A prospective study of the effect of different palliative

radiotherapy fractionation schedules on tumour response and

toxicity in advanced Non Small Cell Lung Cancer (NSCLC)

patients

THESIS

Submitted in partial fulfillment of the

M.SC. Degree in Clinical Oncology

By

Momen Elsayed Hassan Abdelall M.B.B.CH

Cairo University

Radiation oncology resident, National cancer institute, Cairo University

Supervised by

Prof. Mohamed Lotayef Prof. of Radiation Oncology

National Cancer Institute

Cairo University

Prof. Yasser Abd Elkader Prof. of Clinical Oncology

Faculty of Medicine

Cairo University

Prof.

Medi

Dr. Amr Amin

Lecturer of Radiation Oncology

National Cancer Institute

Cairo University

Cairo University

2016

ورام الرئت فىأ لىع التلطيفيت ختلاف الجرعاث الاشعاعيتإ دراست مستقبليت لدراست تأثير

مراحلها المتقدمت

ستيرجادرجة الم ىلع لرسالة للحصى

وراملاج الأـــــى عف

قدمة منـــم

ن عبدالعالــؤمن السيد حســالطبيب : م

راف ــــــــشتحت إ

طيفا.د. محمد ل شعاعلإستاذ علاج الأورام باأ

المعهد القىمى للأورام

جامعة القاهرة

.د. ياسر عبد القادرا علاج الأورامستاذ أ

كلية الطب

جامعة القاهرة

مين ا ود. عمر

شعاعلإورام بامدرس علاج الأ

المعهد القىمى للأورام

جامعة القاهرة

جامعت القاهرة

كليت الطب

6102

List of Tables

Tables page

Table.1: Estimated number of lung cancer cases, Egypt, 2013. 4

Table. 2: The WHO histological classification of lung cancer, 2015. 9

Table .3: Seventh TNM classification of lung cancer, 2010. 13

Table. 4: Stage grouping of lung cancer. 14

Table. 5: The most common manifestations in NSCLC. 16

Table. 6: ECOG Performance Status. 49

Table.7: RTOG Acute Radiation Morbidity 50

Table.8: Patients criteria in both arms. 52

Table.9: The pretreatment thoracic symptoms in both arms. 57

Table .10: The initial severity of the pretreatment thoracic symptoms in both arms. 57

Table .11: Chemotherapy criteria in both arms. 60

Table.12: The effect of both fractionation arms on thoracic symptoms and

PS.

62

Table.13: The effect of both fractionation arms on radiological response of chest tumour. 63

Table.14: Pretreatment FEV1 and FVC in both arms. 65

Table.15: The effect of both arms on FVC and FEV1. 65

Table.16: Post treatment FEV1 and FVC in both arms. 65

Table.17: Some randomized trials of different fractionations used in thoracic palliation

of advanced lung cancer.

67

List of Figures

Figures Page

Figure (1): Gender distribution in both arms. 54

Figure (2): Smoking history in both arms. 54

Figure (3) :Weight loss more than 5% before radiation in both

arms.

55

Figure (4): Pre treatment PS in both arms. 56

Figure (5): Pathology in both arms. 58

Figure (6): Stage of patients in both arms. 59

List of Abbreviations ACS American cancer society

AIS Adenocarcinoma in situ

ASCO American Society of Clinical Oncology

BAC Brochoalveolar carcinoma

BED Biologically effective dose

BTS British Thoracic Society

CNB Core Needle Biopsy

CR Complete Response

CT Computer Tomography

CTCA Cancer Treatment Centers of America

ECOG Eastern cooperative Oncology Group

EGFR Epidermal Growth Gactor Receptor

EUS Endoscopic ultrasound

FEV1 Forced expiratory volume in one second

FNA Fine needle aspiration

FVC Forced vital capacity

HD Higher dose

HIV Human Immunodeficiency Virus

HPO Hypertrophic pulmonary osteoarthropathy

IARC International Agency for Research on Cancer

IPT Immunophenotyping

LCC Large cell carcinoma

LCNEC Large cell neuroendocrine carcinoma

LD Lower dose

LDH Lactate dehydrogenase

MIA Minimally invasive adenocarcinoma

MRI Magnetic Resonance Imaging

NNK Nicotine-derived nitrosamine ketone

NSCLC Non Small Cell Lung Cancer

PD Progressive Disease

PET- CT Positron Emission Tomography - Computed Tomography

PFTS Pulmonary function tests

PR Partial Response

PS Performance Status

QOL Quality Of Life

RTOG Radiotherapy Oncology Group

SCC Squamous cell carcinoma

SCLC Small Cell Lung Cancer

SD Stable Disease

SEER Surveillance, Epidemiology, and End Results

SIADH Syndrome of inappropriate anti-diuretic hormone

SVC Superior vena cava

SVCS Superior vena cava syndrome

SUV max Maximum standardized uptake

TGF β Transforming growth factor

TKI Tyrosine kinase inhibitor

TNM Tumor Node Metastasis

TSNA Tobacco-specific N-nitrosamines

VEGR Vascular Endothelial Growth Factor

VTE Venous Thromoembolis

WHO World Health Organization

Contents

Introduction and Aim of the study …………………………………. 1

Review of Literature

Epidemiology………………………………………………………3

Risk factors of lung cancer…………………………………………4

Pathogenesis of lung cancer………………………………………...7

Pathology of lung cancer…………………………………………...8

Staging and Survival of lung cancer……………………………….12

Prognostic factors of advanced NSCLC……………………………15

Clinical presentation………………………………………………..15

Investigations and metastatic workup………………………………25

Treatment of advanced NSCLC…………………………………… 32

Patients and methods………………………………………………… 48

Results………………………………………………………………… 58

Discussion……………………………………………………………. 67

Summary, Conclusion and Recommendations………………………. 73

References…………………………………………………………… 75

Arabic Summary

Acknowledgement

I would like to express my deepest gratitude and sincerest

thanks to Prof. Yasser Abd Elkader. Prof.of Clinical Oncology,

Faculty of Medicine, Cairo University for giving me his support

and valuable advice.

A sincere appreciation is also expressed to Prof.

Mohamed Lotayef, Prof. of Radiation Oncology, National

Cancer Institute, Cairo University for his advice and comments

during preparation of this work.

Great thanks and deep appreciation are also expressed to

Dr. Amr Amin, Lecturer of Radiation Oncology, National Cancer

Institute, Cairo University.

Momen Elsayed

Abstract Background: Lung cancer is the most common cancer worldwide. The main goals of

treatment in advanced NSCLC patients are prolongation of life and palliation of

symptoms. Radiotherapy is often used as a palliative treatment. Patients and methods:

40 patients with advanced NSCLC who were indicated for thoracic palliative radiation

were randomized into two fractionation arms: 30Gy in 10 fractions over 2 weeks and

27Gy in 6 fractions over 3 weeks (2 fractions per week); 20 patients were included in

each arm. Primary end points were symptomatic assessment, respiratory functions

assessment and response of the thoracic tumour. Secondary end point was toxicity.

Advanced NSCLC patients indicated for palliative thoracic radiotherapy with age up to 65

y and PS 0-2 were included. Patients who had significant cardiac disease, pleural effusion,

asthma and history of thoracic radiotherapy were excluded. At base line and 4 weeks

after treatment, all patients were subjected to full history taking, PS assessment according

to WHO PS, CBC and respiratory function testing (FVC, FEV1). Patients were treated

through 2D radiotherapy technique using two parallel opposing (AP-PA) isocenteric

fields were used. Results: The percentages of all evaluable patients describing any

improvement in the various symptoms were as follows: pain: 82.3%, heamoptysis: 80 % ,

cough: 61.1% and dyspnea: 45.8%. The number of patients achieving symptomatic

improvement was higher in the arm B than arm A without statistical significance. Four

weeks after treatment, 12 out of 40 patients (30% - 6 patients in each arm) had PR of the

primary thoracic lesion through CT chest without significant difference between the two

arms. There was a tendency for improvement in the post treatment mean of FVC and

FEV1 in each arm without statistical significance. No reported cases of skin reaction or

esophagitis in both arms up to 4 weeks after treatment. Eleven out of the 40 patients

(27.5%), 6 in arm B and 5 in arm A, had radiological signs of radiation pneumonitis

without significant difference between both arms. Conclusion: Equal efficacy of the two

schedules in terms of palliative effect, radiological response of the primary thoracic

tumour, respiratory functions and toxicity. So, the prescription of arm B regimen appears

preferable compared to arm A regimen to decrease the load on machines and patients'

visits.

Keywords: Non small cell lung cancer, Thoracic radiation, Symptoms, Randomized

trial.

Introduction and Aim of work

1

Introduction

According to World Health Organization (WHO), lung cancer is the most

common cancer worldwide, accounting for 1.8 million new cases and 1.6 million

deaths in 2012. According to American cancer society (ACS), an estimated 158,040

cases are expected to die from lung cancer in 2015, accounting for approximately

27 % of all cancer deaths.

Tobacco smoking remains the most important modifiable risk factor for lung

cancer. It has been estimated that up to 20% of all cancer deaths worldwide could

be prevented by the elimination of tobacco smoking (Pisani et al. 2002). It was

estimated that 10% of lung cancer deaths among men and 5% among women

worldwide could be attributable to exposure to 8 occupational lung carcinogens,

namely asbestos, arsenic, beryllium, cadmium, chromium, nickel, silica, and diesel

fumes (Fingerhut et al. 2006).

Primary carcinoma of the lung are traditionally classified as either Small Cell

Lung Cancer )SCLC) or Non Small Cell Lung Cancer (NSCLC). NSCLC

constitutes approximately 80% of all primary lung cancers. Adenocarcinoma,

squamous cell carcinoma (SCC) and large cell carcinoma (LCC) constituting the

major histological types (Fong et al. 2003). The primary reason that most patients

with lung cancer present with advanced stage disease is that early-stage disease

does not usually cause significant symptoms, especially when arising in the

periphery of the lung (Spiro et al. 2007). US data collected from 2004-2010

indicate that the 5-year relative survival rate for lung cancer was 16.8%, reflecting a

steady but slow improvement from 12.5% in 1975. Cough is reported to be the most

common presenting symptom of lung cancer. Other respiratory symptoms include

dyspnea, chest pain, and hemoptysis (Corner et al. 2005).

Introduction and Aim of work

2

The main goals of treatment in advanced NSCLC patients are prolongation of

life, palliation of symptoms and improvement of Quality Of Life (QOL)

(Konstantinos et al. 2013). Early initiation of palliative care for advanced or

metastatic NSCLC can reduce symptoms, improve QOL, and prolong survival

(Charles et al. 2013).

The treatment strategy should take into account the histology, molecular

pathology, age, PS, comorbidities, and patient's preferences. Treatment decisions

should ideally be discussed within a multidisciplinary tumor board. Systemic

therapy should be offered to all stage IV NSCLC patients with a PS 0–2. In any

stage of NSCLC, smoking cessation should be highly encouraged because it

improves the outcome (Peters et al. 2012). Radiotherapy is often used as a

palliative treatment for patients with stage IV NSCLC to relieve symptoms (i.e.

hemoptysis, cough, chest pain, dyspnea, etc.) that are caused by locoregional

growth of primary tumor (Kramer et al. 2005).

Aim of the study

This study is a prospective randomized study to compare the effect of two

radiotherapy schedules for thoracic palliation in advanced NSCLC patients (30Gy

in 10 fractions over two weeks and 27Gy in 6 fractions over three weeks, 2

fractions per week) on improvement of pulmonary symptoms, respiratory functions,

radiological response of the primary thoracic tumour and toxicity.

Review of Literature

3

Epidemiology

According to WHO, lung cancer is the most common cancer worldwide,

accounting for 1.8 million new cases and 1.6 million deaths in 2012. According to

ACS, during 2015, an estimated 221,200 new cases of lung cancer were expected to

be diagnosed. Lung cancer causes more deaths than colorectal, breast and prostate

cancers combined. An estimated 158,040 cases are expected to die from lung cancer

in 2015, accounting for approximately 27 % of all cancer deaths.

According to the Surveillance, Epidemiology, and End Results ( SEER )

2011 review, the lung cancer five-year survival rate (17.8%) is lower than many

other leading cancer sites, such as colon (65.4%), breast(90.5%) and prostate (99.6

%). The five-year survival rate for lung cancer is 54 % for cases detected when the

disease is still localized (within the lungs). However, only 15 % of lung cancer

cases are diagnosed at an early stage. For distant tumors (spread to other organs) the

five-year survival rate is only 4%. The SEER data from 2004 to 2008 reported the

median age at diagnosis for cancer of the lung and bronchus was 71 years. No cases

were diagnosed in patients younger than 20 years. Approximately 0.2% of lung

cancers was diagnosed in patients between age 20 and 34 years; 1.5% between 35

and 44 years; 8.8% between 45 and 54 years; 20.9% between 55 and 64 years;

31.1% between 65 and 74 years; 29% between 75 and 84 years; and 8.3% at 85

years and older.

In Egypt in 2013, the estimated number of lung cancer cases constituted 4.2%

from total cancer cases in combined gender. In males, lung cancer cases constituted

about 5.7 % of total malignancies and 2.7 % in females (Table.1) (Ibrahim et al.

2014).

Review of Literature

4

Table.1 :Estimated number of lung cancer cases , Egypt, 2013.

RISK FACTORS

1-Smoking

Tobacco smoking remains the most important modifiable risk factor for lung

cancer. It has been estimated that up to 20% of all cancer deaths worldwide could

be prevented by the elimination of tobacco smoking (Pisani et al. 2002). One in 9

smokers eventually develops lung cancer (Jemal et al. 2005).

The cumulative lung cancer risk among heavy smokers can be as high as

30% compared with a lifetime risk of less than 1% in nonsmokers. The lung cancer

risk is proportional to the number of packs smoked per day, the age of onset of

smoking, the degree of inhalation, the nicotine content of cigarettes, and the use of

unfiltered cigarettes (Harris et al. 2004).

The overall global statistics estimate that 15% of lung cancers in men and up

to 53% in women are not attributable to smoking, with never smokers accounting

for 25% of all lung cancer cases worldwide (Parkin et al. 2002). A more recent

study reported that passive smoking during childhood increased lung cancer risk in

adulthood by 3.6 fold (Vineis et al. 2005 ).The biology of lung cancer differs

between smokers and never-smokers. Recent data have shown that lung cancers in

never-smokers are much more responsive to epidermal growth factor receptor

tyrosine kinase inhibitors (EGFR-TKIs). In addition, K-ras mutations, which predict

a poor response to therapy and shorter survival, are found frequently in smokers,

but less so in non-smokers (Tam et al. 2006).

Male Female Total in combined gender

Lung cancer cases 3304 1586 4890

Total cancer cases 57558 57426 114984

Percentage ( % ) 5.7% 2.7% 4.2%

Review of Literature

5

The International Agency for Research on Cancer (IARC) has identified at

least 50 carcinogens in tobacco smoke. The agents that seem of particular concern

in lung carcinoma are the tobacco-specific N-nitrosamines (TSNAs) formed by

nitrosation of nicotine during tobacco processing and during smoking. Eight

TSNAs have been described, including Nicotine-derived nitrosamine ketone

(NNK), which is known to induce adenocarcinoma of the lung in experimental

animals (Smith et al. 2000).

Smokers who quit for more than 15 years have an 80% to 90% reduction in

their risk for lung cancer compared with persons who continue to smoke. Smokers

who stop smoking even well into middle age avoid most of their subsequent risk for

lung cancer, and stopping before middle age avoids more than 90% of the risk

attributable to tobacco (Peto et al. 2000).

2- Occupational Carcinogens

The IARC has identified arsenic, asbestos, beryllium, cadmium,

chloromethyl ethers, chromium, nickel, radon, silica, and vinyl chloride as

carcinogens. It was estimated that 10% of lung cancer deaths among men and 5%

among women worldwide could be attributable to exposure to 8 occupational lung

carcinogens, namely asbestos, arsenic, beryllium, cadmium, chromium, nickel,

silica, and diesel fumes (Fingerhut et al. 2006). Asbestos is the most widely known

and most common occupational cause of lung cancer. Asbestos is a class of

naturally occurring fibrous minerals consisting primarily of 2 types: (1) serpentine

(chrysotile) and (2) amphibole (amosite, crocidolite, and tremolites).

In a retrospective cohort study published in 1955, Doll noted a 10-fold

increased risk of lung cancer in asbestos textile workers. This risk for lung cancer

associated with asbestos exposure is dose-dependent but varied with the type of

asbestos fiber exposure. The risk for lung cancer seems higher for workers exposed

to amphibole fibers than for those exposed to chrysotile fibers, after adjusting for

similar exposure level. The presence of interstitial fibrosis, such as in the form of