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Med One
Lung Cancer Patient with Bevacizumab
Case Report of First-line Chemotherapy
on One Advanced Lung Cancer Patient
with Bevacizumab combined with
Pemetrexed Disodium and Carboplatin
Pengbo Deng1, Huaping Yang1*, Bingrong Zhao1, Yuanyuan Li1,
Chengping Hu1
1
Department of Respiratory Medicine, Xiangya Hospital, Central South
University, Changsha Hu’nan,410008, China.
*Correspondence: Huaping Yang. Email: liying971@ sina.com
ABSTRACT
One case of male patient with stage-IV lung cancer was reported here,
who had exon 19 deletion mutations in epidermal growth factor
receptor (EGFR). The intrapulmonary and extrapulmonary lesions
occurred a month after applying the gefitinib and erlotinib in turn. The
patient was then switched to the first-line chemotherapy program. The
intrapulmonary and extrapulmonary lesions were significantly improved
four weeks after the combined therapy with pemetrexed disodium +
carboplatin+ bevacizumab (7.5mg/Kg d1), two weeks after the
continuous therapy with pemetrexed disodium + bevacizumab (7.5mg/
Kg d1), and the short-term efficacy was assessed as PR, without
significant adverse effect, which reflects the efficacy of this program
and the good tolerance.
Key Words: Bevacizumab; Chemotherapy; Non-small Cell Lung
Cancer
INTRODUCTION
Funding: The authors received no specific
funding for this work.
The male patient aged 66 years old with a history of smoking was
accepted in our Department of Outpatient on September 14, 2015
because of “coughing for more than one month”. His main symptoms
included dry cough, a small amount of white phlegm, free from fever,
chest pain, bloody sputum, and any other discomforts. It is associated
with an anorexia and weight loss of nearly 10 pounds when it
develops. He had a poor constitution in the past, with a history of
“acute hepatitis”, “type-2 diabetes” and “obsolete pulmonary tuberc
ulosis”. The patient was accepted in our department on September 15.
His lung was scanned with CT and the scanning results indicated that
“space occupied for posterior basal segment of right inferior lung and
enlarged for mediastinal lymph nodes”. The patient was approved to
be subjected to the CT- guided transthoracic needle biopsy,
immunohistochemistry, EGFR gene mutation detection, and systemic
metastases assessment. He was diagnosed as “primary lung cancer,
right lung adenocarcinoma, T4N3M1B (lung, pleura and brain), and
stage-IV EGFR Exon 19 deletion mutation (Fig. 1Aand Fig. 2A) ”.
Fig. 1
Competing Interests: The authors have
declared that no competing interests exist.
A 2015-9-12
DOI: 10.20900/mo.20160012
Received: March 12, 2016
Accepted: May 15, 2016
Published: June 25, 2016
website:http://mo.qingres.com
Copyright: ©2016 Cain et al. This is an
open access article distributed under the
terms of the Creative Commons Attribution
License,which permits unrestricted use,
distribution, and reproduction in any medium,
provided the original author and source are
credited.
Data Availability Statement: All relevant
data are within the paper and its Supporting
Information files.
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Lung Cancer Patient with Bevacizumab
B 2015.10.20
C 2015.11.16
D 2016.1.6
E 2016.2.11
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Lung Cancer Patient with Bevacizumab
F 2016.4.18
Fig.1 A. CT image of lung before the treatment (dated on September 12, 2015); B, C: CT images of lung a month after
administration of gefitinib and erlonat (dated on October 20, 2015 and November 16, 2015) respectively, indicating a significant
progressive disease of lung lesions; D. CT image of lung two and four cycles after using the combined program of Pemetrexed
disodium (500 mg/m2 d1) + Carboplatin (AUC 5 d1) + Bevacizumab (7.5 mg/Kg d1) (dated on January 6,
2016 and February 11, 2016), indicating a significant improvement of lung lesions, and the efficacy is assessed as PR; F.
CT images of lung after maintaining two-cycle treatment using the program of Pemetrexed disodium (500 mg/m2 d1) +
Bevacizumab (7.5 mg/Kg d1) (dated on April 18, 2016), indicating a unchanged lung lesions as before.
Fig. 2
A 2015.9.22
B 2015.11.14
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C 2016.1.7
D 2016.4.10
Fig.2 A. MRI image of head before the treatment (dated on September 22, 2015); B: MRI image of head a month after
administration of gefitinib and erlonat (dated on November 14, 2015), indicating a significant enlargement of intracranial
lesions; D. MRI image of head two cycles after using the combined program of Pemetrexed disodium (500 mg/m2 d1) +
Carboplatin (AUC 5 d1) + Bevacizumab (7.5 mg/Kg d1) (dated on January 7, 2016), indicating a decrease of intracranial
lesions and a significant contraction of surrounding edema zone; F. MRI image of head after maintaining two-cycle
treatment using the program of Pemetrexed disodium (500 mg/m2 d1) + Bevacizumab (7.5 mg/Kg d1) (dated on April 10,
2016), indicating a stable intracranial lesion as before.
After the diagnosis, the patient began to take gefitinib (250 mg, oral administration and once a day) since
September 22, 2015. During the treatment, the cough of the patient was not significantly improved, and the spirit
and appetite were not improved, and no new symptom occurred. He returned to our outpatient for review on
October 20, 2015 and the review result showed that the targeted lesion in the lung increased from 40.9 mm to 50.9
mm (Fig. 1 A-B), with a growth rate of 24.4%. The progressive disease (PD) was assessed and he was advised to
be changed to the chemotherapy for further treatment. He rejected and began to take erlotinib (150mg, oral
administration and once a day). The symptom was still not improved during the treatment and he was gradually
associated with dizziness, backache, hemiparesthesia in the left side, without malignant vomiting. The patient was
reviewed again for his lung with CT (November 16, 2015) one month later, and the reviewed results suggested
that the lung lesion further increased (58.3 mm for the longest diameter) (Fig. 1C), and the lymphangitis
carcinomatosa was significantly progressed. The MRI result of the head showed that the intracranial lesions were
increased (Fig.2B), with an obvious edema. The efficacy was
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assessed as PD and he was recommended again for a chemotherapy treatment.
The patient checked in our department for further treatment on November 23, 2015. The assessment was
made again before the chemotherapy and the inspection results showed that multiple bone metastasis and
multiple enlarged lymph nodes occurred in left shoulder blade, the fourth lumbar, right iliac bone and other
positions of the patient, and the performance status (PS) was only one point. He was administered by Pemetrexed
Disodium (500 mg/m2 d1) + Carboplatin (AUC 5 d1) + Bevacizumab (7.5 mg/Kg d1) since November 26, 2015 for
the chemotherapy treatment and meanwhile, the supportive therapy was provided, such as, dehydration, reduction
of intracranial pressure, promotion of bone repair, relief of pains, waist protection, etc. After his discharge, the
cough symptom of the patients basically disappeared and the dizziness, backache and hemiparesthesia in the left
side were significantly improved and the spirit and sleep quality was also significantly improved. It was basically
normal after reviewing the blood routine examination. The second chemotherapy treatment was successfully
completed on December 18 (the program is idem). The patient checked in the hospital on January 6, 2016 and
proposed for the third chemotherapy. The assessment result before the chemotherapy showed that the
measurable targeted lesion of right lung decreased (3.2 mm, with a decrease rate of 44.8%) (Fig. 1D),
lymphangitis carcinomatosa was significantly decreased and right frontal nodulus lesions were reduced
significantly (Fig. 2C). No new lesion was found. The efficacy was assessed as the partial relief (PR). The third
and fourth chemotherapies were completed on January 9 and January 30,
2016. The efficacy was re-assessed as PR (Fig. 1E) with CT review of lung in the outpatients on February 11.
Since then, the patient had been subjected to the combined administration program of pemetrexed disodium
(500 mg/m2 d1) + bevacizumab (7.5 mg/Kg d1) for the further chemotherapy. CT of lung and MRI of head
were implemented again on April 16, and the results showed that the control of lung lesions and intracranial
lesions were basically the same as before (Fig.1F and Fig. 2D). The symptoms of cough, backache and
hemiparesthesia were not found in the patient and the quality of his life significantly improved. PS was
decreased to zero.
DISCUSSION
In this case, the lung biopsy specimens of patients indicated that there existed EGFR exon 19 deletion
mutation. According to the recommendations of the Guideline of National Comprehensive Cancer Network
(NCCN) in 2015 (1), we developed the therapy program using EGFR tyrosinekinase inhibitors (TKIs) Gefitinib administration. However, the intrapulmonary and extrapulmonary lesions occurred after the gefitinib
and erlotinib were administered to the patient, which indicates that the patient has the primary resistance
against the EGFR Tki.
Under the premise of treatment failure, we re-implemented the combined program of platinum -based
doublets + bevacizumab to the patient according to the recommendations of NSCLC guideline of the NCCN
in 2015 (1) to ensure the improvement of symptoms and living quality of the patient in a short time, including
the contraction and control of primary lesions in lung, spinal, and intracranial lesions. We knew that the new
generation of anticancer drugs for molecular targets might become the research and treatment highlights of
advanced lung cancer and therefore ensure our current treatment program to be developed towards to
“individualization” direction. The genetic locus of EGFR, chinodem microtubule-associated protein-like 4/
anaplastic lymphoma kinase (EML4-ALK) fused genes, etc., needs the presence of specific genetic locus
mutation to ensure the patient to benefit from their corresponding targeted therapy drugs or medications, and
their mutation frequency shall be below 10% in addition to that the EGFR can be up to 50% in the Asian
race. Another molecular targeted drug – vascular molecular targeted drug – represented by bevacizumab
can inhibit the combination of VEGF with its receptor to degenerate the tumor angiogenesis and normalize
the survived blood vessels and inhibit the reproduction of the blood vessels so as to continue to inhibit the
growth and metastasis of the tumors. (2,4) Thus, under the condition that the patient has the primary
resistance against EGFR Tki in this case, the bevacizumab-based chemotherapy program recommended in
the guideline is more suitable for the individualized treatment of this patient and he has indeed benefited
from this treatment program.
A total of 878 patients with relapsed or stage III-IV non-squamous NSCLC was included into the stageIII clinical trials (ECOG4599 Trial (5)) conducted by Sandler. They were classified into two groups at random
and administered with paclitaxel + carboplatin and paclitaxel + carboplatin +bevacizumab, respectively. The
results showed that the overall survival (OS), median PFS and ORR of the bevacizumab-containing group
were all superior to the healthy controls (P ＜ 0.05). The OS of the patients with advanced NSCLC was
prolonged for over one year for the first time in the history. Therefore, FDA approved the combined program
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of paclitaxel + carboplatin +bevacizumab for treatment of advanced non-squamous NSCLC. Another stageIII clinical trial (AVAIL Trial (6)) confirmed the results of ECOG4599 Trial (5) from the aspects of its efficacy
and PFS. The chemotherapy program of combining the bevacizumab with platinum-based doublets was thus
approved by European Medicines Evaluation Agency (EMEA) in 2007 for the first-line treatment of metastatic
NSCLC. In addition, many studies (SAiL(7), ARIES) showed that the bevacizumab enabled the OS of the
patients with advanced NSCLC to be prolonged for over one year. Among the 314 Asian patients in the study
of SAiL, TTP was 8.3 months and median OS was 18.9 months, which are all significantly higher than the
general population.
The up-to-date NSCLC clinical practice guideline of NCCN in 2016 clearly points out that the first-line
chemotherapy program for advanced non-squamous cancer NSCLC has included the doublet chemotherapy
as well as bevacizumab + chemotherapy, and the bevacizumb should be administered until the progressive
disease PD period. The chemotherapy programs are composed of several combinations, namely, paclitaxel
+ carboplatin, paclitaxel + cisplatin, vinorelbine + cisplatin, gemcitabine + cisplatin, pemetrexed disodium +
cisplatin, and docetaxel + cisplatin. In the United States, the common programs are pemetrexed disodium +
cisplatin (carboplatin), and paclitaxel + carboplatin combined (or not combined) with bevacizumb. Forty nine
patients with non-squamous NSCLC were included into a stage-II clinical trial conducted by Patel, et al.(8) All
patients accepted the first-line chemotherapy of pemetrexed disodium + carboplatin combined with
bevacizumb. In the later period, they continuously accepted the chemotherapy of pemetrexed disodium +
bevacizumb. The results showed that the median PFS, OS and ORR reached 7.8 months, 14.1 months and
55%, respectively, and no severe adverse events were observed. Similarly, in a similar stage-II clinical trial
conducted by Japanese Yokoi T (9), the same treatment program was implemented to 26 patients with stage
IIIB-IV NSCLC. The trial results showed that the median PFS and OS reached 8.6 months and 18.6 months,
respectively, which indicates that this treatment program may provide more benefits to the Asian groups.
A similar long- term efficacy was obtained in the clinical observation on “first-line treatment of bevacizumb
combined with pemetrexed disodium + oxaliplatin for advanced NSCLC” carried out by OLIVIER et al. (10) At
the same time, the trial made by POINTBREAK (11) showed that the program of pemetrexed disodium +
carboplatin + bevacizumb was a reasonable option and it was believed that the paclitaxel -based program
had a more toxicity than the pemetrexed disodium based program. This is mainly reflected in neurotoxicity,
but there is no significant difference in the aspect of OS between the two programs. Therefore, we can make
a more appropriate option according to the specific situation of the patients.
In this case, we provided four cycles of combined chemotherapy program of pemetrexed disodium +
carboplatin + bevacizumb (7.5 mg/Kg d1) to the patient and continued the chemotherapy with pemetrexed
disodium + bevacizumb (7.5 mg/Kg d1). In the short- term efficacy assessment, we observe the benefits to
the patients. However, the long-term efficacy of the chemotherapy program combined with bevacizumb
mainly relies on the maintenance administration of this drug and therefore it is necessary to carry out the
closer follow-up observation.
As far as the side effect is concerned, no common myelosuppression, liver and kidney dysfunction,
gastrointestinal reaction, hypertension, proteinuria, thrombosis, hemorrhage and other reactions(12) were
observed temporarily during the treatment process of this case, which indicates a good tolerance of this
combined program for the treatment of advanced NSCLC. However, it may also be such a reason that the
related side effect of the bevacizumab is dose-dependent. (13)
In summary, the combined chemotherapy program of pemetrexed disodium + carboplatin + bevacizumb
(7.5 mg/Kg d1) was implemented for four cycles to a patient with advanced lung cancer who has EGFR exon
19 deletion mutation and the primary resistance against the EGFR Tki, and it was maintained with
pemetrexed disodium + bevacizumb (7.5 mg/Kg d1) for two cycles. The short-term efficacy was assessed as
PR without obvious adverse effect. It reflects the efficacy and good tolerance of this program, which provides
more clinical evidences for clinical application.
FUNDING
1.
National Key Scientific & Technology Support Program: Collaborative innovation of Clinical Research for
chronic obstructive pulmonary disease and lung cancer, NO.2013BAI09B09;
2.
Young Scientists Fund in National Natural Science Foundation of China (Program Number: 81502699).
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