didn’t receive chemotherapy, there were no available data about quality of life , because of unavailability of resources we didn’t use targeted or immune therapies Conclusion: patients with metastatic NSCLC, if molecular tests of gene mutations and checkpoints expressions not available , a four to six cycles of platinum based chemotherapy is indicated in patients with good performance status as regard that chemotherapy showed survival benefit versus best supportive care | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Metastatic; lung; Cancer | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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INTRODUCTION Worldwide, lung cancer occurred in approximately 1.8 million patients in 2012 representing 13% of all new cancer cases) and caused an estimated 1.6 million deaths, lung cancer has the highest mortality rate worldwide .6 In the United States, there will be approximately 234,000 new cases of lung cancer and over 154,000 deaths annually.18 In Egypt ,The lung cancer incidence is about 4.6% of all cancers in both sexes, representing about 6.9% of male cancers (5017 cases) and 2.5% of female cancers (3634 cases) and mortality rate 6.8% in males and 3.8% in females (Globocan fact sheet, Egypt 2012).Lung cancer deaths in Egypt reached 4,429 per 100,000 of population in 2002 .3 Platinum-based chemotherapy remains the standard-of-care for most patients affected by advanced non small cell lung cancer (NSCLC) , Recent evidence emphasized that the optimal number of first-line platinum cycles should be four for any NSCLC histology.3 After the era of advances in the molecular biology, many mutations had been discovered in lung cancers cells, these mutations are currently drive the choice of first line treatment targeted therapy in such patients after the statistical significant survival and clinical benefits with high acceptable toxicity profile that had observed with the use of this class of therapy when compared with chemotherapy as first line treatment17 Recently, the use of immune therapy in the first line treatment either alone or in combination with chemotherapy in selected patients with PDL-1 expression showed a significant superior progression-free survival (PFS) and OS when compared with standard chemotherapy alone. Therefore, the Key-note 024 trial was prematurely stopped in order to allow patients receiving chemotherapy to cross over to the immunotherapy arm.13 The primary objective of this study is to assess the outcome of treatment in patients who presented with metastatic non-small cell lung cancer in term of response to treatment, treatment related toxicity, progression free survival and overall survival. PATIENT AND METHODS This Retrospective study included 56 patients with metastatic non-small cell lung cancer who received systemic treatment at our department during the period between June 1st 2012 and June 1st 2017, and meet the following inclusion criteria; histopathology confirming non-small cell lung cancer either histologically or cytological, age younger than 80 years old, Performance status 0-3 (WHO) and radiological confirmed distant metastases at presentation. Charts of included patients have been retrieved from the archive to collect the following data: Age, sex, special habits (eg. smoking), comorbidity, performance status, histopathology, chemotherapy related details, radiotherapy if received, and finally response to treatment according to RECIST criteria. Overall survival interval was considered as the period between the date of histological diagnosis and the date of the last follow-up (for censored observations) or the date of death (for uncensored observations), while progression free interval was considered as the period between date of the first treatment and the date of the last follow-up (for censored observations), or date of death or disease progression whichever happen first (for uncensored observations). Statistical methods: Data were coded and entered using the statistical package SPSS version 23. Data was summarized using mean, standard deviation, median, minimum and maximum for quantitative variables and frequencies (number of cases) and relative frequencies (percentages) for categorical variables. One-sided log-rank of Kaplan—Meier survival estimates was used for statistical analysis of overall survival and progression free survival, while the unpaired T test and one-way ANOVA test were used in the univariate analysis of the variables. Results of P-values less than 0.05 were considered as statistically significant. Ethical approval: The current investigation was had been executed based on the recommendations approved by the ethical committee, Faculty of Medicine, Al-Azhar University, Cairo, Egypt, before the start of this study.
RESULTS In the study group, the mean age of the 56 included patients was 57.9 (±10.3), male patients were 44 (78.6 %) , and females were 12 (21.4 %), with male to female ratio 3.5 : 1 respectively; 40 patients (71.4 %) were smokers and 16 patients (28.6 %) weren’t smokers; performance status (PS) at presentation was reported 0 for 23 patients (41.1 %), PS I for 18 patients (32.1 %), PS II for 12 patients (21.4 %) and PS III for three patients (5.4 %) All patients had NSCLC with different subtypes: 35 patients (62.5%) had adenocarcinoma, nine patients (16.07 %) had squamous cell carcinoma, seven patients (12.5 %) had undifferentiated carcinoma, four patients (7.14%) hadlarge cell carcinoma and one patient only (1.78 %) had spindle cell (sarcomatoid); as regard pathological grading, 30 Patients (54.5 %) had grade II and 26 patients (45.5 %) had grade 3 tumors; the most common site of metastasis was bone in 21 patients (37.5 %) followed by contralateral lung or pleural metastasis in 18 patients (32.1 %), suprarenal metastasis in 14 patients (25.0 %), brain metastasis in 13 patients (23.2 %) and liver metastasis 6 patients (10.7 %). Table (1) Active treatment was delivered for 43 patients (76.8%) while 13 patients (23.2%) didn’t receive active treatment; 29 patients (51.7 %) received chemotherapy with a median number of four cycles (range 1-9); 21 patients (37.5 %) received Gemcitabine + cisplatin, five patients (8.9 %) received carboplatin + etoposide, tow patients (3.6 %) received paclitaxel + cisplatin and one patient (1.7 %) received carboplatin + paclitaxel; while 37 patients (65.9 %) received palliative radiotherapy of them 14 patients (25 %) missed after end of treatment. On the other hand six patients (10.7 %) missed after first visit, seven patients (12.5 %) managed with best supportive care. Only 7 patients (12.5 %) was able to receive second line chemotherapy: six of them (10.7 %) received taxenes based regimen (paclitaxel or docetaxel) and only one patient (1.7 %) received (cisplatin + navelbine). The most common toxicities showed with chemotherapy :grade 2 – 3 Anemia in 15 patients (51 %) who treated with (cisplatin \gemcitabine) or (carboplatin \ gemcitabine) regimens , G2-3 Nausea and vomiting developed in 14 patients (48.2 %) who received platinum based chemotherapy , however some patients developed another toxicity profiles either related to chemotherapy or radiotherapy but it was insignificant as showed in table ( 2 ) According to RECIST criteria v1.1 response to 1st line chemotherapy was reported in patients charts as following; 11 patients (19.6 %) had partial response, four patients (7.1 %) had stationary disease and 11 patients ( 19.6 % ) developed disease progression, while no assessment was reported in the charts of three patients (5.35%). table (3):
Table 1: Patients and disease criteria
Table 2: Treatment received and toxicity profile
Table 3: Response to treatment
The median progression free survival was 8.9 months for all patients included in this study, however it was 9.3 and 7.5 months for patients who received chemotherapy and didn’t receive any treatment respectively, with no statistical difference between the two group (P= 0.3). Figure (1)
Fig. 1: Median Progression free survival (PFS) curve Median overall survival (MOS) was 10.8 months, at subgroup analysis systemic treatment showed significant improving in overall survival as following : in patients who didn’t receive treatment MOS 10.8 but in patients who received chemotherapy MOS was 13.6 (9.3-17.9) ( P= 0.019). Figure (2)
Fig. 2: median overall survival (MOS) curve On the other hand PFS and OS did not significantly affected by any of the following factors; age, sex, PS, special habits, histopathological subtype, pathological grade , site of metastasis, type of chemotherapy or number of cycles.……………………………………………………………………
DISCUSSION Worldwide, lung cancer occurred in approximately 1.8 million patients representing 13% of all new cancer cases and caused an around 1.6 million deaths, lung cancer has the highest mortality6 In the five years duration of this study the total number of patients who presented to our department were 4636, patients who diagnosed with lung cancer were 152 cases (3.27 %), total number who presented with metastatic Non-small cell lung cancer were 61 (40 % of total lung cancer patients), so in our department, incidence of lung cancer is different from international incidence. Where in Egypt incidence of lung cancer in the period between 2008 and 2011 was 4.22 % of all 3 In our study the mean age was 58 years and male to female ratio was 3.5 : 1 which is different from the published data by Brule, where he reported mean age of 67 years and male to female ratio 1.2 : 1 (Stephanie Y. Brule; et.al 2016), this difference could explained by the higher rate of smokers among Egyptian males and lower rate of smokers among Egyptian females. According to the current treatment guidelines by NCCN and ESMO, all patients who are newly diagnosed with stage IVNSCLC and has none squamous histology or have squamous histology based on small biopsy or nonsmoker should be tested by broad molecular profiling, and 1st line treatment should be based on the result of this testing.12 Up to this moment the targeted therapy not provided by the Egyptian health ministry to none insured patients, that represent the majority patients receiving treatment at our department, because of this the overall survival in the patients included in our study is considered very low compared to the published data in the era of targeted therapy19 With stage IV disease who have a good PS benefit from chemotherapy, usually with a platinum-based regimen is recommended for patients with stage IV NSCLC and negative or unknown test results for ALK rearrangements or sensitizing EGFR mutations, PD-L1 expression less than 1% or unknown and contraindications to immunotherapy. Recommended chemotherapy regimens are based on PS and include platinum agents (eg, cisplatin carboplatin), taxanes (eg, paclitaxel, albumin-bound paclitaxel [also known as nab-paclitaxel], docetaxel), vinorelbine, etoposide, pemetrexed, and gemcitabine .4 Patients included in our study received platinum based chemotherapy mean No of cycles were 4 range (1-9) and radiotherapy used as palliative treatment for symptomatic patients that similar to published data reported that Chemotherapy improves both survival and quality of life in metastatic NSCLC, four cycles of platinum based Chemotherapy (max 6 cycles) is the standard treatment for patient with good Performance status. Patients with border line Performance status =2 may benefit from single agent. Palliative radiotherapy is introduced for symptomatic patients only22, Four to six cycles of platinum based chemotherapy is indicated in patients with metastatic non small cell lung cancer with good performance status , Extending the duration of treatment with the initial platinum based chemotherapy beyond four to six cycles is not recommended 4 In our study we considered grades 2-4 toxicities of chemotherapy among who received chemotherapy , 15 patients (51 %) developed Anemia with cisplatin\gemcitabine or carboplatin \ gemcitabine regimens, 14 patients (48 %) developed Nausea and vomiting in platinum containing chemotherapy, 5 patients (17 %) developed Neutropenia with cisplatin containing regimens , 2 patients (6 %) developed G4 Thrombocytopenia with cisplatin\carboplatin + gemcitabine regimens, 2 patients (6 %) developed Mucositis G2 with carboplatin containing chemotherapy, 3 patients (10 %) developed Diarrhea in cisplatin + gemcitabine regimens, which is similar to worldwide publication.4 Radiotherapy toxicity profile: 29 patients received palliative Rth ,3 of them complained bony pain at site of Rth over bony Mets, 1 patient complained headache after he finished WBI, 2 pts complained hair loss after WBI, 1 patient complained mucositis and dysphagia G2 after he finished palliative Rth to mediastinal mass . This meets previous publications of reported radiotherapy toxicity by.8 In our study group the progression free survival (PFS) had no significant difference between patients who received chemotherapy and those who didn’t receive any treatment median PFS was 9.3 months (7.1-11.4 ) for patients who received chemotherapy and 7.5 months (1.8-13.1) ( P = 0.349) for patients who didn’t receive any treatment that was different with data published by 14 Unfortunately none of our patients received pemetrexed in their treatment due to unavailability of treatment ,that’s why we couldn’t assess survival on adding pemetrexed to chemotherapy regimens , on the other hand A phase III trial in which Survival in the 847 patients with adenocarcinoma was significantly prolonged with cisplatin plus pemetrexed compared with cisplatin plus gemcitabine (median 12.6 versus 10.9 months respectively).21 In our study group median OS was 10.8(3.7-17.9) months in patients didn’t receive active treatment versus 13.6 months (9.3-17.9) in patients received chemotherapy (p value 0.019 ) that was similar to results of data published in(2001)1who reported median OS was ( 13.7 months ) (range 7.4 - 213 weeks ) (p=0.0018).in patients who received chemotherapy) , and different from results of study published in 2016 . 20when Median OS was shorter amongst untreated patients (3.9 vs. 10.7 months in Systemic chemotherapy , ( HR 1.80 [95% CI 1.4–2.3], p < 0.01). The use of immune therapy in the first line treatment either alone or in combination with chemotherapy in selected patients with PDL-1 expression showed a significant superior progression-free survival (PFS) and OS when compared with standard chemotherapy alone. Therefore, according to ESMO guidelines patients of (KEYNOTE-024 trial was prematurely stopped receiving chemotherapy to cross over to the immunotherapy arm .13 Unfortunately Up to this moment immune therapy not provided by the Egyptian health ministry to none insured patients, that represent the majority patients receiving treatment at our department so our patients couldn’t gain benefit of such treatment option .
CONCLUSION In patients with metastatic NSCLC, if molecular tests of gene mutations and checkpoints expressions not available, a four to six cycles of platinum based chemotherapy is indicated in patients with good performance status as regard that chemotherapy showed survival benefit versus best supportive care. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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DOI: 10.1200/JCO.2015.62.0138
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