A case report of metastatic lung adenocarcinoma with long-term survival for over 11 years – PMC
25/09/1445 AH, 7:50 AM
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Medicine (Baltimore). 2019 Jan; 98(4): e14100.
Published online 2019 Jan 25. doi: 10.1097/MD.0000000000014100
PMCID: PMC6358372
PMID: 30681568
A case report of metastatic lung adenocarcinoma with long-term survival for over 11
years
Tatsu Matsuzaki, MD,? Eri Iwami, MD, Kotaro Sasahara, MD, Aoi Kuroda, MD, Takahiro Nakajima, MD, and
Takeshi Terashima, MD
Monitoring Editor: NA.
Abstract
Rationale:
This is the first known report in the English literature to describe a case of metastatic non-small cell
lung cancer that has been controlled for >11 years.
Patient concerns:
A 71-year-old man visited our hospital because of dry cough.
Diagnosis:
Chest computed tomography revealed a tumor on the left lower lobe with pleural e?usion, and tho?
racic puncture cytology indicated lung adenocarcinoma.
Interventions:
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Four cycles of carboplatin and docetaxel chemotherapy reduced the size of the tumor; however, it
increased in size after 8 months, and re-challenge chemotherapy (RC) with the same drugs was per?
formed. Repeated RC controlled disease activity for 6 years. After the patient failed to respond to
RC, erlotinib was administered for 3 years while repeating a treatment holiday to reduce side e?ects.
The disease progressed, and epidermal growth factor receptor (EGFR) gene mutation analysis of
cells from the pleural e?usion detected the T790 M mutation. Therefore, osimertinib was adminis?
tered, which has been e?ective for >1 year.
Outcomes:
The patient has survived for >11 years since the diagnosis of lung cancer.
Lessons:
Long-term survival may be implemented by actively repeating cytotoxic chemotherapy and EGFRtyrosine kinase inhibitor administration.
Keywords: adenocarcinoma, EFGR-TKIs, EGFR gene mutation, long-term survival, non-small cell
lung cancer, re-challenge chemotherapy, T790 M
1. Introduction
The prognosis of patients with advanced non-small cell lung cancer (NSCLC) is poor, and their 1year survival rate after cytotoxic chemotherapy is only 29%.[1] However, the development of epider?
mal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) dramatically improves the prog?
nosis of certain patients. Patients with EGFR-mutant advanced NSCLC receiving EGFR-TKIs have
a median overall survival (OS) more than twice as long as those not receiving EGFR-TKIs (24.3 vs
10.8 months).[2] The 5-year survival rate of patients with EGFR-mutant metastatic lung adenocarci?
noma treated with EGFR-TKIs is 14.6%. [3] However, metastatic NSCLC patients with long-term
survival (>10 years) are still rare.
We treated an advanced NSCLC patient with malignant pleural e?usion who survived for >11 years
and for whom disease progression was controlled using drugs alone without surgery or radiation
therapy.
2. Case presentation
A 71-year-old Japanese man experienced dry cough for 2 weeks and visited the Department of Res?
piratory Medicine at our hospital in August 2007. Enhanced chest-abdomen computed tomography
revealed a tumor with a 3-cm diameter in the left lower lobe and left pleural e?usion (Fig. 1). A 5mm nodule, considered to be lung metastasis, was detected in the left upper lobe. Cytological analy?
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sis of the left pleural e?usion by thoracic puncture led to the diagnosis of lung adenocarcinoma.
Gadolinium-enhanced brain magnetic resonance imaging and bone scintigraphy did not reveal any
other metastases. The tumor was classified as clinical T4N0M1, stage IV according to the TNM
classification of the Union of International Cancer Control (UICC), 6th edition. According to the
UICC 8th edition, it was classified as clinical T4N0M1a, stage IV A. The patient had a history of
hypertension and was a past smoker (60 pack-years) and a company employee. The Eastern Cooper?
ative Oncology Group performance status (ECOG-PS) at the time of admission was 1. The carci?
noembryonic antigen (CEA) level was 97.4 ng/mL (normal, 0–5 ng/ml).
Figure 1
Chest computed tomography (CT) in August 2007. Chest CT scan showing a nodule in the left lower lobe with left
pleural e?usion.
Beginning in August 2007, the patient received carboplatin (CBDCA) and docetaxel (DTX). After 4
cycles, the tumor was reduced to 1 cm in diameter. The 5-mm nodule and pleural e?usion had also
decreased. According to the Response Evaluation Criteria in Solid Tumors version 1.1, partial re?
sponse was achieved, but he experienced progressive disease (PD) after 8 months. Six cycles of rechallenge chemotherapy (RC) using the same regimen were started in August 2008 and were e?ec?
tive. Thereafter, at each recurrence of PD, 4 to 6 cycles of RC were administered, and by 2013, 38
cycles had been completed over 6 years of treatment (Fig. 2A). However, we could no longer control
disease activity using the same chemotherapy regimen. Moreover, primary tumor size evaluation
became di?cult owing to massive pleural e?usion; although not standard, we estimated the e?ect of
treatment using the increase and decrease of CEA as an index. CEA increased from a minimum of
4.6 ng/ml to 33.3 ng/ml in October 2013 during repeated cytotoxic chemotherapy. Although his
EGFR mutation status was unknown, we initiated erlotinib administration and the CEA level de?
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creased. After 8 weeks, the patient developed grade 3 acneiform rash, assessed using the Common
Terminology Criteria for Adverse Events version 5.0, and erlotinib administration was discontinued
for 6 weeks. Cycles of medication and treatment holiday were repeated, and the patient was careful?
ly observed for skin rash. Dose reduction was attempted once, but it was not e?ective, because we
noted an elevated CEA level and intolerable skin rash. For 3 years, 4-week erlotinib administration
was repeated with 4–6-week treatment holiday intervals (Fig. 2B). CEA increased from a minimum
of 3.1 ng/ml to 30.4 ng/ml in January 2017 during treatment with erlotinib. We performed EGFR
mutation analysis using adenocarcinoma cells from the pleural e?usion and detected exon 19 dele?
tion and exon 20 T790 M mutation; therefore, osimertinib was substituted for erlotinib.
Figure 2
Patient’s treatment course. (A) Treatment course using cytotoxic chemotherapy. Chemotherapy with a combination
of carboplatin (CBDCA) and docetaxel (DTX) was performed beginning in August 2007. The tumor and pleural
e?usion repeatedly decreased and increased in size. After each increase, 4 to 6 cycles of the same regimen were
performed until 2013, for a total of 38 cycles over 6 years. Each arrow indicates one cycle. (B) Treatment course
using epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Administration of erlotinib began
in October 2013. Skin disorders interrupted its administration. The patient interrupted and resumed treatment re?
peatedly. Because of the detection of the T790 M mutation in exon 20 in malignant cells from the pleural e?usion,
erlotinib was changed to osimertinib in January 2017, and the administration of the latter is ongoing.
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We continued monthly CEA measurements after beginning osimertinib administration and noted
that the level continued to decrease. In August 2018, the CEA level was 12.1 ng/ml and the ECOGPS was 1. As of the last follow-up, the patient has survived for >11 years since the diagnosis of lung
cancer.
3. Discussion
The clinical data of 10 patients with advanced NSCLC who survived for >5 years were retrospec?
tively reviewed, and a good PS, adenocarcinoma, and a history of EGFR-TKI administration were
the factors contributing to long-term survival.[4] According to another retrospective study,[3] 20 of
137 patients with EGFR-mutant lung adenocarcinoma survived for ?5 years, and exon 19 deletion,
absence of extrathoracic metastases, absence of brain metastasis, and current non-smoking status
were reportedly good prognostic factors. Our case corroborated the good prognostic factors reported
in these studies.
A case of metastatic NSCLC in which the patient survived for 10 years has already been reported;
however, the patient underwent not only chemotherapy but also surgery and radiation therapy.[5] To
the best of our knowledge, ours is the first report in the English literature to describe a metastatic
NSCLC case controlled for >11 years. Moreover, our patient was only treated with chemotherapy
and EGFR-TKIs.
We considered that 4 treatment policies may be the key to success:
1. RC with CBDCA plus DTX;
2. repeated re-challenge erlotinib administration;
3. osimertinib administration after T790 M mutation in exon 20, which confers resistance to
erlotinib; and
4. use of both cytotoxic drugs and EGFR-TKIs. We will particularly focus on the first and second
policies because of the non-standard methods.
The response rate (RR) to RC of platinum doublets containing pemetrexed (PEM) or taxanes is re?
portedly 27.5%, with a progression-free survival (PFS) of 3.9 months and an OS of 8.7 months. This
RR is high, but the PFS and OS are similar to those seen with administration of a single-agent as
second-line treatment.[6] Advanced NSCLC patients for whom RC with 2-drug combination therapy
is performed have a longer median survival than those administered only DTX as second-line treat?
ment.[7] The current evidence that RC is superior to a single agent second-line treatment is not su??
cient, but if the side e?ects are acceptable, RC may be a suitable option.
To safely perform RC using platinum-based 2-drug therapy, it may be necessary to include a treat?
ment holiday period for a certain duration to facilitate physical fitness recovery. Time to progression
of >3 months after ending first-line chemotherapy is a predictor of long-term survival (>2 years) in
advanced NSCLC patients who receive cytotoxic chemotherapy.[8] Advanced NSCLC patients who
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survive for >2 years have a good response to first-line cytotoxic chemotherapy, and a prolonged
treatment-free interval increases long-term survival.[9] In the present case, the treatment holiday af?
ter cytotoxic chemotherapy was approximately 6 months. A prolonged treatment-free interval ap?
pears to be important for restoring physical fitness; therefore, the patient could tolerate the next
treatment.
A meta-analysis of randomized control studies compared cisplatin (CDDP) and CBDCA in ad?
vanced NSCLC patients. Although regimens containing CDDP did not prolong OS, subgroup analy?
sis demonstrated that, when combined with third-generation anticancer drugs, CDDP prolonged OS
more than CBDCA in patients with non-squamous cell carcinoma.[10] In the TAX 326 trial, CBDCA
and DTX combination therapy helped achieve an OS equivalent to that associated with CDDP and
vinorelbine combination therapy; in addition, the CBDCA and DTX combination was well tolerated
and facilitated a high quality of life.[11] Here, 38 cycles of CBDCA and DTX combination therapy
were administered. To perform platinum-based 2-drug RC, it may be advantageous to repeatedly
administer CBDCA rather than CDDP to facilitate tolerability.
When erlotinib toxicity is intolerable, as in our patient who developed a severe skin rash, the dosage
is generally reduced. In patients with EGFR-mutant NSCLC, dose reduction (25 mg/day) of erlotinib
can reduce the toxicity while maintaining e?cacy.[12] In contrast, a prospective phase II trial involv?
ing low-dose erlotinib in patients with EGFR-mutant NSCLC revealed that dose reduction (50
mg/day) is not recommended because of reduced e?cacy.[13] Intermittent erlotinib administration on
alternate days successfully maintained e?cacy while reducing toxicity.[14] Here, disease control was
possible by RC of platinum doublets for approximately 6 cycles after the 6-month treatment holiday.
Therefore, we applied the RC strategy to EGFR-TKI administration. Continued erlotinib administra?
tion was discontinued if side e?ects became intolerable or health-threatening and resumed when
side e?ects disappeared. Toxicity and e?cacy were balanced by allowing an approximately 4–6week treatment holiday after the 4-week erlotinib administration. To the best of our knowledge, we
were the first to employ erlotinib in RC; this method was named repeated re-challenge administra?
tion of erlotinib and was considered to alleviate su?ering due to toxicity. Although there is little evi?
dence to determine whether dose reduction, intermittent administration, or repeated re-challenge
administration is better, it is important to avoid complete cessation of therapy.
The exon 20 mutation in EGFR, leading to the T790 M mutation, is a resistance mechanism to tradi?
tional EGFR-TKIs. Osimertinib treatment is associated with a longer median PFS than chemo?
therapy using PEM plus either CBDCA or CDDP as second-line treatment in T790M-mutant pa?
tients who received EGFR-TKIs. [15] Our patient with the exon 19 deletion and T790 M mutation re?
ceived osimertinib after erlotinib. Even if the tumor develops resistance to conventional EGFRTKIs, it is important to recognize that drugs such as osimertinib are available and may improve
long-term survival.
In EGFR-mutant advanced NSCLC with exon 19 deletion and exon 21 (L858R) mutation, patients
who receive sequential therapy with erlotinib and cytotoxic drugs experience a longer median OS
than those who receive cytotoxic drugs or erlotinib alone.[16] It may be important to administer both
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EGFR-TKIs and cytotoxic drugs throughout the course of treatment.
Although more study is required, RC of CBDCA plus DTX and repeated re-challenge administra?
tion of erlotinib may be an empirical option for long-term survival. To understand the clinical and
biological background of long-term survival cases, accumulation of future cases similar to ours is
warranted.
Acknowledgments
We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Supervision: Takeshi Terashima.
Writing – original draft: Tatsu Matsuzaki.
Writing – review & editing: Eri Iwami, Kotaro Sasahara, Aoi Kuroda, Takahiro Nakajima.
Footnotes
Abbreviations: CBDCA = carboplatin, CDDP = cisplatin, CEA = carcinoembryonic antigen, DTX = docetaxel,
ECOG-PS = Eastern Cooperative Oncology Group performance status, EGFR = epidermal growth factor recep?
tor, EGFR-TKI = epidermal growth factor receptor tyrosine kinase inhibitor, NSCLC = non-small cell lung cancer,
OS = overall survival, PD = progressive disease, PEM = pemetrexed, PFS = progression-free survival, RC = rechallenge chemotherapy, RR = response rate, UICC = Union of International Cancer Control.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-forprofit sectors.
The Ethics Committee of our hospital approved the study and provided permission to publish the results.
The patient provided written informed consent and has provided consent for publication of the case.
The authors declare that they have no conflict of interest.
References
[1] Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy and supportive care versus supportive care alone for
advanced non-small cell lung cancer. Cochrane Database Syst Rev 2010;12:CD007309. [PubMed] [Google Scholar]
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358372/
Page 7 of 9
A case report of metastatic lung adenocarcinoma with long-term survival for over 11 years – PMC
25/09/1445 AH, 7:50 AM
[2] Zhao D, Chen X, Qin N, et al. The prognostic role of EGFR-TKIs for patients with advanced non-small cell lung cancer.
Sci Rep 2017;12:40374. [PMC free article] [PubMed] [Google Scholar]
[3] Lin JJ, Cardarella S, Lydon CA, et al. Five-year survival in EGFR-mutant metastatic lung adenocarcinoma treated with
EGFR-TKIs. J Thorac Oncol 2016;11:556–65. [PMC free article] [PubMed] [Google Scholar]
[4] Kaira K, Takahashi T, Murakami H, et al. Long-term survivors of more than 5 years in advanced non-small cell lung
cancer. Lung Cancer 2010;67:120–3. [PubMed] [Google Scholar]
[5] Kempf E, Planchard D, Le Chevalier T, et al. 10-year long-term survival of a metastatic EGFR-mutated nonsmall cell
lung cancer patient. Eur Respir J 2015;46:280–2. [PubMed] [Google Scholar]
[6] Petrelli F, Coinu A, Cabiddu M, et al. Platinum rechallenge in patients with advanced NSCLC: a pooled analysis. Lung
Cancer 2013;81:337–42. [PubMed] [Google Scholar]
[7] Nagano T, Kim YH, Goto K, et al. Re-challenge chemotherapy for relapsed non-small-cell lung cancer. Lung Cancer
2010;69:315–8. [PubMed] [Google Scholar]
[8] Giroux Leprieur E, Lavole A, Ruppert AM, et al. Factors associated with long-term survival of patients with advanced
non-small cell lung cancer. Respiratology 2012;17:134–42. [PubMed] [Google Scholar]
[9] Van Damme V, Govaerts E, Nackaerts K, et al. Clinical factors predictive of long-term survival in advanced non-small
cell lung cancer. Lung Cancer 2013;79:73–6. [PubMed] [Google Scholar]
[10] Ardizzoni A, Boni L, Tiseo M, et al. Cisplatin- versus carboplatin-based chemotherapy in first-line treatment of
advanced non-small-cell lung cancer: an individual patient data meta-analysis. J Natl Cancer Inst 2007;99:847–57.
[PubMed] [Google Scholar]
[11] Fossella F, Pereira JR, von Pawel J, et al. Randomized, multinational, phase III study of docetaxel plus platinum
combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin
Oncol 2003;21:3016–24. [PubMed] [Google Scholar]
[12] Yeo WL, Riely GJ, Yeap BY, et al. Erlotinib at a dose of 25 mg daily for non-small cell lung cancers with EGFR
mutations. J Thorac Oncol 2010;5:1048–53. [PMC free article] [PubMed] [Google Scholar]
[13] Yamada K, Aono H, Hosomi Y, et al. A prospective, multicenter phase II trial of low-dose erlotinib in non-small cell
lung cancer patients with EGFR mutations pretreated with chemotherapy: Thoracic Oncology Research Group 0911. Eur J
Cancer 2015;51:1904–10. [PubMed] [Google Scholar]
[14] Hata A, Fujita S, Kaji R, et al. Dose reduction or intermittent administration of erlotinib: which is better for patients
su?ering from intolerable toxicities? Intern Med 2013;52:599–603. [PubMed] [Google Scholar]
[15] Mok TS, Wu Y-L, Ahn M-J, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J
Med 2017;376:629–40. [PMC free article] [PubMed] [Google Scholar]
[16] Zhou C, Wu YL, Chen G, et al. Final overall survival results from a randomized, phase III study of erlotinib versus
chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG0802). Ann Oncol 2015;26:1877–83. [PubMed] [Google Scholar]
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358372/
Page 8 of 9
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