Combination Therapy Against

Multidrug Resistance 1st Edition

Mohmmad Younus Wani (Editor)
Visit to download the full and correct content document:
https://textbookfull.com/product/combination-therapy-against-multidrug-resistance-1st
-edition-mohmmad-younus-wani-editor/
More products digital (pdf, epub, mobi) instant
download maybe you interests ...

Deep Learning Applications, Volume 2 M. Arif Wani

https://textbookfull.com/product/deep-learning-applications-
volume-2-m-arif-wani/

Awaiting MacArthur s Return World War II Guerrilla

Resistance against the Japanese in the Philippines 1st
Edition James Villanueva

https://textbookfull.com/product/awaiting-macarthur-s-return-
world-war-ii-guerrilla-resistance-against-the-japanese-in-the-
philippines-1st-edition-james-villanueva/

Decidability of Logical Theories and Their Combination

João Rasga

https://textbookfull.com/product/decidability-of-logical-
theories-and-their-combination-joao-rasga/

Air Release Air Vacuum and Combination Air Valves

Second Edition Ballun

https://textbookfull.com/product/air-release-air-vacuum-and-
combination-air-valves-second-edition-ballun/
Democracy against domination 1st Edition Rahman

https://textbookfull.com/product/democracy-against-
domination-1st-edition-rahman/

Combination Acts Notes on Collective Practice in the

Undercommons First Edition Stevphen Shukaitis

https://textbookfull.com/product/combination-acts-notes-on-
collective-practice-in-the-undercommons-first-edition-stevphen-
shukaitis/

Resistance Band Workout for Seniors Complete Guide to

Resistance Band Workouts for Seniors 1st Edition Julia
Warman

https://textbookfull.com/product/resistance-band-workout-for-
seniors-complete-guide-to-resistance-band-workouts-for-
seniors-1st-edition-julia-warman/

New Framings on Anti Racism and Resistance Volume 2

Resistance and the New Futurity 1st Edition Joanna
Newton

https://textbookfull.com/product/new-framings-on-anti-racism-and-
resistance-volume-2-resistance-and-the-new-futurity-1st-edition-
joanna-newton/

Chemical Resistance of Engineering Thermoplastics 1st

Edition Erwin Baur

https://textbookfull.com/product/chemical-resistance-of-
engineering-thermoplastics-1st-edition-erwin-baur/
COMBINATION THERAPY
AGAINST MULTIDRUG
RESISTANCE
COMBINATION
THERAPY
AGAINST
MULTIDRUG
RESISTANCE
Edited by

Mohmmad Younus Wani

Assistant Professor, Department of Chemistry, College of Science, University of Jeddah,
Jeddah, Saudi Arabia

Aijaz Ahmad
Lecturer, Department of Clinical Microbiology and Infectious Diseases, School of Pathology,
Health Sciences, University of the Witwatersrand, Johannesburg, South Africa and Medical
Scientist, Division of Infection Control, Charlotte Maxeke Johannesburg Academic Hospital,
National Health Laboratory Service (NHLS), Johannesburg, South Africa
Academic Press is an imprint of Elsevier
125 London Wall, London EC2Y 5AS, United Kingdom
525 B Street, Suite 1650, San Diego, CA 92101, United States
50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States
The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom
© 2020 Elsevier Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any means,
electronic or mechanical, including photocopying, recording, or any information storage and
retrieval system, without permission in writing from the publisher. Details on how to seek
permission, further information about the Publisher’s permissions policies and our arrangements
with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency,
can be found at our website: www.elsevier.com/permissions.
This book and the individual contributions contained in it are protected under copyright by the
Publisher (other than as may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience
broaden our understanding, changes in research methods, professional practices, or medical
treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in
evaluating and using any information, methods, compounds, or experiments described herein. In
using such information or methods they should be mindful of their own safety and the safety of
others, including parties for whom they have a professional responsibility.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors,
assume any liability for any injury and/or damage to persons or property as a matter of products
liability, negligence or otherwise, or from any use or operation of any methods, products,
instructions, or ideas contained in the material herein.
Library of Congress Cataloging-in-Publication Data
A catalog record for this book is available from the Library of Congress
British Library Cataloguing-in-Publication Data
A catalogue record for this book is available from the British Library
ISBN: 978-0-12-820576-1

For information on all Academic Press publications

visit our website at https://www.elsevier.com/books-and-journals

Publisher: Andre Gerhard Wolff

Acquisitions Editor: Erin Hill-Parks
Editorial Project Manager: Barbara Makinster
Production Project Manager: Sreejith Viswanathan
Cover Designer: Matthew Limbert

Typeset by SPi Global, India

 Contributors

Aijaz Ahmad Department of Clinical Microbiology and Infectious Diseases,

School of Pathology, Health Sciences, University of the Witwatersrand; Division
of Infection Control, Charlotte Maxeke Johannesburg Academic Hospital,
National Health Laboratory Service (NHLS), Johannesburg, South Africa
Mohamed Fahad AlAjmi Department of Pharmacognosy, College of Pharmacy,
King Saud University, Riyadh, Saudi Arabia
Mahmood A. Alam Lord Kelvin/Adam Smith (LKAS) fellow, Wellcome Centre
for Integrative Parasitology, Institute of Infection, Immunity and Inflammation,
University of Glasgow, Glasgow, Scotland
Othman A. Alghamdi Department of Biological Sciences, Faculty of Science,
University of Jeddah, Jeddah, Kingdom of Saudi Arabia
N. Bakthavatchala Reddy Ural Federal University, Chemical Engineering Insti-
tute, Yekaterinburg, Russian Federation
A. Balakrishna Department of Chemistry, Rajeev Gandhi Memorial College of
Engineering and Technology (Autonomous), Nandyal, Andhra Pradesh, India
Adriano Duse Department of Clinical Microbiology and Infectious Diseases,
School of Pathology, Health Sciences, University of the Witwatersrand; Division
of Infection Control, Charlotte Maxeke Johannesburg Academic Hospital,
National Health Laboratory Service (NHLS), Johannesburg, South Africa
Abdul Hafiz Faculty of Medicine, Umm Al-Qura University, Makkah, Kingdom
of Saudi Arabia
Krishnan Hajela School of Life Sciences, Devi Ahilya Vishwavidyalaya, Indore,
Madhya Pradesh, India
Athar Adil Hashmi Bioinorganic Lab., Department of Chemistry, Jamia Millia
Islamia (Central University), New Delhi, India
Syed Masood Husain Molecular Synthesis and Drug Discovery Unit, Centre of
Biomedical Research, Lucknow, India
Afzal Hussain Department of Pharmacognosy, College of Pharmacy, King Saud
University, Riyadh, Saudi Arabia
Prince F. Iqbal Department of Chemistry, Government Degree College Boys,
Pulwama, Jammu and Kashmir, India
Shama Khan Department of Clinical Microbiology and Infectious Diseases,
School of Pathology, University of Witwatersrand, Johannesburg, South Africa
Md. Khurshid Alam Khan School of Life Sciences, BS Abdur Rahman Crescent
Institute of Science and Technology, Chennai, Tamil Nadu, India

ix
x Contributors

Manzoor Ahmad Malik Bioinorganic Lab., Department of Chemistry, Jamia

Millia Islamia (Central University), New Delhi, India
Musa Marimani Department of Clinical Microbiology and Infectious Diseases,
School of Pathology, Health Sciences, University of the Witwatersrand, Johan-
nesburg, South Africa
Indresh Kumar Maurya Department of Microbial Biotechnology, Panjab Uni-
versity, Chandigarh, India
Arif Mohammed Department of Biological Sciences, Faculty of Science, Univer-
sity of Jeddah, Jeddah, Kingdom of Saudi Arabia
Rifat Munir Department of Clinical Microbiology and Infectious Diseases;
Department of Biosystems, University of Manitoba, Winnipeg, MB, Canada;
Department of Immunology, University of Witwatersrand, Johannesburg,
Gauteng, South Africa
Mohammad Nasiruddin Clinical Genomics and Molecular Diagnostics, Neuberg
Anand Reference Laboratory; Molecular Oncology and Transplant Immunol-
ogy, MedGenome Labs Pvt Ltd., Bangalore, Karnataka, India
Deepak Kumar Semwal Department of Phytochemistry, Faculty of Biomedical
Sciences, Uttarakhand Ayurved University, Dehradun, India
Ruchi Badoni Semwal Department of Chemistry, Pt. Lalit Mohan Sharma Gov-
ernment Postgraduate College, Rishikesh, Uttarakhand, India
Shailesh Kumar Singh Molecular Synthesis and Drug Discovery Unit, Centre
of Biomedical Research, Lucknow, India
G. Sravya Ural Federal University, Chemical Engineering Institute, Yekaterin-
burg, Russian Federation
Sudarkodi Sukumar School of Life Sciences, BS Abdur Rahman Crescent Insti-
tute of Science and Technology, Chennai, Tamil Nadu, India
T.V. Surendra Department of Chemistry, Rajeev Gandhi Memorial College of
Engineering and Technology (Autonomous), Nandyal, Andhra Pradesh, India
C. Suresh Reddy Department of Organic Chemistry, Sri Venkateswara Univer-
sity, Tirupati, Andhra Pradesh, India
Mohmmad Younus Wani Department of Chemistry, College of Science, Univer-
sity of Jeddah, Jeddah, Saudi Arabia
Waseem A. Wani Department of Chemistry, Government Degree College, Tral,
Jammu and Kashmir, India
Md. Zafaryab Department of Zoology, Kirori Mal College, University of Delhi,
New Delhi, Delhi, India; School of Life Sciences, Devi Ahilya Vishwavidyalaya,
Indore, Madhya Pradesh, India
Grigory V. Zyryanov Ural Federal University, Chemical Engineering Institute;
I. Ya. Postovskiy Institute of Organic Synthesis, Ural Division of the Russian
Academy of Sciences, Yekaterinburg, Russian Federation
 Preface

Humans have been plagued by dreadful diseases for centuries, but

during the last few centuries tremendous advances have been made that
have either completely cured or minimized the impact of many diseases.
Today, hundreds of thousands of powerful medicines are used to treat and
often cure conditions that were thought to be incurable or untreatable a
couple of decades ago. But, sadly enough, the misuse, overuse, and abuse
of these drugs have resulted in the development of multidrug resistance
(MDR), which is a global problem of great concern that needs immedi-
ate attention and action. New resistance mechanisms are developing and
spreading globally, more rapidly than the development of new drugs,
therefore threatening our ability to treat any multidrug resistant pathogen
or disease. In 2016, 490,000 people globally developed multidrug-resistant
TB, and drug resistance has also started to complicate the fight against
other diseases like malaria, HIV, and cancer. In recent decades, bacterial
resistance to antibiotics has developed faster than the production of new
antibiotics, making bacterial infections increasingly difficult to treat. In
addition, pharmaceutical companies are showing less interest in devel-
oping new antibiotics. Scientists worry that a particularly virulent and
deadly “superbug” could one day join the ranks of existing untreatable
bacteria, causing a public health catastrophe.
Among the various strategies to combat MDR, combination therapy
shows great promise, as it offers potential benefits such as a broad spec-
trum of efficacy, greater potency than the drugs used in monotherapy, im-
proved safety and tolerability, and reduction in the number of resistant
organisms. Combination therapy (or polytherapy) is the use of a combi-
nation of drugs to treat a drug-resistant infection or disease, on the the-
ory that if one drug can do something, two or three could accomplish
more. While it typically denotes the use of two or more drugs, it can also
include immunotherapy and nonmedical therapies, including psycho-
logical therapy and other means of therapy or treatment. Combination
therapy has been a standard treatment for infections of human immuno-
deficiency virus (HIV), Plasmodium falciparum, Mycobacterium tuberculosis,
and Pseudomonas aeruginosa, and in cystic fibrosis (CF) patients. The grow-
ing clinical studies and the recent FDA approval of different combination
drugs and regimes for the treatment of different diseases clearly argues
that combination therapy affords great opportunities for the discovery
and development of novel medicines in the 21st century.

xi
xii Preface

The time is right to provide a state-of-the-art study of MDR and ther-

apeutic strategies against it. Although a plethora of material is currently
available in the form of research articles and reviews covering the multi-
drug resistance problem, there is no comprehensive coverage of the poten-
tial of combination therapy as an efficient strategy to combat multidrug
resistance in the form of a book. Previous works on combination therapies
are either a chapter in a book or a section in a book chapter. Therefore
a comprehensive book devoted entirely to combination therapy against
multidrug resistance will be an important addition to the literature.
This book is intended to bring to its audience crucial information on
multidrug resistance and the potential of combination therapy as an effi-
cient strategy to combat it. The book will enlighten readers on the views
of experts, from different countries and having a wide spectrum of back-
grounds, who have made significant contributions in understanding drug
resistance and handling it with different combination therapies.
This book will also serve as a comprehensive literature guide for begin-
ning researchers and as reference material for the academic and research
community involved in tackling the multidrug resistance problem. This
book is especially aimed at focusing the attention of researchers in the
pharmaceutical industry toward making use of combination therapy as
a treatment strategy to tackle the drug-resistance problem. This strategy
has already been quite successful in combating drug-resistance in many
cases, but work is still needed, both from the research community and in-
dustrial sectors, to streamline efforts and understand the need to develop
treatment strategies to augment the therapies currently being used. We
hope the readers of this book will find in its pages valuable information
and views on MDR and combination therapies, and will use it to develop
new treatment strategies.

Mohmmad Younus Wani

Aijaz Ahmad
 C H A P T E R

1
Combination therapy: Current
status and future perspectives
Manzoor Ahmad Malika, Mohmmad Younus Wanib,
Athar Adil Hashmia
a
Bioinorganic Lab., Department of Chemistry, Jamia Millia Islamia (Central
University), New Delhi, India, bDepartment of Chemistry, College of
Science, University of Jeddah, Jeddah, Saudi Arabia

Abbreviations
AIDS acquired immunodeficiency syndrome
AMP antimicrobial peptides
ART antiretroviral therapy
ARVs antiretroviral drugs
CDC Centers for Disease Control
DNA deoxyribose nucleic acid
FDA Food and Drug Administration
FDC fixed dose combination
HIV human immunodeficiency virus
MBL metallo-beta-lactamase
MDR multidrug resistance
MRSA methicillin-resistant Staphylococcus aureus
WHO World Health Organization

1.1 Introduction

Our bodies are equipped with natural (specific and nonspecific) de-
fense mechanisms to fight off invading microbes or unwanted changes
that may cause disease. An infection or a disease occurs when the body’s
defense system gives up or loses the battle and that is when drugs come
to our rescue. Possibly the earliest written accounts of medical therapeu-
tics used by humans are found in the famous Ebers papyrus, which is
an almost 20-m long, 110-page medical scroll named after the German

Combination Therapy Against Multidrug Resistance 1 © 2020 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/B978-0-12-820576-1.00001-1
2 1. Combination therapy: Current status and future perspectives

Egyptologist Georg Ebers, who acquired it in 1872. Hundreds of treat-

ment options are described in the Ebers papyrus for diseases afflicting
ancient Egyptians in ∼   1500 BC, and these treatments involved mixing
various herbs, leaves, shrubs, minerals, and animal excreta—forming a
combination (Jones, 2011).
The isolation and characterization of the active principles in medicinal
plants signified a major challenge, which was later met by the develop-
ment of synthetic drugs. Today we have 10,000   + ever-more targeted and
increasingly powerful high-tech medicines that can treat and often cure
conditions that have confounded healers for thousands of years. These
drugs, particularly antibiotics, have moved us from being helpless vic-
tims of epidemics to being able to fight off potentially deadly diseases.
However, sadly enough, with these new medicines has come an increase
in the misuse, overuse, and abuse of some of them, which has led to the
emergence of multidrug resistance (MDR), a global problem of great
concern.
The upsurge in microbial resistance has become a significant threat
worldwide. Development of resistance to the available drug candidates
has resulted in considerable patient mortality and morbidity (Tamma,
Cosgrove, & Maragakis, 2012). Although researchers are involved in the
development of new drug candidates for combating the serious problems
created by rising multidrug resistance (MDR), the situation appears to be
far more complex. During the past two decades, only two new classes
of antibiotics have been introduced into clinical use, but none of them is
assuredly active against gram-negative bacteria. Daptomycin, which was
offered clinically in 2003, lost ground a year later due to the development
of resistance in patients with Enterococcus faecium and MRSA infections
(Worthington & Melander, 2013). Multidrug resistance against other
life-threatening diseases such as malaria, tuberculosis, cancer, and viral
diseases such as HIV/AIDS is already ringing alarm bells; it is feared that
we may lose the battle if new treatment modalities or strategies are not
discovered. Among the various strategies that could augment the current
treatment regimen and add to the armament against multidrug resistance
is combination therapy. It is imperative to examine the influence of drugs
beyond what they can accomplish alone. A combination of drug candi-
dates can act as a multiplier and thereby increase the sum of their benefits.
Drug combinations have been discussed for the treatment of diagnosed
conditions for some time, such as aspolol (a combination of atenolol and
aspirin) for patients diagnosed with cardiovascular disease. For preven-
tive use, Wald and Law proposed the use of a combination of well-known
and inexpensive medications in one pill (called a polypill) for defense
against cardiovascular disease (Wald & Law, 2003). Based on the emerg-
ing and ongoing clinical studies and research outcomes it is now clear that
the use of drug combinations is an effective approach for the treatment
 1.1 Introduction 3

of ­complicated and refractory diseases. The Drug Combination Database

(DCDB) has a collection of 1363 drug combinations (330 approved and
1033 investigational, including 237 unsuccessful usages), involving 904
individual drugs and 805 targets; the purpose of the database is to facili-
tate in-depth analyses and to provide a basis for theoretical modeling and
simulation of such drug combinations (Yanbin et al., 2014). Almost 10,000
clinical trials are presently registered in the United States alone, exploring
combination therapies for the successful eradication of cancer, infectious
diseases, and cardiovascular, neurological, autoimmune, and metabolic
disorders. Numerous research articles contain details on drug combi-
nations. Yet, these numbers are quite modest relative to all possible and
potent combinations that could be tested (Rationalizing combination ther-
apies, 2017). The numbers of US Food and Drug Administration (FDA) ap-
provals of different classes of combination drugs have, however, increased
since the approval of the first combination drugs in the 1940s (Fig. 1.1).
Between the 1940s and 1950s the highest growth rate (37.5%) occurred,
while the lowest growth rate occurred between the 1960s and 1970s (9%).
This initial surge followed by the slowed approval rate of combination
drugs was due to the FDA’s new strict criteria and support guidelines an-
nounced in 1971. Since 1971, a strong indication has been required to show
that a combination drug offers a therapeutic benefit in comparison to each
individual drug entity (Finland, 1974). In 1943, the combination drug hy-
codan (homatropine + hydrocodone), which has been discontinued, was

FIG. 1.1 FDA approval of combination drugs by decade (1940s–2019).

4 1. Combination therapy: Current status and future perspectives

the earliest combination to be approved. Cafergot, a combination of ergot-

amine and caffeine, was approved in 1948, and since then more than 400
new drug combinations have been approved. The FDA approval of drug
combinations for different classes of diseases, including HIV, cancer, and
infectious diseases, is now on the rise, with the majority of drug combina-
tions approved for treating infectious diseases (Fig. 1.1).
Drug combinations can have synergistic or even additive effects.
However, it is imperative to note that not all seemingly rational combina-
tions of drugs will yield better efficacy or safety. For example, a 2004 trial
disclosed that torcetrapib could raise HDL and lower LDL both with and
without an added statin (Brousseau et al., 2004). However, its combination
with atorvastatin (Lipitor) led to a 60% increase in deaths (Nissen et al.,
2007). Therefore, in-depth investigations of the known cases of successful
and unsuccessful drug combinations are needed to recognize the patterns
of valuable drug interactions and to deliver the bases for rational design
of efficient drug combinations.

1.2 Combination rule

A combination drug is a fixed-dose combination (FDC) of two or more

pharmaceutically active ingredients combined in a single dosage form. As
one or both drugs are typically already FDA approved, there might ap-
pear to be no need for approval of many drug combinations. However,
since the FDA approval is for the drugs alone and not for the combination,
FDA approval for the combination is therefore required. For example, to
develop an aztreonam-avibactum combination drug, which involves the
FDA-approved beta-lactamase resistant aztreonam and a non-beta-­lactam-
beta-lactamase inhibitor, avibactum, which also restores aztreonam’s ac-
tivity against isolates expressing multiple beta-lactamases, phase II and
phase III clinical studies were required for FDA approval. Another exam-
ple is the combination of naltraxone HCl and bupropion HCl for weight
management, for which similar clinical trials were required for approval.
In many cases, additional studies beyond those required for the original
approval of the two component drugs are required because the FDA must
apply what is commonly referred to as the “combination rule.” This rule
states that two or more drugs may be combined in a single dosage form
when each component makes a contribution to the claimed effects and
the dosage of each component (amount, frequency, duration) is such that
the combination is safe and effective for a significant patient population
requiring such concurrent therapy as defined in the labeling for the drug.
In order to fulfill the requirements of the combination rule, a combina-
tion must demonstrate that each component contributes to the safety or
efficacy of the product. This typically requires a multifactorial study in
 1.3 Combination therapy: Current status 5

which each component is compared separately and in combination with

a placebo control. For example, if the product aims to combine Drug A
and Drug B, clinical studies with the following treatment arms may be
required to demonstrate that each component contributes to the overall
effect of the drug:
Placebo
Drug A
Drug B
Drug A and Drug B combined.
Developing a triple combination (three-drug combination) may require
eight treatment arms. However, the complexity increases even more when
one considers that the dose of each drug must be justified in terms of dos-
ing frequency, amount of each drug, and duration of each effect. If the
dosage requires clinical justification, the required studies may be so nu-
merous or so large that they may not be logistically or financially possible.

1.3 Combination therapy: Current status

In combination therapy, two or more drug candidates are used together

to achieve better results than the routinely used monotherapy. Typically,
combination therapy has one or more of the following aims: (i) decreasing
the rate at which acquired resistance arises by combining drugs with mini-
mal cross-resistance, such that emergence of resistance requires attainment
of multiple mutations in rapid succession—an unlikely event; (ii) lowering
the doses of drugs with nonoverlapping toxicity and similar therapeutic
profile so as to attain efficiency with fewer side effects; (iii) sensitizing cells
to the action of a drug through the use of another drug (chemosensitiza-
tion) or radiation (radiosensitization), often by altering cell-cycle stage or
growth properties (cytokinetic optimization); and (iv) achieving enhanced
potency by exploiting additivity, or better yet, greater-than-additive ef-
fects, in the biochemical activities of two drugs. The objectives of combi-
nation therapy are not mutually exclusive, and good combinations like
ABV (doxorubicin, bleomycin, vinblastine) or BEP (bleomycin, etoposide,
cisplatin) accomplish several objectives, including positive cytokinetic and
biological interaction (with and without surgery), and reduced toxicity
(Fitzgerald, Schoeberl, Nielsen, & Sorger, 2006). Combination therapy has
been a standard treatment for infections of human immunodeficiency vi-
rus (HIV) and in cystic fibrosis (CF), Plasmodium falciparum, Mycobacterium
tuberculosis, and Pseudomonas aeruginosa patients (Vestergaard et al., 2016).
Previous studies have endorsed that the advantage of combination ther-
apy against MDR P. aeruginosa infections was mainly due to an increased
possibility of selecting an effective agent rather than an in vitro synergy
6 1. Combination therapy: Current status and future perspectives

among antimicrobials or prevention of resistance (Garnacho-Montero, Sa-

Borges, Sole-Violan, et al., 2007). Against other MDR gram-negative bacte-
ria, however, quite a few studies have revealed higher efficiency and lesser
levels of resistance for combination treatment in comparison to monother-
apy (Batirel, Balkan, Karabay, et al., 2014; Daikos, Petrikkos, Psichogiou,
et al., 2009; Zarkotou, Pournaras, Tselioti, et al., 2011). An upsurge in the
survival rate was detected when colistin was administered as part of com-
bination treatments with tigecycline (an aminoglycoside) or meropenem
(particularly for carbapenem, minimal inhibitory concentration (MIC) be-
low 4 mg/L). Higher elimination rates were also confirmed for the combi-
nation of colistin with rifampin compared to colistin monotherapy against
A. baumannii (Durante-Mangoni, Signoriello, Andini, et al., 2013). Similarly,
synergistic effects of fosfomycin have been established with carbapen-
ems (along with a decrease in the appearance of resistance), aminoglyco-
sides, and quinolones (Samonis, Maraki, Karageorgopoulos, et al., 2012).
Lower mortality rates were observed in Klebsiella pneumoniae carbapene-
mase (KPC)-associated infections on using a triple combination therapy
containing a carbapenem, tigecycline, and colistin. A recent metaanalysis,
including studies carried out in the United States, Greece, and Italy, has
related the clinical results of combination therapy versus monotherapy
for treating carbapenemase-producing Enterobacteriaceae infections, pri-
marily KPC bloodstream infections (BSIs) (Tzouvelekis, Markogiannakis,
Piperaki, et al., 2014). A significant difference in the mortality rates for
­carbapenem-containing regimens (18.8%) compared to the noncarbapenem-
containing regimens (30.7) signifies that the presence of a carbapenem
in the combination may afford a better survival benefit. Overall, current
data backs the usage of combination therapy involving colistin and/or
tigecycline along with a carbapenem in the therapy of invasive infections
caused due to carbapenem-resistant K. pneumoniae, specifically in severe
infections.

1.3.1 Bacterial infections

The overuse and misuse of antibiotics in the healthcare and agricul-
tural industries has resulted in the spread of bacterial resistance world-
wide. The recent rise of multidrug resistant (MDR) bacteria, particularly
the strains of earlier susceptible bacteria (notably staphylococci) and other
bacterial species (like those of aerobacter, proteus, and pseudomonas) re-
sistant to the commonly used antibacterial agents has resulted in a call
for the adoption and development of new strategies to tackle this global
issue. The rise of extended-spectrum beta-lactamase (ESBL)-producing
bacteria, carbapenem-hydrolyzing beta-lactamases, or carbapenemases
including metallo-beta-lactamases (MBLs; e.g., New Delhi metallo-β-­
lactamases, plasmid-mediated imipenem-type carbapenemases, Verona
 1.3 Combination therapy: Current status 7

integron-encoded metallo-β-lactamases) and the oxacillinase group of

β-lactamases (OXA)-type carbapenemases (e.g., OXA-23 in A. baumannii
and OXA-48 in K. pneumoniae) has significantly increased the need for
new antibiotics. The delay in the evolution of new antibiotics led to the
successful use of combination drugs to treat multidrug-resistant bacte-
rial infections, which began with the use of a combination of tetracycline
and oleandomycin. Several new combinations or some mixtures of anti-
biotics with several sulfonamides and with other drugs exhibiting phar-
macologic properties have been introduced. Since the FDA approval of
third-generation cephalosporin and the β-lactamase inhibitor combina-
tion ceftazidime/avibactam in 2015, the combination of meropenem with
the β-lactamase inhibitor vaborbactam in 2017 represented a paradigm
shift from the development of new antibiotics to the use of already avail-
able drugs in combination (Table 1.1). As of July 2018, a total of about 48
antibiotics (along with some combinations) and 10 biologicals that target
the WHO priority pathogens Mycobacterium tuberculosis and Clostridium
difficile were in the pipeline (Table 1.2) (WHO, 2018). Quite recently the
FDA approved the antibacterial injection drug Recarbrio, a combination
of imipenem, cilastatin, and relebactum, to treat adults suffering from
complicated urinary tract infections (cUTIs) and complicated intraab-
dominal infections (cIAIs) (FDA, 2019).

TABLE 1.1 FDA-approved new drug combination for treating bacterial infections.
Trade name Combination Treatment

Recarbrio Imipenem, cilastatin, and Treating adults with complicated

relebactam urinary tract infections and complicated
intraabdominal infections

Dalbavancin Dalvance, Xydalba For treatment options for methicillin-

resistant S. aureus (MRSA) infections

Zerbaxa Ceftolozane-tazobactam For the treatment of complicated

intraabdominal and urinary tract
infections and bacterial pneumonia

Avycaz Ceftazidime-avibactam For the treatment of complicated

intraabdominal infections in
combination with metronidazole and
urinary tract infections

Ceftobiprole Zevtera, Mabelio For the treatment of community-

acquired pneumonia and hospital-
acquired pneumonia (HAP) in adults

Coartem Artemether/lumefantrine For the treatment of malaria infections

due to Plasmodium falciparum
8 1. Combination therapy: Current status and future perspectives

TABLE 1.2 Antimalarial combinations deployed for clinical use.

Trade name Combination Treatment

Coartem Artemether and For treating nonsevere malaria

lumefantrine

Malarone Atovaquone and Prevent malaria by interfering with

proguanil the growth of parasites in the red
blood cells of the human body

Fansidar Sulfadoxine and For the treatment of acute,

pyrimethamine uncomplicated P. falciparum malaria

Fansimef Mefloquine-suladoxine For prophylaxis of falciparum

and pyrimethamine malaria

Coarsucam or ASAQ Artesunate/amodiaquine Recommended by the WHO for

uncomplicated falciparum malaria

Artequin or ASMQ Artesunate and Recommended by the WHO for

mefloquine uncomplicated falciparum malaria

Ariplus or Amalar plus Artesunate and Recommended by the WHO for

sulfadoxine/ uncomplicated falciparum malaria
pyrimethamine

Pyramax Pyronaridine and For the treatment of P. falciparum

artesunate and P. vivax

Combination therapy has largely been used to fight MDR bacterial in-
fections and the current focus on their applications using antimicrobial
peptides (AMPs) may permit antibiotics to be potent against resistant bac-
terial strains. Research on a wide range of AMPs displayed promising ac-
tivity against some resistant strains. Increased understanding of the mode
of action of AMPs has revealed similarity and complementarity to conven-
tional antibiotics and the combination of both has led to synergistic effects
in some cases. By joining an antibiotic with an AMP, a new compound
may be obtained with possibly superior activity and reduced side-effects
and toxicity. Such antimicrobial peptide conjugates can act as unique ad-
juvants for the antibiotic by disturbing the resistance mechanisms of bac-
teria, thereby permitting the antibiotic to once again be effective (Sheard,
O’Brien-Simpson, Wade, & Separovic, 2019).
The combination of fosfomycin with other antimicrobial agents has dis-
played good efficiency against multidrug-resistant (MDR) bacteria in both
clinical and in vitro studies. Further studies have been carried out to in-
vestigate the synergism and also the optimal intravenous dosing regimens
of fosfomycin with meropenem against MDR and MBL-producing P. aeru-
ginosa strains. Rifampicin acts as an in vivo as well as in vitro bactericidal
agent but, due to the rapid development of resistance, a combination of
this antibiotic along with another agent is always used to avoid resistance
 1.3 Combination therapy: Current status 9

for treating serious infections. Hamilton-Miller noticed synergy between

fosfomycin and rifampicin against methicillin-resistant Staphylococcus
­aureus (MRSA) and coagulase-negative staphylococci (Katharina, Manfred,
Kristian, Miglioli, & Allerberger, 2001). In a study carried out by Nakazawa
et al., it was revealed that the combination of fosfomycin with various an-
tibiotics enhanced their antimicrobial potential against MRSA (Nakazawa,
Kikuchi, Honda, Isago, & Nozaki, 2003). Yu et al. studied the in vitro an-
tibacterial efficiency of a combination of fosfomycin and other antimicro-
bial agents against KPC-producing Klebsiella pneumoniae. They reported
that the selected five drug combinations (fosfomycin combined with imi-
penem, ertapenem, tigecycline, colistin, or amikacin) displayed notewor-
thy additive effect against 136 KPC-Kp strains in an in vitro checkerboard
assay. Furthermore, the time-kill assays exposed the fact that fosfomycin
improved the bactericidal activity of the five other antimicrobial agents
(Yu et al., 2017).
The high affinity of avibactam (NXL104) (with class A and class
C beta-lactamases) was studied to observe the resistances caused by
­extended-spectrum β-lactamases (ESBLs), K. pneumoniae carbapenemases
(KPCs), the oxacillinase group of b-lactamases (OXA), and ampicillin type
b-lactamases (AmpC) generating organisms. Mostly the combination of
avibactam with ceftazidime has been explored and it is also in clinical de-
velopment in combination with aztreonam and ceftaroline. Among these,
the aztreonam/avibactam combination could conceivably be employed in
NDM-1-producing bacteria, signifying optimistic results in treating KPC
and ESBL-producing strains (Crandon & Nicolau, 2013). In another re-
port, the ceftaroline/avibactam combination has displayed in vitro and
in vivo synergistic activity against ESBL and KPC-producing Klebsiella
species, and against ceftazidime-resistant Enterobacter cloacae strains, but
not against P. aeruginosa and A. baumannii (Sader, Fritsche, Kaniga, Ge, &
Jones, 2005).
A recent report on the inhibition of different targets within the same
pathway involves the targeting of wall teichoic acid synthesis by the natu-
ral product tunicamycin, which prevents the first enzyme in the biosynthe-
sis of wall teichoic acid, the N-acetylglucosamine-1-phosphate transferase
TarO, in S. aureus; it also shows a dramatic synergy with β-­lactam antibi-
otics, reducing the minimum inhibitory concentration (MIC) of oxacillin
against one MRSA clinical isolate from 50 to 0.4 μg/mL at a concentra-
tion of just 0.08 μg/mL (Campbell et al., 2011). Another TarO inhibitor was
later recognized for the ability to enhance the activity of the cephalosporin
cefuroxime against MRSA. The drug ticlopidine (antiplatelet drug) did
not show antibiotic activity alone, but was strongly synergistic with ce-
furoxime against various MRSA strains, dropping MICs by 64-fold. TarO
was identified as the molecular target of ticlopidine and the activity was
shown to be dependent on the presence of the tarO gene (Farha et al., 2013).
 1.3 Combination therapy: Current status 21

TABLE 1.5 FDA-approved/in-clinical-trial drug combinations against different

cancers—cont’d
Drug combination Treatment

Ramucirumab (Cyramza) in combination Metastatic colorectal cancer (mCRC)

with FOLFIRI (made up of folinic acid,
fluorouracil and irinotecan)

Dinutuximab (Unituxin) in combination Pediatric patients with high-risk

with granulocyte-macrophage colony- neuroblastoma
stimulating factor (GM-CSF), interleukin-2
(IL-2), and 13-cis-retinoic acid (RA)

Panobinostat (Farydak), bortezomib, and Multiple myeloma

dexamethasone

Palbociclib (Ibrance) plus letrozole Postmenopausal women with estrogen

receptor (ER)-positive, human epidermal
growth factor receptor 2 (HER2)-negative
advanced breast cancer

Ramucirumab (Cyramza injection) in Metastatic nonsmall cell lung cancer

combination with docetaxel (NSCLC)

Bevacizumab solution for intravenous Platinum-resistant, recurrent epithelial

infusion in combination with paclitaxel, ovarian, fallopian tube, or primary
pegylated liposomal doxorubicin, or peritoneal cancer
topotecan

Ramucirumab (Cyramza) plus paclitaxel Advanced gastric or gastroesophageal

junction (GEJ) adenocarcinoma

Ofatumumab (Arzerra injection), for Chronic lymphocytic leukemia (CLL)

intravenous infusion in combination with
chlorambucil

Trametinib and dabrafenib Unresectable or metastatic melanoma

with a BRAF V600E or V600K mutation as
detected by an FDA-approved test

Data taken from National Cancer Institute (NCI) and FDA website.

TABLE 1.6 FDA approval of HIV medicines—Timeline.

1981 First AIDS cases reported in the United States

1987 Zidovudine (NTRI)

1991 Didanosine (NTRI)

1992 Zalcitabine (NTRI)

1994 Stavudine (NTRI)

1995 Lamivudine (NTRI), Saquinavir (PI)

Continued
Another random document with
no related content on Scribd:
The Project Gutenberg eBook of The conquest of
cancer
This ebook is for the use of anyone anywhere in the United States
and most other parts of the world at no cost and with almost no
restrictions whatsoever. You may copy it, give it away or re-use it
under the terms of the Project Gutenberg License included with this
ebook or online at www.gutenberg.org. If you are not located in the
United States, you will have to check the laws of the country where
you are located before using this eBook.

Title: The conquest of cancer

Author: H. W. S. Wright

Author of introduction, etc.: F. G. Crookshank

Release date: October 25, 2023 [eBook #71960]

Language: English

Original publication: London: Kegan Paul, Trench, Trubner & Co,

1925

Credits: Tim Lindell, Donald Cummings and the Online Distributed

Proofreading Team at https://www.pgdp.net (This book was
produced from images made available by the HathiTrust
Digital Library.)

*** START OF THE PROJECT GUTENBERG EBOOK THE

CONQUEST OF CANCER ***
THE CONQUEST OF CANCER
TO-DAY AND TO-MORROW
A List of the Contents of
this Series will be found
at the end of this volume
 THE
CONQUEST OF CANCER
BY

H. W. S. WRIGHT, M.S., F.R.C.S.

With an Introduction by

F. G. CROOKSHANK, M.D., F.R.C.P.

“Malum immedicabile cancer.” (Ovid, Met. x, 127)

London
KEGAN PAUL, TRENCH, TRUBNER & CO., LTD.
New York: E. P. DUTTON & CO.
1925
 Printed in Great Britain by
F. Robinson & Co., at The Library Press, Lowestoft
 THE CONQUEST OF CANCER

INTRODUCTION
The phrase “Conquest of Cancer”, though perhaps emotive rather
than scientific, nevertheless implies the existence of a very real and
important problem. And this problem, it may be confidently affirmed,
is one that will never be solved, in action, by the efforts of the
medical profession alone. Whatever be the future, and as yet
reserved, revelations of Science, and whatever the further
developments of Art, cancer will not cease to exact its toll unless
medical science and art obtain the intelligent co-operation of an
instructed public. It is for this reason that it has been thought useful
to place before the public this little book, written by a practical
surgeon who has given special attention to the problems of the
laboratory. The book itself, which not only states in simple language
the essential points that should be comprehended by the public, but
puts forward a plan for concerted action, is based upon one of a
series of University Extension lectures given during the winter of
1922–23, at the Shantung Christian University, Tsinan, China, where
Mr Wright is actively engaged in the Surgical Department of the
School of Medicine.

The task of prefacing this essay by some words of introduction has

devolved upon the present writer, not because he either has, or
desires to present, any claim to speak with special authority
concerning Cancer, but by reason of a close personal and
professional friendship that has led him to appreciate very warmly
the knowledge, the sincerity, and the disinterestedness that
characterize Mr Wright’s thought and work. And he is confident that
we may accept what has been said about Cancer at Shantung as an
honest and candid attempt to instruct and to construct, in
detachment from the pribbles and prabbles that have sometimes
confused discussion nearer home.
Now, although the public has the undoubted right to demand
information on this subject, and although, as has been suggested,
without admission of the public to the arena of discussion little can
be done to diminish the present mortality from Cancer, yet is there
real difficulty in communicating knowledge, without engendering
unnecessary fear and alarm and sending the hypochondriac to those
quacks and charlatans who diagnose non-existent disease in order
that they may reap reward by announcing its cure.
Some weaker minds there will always be: so, whenever attention
is directed towards some public danger, there are those who adopt
the possible contingency as a peg on which to hang some ragged
vestment of distracted emotion or thought. Thirty years ago, the
insane feared the telephone: during the Boer War, many thought that
the “scouts were after them”; now-a-days lunatics babble of
persecution by wireless, by Bolsheviks, or even by psycho-analysts.
So, in Victorian times, the malades imaginaires who then thronged
consulting rooms spoke with bated breath of Bright’s disease: to-day,
the hysterical secretly hope to hear the blessed word “Colitis”, and
the hypochondriac as secretly dread the verdict of “Cancer”!
The task of the medical profession is to enlighten the laymen, that
their help may be enlisted, and yet to avoid alike exaggeration and
smooth sayings, false hopes and false fears. Macaulay, in a familiar
passage, once said that there is nothing more ridiculous than the
British public in one of its periodical fits of morality. At present, the
British Public is less concerned than formerly with questions of
morality, but is very much concerned with questions of health.
Perhaps it is not so much health that is sought and desired as
absence of pain and avoidance of death—which is not quite the
same thing. But, though there is nothing intrinsically ridiculous in
seeking the “advancement of morality” or the “conquest of disease”,
the one, no less than the other, may be pursued in a ridiculous and
dangerous manner.
 The adoption of ill-conceived measures, designed to improve
morals or to abolish disease, may, and often does entail
consequences that are even less desirable than the evils it is hoped
to combat. While the prohibition of the consumption or sale of
alcoholic drinks may diminish certain ills, it has yet to be shewn that
the casting out of devils in the name of Beelzebub may not be
followed by possession with others yet more violent. A few years ago
we were adjured to boil all milk, lest we became poisoned by certain
microbes: we are now told that, if all milk be boiled, we are as if
deprived of vitamines, and must suffer accordingly. Instances might
be multiplied; but it should be obvious that moral and physical health
must be considered, not as physical objects, but as relations, or
states of equilibrium. Like all states of adjustment or equilibrium, they
are the result of accommodation: of poise and counterpoise. They
are not always and everywhere to be secured by the throwing of a
certain weight into one or other scalepan, or by the cutting-off so
many inches from the table-leg that seems the longest. So much, at
least, should be recognised by a seriously disturbed public told by
the daily press that so many more people than formerly now die of
cancer; that science has not yet discovered the “cause of cancer”;
but that all may be well if only we live on Nebuchadnezzar food
washed down by paraffin.
Mr Wright’s essay, combining as it does a well-balanced and
sufficient statement of what is known, with the outline of a
constructive proposition that merits careful consideration, and at
least indicates to the public the kind of way in which relative safety
may be obtained under present conditions, seems one that is
eminently suitable for what may be called general reading. The
problem is fairly and lucidly presented: the resources of surgery are
quietly and reasonably demonstrated: and the advantages are
shown of exhibiting that kind of prudence which leads the business
man to seek auditing of his accounts and the sportsman to enquire
how his score stands. But some words may perhaps be added from
the standpoint of one who is a physician, and no surgeon.
 Cancer is a class name given to certain kinds of growths,
otherwise spoken of as tumours (or swellings) and ulcers, which are,
as we say, characterised by malignancy. A growth, tumour, or ulcer
which is not malignant is not called a cancer. By malignancy we
mean a tendency to spread, by local and direct extension (as
spreads a fire), or by convection, as when sparks fly from a
locomotive to a haystack. Malignant tumours or ulcers tend to recur
when removed, and, in the long run, to destroy life.
These general features are associated with certain microscopical
characters found in the tumours or ulcers, so that the nature of any
growth—whether malignant or otherwise—can be sometimes
determined by the surgeon or physician, and sometimes by the
pathologist or microscopist alone, but, as a rule, is most certainly
settled by the physician or surgeon acting in conjunction with the
microscopist. Yet, and this is important, not every cancer does
actually destroy life. Surgeons of the greatest experience, such as
the late Sir Alfred Pearce-Gould, have affirmed that undoubted
cancers do occasionally undergo spontaneous cure, or at least
arrest of growth, even in the absence of any treatment. Again, if
excision is practised early, and sufficiently extensively, recurrence
does not happen, in a certain proportion of cases. Finally, pain is no
necessary or inevitable concomitant of cancer. In many cases pain is
absent, or almost so; death may be due to mechanical
consequences entailed by the growth rather than to destruction of
any vital or sensitive part.
Now, medical men are in the habit of splitting up the group or class
of malignant growths (or “cancers”) into two subsidiary groups or
classes. One of these is named Sarcoma; the other Carcinoma.
Sarcoma is the name given to a group of malignant growths taking
origin in the structures and tissues developed from the “middle layer”
of the embryo: the growths themselves—sarcomata—partake the
nature of the tissues formed from this middle layer. The other group,
of carcinomata, consists of growths taking origin in, and partaking
the nature of one or other of the two remaining embryonic layers and
the structures developed from them.
These two layers form respectively:
 (1) The skin and related structures, and
(2) The lining of the tube passing through the body; its backwaters,
out-growths and appendages.
It is these two layers which, as Mr Wright so aptly remarks, are in
direct contact with the outer world. Now, while the carcinomata
(which constitute the class of cancers chiefly discussed in this book)
in general affect people who have passed the midpoint of life—those
for whom, as Rabelais says, it is midi passé—the sarcomata, which
are less common than the carcinomata, are rather more frequently,
yet not exclusively, found in young people; in those indeed, who
have not reached life’s apogee. It is important that these facts should
be borne in mind, for generalisations founded upon the study of
carcinomata alone cannot be necessarily true in respect of all
Cancer, unless the use of the term cancer be restricted to the class
technically known as carcinoma. To say that Cancer can be
prevented if constipation is avoided is clearly misleading, when we
remember that quite young children, nay, infants, may be the subject
of sarcoma; unless of course we define cancer, as some would do,
as the kind of growth that, ex hypothesi, is prevented when
constipation is avoided. It is confusion of this sort, bred by slovenly
expression out of loose thinking, that is in great part responsible for
the present bewilderment of the public.
Another fertile source of confusion is the obscurity that attends
both the popular and the professional use of the words “cause”,
“causation”, and the like. The public demands that “the” cause of
cancer be discovered, and is prepared to pay generously that this
discovery be made. Unfortunately neither the public, nor men of
science, care overmuch to discuss what they mean by cause and
causation. This is no place in which to trench upon a province
unsuccessfully explored by Locke, by Hume, and by Kant. Yet it is of
vital importance that all doctors, scientists, and laymen should
recognise two different uses of these words.
When we speak about “the” cause of a “disease”, in a generalised
or conceptual sense, as when we say that Koch’s bacillus is “the
cause of tuberculosis”, we are really defining our concept of the
disease in terms of one correlative. We are saying that tuberculosis
is a disease in which Koch’s bacillus is invariably present. A circulus
in definiendo is only just escaped because we happen to know that,
if Koch’s bacillus is injected into certain animals, the “disease” as we
say, develops. Koch’s bacillus is the one constant correlative found
in all cases of the kind that we agree to call tuberculous, by reason
of certain clinical and pathological signs that we find. Possibly even
this statement is not to be taken as absolutely true; though it
represents what we find it convenient to say. But, when we thus
declare Koch’s bacillus to be “the” cause of tuberculosis, we have by
no means exhausted the study of all the correlations that may be
called causal in respect of particular cases. Of ten cases of
tuberculosis, each one exhibiting Koch’s bacillus, we may say that
for each particular case “the” cause of the illness is different.
Thus:
A. is tuberculous because he was gassed in France;
B. is tuberculous because he was infected by his sick wife;
C. is tuberculous because he drank tuberculous milk;
D. is tuberculous because he worked in an ill-ventilated factory;
E. because he was exposed to wet and cold; and
F. because he drank and was dirty.
The difference between a medical cause in the generalised sense,
(where cause means a defining correlative for a concept), and a
medical cause in the particular sense (when we seek to find out or
state the antecedent without which this man would not be as he is
here and now) is one of enormous importance, and one that should
be constantly borne in mind when discussion is commenced. It is
true that it involves the oldest of logical and metaphysical problems
in respect of scientific thought—the question of universals and
particulars; but that does not make it any the more easily shirked. Its
relevance to the question of cancer is this: that the proof of the
production of cancer in men or in animals under one set of
circumstances does not warrant us in saying that that set of
circumstances as known to us involves all the factors without which
cancer cannot occur. And, even if research work demonstrated that,
in every case now called cancer, some parasite or growth-form,
some irritating factor that can be isolated, does actually obtain,
unless it could be shewn that this parasite or factor is never found
except where there is cancer as we now define it, we should have to
proceed to investigate why and how cancer does not always occur
when this factor is present. Just so are we at present seeking to
explain why and how, of so many persons exposed to infection by
Koch’s bacillus, only certain ones do become diseased. If we find
that only those persons who possess a character that we may call
“X” become infected, we shall then have to say that, not Koch’s
bacillus, but the character “X” is “the” cause of tuberculosis. It is thus
that science progresses: not by making the absolute and positive
discoveries that the public is taught to expect, but by arranging and
rearranging our experiential knowledge, as such grows, in terms of
so-called laws and generalisations, that are found progressively
convenient. But such laws and generalisations are not necessarily
the one more “true” than the other, except in relation to the
knowledge that they summarize. If such considerations as these
were more frequently borne in mind, there would be less
unconscious deception, less disappointment, and greater economy
in work and thought.
Explanations of the causation of cancer have been sought in many
directions; and three chief theories have been set out. The most
important, and the most interesting from the point of view of the
practising physician, is that which considers cancer as provoked by
long continued irritation under certain circumstances. This doctrine
seems more “true” in respect of the Carcinomata—the cancers of the
adult and the old, and of tissues in contact with the extra-personal
world—than it is in respect of the Sarcomata—the cancers of the
young, and of those inner parts not exposed to irritation by contact
with the world. Yet sarcomata in real life do often seem to follow
injury, and the tissues in which they form may be obnoxious to
injurious influences of which we know nothing.
Another view is that cancer may be due to a parasite of some kind
or another. Certainly, so far as some lower animals are concerned,
this is true, for certain rat and mice cancers are now known definitely
to be associated with parasites. But then we may say, and properly,
that in such cases the parasites are merely acting as do other
irritants, and are not “specific” causes of cancer.
The third doctrine, or set of doctrines, regards cancers as arising
when parts of the body (or rather, elements in the tissues of certain
parts) no longer act in due subordination to the needs of the whole
organism, but comport themselves “anti-socially”: developing
irregularly; propagating themselves illegitimately; and so becoming
parasitic to the commonwealth of the body. Those who hold this will
admit that, in many cases, this revolutionary tendency is one
provoked by irritation and the like: that sometimes it is a mere
manifestation of irregular decay; and that, when it occurs in young
subjects, it is because some islets of tissue have become misplaced,
tucked away, ill-formed, and hampered in development, and so liable
to provoke trouble later under stress of greater or less urgency. Such
a view has much plausibility; there are flaws in a steel girder; there
are tucked-in edges in even the best bound book, and there are
developmental errors in most of us.
Moreover, there is Dr Creighton’s doctrine of physiological
resistance. A part not put to its proper use is more apt than another
to become cancerous. Certainly, unmarried women are more liable
than are married to suffer cancer of the breast or ovary. Yet married
women are more apt than unmarried to suffer cancer of the womb.
Are we to say that in these latter there has been physiological
misuse, or irritation produced by unhealthy child-bearing? So far is
the problem removed from simplicity!
On the other hand, it is certainly as true as ever, that the gods still
cancel a sense misused, and, if we leave out of account for the
moment the cases in which cancer seems due to developmental
error—and who can say whether even then a child does not suffer
vicariously for some physiological transgression by its parents?—the
doctrine that cancer is due to irritation, whether produced by a clay
pipe, hot drinks, constipation, or crude paraffin, does not really tell us
much more than that. The difficulty is this: How to walk in the way of
physiological righteousness, and how to preach it, without falling into
a dogmatism as stupid as unbelief? Mr Wright tells us how, in
medieval times, the Church declared cancer of the tongue to be
sometimes a judgment on sinners for their blasphemy. Well, I for
one, am not prepared to limit the “misuse” that entails physical
disease and suffering to misuse in the material, or physiological
sense. Organs, through the nerves of the “sympathetic”, are directly
connected with the play of emotions and of feeling-states. I am not
sure that investigation would not shew a correlation—sometimes—
between certain persistent and voluntary mental states (morbid
mental states, that is) and the development of cancer in certain
organs. The “argument” that cancer is infrequent in lunatic asylums,
where the majority are mindless rather than wrongly thoughtful,
evades the question.
The quest for a single causal factor, whose “discovery” will lead us
to “abolish cancer”, is then, it would seem, just one more hunt for the
philosopher’s stone. Yet, to use the formula of “right living” does not
seem to be merely a verbal solution of the difficulty.
If we agree that to live rightly is the best insurance we can make
against cancer, we are probably stating, as compendiously as
possible, all we do and shall ever know, in respect of the causation
of cancer. It is then our duty to ascertain how to live rightly in every
sense of the word, and we may so come to realise that almost every
one of what we call the blessings of civilisation has been purchased
at the expense, in some respect, of right living. For this, heavy
interest has to be paid, and even the efforts of science to put matters
right seem too often not more than the borrowing of fresh capital to
pay off old debts. It is right to call attention to the fact that certain
“uncivilised” races, who live healthily and naturally in respect of food,
drink, and sexual activity, do not suffer from cancer. But it is wrong to
suggest that therefore we should adopt either their dietetic or their
sexual customs. What is one man’s meat is another man’s poison.
Adjustment to our surroundings, right living here and now is what we
need. Though Papuans and Sikhs may be very properly adjusted in
their contexts, it is not their adjustments that may best suit our
cases.
 This problem—that of right living—is the problem of prevention of
cancer put upon the broadest basis. But, until or unless we work this
out, we have to consider how best to avail ourselves of the
knowledge already in our possession. Herein is one merit of Mr
Wright’s plan. He tells people what, in his judgment, they can best
do, here and now. It is a plan to be discussed; but, let it be clearly
understood, it is one submitted by the author for individual
consideration and action. Supposing it to be found, on analysis and
trial, of real value, a cry might at once be raised for its putting into
execution by central or local provision of the necessary facilities: at
first for voluntary acceptance, then for compulsory adoption. Nothing
could be a greater error. In matters of health what is advantageous
for the individual is often not so, or even grossly disadvantageous,
for the State.
Let every member of the State have the opportunity to avail
himself or herself of what Science and Art can do for him: let none
who has the will suffer because he has not the means. But the too
easy provision of means for the avoidance of consequences of
neglect does, very seriously, put a premium on neglect and penalise
those who themselves make effort in the right direction. Again: hard
on individuals though it would seem, there is a very real racial
advantage in the elimination—natural and inevitable, unless we
interfere—of those who will not take advantage of opportunities
offered them. We are not automata: we exercise choice; when the
opportunity of choosing rightly is offered us, if then we choose
wrongly, we have no right to demand escape from the
consequences, at the expense of others.
At any rate, if the facts relating to Cancer are plainly stated, every
man has but himself to blame if he shrink from obtaining such
diagnosis and treatment, as is now available, at the earliest moment.
It were better still that he avoid from the beginning all what we know
to be predisposing causes of cancer: all the errors of omission and
commission in respect of the physiological and spiritual—or physical
and psychical—functions and relations of his Self.
It is the principle, the pursuit of the unattainable ideal, that really
counts. The simple injunction to eat greens and take paraffin is the
physiological counterpart of seeking to make people moral by act of
Parliament, religious by church-going, and intelligent by attendance
at evening lectures. But even if we make all possible effort, we
cannot all hope to escape, and the necessity for seeking early
diagnosis when things go not well is as imperative as is true the
maxim that “A stitch in time saves nine”.
There is perhaps one more question that may be touched upon:
that of the so-called increase of cancer. It is commonly stated that
cancer is increasing: it is as commonly asked if this is really so. As a
matter of fact, the question (which we are usually told can be only
answered by statisticians) is one that statisticians can only answer
when we have agreed what they are to understand by it. And that is
not so easy as may be at first thought.
It is certainly true that, in the British Isles, the number of deaths
certified each year as due to cancer of one form or another is
gradually and steadily increasing, both absolutely and relatively to
the population. But then we have in the first place, to consider
whether cancer is not diagnosed more frequently in ratio to the
cases seen than was formerly the case, and, in the second, to
remember that cancer is, on the whole, a disease suffered during the
second half of life. Now, our population is an older one than it was:
the birth-rate is falling: so many youths who would now be vigorous
men of thirty-five to forty lost their lives in the war; and lives are, on
the whole, longer than they were, owing to a diminishing liability to
suffer from certain ailments other than Cancer.
Supposing that children ceased to be born, at the same time that
the Ministry of Health succeeded in “abolishing” all diseases except
cancer, and the Home Office and Police reduced the probability of
death from accident, from homicide, and from suicide, to vanishing
point. Would we not then all die from either “old age” or from
“cancer”? If so; should we be justified in declaring that cancer had
“enormously increased” since the successful institution of control of
our own deaths and other peoples’ births?
We are, indeed, again confronted with the old problem of the one
and the many, under one of its numberless aspects. From the point