Journal Thoracic Oncology

Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
to a fundamental change in the surgical management of this disease. A brief
mention will be made of advances in the surgical treatment of other thoracic
malignancies.
Keywords: lung cancer, surgery, staging, results
International patterns of radiotherapy practice for non-small cell lung cancer.
Semin Radiat Oncol. 2015;25(2):143-50.
Keywords: lung cancer, radiation oncology, history
PL05: CLOSING PLENARY SESSION: A LIFE IN THORACIC ONCOLOGY - REFLECTIONS FROM
GIANTS ON MILESTONES IN THE TREATMENT ADVANCES IN LUNG CANCER
WEDNESDAY, DECEMBER 7, 2016 - 16:00-18:00
PL05.03 RADIO-ONCOLOGY
David Ball
Radiation Oncology, Peter MacCallum Cancer Centre, East Melbourne/Australia
When I commenced training in radiation oncology in 1973, there were no CT
scanners, calculations were done with slide rules, and chemotherapy, let
alone combined modality therapy, had no established role in the treatment of
non-small cell lung cancer. An influential trial published in the Lancet in 1971(1)
had shown no difference in survival whether patients were randomized
to radiotherapy, chemotherapy, a combination of the two or a policy of
wait-and–see. Yet within 30 years, the standard of care for patients with
inoperable lung cancer being treated for cure, both small cell and non-small
cell, had, ironically, become, and remains, concomitant chemotherapy and
radiotherapy. The outlook for patients generally regarded as incurable at
the outset of my career is that up to one in three selected patients can now
expect to live five years as a result of chemoradiation. Patients with stage
I non-small cell lung cancer can have their cancer successfully ablated by
non-invasive stereotactic radiotherapy in 90% of cases. The developments
which led to these changes can be grouped according to three main themes:
the impact of the computer revolution; a better understanding of the natural
history and biology of the disease, and the introduction of mutimodality
therapy. The computer revolution: imaging, treatment planning and delivery
Better identification and delineation of the tumor are critical to the success
of radiotherapy, in particular avoidance of the catastrophic “geographic
miss”. Without computers, the CT and hybrid PET/CT scanners could not have
been possible. These dramatically improved the accuracy of staging as well
as providing 3D information on the relationship of the soft tissue target to
the nearby dose-limiting organs at risk. As computing power increased it
became possible to create 4D images of moving tumours, and to image the
target with on-board CT scanners attached to the linac immediately before
treatment, so making image guided stereotactic ablative radiotherapy
possible. Powerful computerised treatment planning systems are now able
to create complex dose distributions conforming to the irregularities of any
target volume, and to provide dose-volume metrics predictive of risks of
normal tissue damage. Improved understanding of the natural history and biology
of the disease The recognition that the central nervous system is a sanctuary
site which can harbour metastatic disease leading to treatment failure in
spite of successful chemotherapeutic eradication of extracranial disease,
particularly in small cell lung cancer, led to the introduction of prophylactic
cranial irradiation. The British study of continuous hyperfractionated
accelerated radiotherapy (CHART) which was given over 12 days to patients
with inoperable non-small cell lung cancer resulted in better survival than
treatment given over six weeks, even though the total dose was lower. This
trial provided clinical support for the notion of treatment induced accelerated
repopulation, and reinforced the principle that total treatment times should
be kept short in both small cell and non-small cell lung cancer, both when
radiotherapy is used alone, and when in combination with chemotherapy.
Multimodality therapy The limitations of single modality therapy for a disease
with a high propensity for developing genetically determined resistance have
long been recognised, and have stimulated the development of strategies
simultaneously employing non-cross resistant therapies to maximise tumor
cell kill, in line with the principles espoused by Goldie and Coldman.(2) The use
of concomitant platinum based chemotherapy with high dose radiotherapy
is now well established by meta analysis as improving survival of both nonsmall
cell and small cell lung cancers, but it is also more toxic. Amelioration of
these toxicities represents a major challenge for the future. Future directions
It is likely that the technical progress in radiation treatment planning and
delivery is close to a plateau, and that future progress will depend more on
understanding the biology of the disease and its response, and that of the
normal tissues, to radiation damage. Biomarkers of response and toxicity, so
spectacularly harnessed to advantage by our medical oncology colleagues,
are desperately needed to tailor the radiotherapy prescription to the
needs of each individual and their cancer. Finally, it is evident that in many
jurisdictions, including industrialised wealthy nations, that many patients are
either receiving substandard radiotherapy that might increase their chances
of cure, or are not receiving treatment at all.(3) Unless these problems can
be addressed, the benefits of the remarkable advances in technology and
biology documented above will shamefully be restricted to only a fraction
of those afflicted with locoregional disease. 1. Durrant KR, Berry RJ, Ellis F,
Ridehalgh FR, Black JM, Hamilton WS. Comparison of treatment policies
in inoperable bronchial carcinoma. Lancet. 1971;1(7702):715-9. 2. Goldie JH,
Coldman AJ, Gudauskas GA. Rationale for the use of alternating non-crossresistant
chemotherapy. Cancer Treat Rep. 1982;66(3):439-49. 3. Vinod SK.
PL05: CLOSING PLENARY SESSION: A LIFE IN THORACIC ONCOLOGY - REFLECTIONS FROM
GIANTS ON MILESTONES IN THE TREATMENT ADVANCES IN LUNG CANCER
WEDNESDAY, DECEMBER 7, 2016 - 16:00-18:00
PL05.04 TRANSLATIONAL LUNG CANCER RESEARCH
Nagahiro Saijo
Japanese Society of Medical Oncology, Tokoyo/Japan
Lung cancer is a leading cause of cancer death in the world. The survival
benefit of chemotherapy was rarely observed in NSCLC until the development
of Cisplatin. Platinum doublets including 2nd/3rd generation cytotoxic drugs
showed minor prolongation of survival but the effect reached a plateau.
JCOG conducted key RCTs to develop new standards against SCLC but a
breakthrough has not been observed yet. Two recent major therapeutic
advancements in NSCLC are immunotherapies to inhibit immune checkpoints
and development of targeted drugs for driver mutations.
Translational Research in Immune Checkpoint inhibitors
Immunotherapy of cancer has a long history without success because of
wrong strategy of immune stimulation with non-specific immunostimulators,
biological response modifiers and recently by peptide antigens. After
introduction of idea on immune checkpoint inhibition by Dr. James Allison,
the studies of this fields were dramatically activated. Currently two anti-PD-1
antibodies such as Nivolumab and Pembrolizumab have been approved for
the treatment of NSCLC based on reproducible effects of tumor shrinkage
and survival benefit. In second line treatment, both antibodies significantly
improved survival compared with standard care of cytotoxic chemotherapy
irrespective of patient selection. Recent press release announced that
Nivolumab failed to demonstrate benefit for PFS compared to cytotoxic
chemotherapy (CheckMate-026), on the other hand Pembrolizumab
demonstrated superior PFS and OS (KEYNOTE-024). Both of the trials patient
selection was done based on PD-L1 expression in lung cancer cells. In spite
of positive data on survival, RR in various trials against advanced NSCLC
with or without prior chemotherapy ranges from 15-25% for both drugs
and median survival is almost same in anti-PD1 Ab and cytotoxic drugs.
The most important issue will be how to concentrate responsive patient
population or how to eliminate in effective patients. Although there is a
tendency of correlation between PD-L1 expression and objective response/
survival, responders to Ab are experienced even in PD-L1 negative patients.
There are many problems in PD-L1 screening. There is no comparative data
of various PD-1 tests used in various clinical trials. Each PD-1 test uses
different antibody. Each test uses a different definition and cut off point
that defines PD-1 positivity. There is no data on best sample, paraffin-fixed
vs fresh tissue, primary site tumor vs metastatic tissue. PD-1 expression is
not stable and influenced by many factors. There is no reliable validation
and standardization. In tumor cells, mutation burden may influence on
antigenicity. In colorectal cancer, microsatellite instability has related with
response to anti-PD-1 antibody, but it is not yet clear whether mutation
burden really increases antigenicity. CD8 lymphocytes infiltration is also
considered to be one of the biomarkers for anti-PD-1 Ab response. However, it
is too objective and seems to be quite difficult to quantify CD 8 lymphocytes
infiltration. The most important thing will be the function of killer T
lymphocytes which can respond to target antigens and to kill tumor cells. The
best method may be quantitative measurements of cytotoxicity in killer T cell
on tumor cells. The techniques to demonstrate this process are mandatory for
successful patient selection in the treatment with anti-PD-1 antibody.
Translational Drug Development for Precision Medicine
Recent development of molecular target drugs in lung cancer really reflects
progress of translational studies. EGFR-TKIs are one of the most important
drugs and changed concept of treatment of lung cancer. Finding on many rare
driver mutations forced to reclassify lung cancer to various genomic subtypes.
Innovative technologies for genomic medicine changes one size fit medicine
to precision medicine. For discovery of drugs to each genomic subtype of lung
cancer, nationwide and global screening network should be mandatory.
In Japan LC-SCRUM Japan leaded by Dr. Koichi Goto, National Cancer Center
Hospital East, started in February 2013 to find out new seeds against lung
cancer by the support of government.. At the beginning, tumor tissues were
analyzed for ALK/ROS1/RET fusions using RT-PCR in EGFR –Mt negative
patients and the detected fusions were confirmed by FISH. From March 2015,
multiplex diagnostic kit using NGS was introduced and this project expanded
as SCRUM-Japan including other histological types of lung cancer such as SQ
and SM as well as GI malignancy.
14 pharmaceutical companies started to support this project. No. of
institutions joined in the network increased to 200 In Non-SQ NSCLC, 159 and
96 for SQ and SM, respectively on March, 2016. More than 2,500 samples were
analyzed. Rare mutations including ROS(91), RET(54) and ALK(40) fusions,
ERB2 mutation/amplification(48), BRAF mutation(16), MET amplification/
S6 Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017