April 2015 Literature Review - Caring Ambassadors Lung Cancer

Transcription

Caring Ambassadors Lung Cancer Program
Literature Review, April 2015
BASIC AND APPLIED SCIENCE, PRE-CLINICAL STUDIES
SCREENING, DIAGNOSIS AND STAGING
CLINICAL TRIALS, COHORT STUDIES, PILOT STUDIES
NSCLC SURGERY
NSCLC CHEMOTHERAPY
NSCLC RADIOTHERAPY
SMALL CELL LUNG CANCER (SCLC)
PALLIATIVE AND SUPPORTIVE CARE
COMPLEMENTARY AND ALTERNATIVE THERAPY
MISCELLANEOUS WORKS
1-3
3-7
7-8
8-12
12-14
14-18
18-21
21-23
23-26
BASIC AND APPLIED SCIENCE, PRE-CLINICAL STUDIES
No impact of passive smoke on the somatic profile of lung cancers in never-smokers. Couraud S1,
Debieuvre D1, Moreau L1, et al. Eur Respir J. 2015 Mar 5. pii: ERJ-00973-2014. [Epub ahead of print]
EGFR and HER2 mutations and ALK rearrangement are known to be related to lung cancer in neversmokers, while KRAS, BRAF and PIK3CA mutations are typically observed among smokers. There is
still debate surrounding whether never-smokers exposed to passive smoke exhibit a "smoker-like" somatic
profile compared with unexposed never-smokers. Passive smoke exposure was assessed in the French
BioCAST/IFCT-1002 never-smoker lung cancer cohort and routine molecular profiles analyses were
compiled. Of the 384 patients recruited into BioCAST, 319 were tested for at least one biomarker and
provided data relating to passive smoking. Overall, 219 (66%) reported having been exposed to passive
smoking. No significant difference was observed between mutation frequency and passive smoke
exposure (EGFR mutation: 46% in never exposed versus 41% in ever exposed; KRAS: 7% versus 7%;
ALK: 13% versus 11%; HER2: 4% versus 5%; BRAF: 6% versus 5%; PIK3CA: 4% versus 2%). We
observed a nonsignificant trend for a negative association between EGFR mutation and cumulative
duration of passive smoke exposure. No association was found for other biomarkers. There is no clear
association between passive smoke exposure and somatic profile in lifelong, never-smoker lung cancer.
PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking
crizotinib-resistant ROS1 mutations. Zou HY1, Li Q2, Engstrom LD2, et al. Proc Natl Acad Sci U S A.
2015 Mar 17;112(11):3493-8. doi: 10.1073/pnas.1420785112. Epub 2015 Mar 2.
Oncogenic c-ros oncogene1 (ROS1) fusion kinases have been identified in a variety of human cancers and
are attractive targets for cancer therapy. The MET/ALK/ROS1 inhibitor crizotinib (Xalkori, PF02341066) has demonstrated promising clinical activity in ROS1 fusion-positive non-small cell lung
cancer. However, emerging clinical evidence has shown that patients can develop resistance by acquiring
secondary point mutations in ROS1 kinase. In this study we characterized the ROS1 activity of PF06463922, a novel, orally available, CNS-penetrant, ATP-competitive small-molecule inhibitor of
ALK/ROS1. In vitro, PF-06463922 exhibited subnanomolar cellular potency against oncogenic ROS1
fusions and inhibited the crizotinib-refractory ROS1(G2032R) mutation and the ROS1(G2026M)
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Caring Ambassadors Lung Cancer Program Literature Review © 2015
gatekeeper mutation. Compared with crizotinib and the second-generation ALK/ROS1 inhibitors ceritinib
and alectinib, PF-06463922 showed significantly improved inhibitory activity against ROS1 kinase. A
crystal structure of the PF-06463922-ROS1 kinase complex revealed favorable interactions contributing
to the high-affinity binding. In vivo, PF-06463922 showed marked antitumor activity in tumor models
expressing FIG-ROS1, CD74-ROS1, and the CD74-ROS1(G2032R) mutation. Furthermore, PF06463922 demonstrated antitumor activity in a genetically engineered mouse model of FIG-ROS1
glioblastoma. Taken together, our results indicate that PF-06463922 has potential for treating ROS1
fusion-positive cancers, including those requiring agents with CNS-penetrating properties, as well as for
overcoming crizotinib resistance driven by ROS1 mutation.
IL-24 Inhibits Lung Cancer Cell Migration and Invasion by Disrupting The SDF-1/CXCR4
Signaling Axis. Panneerselvam J1, Jin J2, Shanker M2, et al. PLoS One. 2015 Mar 16;10(3):e0122439.
doi: 10.1371/journal.pone.0122439. eCollection 2015.
BACKGROUND: The stromal cell derived factor (SDF)-1/chemokine receptor (CXCR)-4 signaling
pathway plays a key role in lung cancer metastasis and is molecular target for therapy. In the present
study we investigated whether interleukin (IL)-24 can inhibit the SDF-1/CXCR4 axis and suppress lung
cancer cell migration and invasion in vitro. Further, the efficacy of IL-24 in combination with CXCR4
antagonists was investigated. METHODS: Human H1299, A549, H460 and HCC827 lung cancer cell
lines were used in the present study. The H1299 lung cancer cell line was stably transfected with
doxycycline-inducible plasmid expression vector carrying the human IL-24 cDNA and used in the present
study to determine the inhibitory effects of IL-24 on SDF-1/CXCR4 axis. H1299 and A549 cell lines were
used in transient transfection studies. The inhibitory effects of IL-24 on SDF1/CXCR4 and its
downstream targets were analyzed by quantitative RT-PCR, western blot, luciferase reporter assay, flow
cytometry and immunocytochemistry. Functional studies included cell migration and invasion assays.
PRINCIPAL FINDINGS: Endogenous CXCR4 protein expression levels varied among the four human
lung cancer cell lines. Doxycycline-induced IL-24 expression in the H1299-IL24 cell line resulted in
reduced CXCR4 mRNA and protein expression. IL-24 post-transcriptionally regulated CXCR4 mRNA
expression by decreasing the half-life of CXCR4 mRNA (>40%). Functional studies showed IL-24
inhibited tumor cell migration and invasion concomitant with reduction in CXCR4 and its downstream
targets (pAKTS473, pmTORS2448, pPRAS40T246 and HIF-1α). Additionally, IL-24 inhibited tumor cell
migration both in the presence and absence of the CXCR4 agonist, SDF-1. Finally, IL-24 when combined
with CXCR4 inhibitors (AMD3100, SJA5) or with CXCR4 siRNA demonstrated enhanced inhibitory
activity on tumor cell migration. CONCLUSIONS: IL-24 disrupts the SDF-1/CXCR4 signaling pathway
and inhibits lung tumor cell migration and invasion. Additionally, IL-24, when combined with CXCR4
inhibitors exhibited enhanced anti-metastatic activity and is an attractive therapeutic strategy for lung
metastasis.
Dual inhibition of allosteric mitogen-activated protein kinase (MEK) and phosphatidylinositol 3kinase (PI3K) oncogenic targets with a bifunctional inhibitor. Van Dort ME1, Galbán S2, Wang H3,
et al. Bioorg Med Chem. 2015 Apr 1;23(7):1386-94. doi: 10.1016/j.bmc.2015.02.053. Epub 2015 Mar 6.
The MAP kinase (Ras/MEK/ERK) and PI3K/Akt/mTOR oncogenic signaling pathways are central
regulators of KRAS-mediated transformation. Molecular reciprocity between the Ras/MEK/ERK and
PI3K/Akt/mTOR pathways provides cancer cells with the ability to evade treatment when targeting only
one pathway with monotherapy. Multi-kinase targeting was explored through the development of a single
bivalent chemical entity by covalent linking of high-affinity MEK and PI3K inhibitors. A prototype dualacting agent (compound 8) designed using the PI3K inhibitor ZSTK474 and the Raf/MEK inhibitor
RO5126766 as scaffolds displayed high in vitro inhibition of both PI3K (IC50=172nM) and MEK1
(IC50=473nM). Additionally, compound 8 demonstrated significant modulation of MEK and PI3K
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signaling pathway activity in human A549 human lung adenocarcinoma cells and pancreatic cancer cells
(PANC-1) and also decreased cellular viability in these two cell lines.
Tricetin, a dietary flavonoid, suppresses benzo(a)pyrene induced human non small cell lung cancer
bone metastasis. Hung JY1, Chang WA2, et al. Int J Oncol. 2015 Mar 4. doi: 10.3892/ijo.2015.2915.
[Epub ahead of print]
This is the first study to demonstrate that benzo(a)-pyrene (BaP) was able to enhance the production of
parathyroid hormone related protein (PTHrP) by human non small cell lung cancer H460 cells. Such
effect would further contribute to bone metastasis of lung cancer by increasing osteoclastogenesis. This
study is also the first to reveal that tricetin (TCN), a flavonoid derivative found in Myrtaceae pollen and
Eucalyptus honey, was able to reverse BaP mediated bone resorption activity of lung cancer cells. Human
non small cell lung cancer H460 cells were treated with BaP to generate conditioned medium. When
osteoblasts were cultured with BaP H460 CM, their expression of osteoclastogenesis activator
macrophage colony stimulating factor (M CSF) and receptor activator of nuclear factor κB ligand
(RANKL) was increased. BaP H460 CM reduced the production of osteoprotegerin (OPG), an
osteoclastogenesis inhibitor, in osteoblasts. Osteoclastogenesis and bone resorption activity of H460 cells
were increased by BaP H460 CM. With BaP mediated PTHrP upregulation, IL 8 secretion in H460 cells
was increased contributing to human non small cell lung cancer mediated osteoclast differentiation and
bone resorption. Moreover, TCN suppressed BaP mediated bone resorption. Therefore, TCN may be a
novel agent for treatment of non small cell lung cancer patients with bone metastasis.
SCREENING, DIAGNOSIS AND STAGING
The Relations between False Positive and Negative Screens and Smoking Cessation and Relapse in
the National Lung Cancer Screening Trial: Implications for Public Health.
Clark MA1, Gorelick JJ2, Sicks JD2, Park ER3, Graham AL4, Abrams DB5, Gareen IF6. Nicotine Tob
Res. 2015 Mar 6. pii: ntv037. [Epub ahead of print]
INTRODUCTION: Lung screening is an opportunity for smoking cessation and relapse prevention, but
smoking behaviors may differ across screening results. Changes in smoking were evaluated among
18,840 current and former smokers aged 55-74 scheduled to receive three annual lung screenings.
METHODS: Participants were randomized to low-dose CT or single-view chest radiography in the
American College of Radiology/National Lung Screening Trial (NLST). Outcome measures included
point and sustained (6-month) abstinence and motivation to quit among smokers; and relapse among
smokers who quit during follow-up, recent quitters (quit < 6 months), and long-term former smokers (quit
≥ 6 months). RESULTS: During five years of follow-up, annual point prevalence quit rates ranged from
11.6%-13.4%; 48% of current smokers reported a quit attempt and 7% of long-term former smokers
relapsed. Any false positive screening result was associated with subsequent increased point
(multivariable hazard ratio HR=1.23, 95% CL: 1.13, 1.35) and sustained (HR=1.28, 95% CL: 1.15, 1.43)
abstinence among smokers. Recent quitters with ≥1 false positive screen were less likely to relapse
(HR=0.72, 95% CL: 0.54, 0.96). Screening result was not associated with relapse among long-term
former smokers or among baseline smokers who quit during follow-up. CONCLUSIONS: A false
positive screen was associated with increased smoking cessation and less relapse among recent quitters.
Consistently negative screens were not associated with greater relapse among long-term former smokers.
Given the Affordable Care Act requires most health plans to cover smoking cessation and lung screening,
the impact and cost-effectiveness of lung screening could be further enhanced with the addition of
smoking cessation interventions.
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Small RNA Sequencing for Profiling MicroRNAs in Long-Term Preserved Formalin-Fixed and
Paraffin-Embedded Non-Small Cell Lung Cancer Tumor Specimens. Buitrago DH1, Patnaik SK2,
Kadota K3, Kannisto E2, Jones DR1, Adusumilli PS4. PLoS One. 2015 Mar 26;10(3):e0121521. doi:
10.1371/journal.pone.0121521.
BACKGROUND: The preservation of microRNAs in formalin-fixed and paraffin-embedded (FFPE)
tissue makes them particularly useful for biomarker studies. The utility of small RNA sequencing for
microRNA expression profiling of FFPE samples has yet to be determined. METHODS: Total RNA was
extracted from de-paraffinized and proteinase K-treated FFPE specimens (15-20 years old) of 8 human
lung adenocarcinoma tumors by affinity chromatography on silica columns. MicroRNAs in the RNA
preparations were quantified by the Illumina HiSeq 2000 sequencing platform with sequencing libraries
prepared with the TruSeq Small RNA Sample Preparation Kit (version 2.0) to obtain unpaired reads of 50
b for small RNA fragments. MicroRNAs were also quantified using Agilent Human miRNA (release
16.0) microarrays that can detect 1,205 mature microRNAs and by quantitative reverse transcription
(RT)-PCR assays. RESULTS: Between 9.1-16.9 million reads were obtained by small RNA sequencing
of extracted RNA samples. Of these, only 0.6-2.3% (mean = 1.5%) represented microRNAs. The
sequencing method detected 454-625 microRNAs/sample (mean = 550) compared with 200-349 (mean =
286) microRNAs detected by microarray. In Spearman correlation analyses, the average correlation
coefficient for the 126 microRNAs detected in all samples by both methods was 0.37, and >0.5 for 63
microRNAs. In correlation analyses of the sequencing- and RT-PCR-based measurements, the
coefficients were 0.19-0.95 (mean = 0.73) and >0.7, respectively, for 7 of 9 examined microRNAs. The
average inter-replicate Spearman correlation coefficient for the sequencing method was 0.81.
CONCLUSIONS: Small RNA sequencing can be used to obtain microRNA profiles of FFPE tissue
specimens with performance characteristics similar to those of microarrays, in spite of the fragmentation
of ribosomal and messenger RNAs that reduces the method's informative capacity. The accuracy of the
method can conceivably be improved by increasing sequencing depth and/or depleting FFPE tissue RNAs
of ribosomal RNA fragments.
FDG Uptake on Positron Emission Tomography Correlates with Survival and Time to Recurrence
in Patients with Stage I Non-Small Cell Lung Cancer. Kwon W1, Howard BA, Herndon JE, Patz EF
Jr. J Thorac Oncol. 2015 Mar 25. [Epub ahead of print]
INTRODUCTION: Patients with stage I NSCLC have a wide variation in outcomes, most likely because
there are undetected metastases at presentation. We retrospectively reviewed patients with early stage
lung cancer to determine if FDG uptake of the primary tumor as measured on PET at the time of diagnosis
was associated with overall survival or time to recurrence. METHODS: We reviewed the Tumor
Registry at our institution and identified 336 consecutive patients diagnosed with stage I NSCLC over a 5
year period who underwent an FDG-PET/ CT within 90 days prior to surgery. Kaplan-Meier curves were
used to describe the survival and time to recurrence experience within subgroups defined by PET
SUVmax. Cox proportional hazards model was used to assess the impact of PET SUVmax as a
continuous variable on overall survival and time to recurrence. Logistic regression was used to analyze
the effect of SUVmax on dichotomized outcomes. RESULTS: Three hundred thirty-six consecutive
patients (176 women, 160 men)with stage I NSCLC were retrospectively reviewed. Mean SUVmax was
9.2 +/- 6.9 (range,0.6-30.3). The hazard or risk of dying and recurrence increased significantly as
SUVmax increased (p=0.0008 and p=0.024, respectively). CONCLUSIONS: Preoperative FDG uptake
in the primary tumor in patients with stage I disease is associated with overall survival and time to
recurrence. This may be useful in identifying early stage patients who may benefit from more aggressive
therapy following surgical resection.
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Bronchoscopic transparenchymal nodule access (BTPNA): first in human trial of a novel procedure
for sampling solitary pulmonary nodules. Herth FJ1, Eberhardt R1, Sterman D2, Silvestri GA3,
Hoffmann H4, Shah PL5. Thorax. 2015 Apr;70(4):326-32. doi: 10.1136/thoraxjnl-2014-206211. Epub
2015 Mar 6.
INTRODUCTION: The promise of benefits from lung cancer screening is tempered by the false positive
rate and the need to perform diagnostic procedures to determine the aetiology of the solitary pulmonary
nodules (SPN) identified. We have developed a novel procedure which allows sampling of SPNs via a
transparenchymal approach, and report the results from this as a first in human trial. METHODS: This
study was a prospective single-arm interventional study. We recruited patients with a SPN detected on CT
imaging, which was suspicious for lung cancer, who were suitable for surgical resection. Using the
subject's CT, an optimal airway wall point of entry (POE), and an avascular path through lung tissue from
the POE to the SPN was calculated. A tunnel tract was created from the POE to the nodule using a set of
catheter-based tools under fused fluoroscopy guidance. The patients proceeded to surgical resection
immediately after the biopsy. The participants were followed-up for 6 months after the procedure. The
primary endpoint of the study was to evaluate the feasibility to access and biopsy the nodule. RESULTS:
Twelve patients were recruited, and a tunnel pathway created in 10 patients. There were no adverse events
during the procedures. Adequate biopsies were obtained from 10 patients (83%), which correlated with
the histological findings from the surgical resection. Inspection of the resected lobes did not raise any
safety concerns and indicated appropriately tunnelled pathways to the nodule. CONCLUSIONS: This
first in human study demonstrates that bronchoscopic transparenchymal access of SPNs is feasible.
MiR-205 and MiR-375 MicroRNA Assays to Distinguish Squamous Cell Carcinoma from
Adenocarcinoma in Lung Cancer Biopsies. Patnaik S1, Mallick R, Kannisto E, Sharma R, Bshara W,
Yendamuri S, Dhillon SS. J Thorac Oncol. 2015 Mar;10(3):446-53. doi:
10.1097/JTO.0000000000000423.
INTRODUCTION: Identification of adenocarcinoma (AC) and squamous cell carcinoma (SCC)
histology of non-small-cell lung cancer (NSCLC) in biopsies is clinically important but can be inaccurate
by routine histopathologic examination. We quantify this inaccuracy at a cancer center, and evaluate the
utility of a microRNA-based method to histotype AC/SCC in biopsies. METHODS: RNA was extracted
from tissue sections with greater than 90% tumor content that were macro- or micro-dissected from
formalin-fixed, paraffin-embedded biopsy specimens. MicroRNAs in RNA from the biopsies and from
resected tumors were quantified by TaqMan reverse transcription-polymerase chain reaction assays and
normalized against the RNU6B housekeeping RNA. Publicly available microRNA expression datasets
were examined. RESULTS: NSCLC subtyping of small biopsy specimens by routine histopathologic
examination either failed or mistyped the histology of 21% of 190 cases. Using 77 resectates, an reverse
transcription-polymerase chain reaction-based assay of microRNAs miR-21, miR-205, and miR-375 was
developed to identify AC and SCC subtypes of NSCLC. This method identified the AC/SCC histotypes of
25 biopsies with an accuracy of 96%, and correctly histotyped all 12 cases for which the histology had
been mistyped by routine histopathologic examination of the biopsy. Examination of publicly available
datasets identified miR-205 and miR-375 as microRNAs with the best ability to histotype AC and SCC,
and that levels of the two microRNAs in AC or SCC are unaffected by the pathologic stage of the tumor
or the age or race of the patient. CONCLUSIONS: Histotypic microRNA assays can aid the subtyping of
NSCLC biopsies as AC or SCC by standard histopathologic methods.
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Intraoperative core needle biopsy under complete video-assisted thoracic surgery for indeterminate
tumor of lung. Isaka T1, Takahashi K, Maehara T, Masuda M. Surg Endosc. 2015 Mar 5. [Epub ahead of
print]
BACKGROUND: The accuracy, feasibility, and safety of intraoperative core needle biopsy under
complete video-assisted thoracic surgery (VATS) (V-CNB) for indeterminate tumors are examined
retrospectively, as well as the possibility of pleural dissemination. METHODS: The diagnostic yield and
complications of V-CNB were evaluated for a total of 95 patients who underwent V-CNB for
indeterminate tumor during the period of April 2002 through March 2012. Moreover, operation time,
number of auto-suture instruments used for resection of the lung, and pleural dissemination were
compared between the patients who underwent V-CNB (n = 44) and those who did not (n = 87, non-VCNB) among stage I primary lung cancer patients, for whom lobectomy was performed under complete
VATS during the same period. RESULTS: Of the 95 patients, eighty three had primary lung cancer, four
had metastatic lung cancer, and eight had benign tumor. Sensitivity, specificity, and accuracy were 94.3,
87.5, and 93.7 %, respectively. There were no complications associated with V-CNB. Among stage I
primary lung cancer, for which lobectomy and lymph node dissection were performed, there was no
significant difference between the V-CNB group and the non-V-CNB group for tumor size (23.5 and 24.7
mm, p = 0.482), distance between pleura and tumor (3.4 and 5.0 mm, p = 0.202), operation time (228 and
217 min, p = 0.186), and number of auto-suture instruments used for resection of the lung (4.77 and 4.61,
p = 0.533). There was no pleural dissemination in the V-CNB group, although there were two cases (2.3
%) in the non-V-CNB group. CONCLUSION: V-CNB diagnosed small-sized indeterminate lung tumors
accurately during complete VATS operation, without any complications. V-CNB can reduce the use of
auto-suture instruments necessary for performing wedge resection on frozen section diagnosis prior to
lobectomy without increasing operation time and the risk of pleural dissemination.
Endobronchial Ultrasound-guided Transbronchial Needle Aspiration for Systematic Nodal Staging
of Lung Cancer in Patients with N0 Disease by Computed Tomography and Integrated Positron
Emission Tomography-Computed Tomography. Ong P1, Grosu H, Eapen GA, et al. Ann Am Thorac
Soc. 2015 Mar;12(3):415-9. doi: 10.1513/AnnalsATS.201409-429OC.
RATIONALE: Data regarding the sensitivity of endobronchial ultrasound-guided transbronchial needle
aspiration (EBUS-TBNA) for staging of lung cancer in patients with radiographic N0 disease is scant and
inconsistent. With increasing use of nonoperative ablative therapies, studies focusing on the performance
characteristics of EBUS-TBNA in this population are important. OBJECTIVES: To evaluate the
sensitivity and negative predictive value (NPV) of EBUS-TBNA in patients with non-small cell lung
cancer and radiographic N0 disease both by computed tomography (CT) and positron emission
tomography (PET)-CT. METHODS: This was a retrospective review of EBUS-TBNA performed for
lung cancer staging at two major academic centers from 2009 to 2014. Patients with radiographic N0
disease (lymph nodes [LN] ≤ 1 cm in the short axis and maximum standardized uptake value ≤ 2.5 by
PET-CT) were included. Primary outcome was sensitivity and NPV of EBUS-TBNA.
MEASUREMENTS AND MAIN RESULTS: Two hundred twenty patients with radiographic N0
disease underwent EBUS-TBNA, and 734 LN were sampled (median 3, range 1-6). Median LN diameter
was 0.72 cm. One hundred patients (45.5%) underwent surgery, and 120 patients (54.5%) had nonsurgical
therapy. N status was up-staged in 49 patients (22.3%): 18 by EBUS-TBNA (N1 = 11, N2 = 6, N3 = 1), 27
by surgery (N1 intralobar = 16, N1 extralobar = 3, N2 = 8 [5 LN in stations 4 and 7, and 3 LN in stations
5-6), and 4 by imaging follow-up (N1 = 2, N2 = 2). Overall false-negative rate of EBUS was 14.1%
(sensitivity, 36.7%; specificity, 100%; and NPV, 84.7%). False-negative rate was 27 and 3.3% in surgical
and nonsurgical populations, respectively. Excluding patients with occult disease "outside" the reach of
EBUS, the overall false-negative rate of EBUS-TBNA was 5.5% (sensitivity, 60%; specificity, 100%; and
NPV, 93.4%). CONCLUSIONS: This is the largest report of EBUS-TBNA in patients with N0 disease
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by "integrated" PET-CT. The majority of false-negative EBUS results were in LN stations outside its
reach. In our study, both sensitivity and NPV of EBUS-TBNA were lower than early reports despite more
extensive LN sampling. Given the high false-negative rate of imaging modalities, EBUS-TBNA may still
play an important role in patients with radiographic N0 disease, particularly when nonsurgical ablative
therapies are planned. Prospective studies are needed to corroborate our findings in the nonsurgical
population.
CLINICAL TRIALS, COHORT STUDIES, PILOT STUDIES
NSCLC - SURGERY
Uniportal video-assisted thoracoscopic lobectomy: an alternative to conventional thoracoscopic
lobectomy in lung cancer surgery? Chung JH1, Choi YS2, Cho JH3, Kim HK3, Kim J3, Zo JI3, Shim
YM3. Interact Cardiovasc Thorac Surg. 2015 Mar 3. pii: ivv034. [Epub ahead of print]
OBJECTIVES: Although the standard video-assisted thoracoscopic surgery (VATS) approach is
generally performed through two to four incisions, uniportal VATS pulmonary resection has recently been
reported to be a promising, less invasive alternative. To evaluate the adequacy of uniportal VATS
lobectomy as an alternative to conventional VATS lobectomy in lung cancer, we analysed and compared
the outcomes of uniportal and conventional VATS lobectomies. METHODS: Retrospective
observational data for patients who underwent VATS lobectomy at Samsung Medical Center between
January 2013 and February 2014 due to a diagnosis of lung cancer were collected. Perioperative factors
such as operative time, postoperative chest tube duration, postoperative hospital stay, complication rate,
conversion rate, reoperation rate and mortality were compared between the uniportal and conventional
VATS groups. RESULTS: A total of 90 uniportal VATS lobectomies and 60 conventional VATS
lobectomies were attempted. Fifty-eight (64.5%) cases were completed as uniportal VATS lobectomies,
and 51 (85%) cases as conventional VATS lobectomies. There were 32 (35.5%) conversions of uniportal
VATS lobectomy cases, including four conversions to three-port VATS, 18 to two-port VATS and 10 to
open thoracotomy. No differences in postoperative complications, postoperative 30-day mortality or
reoperation rate were noted between the two groups. There was no difference in operative time, number of
removed lymph nodes, chest tube duration or length of postoperative hospital stay between the uniportal
VATS group and conventional VATS group. CONCLUSIONS: The similar perioperative results of
uniportal VATS lobectomy compared with conventional VATS lobectomy suggest that uniportal VATS is
a viable alternative approach to the conventional VATS approach in selected patients, especially in
patients with early peripheral lung cancer with good anatomy and in good general condition.
Minimally Invasive Resection of Early Lung Cancers. Cheng AM, Wood DE. Oncology (Williston
Park). 2015 Mar 15;29(3). pii: 204255.
Low-dose computed tomography (LDCT) screening decreases lung cancer mortality in high-risk
individuals and has now been approved and adopted for lung cancer screening in the United States. As
more LDCT lung cancer screening programs are implemented, more patients with early-stage lung cancer
who could benefit from surgical intervention will be identified. Although lobectomy currently remains the
standard of care for early-stage non-small-cell lung cancer (NSCLC), thoracic surgeons are increasingly
adopting minimally invasive surgery via thoracoscopy as a viable-and perhaps even preferred-approach
for select lung cancer resections. Video-assisted thoracic surgery (VATS) lobectomy has been associated
with decreased perioperative morbidity, and similar rates of locoregional recurrence and cancer-free
survival can be achieved compared with the standard open surgical procedure. However, as lung cancers
are detected at earlier stages, the optimal extent of lung resection for long-term cure continues to be
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investigated. For patients with very small-sized lung tumors and indolent lesions, cancer-free survival
may not necessarily be compromised by undergoing less invasive approaches that intentionally resect less
lung tissue, such as sublobar resections (eg, segmentectomy and wedge resection). This review looks at
the current data and guidelines for thoracoscopic resection of stage I NSCLC and discusses the potential
for limited lung resection in patients with the disease.
Efficacy and safety of stereotactic ablative radiotherapy in patients with previous pneumonectomy.
Giaj Levra N1, Filippi AR, Guarneri A, Badellino S, Mantovani C, Ruffini E, Ricardi U. Tumori. 2015
Mar 11;0(0):0. doi: 10.5301/tj.5000227. [Epub ahead of print]
BACKGROUND: Thoracic surgery for a newly diagnosed primary lung tumor following a previous
pneumonectomy is rarely indicated. Stereotactic ablative radiotherapy (SABR) might represent a curative
option. This report focuses on outcomes, toxicity and quality of life (QoL) after SABR. METHODS:
Nine patients were treated with SABR between 2004 and 2011; median time since surgery was 8.4 years.
In 4 cases, a histological confirmation was possible with bronchoscopy. In 5 cases, the clinical proof of
malignancy was based on radiological criteria. Forced expiratory volume in 1 second (FEV1) and
diffusing capacity of the lung for carbon monoxide (DLCO) were tested in all patients. A SABR
biologically equivalent dose of >100 Gy was prescribed in all cases. QoL questionnaire forms were
administered before SABR and during follow-up. RESULTS: Median follow-up was 41.8 months. We
did not observe grade ≥3 acute toxicity, and concerning late toxicity, we registered 2 cases. QoL was
decreased during the first 12 months of follow-up, followed by a progressive improvement after this time.
One patient had a local relapse at 7.4 years; 1 developed a new nodule at 5.5 years, associated with
metastases; and 1 developed a new nodule without any systemic disease at 3 years. There were 2 cancerrelated deaths (18.2%) at 3 and 12 months after progression. CONCLUSIONS: Data support efficacy
and safety of SABR in patients with a new primary lung cancer following previous pneumonectomy, with
acceptable acute, late toxicity profile and without significant impairment of QoL. Our results were
comparable to those in the literature.
NSCLC - CHEMOTHERAPY
Three-arm, randomized, phase 2 study of carboplatin and paclitaxel in combination with
cetuximab, cixutumumab, or both for advanced nonsmall cell lung cancer (NSCLC) patients who
will not receive bevacizumab-based therapy: An Eastern Cooperative Oncology Group (ECOG)
study (E4508). Hanna NH1, Dahlberg SE, Kolesar JM, et al. Cancer. 2015 Mar 4. doi:
10.1002/cncr.29308. [Epub ahead of print]
BACKGROUND: Preclinical evidence supports the clinical investigation of inhibitors to the insulin-like
growth factor receptor (IGFR) and the epidermal growth factor receptor (EGFR) either alone or in
combination as treatment for patients with nonsmall cell lung cancer (NSCLC). METHODS: Patients
with chemotherapy-naïve, advanced NSCLC who had an Eastern Cooperative Oncology Group
performance status of 0 or 1 were eligible. Patients were randomized to receive carboplatin intravenously
at an area under the plasma drug concentration-time curve of 6.0 plus paclitaxel 200 mg/m2 intravenously
on day 1 every 3 weeks combined with either intravenous cetuximab weekly (arm A), intravenous
cixutumumab every 2 weeks (arm B), or both (arm C). Patients who had nonprogessing disease after 12
weeks of therapy were permitted to continue on maintenance antibody therapy until they developed
progressive disease. The primary endpoint was progression-free survival (PFS). The study design required
180 eligible patients and had 88% power to detect a 60% increase in median PFS for either comparison
(arm A vs arm C or arm B vs arm C) using the log-rank test. RESULTS: From September 2009 to
December 2010, 140 patients were accrued. The study was closed to accrual early because of an excessive
number of grade 5 events reported on arms A and C. Thirteen patients died during treatment (6 patients on
8
arm A, 2 patients on arm B, and 5 patients on arm C), including 9 within approximately 1 month of
starting therapy. The estimated median PFS for arms A, B, and C were similar at 3.4 months, 4.2 months,
and 4 months, respectively. CONCLUSIONS: On the basis of the apparent lack of efficacy and excessive
premature deaths, the current results do not support the continued investigation of carboplatin, paclitaxel,
and cixutumumab either alone or in combination with cetuximab for patients with advanced NSCLC.
Modulation of NF-κB/miR-21/PTEN Pathway Sensitizes Non-Small Cell Lung Cancer to Cisplatin.
Yang Z1, Fang S1, Di Y1, Ying W1, Tan Y1, Gu W1. PLoS One. 2015 Mar 23;10(3):e0121547. doi:
10.1371/journal.pone.0121547. eCollection 2015.
BACKGROUND: Platinum-based chemotherapy is a standard strategy for non-small cell lung cancer
(NSCLC), while chemoresistance remains a major therapeutic challenge in current clinical practice. Our
present study was aimed to determine whether inhibition of the NF-κB/miR-21/PTEN pathway could
increase the sensitivity of NSCLC to cisplatin. METHODS: The expression of miR-21 in NSCLC tissues
was determined using in situ hybridization. Next, the effect of miR-21 on the sensitivity of A549 cells to
cisplatin was determined in vitro. Whether miR-21 regulated PTEN expression was assessed by luciferase
assay. Furthermore, whether NF-κB targeted its binding elements in the miR-21 gene promoter was
determined by luciferase and ChIP assay. Finally, we measured the cell viability and apoptosis under
cisplatin treatment when NF-κB was inhibited. RESULTS: An elevated level of miR-21 was observed in
NSCLC lung tissues and was related to a short survival time. Exogenous miR-21 promoted cell survival
when exposed to cisplatin, while miR-21 inhibition could reverse this process. The RNA and protein
levels of PTEN were significantly decreased by exogenous miR-21, and the 3'-untranslated region of
PTEN was shown to be a target of miR-21. The expression of miR-21 was regulated by NF-κB binding to
its element in the promoter, a finding that was verified by luciferase and ChIP assay. Hence, inhibition of
NF-κB by RNA silencing protects cells against cisplatin via decreasing miR-21 expression.
CONCLUSION: Modulation of the NF-κB/miR-21/PTEN pathway in NSCLC showed that inhibition of
this pathway may increase cisplatin sensitivity.
Switch maintenance treatment with oral vinorelbine and bevacizumab after induction
chemotherapy with cisplatin, gemcitabine and bevacizumab in patients with advanced nonsquamous non-small cell lung cancer: a phase II study. Petrioli R1, Francini E, Fiaschi AI, et al. Med
Oncol. 2015 Apr;32(4):587. doi: 10.1007/s12032-015-0587-x. Epub 2015 Mar 22.
The present study evaluated the efficacy and safety of cisplatin (Cis), gemcitabine (Gem) and
bevacizumab (Bev), followed by maintenance treatment with Bev and oral vinorelbine (Vnb), in patients
with advanced non-squamous non-small cell lung cancer (NSCLC). The patients were administered six
cycles of induction chemotherapy consisting of intravenously (i.v.) Cis 70 mg/m(2) on day 1 plus i.v.
Gem 1000 mg/m(2) on days 1 and 8, plus i.v. Bev 7.5 mg/kg on day 1, every 3 weeks. Patients who did
not experience tumor progression remained on maintenance treatment with Bev combined with oral Vnb
60 mg/m(2) weekly until occurrence of disease progression or unacceptable toxicity. Thirty-seven patients
were enrolled: The median age was 67 years (range 38-81); 22 patients were male, and 30 patients had
stage IV tumors. The response rate was 32.4 % (95 % CI 18-49.7). The 9-month disease-control rate was
45.9 %. The median PFS was 8.4 months (95 % CI 4.4-10.7), and the median OS was 18.1 months (95 %
CI 15.3-20.8 months). Grade 3-4 neutropenia occurred in 6 (16.2 %) patients and grade 3-4
thrombocytopenia in four (10.8 %) patients during induction chemotherapy. Bev- or Vnb-associated
toxicities were mild. Switch maintenance treatment with Bev and oral Vnb after first-line Cis, Gem and
Bev is feasible in patients with non-squamous NSCLC and may achieve encouraging results in terms of
PFS and OS.
9
Adjuvant chemotherapy for resected early-stage non-small cell lung cancer. Burdett S1, Pignon JP,
Tierney J, et al. Cochrane Database Syst Rev. 2015 Mar 2;3:CD011430. [Epub ahead of print]
BACKGROUND: To evaluate the effects of administering chemotherapy following surgery, or
following surgery plus radiotherapy (known as adjuvant chemotherapy) in patients with early stage nonsmall cell lung cancer (NSCLC),we performed two systematic reviews and meta-analyses of all
randomised controlled trials using individual participant data. Results were first published in The Lancet
in 2010. OBJECTIVES: To compare, in terms of overall survival, time to locoregional recurrence, time
to distant recurrence and recurrence-free survival:A. Surgery versus surgery plus adjuvant chemotherapy
B. Surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapy in patients
with histologically diagnosed early stage NSCLC.(2)To investigate whether or not predefined patient
subgroups benefit more or less from cisplatin-based chemotherapy in terms of survival. SEARCH
METHODS: We supplemented MEDLINE and CANCERLIT searches (1995 to December 2013) with
information from trial registers, handsearching relevant meeting proceedings and by discussion with
trialists and organisations. SELECTION CRITERIA: We included trials of a) surgery versus surgery
plus adjuvant chemotherapy; and b) surgery plus radiotherapy versus surgery plus radiotherapy plus
adjuvant chemotherapy, provided that they randomised NSCLC patients using a method which precluded
prior knowledge of treatment assignment. DATA COLLECTION AND ANALYSIS: We carried out a
quantitative meta-analysis using updated information from individual participants from all randomised
trials. Data from all patients were sought from those responsible for the trial. We obtained updated
individual participant data (IPD) on survival, and date of last follow-up, as well as details of treatment
allocated, date of randomisation, age, sex, histological cell type, stage, and performance status. To avoid
potential bias, we requested information for all randomised patients, including those excluded from the
investigators' original analyses. We conducted all analyses on intention-to-treat on the endpoint of
survival. For trials using cisplatin-based regimens, we carried out subgroup analyses by age, sex,
histological cell type, tumour stage, and performance status. MAIN RESULTS: We identified 35 trials
evaluating surgery plus adjuvant chemotherapy versus surgery alone. IPD were available for 26 of these
trials and our analyses are based on 8447 participants (3323 deaths) in 34 trial comparisons. There was
clear evidence of a benefit of adding chemotherapy after surgery (hazard ratio (HR)= 0.86, 95%
confidence interval (CI)= 0.81 to 0.92, p< 0.0001), with an absolute increase in survival of 4% at five
years.We identified 15 trials evaluating surgery plus radiotherapy plus chemotherapy versus surgery plus
radiotherapy alone. IPD were available for 12 of these trials and our analyses are based on 2660
participants (1909 deaths) in 13 trial comparisons. There was also evidence of a benefit of adding
chemotherapy to surgery plus radiotherapy (HR= 0.88, 95% CI= 0.81 to 0.97, p= 0.009). This represents
an absolute improvement in survival of 4% at five years.For both meta-analyses, we found similar
benefits for recurrence outcomes and there was little variation in effect according to the type of
chemotherapy, other trial characteristics or patient subgroup.We did not undertake analysis of the effects
of adjuvant chemotherapy on quality of life and adverse events. Quality of life information was not
routinely collected during the trials, but where toxicity was assessed and mentioned in the publications, it
was thought to be manageable. We considered the risk of bias in the included trials to be low.
AUTHORS' CONCLUSIONS: Results from 47 trial comparisons and 11,107 patients demonstrate the
clear benefit of adjuvant chemotherapy for these patients, irrespective of whether chemotherapy was
given in addition to surgery or surgery plus radiotherapy. This is the most up-to-date and complete
systematic review and individual participant data (IPD) meta-analysis that has been carried out.
10
Phase II Trial of Gefitinib in Combination with Bevacizumab as First-Line Therapy for Advanced
Non-Small Cell Lung Cancer with Activating EGFR Gene Mutations: The Okayama Lung Cancer
Study Group Trial 1001. Ichihara E1, Hotta K, Nogami N, et al. J Thorac Oncol. 2015 Mar;10(3):48691. doi: 10.1097/JTO.0000000000000434.
PURPOSE: Whether bevacizumab enhances the effect of the epidermal growth factor receptor (EGFR)
inhibitor gefitinib on EGFR mutant non-small cell lung cancers (NSCLCs) remains unknown. We
conducted a phase II trial to investigate the efficacy and safety of gefitinib when combined with
bevacizumab as first-line therapy in patients with advanced NSCLC harboring EGFR gene mutations.
METHODS: In this trial, 42 patients with a performance status of 0 to 2 received gefitinib (250 mg/d)
and bevacizumab (15 mg/kg, every 3 weeks). The primary end point of this study was the 1-year
progression-free survival (PFS) rate. We assumed that a 1-year PFS rate of 55% would indicate potential
usefulness and that a 1-year PFS rate of 40% would constitute the lower limit of interest. RESULTS:
Forty-two patients were enrolled in the study with a median age of 73 (range 42-86) years. Activating
EGFR gene mutations included exon 19 deletion (57%) and L858R point mutations in exon 21 (38%).
The objective response rate was 73.8% and included two complete responses. The 1-year PFS rate and
median PFS time were 56.7% (95% confidence interval [CI] 39.9-70.5) and 14.4 months (95% CI 10.119.2), respectively. The median PFS differed significantly between EGFR exon 19 deletion and the
L858R point mutation (18.0 versus 9.4 months, respectively; p = 0.006). The median overall survival had
not yet been reached. Severe adverse events included grade 3 skin rash (15%), hypertension (17%),
aspartate transaminase/alanine aminotransferase elevation (17%), proteinuria (7%), intracranial
hemorrhage (2%), and grade 4 perforation of the digestive tract (2%). There were no treatment-related
deaths. CONCLUSION: Gefitinib in combination with bevacizumab as first-line therapy seems to be a
favorable and well-tolerated treatment for patients with advanced NSCLC with activating EGFR gene
mutations, especially those with EGFR exon 19 deletion mutations, although the primary end point was
not met because the lower limit of the CI was less than 40%.
Adjuvant Chemotherapy in Resected Stage II Non-small Cell Lung Cancer: Evaluating the Impact
of Dose Intensity and Time to Treatment. Ramsden K1, Laskin J1, Ho C2. Clin Oncol (R Coll Radiol).
2015 Mar 19. pii: S0936-6555(15)00102-8. doi: 10.1016/j.clon.2015.03.001. [Epub ahead of print]
AIMS: Platinum-based adjuvant chemotherapy is the standard of care for resected stage II non-small cell
lung cancer (NSCLC). The purpose of this population-based study was to identify factors that predict for
receiving adjuvant therapy and to assess the effect of delayed administration and dose reduction on
survival. MATERIALS AND METHODS: The British Columbia Cancer Agency provides cancer care
to 4.6 million individuals across a large and varied geographical area. A retrospective review was
conducted of all referred patients with resected stage II NSCLC between 2005 and 2010. Baseline
characteristics, systemic therapy details and outcomes were recorded. RESULTS: Of 258 stage II
NSCLC patients, 158 received adjuvant chemotherapy (61%). No-adjuvant versus adjuvant population:
men 52%/57%, median age 67/62, Eastern Cooperative Oncology Group (ECOG) ≤ 1 55%/75%,
Charlson comorbidity score (CCS) ≤ 1 61%/74%, pneumonectomy 11%/26%. In patients who received
chemotherapy, treatment details were: cisplatin/carboplatin based 81%/19%, median cycles delivered 4,
median time from surgery to adjuvant chemotherapy 8 weeks, 72% received ≥ 80% (cisplatin < 256
mg/m2 and carboplatin < AUC 19.2) total planned dose. On multivariate analysis younger age, better
ECOG and pneumonectomy were predictive of adjuvant treatment. Overall survival of adjuvant-treated
patients was inferior for those with CCS ≥ 2, age ≥ 70 and reduced dose intensity on multivariate analysis.
The surgery to chemotherapy interval did not affect overall survival. CONCLUSIONS: Pneumonectomy
and factors associated with better functional status predicted for receiving adjuvant chemotherapy. For
patients who received adjuvant chemotherapy the total platinum dose given affected survival but time
11
from surgery did not. A higher platinum dose delivery was important in maintaining the efficacy of
adjuvant chemotherapy for resected stage II NSCLC in this retrospective population-based study.
A randomized trial comparing adjuvant chemotherapy with gemcitabine plus cisplatin with
docetaxel plus cisplatin in patients with completely resected non-small-cell lung cancer with quality
of life as the primary objective. Barlesi F1, Chouaid C2, Crequit J3, et al. Interact Cardiovasc Thorac
Surg. 2015 Mar 11. pii: ivv050. [Epub ahead of print]
OBJECTIVES: Adjuvant chemotherapy with vinorelbine plus cisplatin (VC) improves survival in
resected non-small-cell lung cancer (NSCLC), but has negative impact on quality of life (QoL). In
advanced NSCLC, gemcitabine plus cisplatin (GC) and docetaxel plus cisplatin (DC) exhibit comparable
efficacy, with possibly superior QoL compared to VC. This trial investigated these regimens in the
adjuvant setting. METHODS: Patients with Stage IB to III NSCLC were eligible following standardized
surgery. Overall, 136 patients were included, with 67 and 69 assigned to the GC and DC arms,
respectively. Cisplatin (75 mg/m2, Day [D] 1) plus gemcitabine (1250 mg/m2, D1 and D8) or docetaxel
(75 mg/m2 D1) were administered for three cycles. Primary end-point was QoL (EORTC QLQ-C30),
with the study designed to detect a 10-point difference between arms. Overall survival, safety and cost
were secondary end-points. RESULTS: No between-group imbalance was observed in terms of patient
characteristics. At inclusion, global health status (GHS) scores (/100) were 63.5 and 62.7 in GC and DC,
respectively (P = 0.8), improving to 64.5 and 65.4 after 3 months (P = 0.8). No significant difference in
functional or symptoms scores was observed between the arms except for alopecia. Grade 3/4
haematological and non-haematological toxicities were found in 33.8 and 21.7% (P = 0.11), and 33.8 and
26.1% (P = 0.33) of patients, in GC and DC, respectively. At 2 years, 92.9 and 89.8% of patients
remained alive in GC and DC, respectively (P = 0.88). CONCLUSIONS: DC and GC adjuvant
chemotherapies for completely resected NSCLC were well tolerated and appear free of major QoL
effects, and are therefore representing candidates for comparison with the standard VC regimen.
NSCLC - RADIOTHERAPY
Stereotactic Ablative Body Radiotherapy for Lung Cancer. Franks KN1, Jain P2, Snee MP2. Clin
Oncol (R Coll Radiol). 2015 Mar 4. pii: S0936-6555(15)00030-8. doi: 10.1016/j.clon.2015.01.006. [Epub
ahead of print]
Lung stereotactic ablative radiotherapy (SABR) is a method of delivering high 'ablative' doses of
radiotherapy to tumours in the lung. It was developed at the Karolinska Institute in the early 1990s using
the methods established in cranial radiosurgery with multiple beams prescribed to an isodose and using a
custom designed stereotactic body frame for immobilisation. Since then, aligned with the advances in
radiotherapy technology and techniques (e.g. four-dimensional computed tomography simulation and
image-guided radiotherapy), there has been a rapid increase in the use of lung SABR for both early stage
lung cancer and lung metastases. For peripheral primary lung cancers less than 5 cm in diameter, high
rates of local control and low levels of acute and late toxicity are consistently reported in the published
literature. Compared with historical control rates of stage I lung cancers treated with conventionally
fractionated radiotherapy, SABR seems to offer higher rates of local control, lower levels of acute toxicity
and a better quality of life after treatment. However, the full results of randomised controlled trials of
SABR versus conventionally fractionated are awaited and will provide higher-level evidence. For central
lung tumours, very high SABR doses can be associated with significant toxicity. Dose-adapted
fractionation schedules seem to have much lower rates of toxicity and prospective trials, including the
completed RTOG 0813 study and the on-going EORTC LUNGTEC study, should provide further
evidence of safety and establish organ at risk tolerances. SABR can also be used for tumours metastatic to
the lung with high rates of local control and is a reasonable alternative to surgery in selected patients.
12
Going forward, prospective trials are underway to establish the safety and efficacy of SABR in
oligometastatic disease. Population-based outcomes will be crucial in supporting/establishing SABR as
the treatment of choice in medically inoperable patients with peripheral stage I lung cancers. Randomised
phase III trials will hopefully extend the evidence base and show the safety and the utility of SABR in
early central tumours and oligometastatic disease.
Bayesian network models for error detection in radiotherapy plans. Kalet AM1, Gennari JH, Ford
EC, Phillips MH. Phys Med Biol. 2015 Apr 7;60(7):2735-49. doi: 10.1088/0031-9155/60/7/2735. Epub
2015 Mar 13.
The purpose of this study is to design and develop a probabilistic network for detecting errors in
radiotherapy plans for use at the time of initial plan verification. Our group has initiated a multi-pronged
approach to reduce these errors. We report on our development of Bayesian models of radiotherapy plans.
Bayesian networks consist of joint probability distributions that define the probability of one event, given
some set of other known information. Using the networks, we find the probability of obtaining certain
radiotherapy parameters, given a set of initial clinical information. A low probability in a propagated
network then corresponds to potential errors to be flagged for investigation. To build our networks we
first interviewed medical physicists and other domain experts to identify the relevant radiotherapy
concepts and their associated interdependencies and to construct a network topology. Next, to populate
the network's conditional probability tables, we used the Hugin Expert software to learn parameter
distributions from a subset of de-identified data derived from a radiation oncology based clinical
information database system. These data represent 4990 unique prescription cases over a 5 year period.
Under test case scenarios with approximately 1.5% introduced error rates, network performance produced
areas under the ROC curve of 0.88, 0.98, and 0.89 for the lung, brain and female breast cancer error
detection networks, respectively. Comparison of the brain network to human experts performance (AUC
of 0.90 ± 0.01) shows the Bayes network model performs better than domain experts under the same test
conditions. Our results demonstrate the feasibility and effectiveness of comprehensive probabilistic
models as part of decision support systems for improved detection of errors in initial radiotherapy plan
verification procedures.
Safety and Palliative Efficacy of Single-Dose 8-Gy Reirradiation for Painful Local Failure in
Patients With Stage IV Non-Small Cell Lung Cancer Previously Treated With Radical
Chemoradiation Therapy. Topkan E1, Yildirim BA2, Guler OC2, Parlak C2, Pehlivan B3, Selek U4. Int
J Radiat Oncol Biol Phys. 2015 Mar 15;91(4):774-80. doi: 10.1016/j.ijrobp.2014.12.010.
PURPOSE: To investigate the safety and efficacy of single-dose 8-Gy palliative chest reirradiation (CRI)
in metastatic non-small cell lung cancer (M-NSCLC) patients with painful thoracic failures (TF) within
the previous radiation portal. PATIENTS AND METHODS: We retrospectively analyzed the clinical
data of 78 M-NSCLC patients who received single-dose 8-Gy CRI for painful TF after concurrent
chemoradiation therapy to a total radiation dose of 52 to 66 Gy between 2007 and 2012. Primary
endpoints included significant pain relief (SPR) defined as a ≥2 point decrement in the Visual Analogue
Scale for Pain inventory (VAS-P), time to pain relief, and duration of pain control. Secondary objectives
were survival and prognostic factors. RESULTS: Treatment was well tolerated, with only 5.1% grade 3
pneumonitis and 1.3% grade 2 esophagitis. Pre-CRI median and post-CRI minimum VAS-P were 7 and 3
(P<.001), respectively. SPR was noted in 67 (85.9%) patients, and only 3 (3.9%) scored progressive pain.
Median time to lowest VAS-P and duration of pain control were 27 days and 6.1 months, respectively.
Median overall survival (OS) was 7.7 months, and the 1-year OS rate was 26.5%. On multivariate
analyses, lower Eastern Cooperative Oncology group score (1-2; P<.001), absence of anemia (P=.001),
and fewer metastatic sites (1-2; P<.001) were found to be associated with longer OS. CONCLUSIONS:
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Single-dose 8-Gy CRI provides safe, effective, and durable pain palliation for TF in radically irradiated
M-NSCLC patients. Because of its convenience, lower cost, and higher comfort, the present protocol can
be considered an appropriate option for patients with limited life spans.
Intensity-modulated radiotherapy and volumetric-modulated arc therapy have distinct clinical
advantages in non-small cell lung cancer treatment. Zhang J1, Yu XL, Zheng GF, Zhao F. Med Oncol.
2015 Apr;32(4):546. doi: 10.1007/s12032-015-0546-6. Epub 2015 Mar 1.
This study was conducted to compare the efficacy of intensity-modulated radiotherapy (IMRT) and
volumetric-modulated arc therapy (VMAT) in delivering the planned dosage in the treatment of non-small
cell lung cancer (NSCLC). Between September 2013 and March 2014, 125 NSCLC patients were
randomly chosen and allocated to the IMRT group (n = 65) and VMAT group (n = 60). We compared
multiple parameters such as target dose, organ dosimetry, monitor unit (MU) and time of therapy between
IMRT and VMAT groups. The prescribed dose coverage of both planning techniques was 95 % of the
planning target volumes (PTVs). PTV 95 % and homogeneous index in IMRT plan were greater than
those in VMAT plan (both P < 0.05), while no significant difference in conformity index was observed (P
> 0.05). The mean total lung V5 and V10 in VMAT group were markedly higher than those in IMRT
group, but the V20, V30, and V40 in VMAT group were significantly lower (all P < 0.05), but no
statistically significant difference was observed in V15 and V20 (P > 0.05). Furthermore, the planning
spine and esophagus at risk volume showed no statistical significances in both groups (P > 0.05). MU of
IMRT plan was about 4.2 % less than that of VMAT plan, which was statistically significant (P < 0.001).
Both IMRT and VMAT had significant advantages in the treatment of NSCLC. The IMRT may be better
for NSCLC patients with poor pulmonary function, and VMAT may be recommended for NSCLC
patients with normal pulmonary function.
SMALL CELL LUNG CANCER - SCLC
DNA methylation in small cell lung cancer defines distinct disease subtypes and correlates with high
expression of EZH2. Poirier JT1, Gardner EE2, Connis N3, et al. Oncogene. 2015 Mar 9. doi:
10.1038/onc.2015.38. [Epub ahead of print]
Small cell lung cancer (SCLC) is an aggressive malignancy characterized by early metastasis, rapid
development of resistance to chemotherapy and genetic instability. This study profiles DNA methylation
in SCLC, patient-derived xenografts (PDX) and cell lines at single-nucleotide resolution. DNA
methylation patterns of primary samples are distinct from those of cell lines, whereas PDX maintain a
pattern closely consistent with primary samples. Clustering of DNA methylation and gene expression of
primary SCLC revealed distinct disease subtypes among histologically indistinguishable primary patient
samples with similar genetic alterations. SCLC is notable for dense clustering of high-level methylation in
discrete promoter CpG islands, in a pattern clearly distinct from other lung cancers and strongly correlated
with high expression of the E2F target and histone methyltransferase gene EZH2. Pharmacologic
inhibition of EZH2 in a SCLC PDX markedly inhibited tumor growth.
Significance of programmed cell death-ligand 1 expression and its association with survival in
patients with small cell lung cancer. Ishii H1, Azuma K, Kawahara A, et al. J Thorac Oncol. 2015
Mar;10(3):426-30. doi: 10.1097/JTO.0000000000000414.
BACKGROUND: Programmed cell death 1 receptor-ligand interaction is a major pathway often hijacked
by tumors to suppress immune control. The aim of this retrospective study was to investigate the
prevalence and prognostic roles of programmed cell death -ligand 1 (PD-L1) expression in small cell lung
cancer (SCLC). METHODS: The expression of PD-L1 was evaluated by immunohistochemical analysis
in 102 specimens of SCLC. Tumors with staining in over 5% of tumor cells were scored as positive for
14
PD-L1 expression. Survival analysis was performed using the Kaplan-Meier method. RESULTS:
Expression of PD-L1 in tumor cells was observed in 71.6% (73 of 102) of SCLCs, and was significantly
correlated with a limited disease (LD) stage. SCLC patients with PD-L1-positive tumors showed
significantly longer overall survival (OS) than those with PD-L1-negative (median OS, 16.3 versus 7.3
months; p < 0.001, respectively). Multivariate analyses demonstrated that a good performance status, LD
stage, and expression of PD-L1 were significantly predictive of better OS, independently of other factors.
We found no relevance between PD-L1 expression and progression-free survival for first-line treatment in
LD- and extensive disease-SCLC patients. CONCLUSIONS: In patients with SCLC, expression of PDL1 is positively correlated with a LD stage, and is independently predictive of a favorable outcome.
Is stereotactic radiosurgery a rational treatment option for brain metastases from small cell lung
cancer? A retrospective analysis of 70 consecutive patients. Yomo S1, Hayashi M. BMC Cancer.
2015;15(1):1103. doi: 10.1186/s12885-015-1103-6. Epub 2015 Mar 4.
BACKGROUND: Because of the high likelihood of multiple brain metastases (BM) from small cell lung
cancer (SCLC), the role of focal treatment using stereotactic radiosurgery (SRS) has yet to be determined.
We aimed to evaluate the efficacy and limitations of upfront and salvage SRS for patients with BM from
SCLC. METHODS: This was a retrospective and observational study analyzing 70 consecutive patients
with BM from SCLC who received SRS. The median age was 68 years, and the median Karnofsky
performance status (KPS) was 90. Forty-six (66%) and 24 (34%) patients underwent SRS as the upfront
and salvage treatment after prophylactic or therapeutic whole brain radiotherapy (WBRT), respectively.
Overall survival (OS), neurological death-free survival, remote and local tumor recurrence rates were
analyzed. RESULTS: None of our patients were lost to follow-up and the median follow-up was 7.8
months. One-and 2-year OS rates were 43% and 15%, respectively. The median OS time was 7.8 months.
One-and 2-year neurological death-free survival rates were 94% and 84%, respectively. In total, 219/292
tumors (75%) in 60 patients (86 %) with sufficient radiological follow-up data were evaluated. Six-and
12-month rates of remote BM relapse were 25% and 47%, respectively. Six-and 12-month rates of local
control failure were 4% and 23%, respectively. Repeat SRS, salvage WBRT and microsurgery were
subsequently required in 30, 8 and one patient, respectively. Symptomatic radiation injury, treated
conservatively, developed in 3 patients. CONCLUSIONS: The present study suggested SRS to be a
potentially effective and minimally invasive treatment option for BM from SCLC either alone or after
failed WBRT. Although repeat salvage treatment was needed in nearly half of patients to achieve control
of distant BM, such continuation of radiotherapeutic management might contribute to reducing the rate of
neurological death.
Upregulation of the inwardly rectifying potassium channel Kir2.1 (KCNJ2) modulates multidrug
resistance of small-cell lung cancer under the regulation of miR-7 and the Ras/MAPK pathway.
Liu H1, Huang J, Peng J, Wu X, Zhang Y, Zhu W, Guo L. Mol Cancer. 2015 Dec;14(1):298. doi:
10.1186/s12943-015-0298-0. Epub 2015 Mar 12.
BACKGROUND: KCNJ2/Kir2.1, a member of the classical inwardly rectifying potassium channel
family, is commonly expressed in a wide range of tissues and cell types. Previous studies indicated that
Kir2.1 may be associated with SCLC multidrug resistance (MDR). However, whether Kir2.1 can regulate
MDR and its underlying mechanisms remain poorly understood in SCLC. METHODS: KCNJ2/Kir2.1
expression was examined in tissues from fifty-two SCLC cases by immunohistochemistry.
Overexpression or knockdown of KCNJ2/Kir21 was performed in multidrug-resistant SCLC cell lines
(H69AR and H446AR) and their parental cell lines (H69 and H446) to assess its influence on cell growth,
apoptosis, the cell cycle and chemoresistance. RESULTS: KCNJ2/Kir2.1 was expressed in 44.23%
(23/52) of SCLC tissues. Overexpression of KCNJ2/Kir2.1 was correlated with the clinical stage and
chemotherapy response in SCLC patients. Knockdown of KCNJ2/Kir2.1 expression using KCNJ2/Kir2.1
15
shRNA in H69AR and H446AR cells inhibited cell growth and sensitized the cancer cells to
chemotherapeutic drugs by increasing cell apoptosis and cell cycle arrest. Forced KCNJ2/Kir2.1
expression in H69 and H446 cells promoted cell growth and enhanced multidrug resistance via reduced
drug-induced apoptosis accompanied by cell cycle arrest. KCNJ2/Kir2.1 expression was also influenced
by PKC and MEK inhibitors. In addition, multidrug resistance protein 1 (MRP1/ABCC1) was confirmed
to interact with KCNJ2/Kir2.1 by Co-IP assays. CONCLUSIONS: KCNJ2/Kir2.1 modulates cell growth
and drug resistance by regulating MRP1/ABCC1 expression and is simultaneously regulated by the
Ras/MAPK pathway and miR-7. KCNJ2/Kir2.1 may be a prognostic predictor and a potentially novel
target for interfering with chemoresistance in SCLC.
Chemotherapy With or Without Maintenance Sunitinib for Untreated Extensive-Stage Small-Cell
Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase II Study-CALGB 30504
(Alliance). Ready NE1, Pang HH2, Gu L2, et al.
Otterson GA2, Thomas SP2, Miller AA2, Baggstrom M2, Masters GA2, Graziano SL2, Crawford J2,
Bogart J2, Vokes EE2.
PURPOSE: To evaluate the efficacy of maintenance sunitinib after chemotherapy for small-cell lung
cancer (SCLC). PATIENTS AND METHODS: The Cancer and Leukemia Group B 30504 trial was a
randomized, placebo-controlled, phase II study that enrolled patients before chemotherapy (cisplatin 80
mg/m2 or carboplatin area under the curve of 5 on day 1 plus etoposide 100 mg/m2 per day on days 1 to 3
every 21 days for four to six cycles). Patients without progression were randomly assigned 1:1 to placebo
or sunitinib 37.5 mg per day until progression. Cross-over after progression was allowed. The primary
end point was progression-free survival (PFS) from random assignment for maintenance placebo versus
sunitinib using a one-sided log-rank test with α = .15; 80 randomly assigned patients provided 89% power
to detect a hazard ratio (HR) of 1.67. RESULTS: One hundred forty-four patients were enrolled; 138
patients received chemotherapy. Ninety-five patients were randomly assigned; 10 patients did not receive
maintenance therapy (five on each arm). Eighty-five patients received maintenance therapy (placebo, n =
41; sunitinib, n = 44). Grade 3 adverse events with more than 5% incidence were fatigue (19%),
decreased neutrophils (14%), decreased leukocytes (7%), and decreased platelets (7%) for sunitinib and
fatigue (10%) for placebo; grade 4 adverse events were GI hemorrhage (n = 1) and pancreatitis,
hypocalcemia, and elevated lipase (n = 1; all in same patient) for sunitinib and thrombocytopenia (n = 1)
and hypernatremia (n = 1) for placebo. Median PFS on maintenance was 2.1 months for placebo and 3.7
months for sunitinib (HR, 1.62; 70% CI, 1.27 to 2.08; 95% CI, 1.02 to 2.60; one-sided P = .02). Median
overall survival from random assignment was 6.9 months for placebo and 9.0 months for sunitinib (HR,
1.28; 95% CI, 0.79 to 2.10; one-sided P = .16). Three sunitinib and no placebo patients achieved complete
response during maintenance. Ten (77%) of 13 patients evaluable after cross-over had stable disease on
sunitinib (6 to 27 weeks). CONCLUSION: Maintenance sunitinib was safe and improved PFS in
extensive-stage SCLC.
Risk of hippocampal metastases in small cell lung cancer patients at presentation and after cranial
irradiation: a safety profile study for hippocampal sparing during prophylactic or therapeutic
cranial irradiation. Kundapur V1, Ellchuk T2, Ahmed S3, Gondi V4. Int J Radiat Oncol Biol Phys. 2015
Mar 15;91(4):781-6. doi: 10.1016/j.ijrobp.2014.12.026.
PURPOSE: Neurocognitive impairment (NI) in patients with small cell lung cancer (SCLC) after whole
brain radiation treatment (WBRT) is a significant cause of morbidity. Hippocampal avoidance (HA)
during WBRT may mitigate or prevent NI in such patients. However, this has not been tested in SCLC
patients. The estimated risk of metastases in the HA region (HM) in patients with SCLC at diagnosis or
after WBRT is unknown. Our study aimed to determine the risk of HM in patients with SCLC and to
assess correlated clinical factors. METHODS AND MATERIALS: Patients with SCLC who
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experienced brain metastases (BM) at presentation (de novo) or after WBRT treated at the Saskatoon
Cancer Centre between 2005 and 2012 were studied. Relevant neuroimaging was independently reviewed
by a neuroradiologist. HM was defined as metastases within 5 mm of the hippocampus. Logistic
regression analysis was performed to assess correlation between various clinical variables and HM.
RESULTS: Seventy eligible patients were identified. Of 59 patients presenting with de novo BM, 3
patients (5%, 95% confidence interval [CI]: 0%-10.7%) had HM. Collectively there were 359 (range, 133) de novo BM with 3 (0.8%, 95% CI: 0%-1.7%) HM deposits. Twenty patients experienced progression
of metastatic disease in the brain after WBRT. Of the 20 patients, only 1 patient (5%, 95% CI: 0%-14.5%)
experienced HM. On logistic regression, no factors significantly correlated with HM. CONCLUSION:
The overall incidence of HM before or after WBRT in SCLC patients is low, providing preliminary
support for the safety of HA during planned clinical trials of HA-WBRT for SCLC.
Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer.
Blackhall F1. Ann Oncol. 2015 Mar;26 Suppl 2:ii15. doi: 10.1093/annonc/mdv089.5.
Increased glycolytic rates in cancer cells generate high levels of lactate that are exported by the
monocarboxylate transporters (MCTs) 1-4. AZD3965 is an orally bioavailable inhibitor of MCT-1 that
was originally developed by AstraZeneca (Macclesfield, England, UK) for use in transplant rejection /
autoimmune disease. It has increased selectivity for MCT1 over MCT2 and does not inhibit MCT4. A
Cancer Research UK phase I study of AZD3965 in solid tumours is ongoing (NCT01791595). Small cell
lung cancer (SCLC) is a highly proliferative tumour proposed to be reliant on glycolysis. We therefore
conducted preclinical evaluation of AZD3965 in SCLC cell lines and xenografts with the aims to
determine its therapeutic potential and putative predictive biomarkers for application in clinical trials. A
cohort of tumour biopsies from SCLC patient s was also assessed for expression and clinical significance
of MCT1, MCT4 and the hypoxia marker, CAIX. In seven SCLC cell lines sensitivity to AZD3965 varied
and was highest in hypoxic culture conditions. Resistance was associated with high expression of MCT4.
Treatment of the COR-L103 SCLC xenograft model with AZD3965 resulted in growth inhibition and
increased levels of intratumour lactate. A tissue microarray (TMA) was constructed for 78 patients,
immunostained with anti-MCT1, MCT4 and CAIX antibodies and scored by two independent observers.
Clinical outcome data was available for 47 patients. Patients were stratified into MCT1 high/low, MCT4
high/low or CAIX high/low based on the median immunoscore from the complete TMA dataset. There
were no significant associations with known clinical prognostic factors such as lactate dehydrogenase.
Higher MCT1 expression was significantly associated with worse survival in univariate analysis (p =
0.014). A pattern of high MCT1 and hypoxia marker CAIX expression with low MCT4 expression was
observed in 21% of SCLC cases. The preclinical results provide a rationale to evaluate AZD3965 in
patients with SCLC, in particular those with presence of hypoxia, high MCT1 and low MCT4 expression.
(Polanski et al. 2013 Clin Cancer Res; 20(4) 926-937).
Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination
therapy for small-cell lung cancer. Faber AC1, Farago AF2, Costa C3, et al. Proc Natl Acad Sci U S A.
2015 Mar 17;112(11):E1288-96. doi: 10.1073/pnas.1411848112. Epub 2015 Mar 3.
BH3 mimetics such as ABT-263 induce apoptosis in a subset of cancer models. However, these drugs
have shown limited clinical efficacy as single agents in small-cell lung cancer (SCLC) and other solid
tumor malignancies, and rational combination strategies remain underexplored. To develop a novel
therapeutic approach, we examined the efficacy of ABT-263 across >500 cancer cell lines, including 311
for which we had matched expression data for select genes. We found that high expression of the
proapoptotic gene Bcl2-interacting mediator of cell death (BIM) predicts sensitivity to ABT-263. In
particular, SCLC cell lines possessed greater BIM transcript levels than most other solid tumors and are
among the most sensitive to ABT-263. However, a subset of relatively resistant SCLC cell lines has
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concomitant high expression of the antiapoptotic myeloid cell leukemia 1 (MCL-1). Whereas ABT-263
released BIM from complexes with BCL-2 and BCL-XL, high expression of MCL-1 sequestered BIM
released from BCL-2 and BCL-XL, thereby abrogating apoptosis. We found that SCLCs were sensitized
to ABT-263 via TORC1/2 inhibition, which led to reduced MCL-1 protein levels, thereby facilitating
BIM-mediated apoptosis. AZD8055 and ABT-263 together induced marked apoptosis in vitro, as well as
tumor regressions in multiple SCLC xenograft models. In a Tp53; Rb1 deletion genetically engineered
mouse model of SCLC, the combination of ABT-263 and AZD8055 significantly repressed tumor growth
and induced tumor regressions compared with either drug alone. Furthermore, in a SCLC patient-derived
xenograft model that was resistant to ABT-263 alone, the addition of AZD8055 induced potent tumor
regression. Therefore, addition of a TORC1/2 inhibitor offers a therapeutic strategy to markedly improve
ABT-263 activity in SCLC.
PALLIATIVE AND SUPPORTIVE CARE
Concealment of lung cancer diagnosis: prevalence and correlates. Gonzalez BD1, Jim HS, Cessna
JM, Small BJ, Sutton SK, Jacobsen PB. Psychooncology. 2015 Mar 9. doi: 10.1002/pon.3793. [Epub
ahead of print]
BACKGROUND: Lung cancer has a commonly understood behavioral etiology. Thus, lung cancer
patients are often blamed for their illness and may seek to avoid this blame by concealing their diagnosis
from others. This study sought to determine the prevalence of concealment and identify demographic,
clinical, and psychosocial correlates of concealment among lung cancer patients. METHODS: A sample
of 117 lung cancer patients receiving chemotherapy for non-small cell or small cell lung cancer was
recruited and completed self-report demographic questionnaires, a measure of diagnosis concealment
designed and pilot tested for this study, and standard measures of psychosocial variables. Clinical factors
were assessed via a medical chart review. RESULTS: Thirty participants (26%) reported concealing their
diagnosis in the previous month, most frequently from casual friends and close friends. Reported reasons
for concealment largely reflected concern for others. Univariate analyses indicated that those who
concealed their lung cancer diagnosis reported more internalized shame related to their illness and use of
positive reappraisal as a coping strategy (ps ≤ 0.02). In addition, those who concealed were more likely to
have used alcohol in the previous month and have a more recent recurrence, among those who had a
recurrence (ps ≤ 0.04). Multivariate analyses indicated that internalized shame and use of positive
reappraisal accounted for significant unique variance in concealment above and beyond that accounted for
by use of alcohol (ps < 0.05). CONCLUSIONS: Future research should aim to replicate and extend these
findings with longitudinal designs to elucidate the directionality of the associations observed in this study.
Treatment Toxicity in Elderly Patients With Advanced Non-Small Cell Lung Cancer. Kale MS1,
Mhango G, Gomez JE, Sigel K, Smith CB, Bonomi M, Wisnivesky JP. Am J Clin Oncol. 2015 Mar 13.
OBJECTIVES: Toxicity is a main concern limiting the use of chemotherapy and radiotherapy (RT) for
elderly patients with non-small cell lung cancer (NSCLC). The objective of this study was to assess the
rates of treatment-related toxicity among elderly stage IIIB and IV NSCLC patients. MATERIALS AND
METHODS: We used the Surveillance, Epidemiology, and End Results registry linked to Medicare
records to identify 2596 stage IIIB and 14,803 stage IV NSCLC patients aged 70 years and above,
diagnosed in 2000 or later. We compared rates of toxicity requiring hospitalization according to treatment
(chemotherapy, RT, or chemoradiation [CRT]) in unadjusted and adjusted models controlling for
selection bias using propensity scores. RESULTS: Among stage IIIB patients, rates of any severe toxicity
were 10.1%, 23.8%, 30.4%, and 39.2% for patients who received no treatment, RT, chemotherapy alone,
and CRT, respectively. In stage IV patients, rates of any severe toxicity were 31.5% versus 13.5% among
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those treated with and without chemotherapy, respectively. In stage IIIB patients treated with CRT, the
most common toxicities was esophagitis (odds ratio, 48.5; 95% confidence interval, 6.7-350.5). Among
stage IV patients treated with chemotherapy, the risk of toxicity was highest for neutropenia (odds ratio,
8.4; 95% confidence interval, 6.1-11.5). CONCLUSIONS: Toxicity was relatively common among stage
IIIB patients with up to a 6-fold increase in elderly individuals treated with CRT and a 4-fold increase in
toxicities among stage IV patients. This information should be helpful to guide discussions about the riskbenefit ratio of chemotherapy and RT in elderly patients with advanced NSCLC.
How do patients share news of a cancer diagnosis with family/friends; new understandings of the
process after bad news has been broken. Ewing G1, Ngwenya N2, Farquhar M3, Benson J3, Gilligan
D4, Seymour J5, Bailey S6. BMJ Support Palliat Care. 2015 Mar;5(1):114. doi: 10.1136/bmjspcare-2014000838.32.
INTRODUCTION: Extensive research exists on how bad news is broken by physicians to patients, but
little is known about the subsequent stage: when patients face the difficult task of sharing this news with
family members and friends. AIMS: To understand the experience of sharing news of a lung cancer
diagnosis with wider family members and friends to inform a supportive intervention to prepare patients
for sharing bad news. Methods Qualitative interviews with 20 patients with lung cancer and 17 family
members/friends present at diagnosis-giving to explore experiences of receiving their diagnosis and how
news was shared with wider family/friends.Thematic framework analysis was conducted. RESULTS:
Three key findings: (1) sharing bad news happened over time, at any point along the illness trajectory-it
was a process, not a discrete event; (2) timing of sharing bad news was very individual-people needed to
feel ready to share their diagnosis and had to prepare themselves to do so; (3) regardless of when news
was shared it had consequences in terms of the reactions of those told, which required managing.
Illustrative timelines of processes of early and later sharing of bad news will be presented.
CONCLUSIONS: Understanding sharing bad news as a process which happens over time is a significant
finding for design and delivery of a supportive intervention. Preparing patients to share news of a lung
cancer diagnosis, which often presents at an advanced stage, is highly relevant for future palliative care
delivery.
Perceptions of lung cancer and potential impacts on funding and patient care: a qualitative study.
Tran K1, Delicaet K, Tang T, Ashley LB, Morra D, Abrams H. J Cancer Educ. 2015 Mar;30(1):62-7. doi:
10.1007/s13187-014-0677-z.
The objective of this study was to explore health-care professionals', health administrators', and not-forprofit cancer organization representatives' perceptions of lung cancer-related stigma and nihilism and the
perceived impacts on funding and patient care. This is a qualitative descriptive study using semistructured interviews, which was conducted in Ontario, Canada. Seventy-four individuals from medical
oncology, radiation oncology, thoracic surgery, respirology, pathology, radiology, primary care, palliative
care, nursing, pharmacy, social work, genetics, health administration, and not-for-profit cancer
organizations participated in this study. Participants described lung cancer-related stigma and nihilism and
its negative impact on patients' psychological health, lung cancer funding, and patient care. The feeling of
guilt and shame experienced by lung cancer patients as a result of the stigma associated with the disease
was described. In terms of lung cancer funding, stigma was described as a reason lung cancer receives
significantly less research funding compared to other cancers. In terms of patient care, lung cancer-related
nihilism was credited with negatively impacting physician referral patterns with the belief that lung cancer
patients were less likely to receive referrals for medical treatment. Health-care professionals, health
administrators, and not-for-profit cancer organization representatives described lung cancer-related stigma
and nihilism with far-reaching consequences. Further work is needed to increase education and awareness
about lung cancer to reduce the stigma and nihilism associated with the disease.
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Palliative radiotherapy with or without additional care by a multidisciplinary palliative care team
in patients with newly diagnosed cancer: a retrospective matched pairs comparison. Nieder C1,
Dalhaug A, Pawinski A, Haukland E, Mannsåker B, Engljähringer K. Radiat Oncol. 2015 Dec;10(1):365.
doi: 10.1186/s13014-015-0365-0. Epub 2015 Mar 7.
PURPOSE: To analyze survival after early palliative radiotherapy (RT) in patients managed exclusively
by regular oncology staff or a multidisciplinary palliative care team (MPCT) in addition. METHODS:
Retrospective matched pairs analysis. Comparison of two groups of 29 patients each: MPCT versus none.
Early RT started within three months after cancer diagnosis. RESULTS: Bone and brain metastases were
common RT targets. No significant differences in baseline characteristics were observed between both
groups. Twelve patients in each group had non-small cell lung cancer. Median performance status was 2
in each group. Twenty-seven patients in each group had distant metastases. Median survival was not
significantly different. In multivariate analysis, MPCT care was not associated with survival, while
performance status and liver metastases were. Rate of radiotherapy during the last month of life was
comparable. Only one patient in each group failed to complete radiotherapy. CONCLUSIONS: MPCT
care was not associated with survival in these two matched groups of patients. The impact of MPCT care
on other relevant endpoints such as symptom control, side effects and quality of life should be
investigated prospectively.
Minimal important difference of the 6-minute walk distance in lung cancer. Granger CL1, Holland
AE2, Gordon IR3, Denehy L4. Chron Respir Dis. 2015 Mar 6. pii: 1479972315575715. [Epub ahead of
print]
The 6-minute walk distance (6MWD) is one of the most commonly used measures of functional capacity
in lung cancer, however, the minimal important difference (MID) has not been established. The aims of
this exploratory study are, in lung cancer, to estimate (1) the MID of the 6MWD and (2) relationship
between 6MWD, demographic and disease-related factors. Fifty-six participants with stage I-IV lung
cancer completed the 6MWD prior to treatment and 10 weeks later. No exercise intervention occurred.
Additional measures included European Organization for Research and Treatment of Cancer
questionnaire (EORTC-QLQ-C30) and questionnaires assessing function, physical activity and
symptoms. MID was calculated using anchor- and distribution-based methods. The mean 6MWD decline
in participants classed as deteriorated was 60 m compared with 16 m in participants classed as notdeteriorated (p = 0.01). The receiver operating curve indicated a cut-off value for clinically relevant
change to be 42 m (95% confidence interval (CI) 6-75) (area under curve = 0.66, 95% CI 0.51-0.81) or a
9.5% change. Distribution-based methods indicated an MID between 22 m (95% CI 18-26) and 32 m
(95% CI 20-42). Higher 6MWD correlated with better function (r = -0.42, p = 0.001), physical activity (r
= 0.56, p < 0.005) and dyspnoea (r = -0.44, p = 0.001). The MID for deterioration of the 6MWD in lung
cancer is estimated to be between 22 m and 42 m or a change of 9.5%.
The Impact of a Multidimensional Exercise Intervention on Physical and Functional Capacity,
Anxiety, and Depression in Patients With Advanced-Stage Lung Cancer Undergoing
Chemotherapy. Quist M1, Adamsen L2, Rørth M3, Laursen JH3, Christensen KB2, Langer SW3. Integr
Cancer Ther. 2015 Mar 22. pii: 1534735415572887. [Epub ahead of print]
INTRODUCTION: Patients with advanced-stage lung cancer face poor survival and experience cooccurring chronic physical and psychosocial symptoms. Despite several years of research in exercise
oncology, few exercise studies have targeted advanced lung cancer patients undergoing chemotherapy.
The aim of the present study was to investigate the benefits of a 6-week supervised group exercise
intervention and to outline the effect on aerobic capacity, strength, health-related quality of life (HRQoL),
anxiety, and depression. METHODS: VO2peak was assessed using an incremental exercise test. Muscle
strength was measured with one repetition maximum test (1RM). HRQoL, anxiety, and depression were
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assessed using Functional Assessment of Cancer Therapy-Lung (FACT-L) scale and the Hospital Anxiety
and Depression Scale (HADS). RESULTS: One hundred and forthteen patients with advanced stage lung
cancer were recruited. Forty-three patients dropped out. No serious adverse events were reported.
Exercise adherence in the group training was 68%. Improvements in VO2peak (P < .001) and 6-minute
walk distance (P < .001) and muscle strength measurements (P < .05) were seen. There was a reduction in
anxiety level (P = .0007) and improvement in the emotional well-being parameter (FACT-L) but no
statistically significant changes in HRQoL were observed. CONCLUSION: The results of the present
study show that during a 6-week hospital-based supervised, structured, and group-based exercise
program, patients with advanced-stage lung cancer (NSCLC IIIb-IV, ED-SCLC) improve their physical
capacity (VO2peak, 1RM), functional capacity, anxiety level, and emotional well-being, but not their
overall HRQoL. A randomized controlled trial testing the intervention including 216 patients is currently
being carried out.
What bothers lung cancer patients the most? A prospective, longitudinal electronic patientreported outcomes study in advanced non-small cell lung cancer. LeBlanc TW1, Nickolich M,
Rushing CN, Samsa GP, Locke SC, Abernethy AP. Support Care Cancer. 2015 Mar 21. [Epub ahead of
print]
PURPOSE: Patients with advanced non-small cell lung cancer (aNSCLC) face a significant symptom
burden. Little is known about the frequency and severity of symptoms over time, so we longitudinally
characterized patients' symptoms using the Patient Care Monitor (PCM) version 2.0, an electronic
symptom-assessment tool. METHODS: Ninety-seven patients with aNSCLC completed the PCM at up
to four clinic visits. We analyzed symptom data by incidence, severity, type (functional vs. nonfunctional), proximity to death, and cancer anorexia-cachexia syndrome status (CACS). RESULTS:
Functional concerns predominated, even in the non-CACS group. Average severity among the top 5
symptoms was worse for functional than nonfunctional items (mean difference 0.62, 95 % CI 0.22-1.01,
P = 0.003). Severe dyspnea and fatigue were the most prevalent nonfunctional symptoms;
moderate/severe dyspnea was reported by at least 29 % of patients, and fatigue by over 50 %. Depression
was reported infrequently, with over half of patients at each visit reporting "none"; moderate or severe
depression was reported in only 2.5-9.3 and 3.4-6.2 % of patients, respectively. The average number of
moderate/severe symptoms increased with proximity to death; 84 % reported moderate/severe fatigue in
the last 3 months of life, compared to 48 % at ≥12 months from death (P = 0.007). CONCLUSIONS:
Patients with aNSCLC face a significant symptom burden, which increases with proximity to death.
Symptom type and severity vary by proximity to death, but even patients without overt CACS report
significant functional symptoms throughout. We recommend an individualized approach to palliative
symptom intervention in advanced lung cancer, based on detailed symptom assessment and tracking.
COMPLEMENTARY & ALTERNATIVE THERAPY
Comprehensive geriatric assessment and traditional Chinese medicine intervention benefit
symptom control in elderly patients with advanced non-small cell lung cancer. Xue D1, Han S, Jiang
S, et al. Med Oncol. 2015 Apr;32(4):563. doi: 10.1007/s12032-015-0563-5. Epub 2015 Mar 15.
The aim of this study was to observe the symptom improvement and clinical benefit in elderly patients
with advanced non-small cell lung cancer (NSCLC) stratified on the basis of CGA findings after
treatment with a combination of traditional Chinese medicine and Western medicine. Twenty-four elderly
advanced NSCLC patients with a mean age of 73.0 ± 5.3 (65-83) years were categorized into three
stratifications according to CGA results, namely function independent, mildly function impaired, and
function dependent. They received standardized therapy, individualized therapy, and best supportive care,
respectively. The patients receiving standardized therapy and individualized therapy were randomized
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into two groups, with or without traditional Chinese medicine for symptom control, while for all the
patients receiving best supportive care, traditional Chinese medicine was administered. Nine non-elderly
NSCLC patients (<65 years old) were enrolled as control and treated in accordance with NCCN NSCLC
treatment guidelines. EORTC QLQ-C30 core scale, LC13 scale, and MDASI-TCM scale were used to
assess relevant symptoms before and after treatment. After treatment for 3 weeks, it was shown by QLQC30+LC13 scales, for function-dependent patients, that the physical and role performances and the global
health status were improved and the symptoms of fatigue and cough were alleviated; by MDASI-TCM
scale, the symptoms of fatigue, cough, and expectoration were improved. In function-independent and
mildly function-impaired elderly patients, there were no significant changes in functional status and
symptoms. But in non-elderly patients, the physical and social performances were lowered, and the
symptoms of fatigue, constipation, and poor appetite were aggravated. The elderly patients with advanced
NSCLC were categorized on the basis of CGA findings, and traditional Chinese medicine may be
beneficial to symptom control of function-dependent patients.
Chemical components from the leaves of Ardisia insularis and their cytotoxic activity. Van NT1,
Vien TA, Van Kiem P, et al. Arch Pharm Res. 2015 Mar 21. [Epub ahead of print]
One new oleanane triterpene glycoside, ardinsuloside (1), and twelve known compounds,
demethoxybergenin (2), norbergenin (3), bergenin (4), 4-O-galloylbergenin (5), quercitrin (6), myricitrin
(7), myricetin 3-O-(3''-O-galloyl)-α-L-rhamnopyranoside (8), desmanthine-2 (9), epicatechin 3-O-galloyl
ester (10), 3'-methoxyepicatechin 3-O-galloyl ester (11), gallic acid (12), and methyl galloate (13) were
isolated from the leaves of Ardisia insularis. Their structures were established on the basis of spectral and
chemical evidence, which were in agreement with those reported in literature. The cytotoxic activities of
these compounds were evaluated on three cancer cell lines namely A-549 (human lung cancer), HT-29
(Human colon adenocarcinoma), and OVCAR (human ovarian carcinoma). The results revealed that
compound 1 inhibited A-549, HT-29, and OVCAR cell lines with IC50 values of 8.5 ± 1.2, 16.4 ± 3.1,
and 13.6 ± 2.4 μM, respectively. The remaining compound showed weak cytotoxic activity. This result
indicated that compound 1 could be useful in the treatment of cancer disease.
Trichosanthes kirilowii Fruits Inhibit Non-Small Cell Lung Cancer Cell Growth Through Mitotic
Cell-Cycle Arrest. Ni L1, Zhu X, Gong C, Luo Y, Wang L, Zhou W, Zhu S, Li Y. Am J Chin Med. 2015
Mar 17:1-16. [Epub ahead of print]
Lung cancer is the leading cause of cancer-related death worldwide. Non-small cell lung cancer (NSCLC)
accounts for 80% of lung cancer cases and the reported overall 5-year survival rate is less than 5%.
Natural medicines have attracted much attention due to their lower toxicity and fewer side effects.
Trichosanthes kirilowii Maxim (TKM) fruits are commonly used in cancer treatment in combination with
other Chinese medicinal herbs. However, little is known about their biological functions and mechanisms
in NSCLC cells. In this study, we investigated the efficacy of TKM fruits in NSCLC cells using cell
proliferation, invasion, migration, and anchorage independent assays and a Xenograft NSCLC tumor
model, and explored the possible biological mechanism by flow cytometric analysis, cDNA microarray
and real-time PCR. Results showed that TKM fruits significantly suppressed NSCLC cell proliferation,
migration, invasion, tumorigenicity and tumor growth, and significantly extended the survival time of
NSCLC-bearing mice. Flow cytometric analysis showed that TKM fruits significantly induced G2-M
arrest, necrosis and apoptosis in NSCLC cells. cDNA microarray analysis revealed that TKM fruits
regulated the differential expression of 544 genes, and the differential expression of selected genes was
also confirmed. Gene ontology (GO) analysis showed that 18 of first 20 biological processes were
involved in cell cycle and mitosis. These results indicate that TKM fruits have certain inhibitory effect on
NSCLC cells through cell-cycle and mitosis arrest, and suggest that TKM fruits may be an important
22
resource for developing new antitumor drugs, and a potent natural product for treating patients with
NSCLC.
MISCELLANEOUS WORKS
Lung cancer stigma as a barrier to medical help-seeking behavior: Practice implications. CarterHarris L1. J Am Assoc Nurse Pract. 2015 Mar 3. doi: 10.1002/2327-6924.12227. [Epub ahead of print]
PURPOSE: The purpose of this study was to examine the relationship of perceived lung cancer stigma
and timing of medical help-seeking behavior in symptomatic individuals. DATA SOURCES: A
convenience sample was recruited from an academic thoracic oncology clinic and community hospitalbased outpatient radiation center in a large city in the southeastern United States. This descriptive, crosssectional study used survey methodology and semistructured interviews to examine the relationship of
perceived lung cancer stigma and delayed medical help seeking finding a statistically significant positive
correlation. Additional examination revealed positive correlations between the stigma and shame, social
isolation, and smoking-related stigma subscales and delay. The discrimination-related subscale was not
associated with delay. In addition, smoking status was not related to perceived lung cancer stigma.
CONCLUSIONS: Findings support an association between lung cancer stigma and delayed medical
help-seeking behavior. Therefore, lung cancer stigma is a potential barrier to timely medical help-seeking
behavior in lung cancer symptoms, which can have important patient outcome implications.
IMPLICATIONS FOR PRACTICE: As primary care nurse practitioners, awareness that lung cancer
stigma exists for patients is essential regardless of smoking status and efforts to decrease this barrier to
timely health care are important.
Exposure to secondhand tobacco smoke and the frailty syndrome in US older adults. GarcíaEsquinas E1, Navas-Acien A, Rodríguez-Artalejo F. Age (Dordr). 2015 Apr;37(2):9762. doi:
10.1007/s11357-015-9762-4. Epub 2015 Mar 15.
Exposure to secondhand tobacco smoke (SHS) is a well-established risk factor for cardiovascular disease
and lung cancer in nonsmoking adults. However, few studies have focused on the health consequences of
exposure to SHS in older adults. This is the first study to assess the association between SHS and the
frailty syndrome in the nonsmoking older adult population. Cross-sectional study was conducted among
2059 nonsmoking adults aged ≥60 years who participated in the third US National Health and Nutrition
Examination Survey and had completed a physical examination. Exposure to SHS was assessed by serum
cotinine concentrations and by self-reported data from the home questionnaire. Frailty was ascertained
with a slight modification of the Fried criteria. Analyses were performed with logistic regression and
adjusted for the main confounders. The median (interquartile range) concentration of serum cotinine was
0.095 (IQR 0.035-0.211) ng/mL. The prevalence of frailty was 6.0 %. The odds ratios (95 % confidence
interval [CI]) of frailty comparing the second, third, and fourth to the lowest quartile of serum cotinine
were, respectively, 1.44 (0.67-3.06), 1.46 (0.75-2.85), and 2.51 (1.06-5.95), p value for trend 0.04. An
increased frequency of frailty was also observed in participants reporting to live with ≥2 smokers at home
(odds ratio 5.37; 95 % CI 1.13-25.5). In the US nonsmoking older adult population, exposure to SHS was
associated with an increased frequency of frailty. More efforts are needed to protect older adults from
SHS, especially at home and in other areas not covered by smoke-free regulations.
Survival and Racial Differences of Non-Small Cell Lung Cancer in the United States Military.
Brzezniak C1, Satram-Hoang S, Goertz HP, et al. J Gen Intern Med. 2015 Mar 25. [Epub ahead of print]
BACKGROUND: Lung cancer is the leading cause of cancer-related death in the United States (US)
Military and worldwide, with non-small cell lung cancer (NSCLC) accounting for 87 % of cases.
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OBJECTIVES: Using a US military cohort who receives equal and open access to healthcare, we sought
to examine demographic, clinical features and outcomes with NSCLC. DESIGN AND ARTICIPANTS:
We conducted a retrospective cohort analysis of 4,751 patients, aged ≥ 18 years and diagnosed with a first
primary NSCLC between 1 January 2003 and 31 December 2013 in the US Department of Defense (DoD)
cancer registry. MAIN MEASURES: Differences by patient and disease characteristics were compared
using Chi-square and t-test. Kaplan Meier curves and Cox proportional hazards regression assessed
overall survival. RESULTS: The mean age at diagnosis was 66 years, 64 % were male, 72 % were
Caucasian, 41 % were diagnosed at early stage, 77 % received treatment and 82 % had a history of
tobacco use. Mean age at diagnosis was highest among Caucasians (67 years) and lowest among African
Americans (AA; 62 years). Asian/Pacific Islanders (PI) were more likely to be female (p < 0.0001), have
adenocarcinoma histology (p = 0.0003) and less likely to have a history of tobacco use (p < 0.0001)
compared to other racial/ethnic groups. In multivariable survival analysis, older age, male gender,
increasing stage, not receiving treatment, and tobacco history were associated with higher mortality risk.
Untreated patients exhibited a 39 % higher mortality risk compared to treated patients (HR = 1.39; 95%CI
= 1.23-1.57). Compared to Caucasian patients, Asian/PIs demonstrated a 20 % lower risk of death (HR =
0.80; 95%CI = 0.66-0.96). There was no difference in mortality risk between AAs and Hispanics
compared to Caucasians. CONCLUSION: The lack of significant outcome disparity between AAs and
Caucasians and the earlier stage at diagnosis than usually seen in civilian populations suggest that equal
access to healthcare may play a role in early detection and survival.
Improving Survival in Patients Treated for a Lung Cancer Using Self-Evaluated Symptoms
Reported Through a Web Application. Denis F1, Yossi S, Septans AL, et al. Am J Clin Oncol. 2015
Mar 24. [Epub ahead of print]
OBJECTIVES: We retrospectively compared survivals in patients with a lung cancer history and
followed by the so-called sentinel Web-application that allows early detection of relapse and early
palliative care initiation versus a conventional follow-up in our center. METHODS: The survival in 98
consecutive patients with lung cancer was assessed. The first part of them (the control arm) was
retrospectively recruited between March 2011 and August 2012. The second half of them (the
experimental arm) was prospectively recruited between August 2012 and December 2013 to weekly fill a
form of 11 self-assessed symptoms, then processed by the "sentinel" Web-application. Data were sent to
this sentinel application in real-time between planned visits. An email alert was sent to the oncologist
when self-scored symptoms matched some predefined criteria. Follow-up visit and imaging were then
organized after a phone call for confirming the suspect symptoms. In the control arm (49 patients), a
common follow-up was applied (visit and imaging every 2 to 6 mo according to stage of tumor and kind
of treatment). RESULTS: Median follow-up duration was 12.3 months in the experimental arm and 16.7
months in the control arm (P=0.27). Survival was significantly better in the sentinel arm than in the
control arm (P=0.0014). Median survival was 16.7 months in the control arm and 22.4 months in the
experimental arm. One-year survival was 86.6% in the experimental arm and 59.1% in the control arm.
CONCLUSIONS: Survival may be improved by early detection of relapse and early palliative care
initiation by using sentinel-like Web-application.
Patient Perspectives and Preferences for Communication of Medical Imaging Risks in a Cancer
Care Setting. Thornton RH1, Dauer LT, Shuk E, et al. Radiology. 2015 Mar 24:132905. [Epub ahead of
print]
PURPOSE: To identify opportunities for improving patient-centered communication about diagnostic
imaging tests that involve the use of radiation in a cancer care setting. MATERIALS AND METHODS:
Institutional review board approval and informed consent were obtained for this HIPAA-compliant study.
Patient knowledge, information sources, and communication preferences were assessed in six focus
24
groups during 2012. The groups consisted of patients undergoing treatment for metastatic colorectal
carcinoma, women treated within the past 6 months for early-stage breast carcinoma, men undergoing
surveillance after testicular cancer treatment, parents of patients treated for stage I-III neuroblastoma,
patients in a thoracic oncology survivorship program, and participants in a lung cancer screening program.
A multidisciplinary research team performed thematic content analysis of focus group transcripts. Highlevel findings were summarized during consensus conferences. RESULTS: Although they were aware of
the long-term risk of cancer from exposure to ionizing radiation, most participants reported that their
health care provider did not initiate discussion about benefits and risks of radiation from imaging tests.
Most patients obtained information by means of self-directed internet searches. Participants expressed
gratitude for tests ("That CT saved my daughter's life," "I'd rather have the radiation dosage than being
opened up"), yet they expressed concern about having to initiate discussions ("If you don't ask, nobody is
going to tell you anything") and the desire to be offered information concerning the rationale for ordering
specific imaging examinations, intervals for follow-up imaging, and testing alternatives. Participants
believed that such information should be available routinely and that conversation with their personal
physician or endorsed, readily available reference materials were ideal methods for information exchange.
Understanding imaging radiation risks and active participation in decision making about imaging were
especially important to cancer survivors. CONCLUSION: A substantial gap exists between patient
expectations and current practices for providing information about medical imaging tests that involve the
use of radiation. © RSNA, 2015 Online supplemental material is available for this article.
Nivolumab: targeting PD-1 to bolster antitumor immunity. Brahmer JR1, Hammers H, Lipson EJ.
Future Oncol. 2015 Mar 23:0. [Epub ahead of print]
Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, blocks PD-1 and can
restore anticancer immune responses by abrogating PD-1 pathway-mediated T cell inhibition. Nivolumab
is approved in Japan and the USA for the treatment of patients with advanced melanoma. A Phase I trial
reported overall objective response rates of 17, 32 and 29% in patients with advanced non-small-cell lung
cancer, melanoma and renal cell carcinoma, respectively, which included many heavily pretreated
patients. 1-/2-year overall survival rates were 42%/24%, 63%/48% and 70%/50% for non-small-cell lung
cancer, melanoma and renal cell carcinoma, respectively. Nivolumab significantly improved survival
versus dacarbazine in previously untreated patients with metastatic melanoma in a Phase III trial.
Nivolumab is associated with a manageable adverse event profile. Numerous clinical trials are
investigating nivolumab alone or in combination with other therapies in multiple cancer settings.
Perspectives of African Americans on Lung Cancer: A Qualitative Analysis. Lathan CS1, Waldman
LT2, Browning E2, Gagne J2, Emmons K2. Oncologist. 2015 Mar 20. pii: theoncologist.2014-0399.
BACKGROUND: Disparities in incidence and mortality for lung cancer in African Americans are well
documented; however, the extent to which disparities reflect differences in patient perceptions of tobacco
and lung cancer treatment is unclear. The objective of this study was to explore African Americans'
knowledge of lung cancer, perceived risk, interest in smoking cessation, attitudes toward lung cancer
treatment, and lung cancer diagnosis and treatment experiences. PATIENTS AND METHODS: The
cohort comprised 32 African-American current and former smokers without a cancer diagnosis who
participated in focus groups and 10 African Americans with lung cancer who participated in in-depth
interviews. Transcripts were analyzed using a modified grounded theory approach. RESULTS:
Participants without a cancer diagnosis were aware of the link between smoking and lung cancer, the
common symptoms of the disease, and its poor prognosis. They desired specific, personalized smokingcessation information. If diagnosed, the majority reported, they would seek medical care. Most believed
that insurance and socioeconomic factors were more likely to affect treatment access than racial
25
discrimination. Participants with a cancer diagnosis were also aware of the relationship between smoking
and lung cancer. They felt their treatment plans were appropriate and trusted their physicians. Most did
not believe that race affected their care. CONCLUSION: This qualitative study suggests that AfricanAmerican smokers are aware of the relationship between smoking and lung cancer and are interested in
smoking-cessation treatment. These data also indicate that lung cancer disparities are unlikely to be
associated with differential willingness to receive care but that African Americans may perceive financial
and insurance barriers to lung cancer treatment.
Pulmonologist Involvement, Stage-Specific Treatment, and Survival in Adults with Non-Small Cell
Lung Cancer and COPD. Deepak JA1, Ng X, Feliciano J, Mao L, Davidoff AJ. Ann Am Thorac Soc.
2015 Mar 11. [Epub ahead of print]
RATIONALE: Up to 80% of lung cancer patients have comorbid chronic obstructive pulmonary disease
(COPD). Many of them are poor candidates for stage specific lung cancer treatment due to diminished
lung function and poor functional status, and many forego treatment. The negative effect of COPD may
be moderated by pulmonologist-guided management. Objectives This study examined the association
between pulmonologist management and the probability of receiving the recommended stage-specific
treatment modality and overall survival among non-small cell lung cancer (NSCLC) patients with preexisting COPD. Methods Early and advanced stage NSCLC cases diagnosed between 2002 and 2005 with
a prior COPD diagnosis (3-24 months before NSCLC diagnosis) were identified in Surveillance,
Epidemiology, and End Results tumor registry data linked to Medicare claims. Study outcomes included
receipt of recommended stage-specific treatment (surgical resection for early stage NSCLC and
chemotherapy for advanced stage NSCLC (AdvNSCLC) and overall survival. Pulmonologist
management was considered present if >=1 Evaluation & Management visit claims with pulmonologist
specialty were observed within 6-months after NSCLC diagnosis. Stage-specific multivariate logistic
regression tested association between pulmonologist management and treatment received. Cox
proportional hazard models examined the independent association between pulmonologist care and
mortality. Two-stage-residual inclusion instrumental variable (2SRI-IV) analyses tested and adjusted for
potential confounding based on unobserved factors or measurement error. Measurements and Main
Results The cohorts included 5,488 early stage, and 6,426 AdvNSCLC disease with pre-existing COPD.
Pulmonologist management was recorded for 54.9% of early stage and 35.7% of AdvNSCLC patients. Of
those patients with pulmonologist involvement, 58.5% of early NSCLC received surgical resection, and
43.6% of AdvNSCLC received chemotherapy. Pulmonologist management post NSCLC diagnosis was
associated with increased surgical resection rates [OR:1.26; CI:1.11-1.45] for early NSCLC and increased
chemotherapy rates [OR:1.88; CI:1.67-2.10 ] for AdvNSCLC. Pulmonologist management was also
associated with reduced mortality risk for early stage but not AdvNSCLC patients. Conclusions
Pulmonologist management had a positive association with rates of stage-specific treatment in both
groups and overall survival in early stage NSCLC. These results provide preliminary support for the
recently published guidelines emphasizing the role of pulmonologists in lung cancer management.
26

April 2015 Literature Review - Caring Ambassadors Lung Cancer

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