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  Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 1  |  Page : 132-135
 

Epidermal growth factor receptor positive lung cancer: The nontrial scenario


Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication1-Dec-2017

Correspondence Address:
Dr. K Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.219583

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 » Abstract 

PURPOSE: The aim of this study was to report the median overall survival (OS) in epidermal growth factor receptor (EGFR) mutation-positive patients who were managed out of a clinical trial. METHODS: Nonsmall cell lung cancer patients harboring activating EGFR mutations who were either ineligible or refused participation in a clinical trial were selected for this analysis. The reason for not participating in trial, staging, treatment, and outcome details were obtained from a prospective lung cancer database. The Kaplan–Meier method was used to estimate OS. Log-rank test and Cox proportion hazard model were used for univariate and multivariate analysis, respectively. RESULTS: We included 225 patients in this analysis. The median age of the cohort was 56 years (range 29–85 years). A compromised Eastern Cooperative Oncology Group performance status (PS) of >2 was the major reason (83 patients, 36.9%) for ineligibility of patients in a clinical trial. The major reason provided by eligible patients for refusal to participate in a clinical trial was long distance of travel and inability to comply with the study-mandated follow-up visits (65 patients, 28.9%). The median OS in patients with PS 0–2 was 18.17 months (95% confidence interval [CI]: 15.6–20.8 months) and it was 12.1 months (95% CI: 9.0–15.2 months) in patients with PS 3–4 (hazard ratio - 0.579 [95% CI: 0.398–0.843] P = 0.004). CONCLUSION: EGFR positive patients who were ineligible for a clinical trial due to poor PS had lower survival; however, patients with good PS treated off-trial had similar OS to that reported in multiple clinical trials.


Keywords: Epidermal growth factor receptor mutation, lung cancer, nontrial, palliative chemotherapy


How to cite this article:
Noronha V, Patil V M, Joshi A, Tandon N, Sharma V, Ramaswamy A, More S B, Gaud S, Prabhash K. Epidermal growth factor receptor positive lung cancer: The nontrial scenario. Indian J Cancer 2017;54:132-5

How to cite this URL:
Noronha V, Patil V M, Joshi A, Tandon N, Sharma V, Ramaswamy A, More S B, Gaud S, Prabhash K. Epidermal growth factor receptor positive lung cancer: The nontrial scenario. Indian J Cancer [serial online] 2017 [cited 2019 Oct 18];54:132-5. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/132/219583



 » Introduction Top


Lung cancer remains the leading cause of cancer-related mortality worldwide.[1] In India, about 63,000 new cases are diagnosed each year with an estimated 52,000 deaths accounting for about 8% of all cancer deaths.[1] Major treatment refinements have occurred in nonsmall cell lung cancer (NSCLC) over the last decade as a result of multiple well-conducted randomized studies. At present, international guidelines recommend treatment of NSCLC based on histology and actionable mutation profile.[2],[3] The median overall survival (OS) with a platinum doublet reported in the early 21st century ranged between 7 and 8 months in Stage IV NSCLC.[4] Currently, the median OS of epidermal growth factor receptor (EGFR) mutation positive NSCLC patients in various clinical trials has consistently been reported to be in the range of 19.3–30.5 months.[5],[6] Even in EGFR and anaplastic lymphoma kinase mutation negative NSCLC patients, the reported median OS with a paclitaxel-platinum-bevacizumab regimen is 12.3 months.[7] However, these figures apply to patients who were enrolled on major randomized trials, and these patients were selected only if they fulfilled strict inclusion and exclusion criteria. In routine practice, only 11% of lung cancer patients are eligible for clinical trials; thus, the vast majority are treated off-trial.[8] The outcomes in this group of patients are seldom reported. We assume that these outcomes (seen in routine clinical practice) would be similar or may be slightly inferior to those reported in the major clinical studies. We use the outcome data obtained from clinical trials to counsel patients that we treat off-trial; however, we do not know whether the outcomes will be similar in routine care. The aim of our study was to report the median OS in EGFR mutation positive patients who were treated off-trial.


 » Methods Top


Patient selection

In August 2010, we started a randomized clinical trial at our center that recruits EGFR positive NSCLC patients. This trial is still actively recruiting, as on date (March 2016). Patients who were screened for this study but were either not eligible or who refused to participate between August 2010 and December 2014 were selected for this analysis. The details of these patients were obtained from the prospective lung cancer audit database that is maintained in the department of medical oncology. The lung cancer audit is an Institutional Ethics Committee approved observational protocol, is registered with the Clinical Trials Registry - India (registration number: CTRI/2013/01/003335), and patients sign a written informed consent before their information being recorded as part of the lung cancer audit.

For the purpose of this current study, the reasons for not participating in the clinical trial for EGFR positive patients were divided as follows:

  • Not eligible for the trial due to poor Eastern Cooperative Oncology Group (ECOG) performance status (PS)
  • Not eligible for the trial due to uncontrolled comorbidity
  • Eligible but not willing to participate because of long distance of travel
  • Eligible but not willing, no reason provided.


Pretreatment evaluation

As per our institutional policy, patients underwent physical examination and routine baseline blood testing (complete hemogram, renal and liver function tests). For assessment of the extent of disease, a contrast-enhanced computed tomography of the chest and upper abdomen was obtained. Imaging of other sites was obtained only if the patient had specific symptoms or there was suspicion of specific metastases on clinical evaluation.

Epidermal growth factor receptor mutation analysis

DNA was extracted from the formalin-fixed paraffin-embedded blocks of the patients who had pathologically proven adenocarcinoma and amplified for the exons 18, 19, 20, and 21 using a nested-polymerase chain reaction method using TaqMan probe. Details of the procedure have been published by us earlier.[9]

Treatment received and follow-up

Based on various clinical factors including age, comorbidities, PS, and the urgency to start therapy, first-line therapy consisted of either an oral EGFR-targeted tyrosine kinase inhibitor (TKI), i.e., TKIs (erlotinib or gefitinib) or chemotherapy (in patients in whom urgent therapy was needed, and results of the EGFR mutation testing were not yet available). The patients underwent routine evaluation including hemogram and biochemical tests before each cycle of chemotherapy and every 2–3 months in patients on TKI. Dose reduction was done in patients with life-threatening hematological or nonhematological complications, and therapy was postponed until the toxicity had decreased to below Grade 3 in case of adverse events. Assessment of radiological response was done at approximately two-monthly intervals and at symptomatic progression. Chemotherapy or targeted therapy was discontinued at the time of progression of disease, intolerable side effects, or decision of the patient. At progression, therapy offered was based on the ECOG PS of the patient. Patients continued to be followed after progression, as per routine standards.

Statistical analysis

SPSS for Windows, Version 16.0. (Chicago, SPSS Inc.) was used for statistical analysis. Descriptive statistics are presented. Chi-square test was used for comparison. OS was calculated from the date of start of therapy to the date of death from any cause. The Kaplan–Meier method was used to estimate survival. Log-rank test was used for univariate analysis while Cox proportional hazard model was used for multivariate analysis.


 » Results Top


Demographic details

We included 225 patients in our analysis. The median age was 56 years (range 29–85 years). Males predominated at 61.8% (139 males). Comorbidities such as type 2 diabetes mellitus were present in 41 patients (18.2%) and 44 patients (19.6%) had hypertension. Sixty-one patients (27.1%) had uncontrolled comorbidities. The ECOG PS was 0–1 in 109 patients (48.4%), 2 in 33 patients (14.7%), and 3–4 in 83 patients (36.9%). History of smoking in the past was present in 59 patients (26.2%) and history of oral tobacco use was present in 47 patients (20.9%). The median hemoglobin level was 12.7 g/dl (interquartile range [IQR]: 11.4–13.9 g/dl) and the median serum albumin level was 4 g/dl (IQR: 3.5–4.2 g/dl). Sixty-five patients (28.9%) lived outside the state, in which our center was located and had no local social support.

Tumor details

The histopathology was adenocarcinoma in 210 patients (93.3%), poorly differentiated carcinoma in six patients (2.7%), squamous cell carcinoma in 6 patients (2.7%), and adenosquamous carcinoma in three patients (1.3%). The types of EGFR mutations were exon 19 deletion in 116 patients (51.6%), exon 21 mutation in 95 patients (43.1%), and exon 18 in 12 patients (5.3%). All patients had Stage IV disease. One hundred and twenty-two patients (54.2%) had disease restricted to thorax. Among the 103 patients with distant metastases, the sites of metastases were bone in 58 patients, liver in 39 patients, and brain in 28 patients.

Reason for nonparticipation in the study

The reasons for not participating in the study are shown in [Table 1]. Poor ECOG PS of 3 or 4 was the major reason (83 patients, 36.9%) for ineligibility of patients for the study. The predominant reason provided by eligible patients for refusal to participate in the was long distance of travel (65 patients, 28.9%).
Table 1: Reasons for nonparticipation in the study

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Selection of treatment

Poor performance status patients (performance status 3–4, n = 83)

Among the 83 patients with poor PS, 75 patients (90.4%) were started on TKI. The remaining 8 patients were started on first-line chemotherapy. Among the eight patients started on chemotherapy, one was started on weekly paclitaxel and the rest were started on weekly combination chemotherapy with paclitaxel + carboplatin.

Good performance status patients (performance status 0–2, n = 142)

Out of the 142 patients with PS 0–2, only 35 patients (24.6%) were started on TKI. These 35 patients were started on TKI. The remaining of the 107 patients was started on first-line chemotherapy as these patients were unwilling to wait for the mutation analysis report due to the long distance of travel and wanted immediate start of treatment.

Treatment details

The first-line treatment received was TKI in 110 patients (48.89%) and chemotherapy in 115 patients (51.11%). The specific TKI was gefitinib in 82 patients (74.5%, n = 110) and erlotinib in 28 patients (25.5%, n = 110). The chemotherapy regimen was pemetrexed with platinum in 84 patients (73.0%), paclitaxel with platinum in 17 patients (14.8%), gemcitabine with platinum in 13 patients (11.8%), and single-agent paclitaxel delivered weekly in one patient (0.4%).

Post first-line therapy

Following progression on first-line chemotherapy, 73 patients (63.5%, n = 115) received second-line treatment; 51 patients received gefitinib and 22 patients received erlotinib. Following progression on first-line TKI, 42 patients (38.2%, n = 110) received second-line pemetrexed + platinum. Poor PS at progression precluded second-line therapy in the other patients.

Overall survival

The median OS for the entire cohort was 16.0 months (95% confidence interval [CI]: 12.7–19.4 months). On multivariate analysis among the tested variables which included ECOG PS (0–2 vs. 3–4), a number of sites of metastases, site of metastasis, type of EGFR mutation, and presence of uncontrolled comorbidities, the only factor that significantly predicted for OS was ECOG PS. The median OS in patients with PS 0–2 was 18.17 months (95% CI: 15.6–20.8 months) whereas it was 12.1 months (95% CI: 9.0–15.2 months) in patients with PS 3–4. (hazard ratio [HR] - 0.579 [95% CI: 0.398–0.843] P = 0.004) [Figure 1].
Figure 1: Overall survival of patients according to their performance status

Click here to view


Among patients with ECOG PS 0–2, the median OS was 23.7 months in patients who received first-line TKI compared to 18.2 months in patients who received upfront chemotherapy (P = 0.635). On multivariate analysis among the tested variables (in ECOG PS 0–2 patients) which included the number of sites of metastases, site of metastasis, type of EGFR mutation, and presence of uncontrolled comorbidities, the only factor significantly predicting for OS was presence or absence of liver metastases. Patients with PS 0–2, but with liver metastasis had a median survival of 9.6 months compared to 18.4 months in patients without liver metastasis (P = 0.026). The hazard ratio was 1.914 (95% CI: 1.07–3.42) [Figure 2].
Figure 2: Overall survival in Eastern Cooperative Oncology Group performance status 0–2 patients according to presence or absence of liver metastasis

Click here to view



 » Discussion Top


The results of our study highlight the complex nature of patients seen in lung cancer clinics. As opposed to patients treated in trial settings, the patients in our analysis who had been screen failed for an interventional trial had different characteristics. Nearly 36.9% of these patients had ECOG PS 3–4 and nearly one-fourth of the rest of the patients had uncontrolled comorbidities. Among patients who were fit and eligible to participate in the trial did not participate due to logistical issue, i.e. long travel distance. The reasons for not participating in our interventional study are very similar to those reported from the Vanderbilt-Ingram Cancer Center by Keedy et al. The common reasons for nonparticipation in their patients were long distance of travel (29%), poor PS (19%), comorbidities (17%), and patient's refusal (19%).[8]

The selection of first-line therapy (either TKI or chemotherapy) in our patients was dictated by the ECOG PS and the patient's choice, rather than by the results of the EGFR mutation analysis. All NSCLC patients are initially prescreened for our EGFR positive interventional clinical trial. At the time of prescreening, the EGFR mutation reports are not available. Patients are informed about the study and are told to follow up after 1–2 weeks with the mutation analysis report. Patients with a poor PS or with an indication for urgent therapy or patients who were not willing to wait for the results of EGFR mutation analysis report or unwilling to participate in the trial regardless of the results of the mutation analysis were prescreen failures. These patients were counseled about the poor prognosis and were offered treatment according to treating physician's discretion. Not surprisingly, given the compromised PS of these patients, the majority of these patients were started on oral TKI. Patients with PS 0–2 who either were ineligible or who refused to participate in the study were counseled to wait for the EGFR analysis report. All patients, except for 35 patients, were unwilling to wait. The reasons for unwillingness to wait were not systematically documented. In an attempt to understand why patients are unwilling to wait for the results of molecular testing in lung cancer, we have planned and executed a study addressing this issue. In the patients who were not willing to wait for the results of EGFR mutation testing, systemic chemotherapy was offered.

The median OS of the entire cohort was only 16.0 months. This is substantially lower than the attractive median survivals reported in studies that included activating EGFR-mutation positive patients. The lower survival results, however, seem logical when the characteristics of these patients are studied and the survival is adjusted for confounding poor prognostic factors. Patients with poor PS had a much lower median OS than patients with ECOG PS 0–2. The median OS in poor PS patients was only 12.0 months as compared to the 18.0 months OS noted in patients with good PS. In addition, among the patients with good PS, there was a suggestion of a slightly numerically better survival among patients who were treated with upfront TKI compared to those treated with first-line chemotherapy although this difference was not statistically significant. A similar OS has been reported in multiple studies in patients treated with oral TKI (either erlotinib or gefitinib).[5],[6],[10] Thus, at first glance, our survival results significantly differ from those previously reported in the literature. However, on dissection of our results, the median OS of 18.17 months in patients with PS 0–2 irrespective of the presence of comorbidities appears similar to that reported in literature.[5] This is reassuring.

The common perception among oncologists is that patients treated on a clinical trial have better survival compared to patients treated off-trial. The results of our analysis suggest that this is mainly because of confounding variables that impact on survival of patients in routine care but have a limited impact in trial settings due to the rigorous inclusion and exclusion criteria. A recent report by Lamont et al. highlighted this point. In advanced lung and pancreatic cancer patients, the trial data seemed to correctly estimate survival for young Medicare patients between the ages of 65–74 years; however, they failed to estimate the survival in older patients.[11] The reason was that the older patients were inadequately represented in clinical trials; thus, the results of the trials could not be extrapolated to this patient group. Similar outcomes in trial and nontrial settings in advanced lung cancer patients have been published by Tanai et al.[12] A systematic analysis by Peppercorn et al. comparing the outcomes of patients treated in clinical trials to that of patients treated in routine care concluded that there was insufficient evidence to conclude that trial patients had superior outcomes.[13]


 » Conclusion Top


Patients who are treated off-trial, but who fulfill the inclusion and exclusion criteria of that trial, should have similar outcomes to the trial. However, if the patient would not have been eligible for the clinical trial because of confounding factors such as old age or poor PS, then the patient outcome will possibly be poorer than that described in the trial patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

1.
Globocan 2012. Available from: http://www.globocan.iarc.fr/Default.aspx. [Last cited on 2015 Aug 19].  Back to cited text no. 1
    
2.
Ettinger DS, Akerley W, Borghaei H, Chang AC, Cheney RT, Chirieac LR, et al. Non-small cell lung cancer, version 2.2013. J Natl Compr Canc Netw 2013;11:645-53.  Back to cited text no. 2
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Peters S, Adjei AA, Gridelli C, Reck M, Kerr K, Felip E; ESMO Guidelines Working Group. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012;23 Suppl 7:vii56-64.  Back to cited text no. 3
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4.
Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92-8.  Back to cited text no. 4
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5.
Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239-46.  Back to cited text no. 5
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6.
Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380-8.  Back to cited text no. 6
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7.
Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542-50.  Back to cited text no. 7
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8.
Keedy VL, Horn L, Hayes A, Spencer B, Garcia G, Campbell N, et al. J Clin Oncol 27:15s, 2009 (suppl; abstr 6633).  Back to cited text no. 8
    
9.
Noronha V, Prabhash K, Thavamani A, Chougule A, Purandare N, Joshi A, et al. EGFR mutations in Indian lung cancer patients: Clinical correlation and outcome to EGFR targeted therapy. PLoS One 2013;8:e61561.  Back to cited text no. 9
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10.
Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomised phase 3 trial. Lancet Oncol 2010;11:121-8.  Back to cited text no. 10
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11.
Lamont EB, Schilsky RL, He Y, Muss H, Cohen HJ, Hurria A, et al. Generalizability of trial results to elderly Medicare patients with advanced solid tumors (Alliance 70802). J Natl Cancer Inst 2014;107:336.  Back to cited text no. 11
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12.
Tanai C, Nokihara H, Yamamoto S, Kunitoh H, Yamamoto N, Sekine I, et al. Characteristics and outcomes of patients with advanced non-small-cell lung cancer who declined to participate in randomised clinical chemotherapy trials. Br J Cancer 2009;100:1037-42.  Back to cited text no. 12
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13.
Peppercorn JM, Weeks JC, Cook EF, Joffe S. Comparison of outcomes in cancer patients treated within and outside clinical trials: Conceptual framework and structured review. Lancet 2004;363:263-70.  Back to cited text no. 13
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