Published online: 2019-11-04

THIEME
138 Cancer Therapy:
Review Article A Brief Outline Kayal 

Cancer Therapy: A Brief Outline

Smita Kayal1

1 Department of Medical Oncology, Jawaharlal Institute of Address for correspondence Smita Kayal, MD, DM, Department
Postgraduate Medical Education and Research, Pondicherry, of Medical Oncology, Regional Cancer Centre, Jawaharlal Institute of
Puducherry, India Postgraduate Medical Education and Research, Dhanvantari Nagar,
Puducherry 605006, India (e-mail: kayalsmita@gmail.com).

Ann Natl Acad Med Sci (India) 2019;55:138–144

Abstract Modern cancer treatment has evolved over several years to reach the current era
of precision therapy. Exciting developments in all modalities of cancer treatment
and rapidly growing arena of translational research are contributing to the steady
improvement in clinical outcomes. Although several old and new challenges have to
Keywords be overcome, parallel technological advances in the tools and techniques of drug dis-
►►cancer covery has promise for future. An outline of the overall approach to cancer manage-
►►treatment ment and a broad perspective of multimodality treatment methods are discussed in
►►review this brief review.

Introduction with locoregional treatment modalities, like surgery and

radiotherapy. Also, depending on the stage and disease
History of modern cancer treatment dates back to about extent, systemic chemotherapy is added as adjunct to local
200 years, although cancer is as old as humankind or even treatment to prevent recurrences and thereby improve sur-
life.1-3 The incidence rate for all cancers in all age groups com- vival. Metastatic solid tumors and all hematological malig-
bined is progressively rising, from 182.3 per 100,000 in 2012 nancies are principally treated with systemic chemotherapy.
to 197.9 per 100,000 in 2018 globally. Nevertheless, mortal- Locoregional treatment with surgery or radiotherapy is also
ity rates overall have been marginally but steadily declining considered for certain metastatic solid tumors (e.g., germ cell
over the past few decades, from 102.4 per 100,000 in 2012 to tumor, colorectal cancer, renal cell carcinoma, pediatric solid
101.1 per 100,000 in 2018.4 GLOBOCAN 2018 estimated an tumors) and hematological malignancies (e.g., lymphomas
incidence of 18.1 million new cancer cases and 9.6 million with bulky or residual disease, plasmacytoma) as component
cancer deaths worldwide for 2018.4 Growing understand- of main treatment plan or for palliation. Other components of
ing of cancer biology, parallel advances in diagnosis and risk systemic therapy include hormone therapy, various targeted
stratification, improved cancer treatment modalities, new agents, monoclonal antibodies, and immunotherapy which
drug discoveries and better supportive care, and cooperative are used in the course of treatment of different solid and
group trials, all have resulted in significant rise of survival for hematological malignancies. Thus, treatment of cancer gen-
both childhood and adult cancers. In this very brief review erally requires multimodality approach which has to be tai-
on cancer therapy, we attempt to summarize the principles lored as per the cancer type, stage, and biology, and accord-
of cancer treatment and their application and challenges in ing to the patient’s clinical risk group and demographic
clinical practice for the beginners in oncology. characteristics. ►Fig. 1 summarizes the available modalities
and multimodal approach to cancer treatment.

Cancer Treatment Modalities Locoregional Therapy

Cancer is broadly divided into solid tumors and hemato- Earliest treatment of cancer in the 1800s for patients with
logical malignancies. The intent of cancer therapy may be localized tumor growths consisted of radical anatomical
curative or palliative depending on the disease and patient dissection based on Halstedian concepts of orderly contig-
characteristics. Solid tumors of different organs are gener- uous tumor spread and consideration of cancer as locore-
ally staged as localized, locoregional, or metastatic disease. gional disease autonomous of its host. In early 1900s, radio-
Localized and regional solid tumors are primarily treated therapy emerged as a modality of cancer cell kill through

DOI https://doi.org/ ©2019 National Academy of

10.1055/s-0039-3399406 Medical Sciences (India)
ISSN 0379-038X.
 Cancer Therapy: A Brief Outline Kayal 139

Fig. 1 Cancer treatment modalities: Locoregional treatment modalities such as surgery and radiotherapy are used to treat early stage solid
tumors. Systemic therapy such as cytotoxic chemotherapy, hormone therapy, targeted drugs, and immunotherapy are used alone or in differ-
ent combinations to treat hematological malignancies, as adjunct therapy for early or locally advanced solid tumors and as palliative therapy
for metastatic solid tumors. Hematopoietic stem cell transplant is used for various indications in the treatment of hematological malignancies.
Advances in supportive care have supplemented the administration of all these intense treatment modalities.

ionizing radiation that disrupts various pathways of cell and translational cancer research. ►Fig. 2 summarizes the
cycle.5 Radiotherapy thus provided an alternative or adjunct major classes of cytotoxic drugs and targeted agents. Addi-
modality of locoregional treatment for various solid tumors. tionally, several supportive care drugs used to treat various
In the past two to three decades, significant technological side effects of cancer therapy as nausea and vomiting, myelo-
advances in the conduct of surgery (e.g., endoscopic surgery, suppression, febrile neutropenia, gastrointestinal toxicities,
laparoscopic surgery, robotic surgery) and delivery of radio- neuropathy, and others have developed in parallel, allowing
therapy (e.g., intensity-modulated radiotherapy, volumet- for timely and adequate delivery of intensive treatment pro-
ric modulated arc therapy, stereotactic body radiotherapy) tocols. Systemic chemotherapy is administered as cycles or
have led to more precision in locoregional treatment, more periodic courses, with interval between two doses of an aver-
organ preservation methods, and reduced morbidity. Parallel age 3 to 4 weeks, to allow adequate time for normal cells to
advances in reconstructive surgeries and various rehabili- recover from collateral cytotoxicity.
tation procedures have improved quality of life for patients Combination therapy with enterally or parenterally
with early stage solid tumors. administered cytotoxic drugs with different mechanisms
of action and differing dose limiting toxicities forms
Systemic Therapy the mainstay of treatment of hematological malignan-
Systemic anticancer treatment started with the discovery of cies. Optimization of drug dose, regimen, and schedule
cytotoxic chemotherapy in the late 1940s, the first few drugs over decades through conduct of cooperative group tri-
being nitrogen mustard compounds and antifolates used in als have led to significant cure rates in acute leukemias
the treatment of leukemias and lymphomas. Since then, from and lymphomas and prolonged progression-free survival
1949 to 2014, a total of 150 medicines has been approved in myeloma. Novel cytotoxic drugs, targeted agents, and
including cytotoxic drugs and targeted agents with an indi- monoclonal antibodies are used either as single agent
cation for at least one type of cancer.6 Most of the cytotoxic or in combination for treatment of relapsed/refractory
drugs are alkylating agents, antimicrotubule agents, anti- ­diseases and for particular indications have moved to the
metabolites, and topoisomerase inhibitors which work in first line therapy (e.g., rituximab in B cell lymphomas). A
different phases of cell cycle, while most of the targeted few targeted agents have changed the treatment paradigm
drugs belong to signal transduction inhibitors, gene expres- of some diseases, for example, imatinib, a tyrosine kinase
sion modulators, apoptosis inducers, hormone therapies, inhibitor targeting BCR-ABL, introduced in 2001 in the
angiogenesis inhibitors, immune modulators, and monoclo- treatment of chronic myeloid leukemia have o ­ bviated the
nal antibodies which targets one or more of the hallmarks of need for upfront allogeneic stem cell transplant in this dis-
cancer pathogenesis. In the past 5 years from 2015 to 2019, ease. Similarly, all-trans-retinoic acid and arsenic trioxide
approximately 60 new anticancer medicines, latest being the targeting and releasing the differentiation block in acute
immunotherapy group of drugs, have been approved and promyelocytic leukemia caused by the PML-RARA trans-
several older drugs are being approved for newer indications, location have resulted in cure rates of 80 to 90% with a
underscoring the steadily escalating efforts in drug discovery ­chemotherapy-free protocol.

Annals of the National Academy of Medical Sciences (India) Vol. 55 No. 3/2019
140 Cancer Therapy: A Brief Outline Kayal

Fig. 2 (A) Cytotoxic class of drugs acting on different phases of cell cycles. (B) Table illustrating the major classes and components of cyto-
toxic chemotherapy. (C) Simplified illustration of families of targeted agents and their respective subcellular targets in the cell, nucleus, and
microenvironment.

In solid tumors, the evolving concept of operable can- antibodies, and immunotherapy, several sequential lines
cer being systemic disease with potential for dissemination of treatment can be administered safely even for advanced
through lymphatics and blood stream even in early stages diseases with resultant improvement in clinical outcomes
and recognition of complex host–tumor interrelationship for many of the common malignancies such as breast, pros-
affecting disease biology, which were contrary to the old tate, lung, and colorectal cancers. Yet, treatment intent still
Halstedian principles, led to the experiments for adjuvant remains palliative and not curative in majority of metastatic
systemic therapy in the treatment of localized disease. These solid tumors, nevertheless, provides better quality of life and
experiments of systemic therapy as adjunct to surgery led considerable prolongation of survival.
by Fisher and colleagues in the 1970s, concluded that two
paradigms govern the management of cancer, first is relat-
Multimodality Approach
ed to the use of surgery to eradicate local and regional dis-
ease; the second is related to the eradication of systemic Multidrug, multiphase combination chemotherapy reg-
disease (micrometastases).7 The treatment of patients who imens comprising of cytotoxic drugs, targeted agents,
has no identifiable metastatic disease with systemic adjuvant monoclonal antibodies, etc. in defined schedule forms the
therapy (after surgery) or neoadjuvant therapy (before sur- basis of treatment of hematological cancers. Radiothera-
gery) with either hormonal agents (e.g., tamoxifen in breast py is generally given for bulky or residual disease sites in
­cancer), targeted or cytotoxic chemotherapy, or both have lymphoma, for prophylactic or therapeutic cranial irradia-
resulted in decreased local and regional recurrences as well tion in leukemias, and as single modality radical treatment
as distant metastases after minimal conservative surgery and for plasmacytoma. ►Table 1 shows an outline of some of
have improved survival in patients of various solid tumors to the most widely used treatment protocols for some com-
the tune of 4 to 15% absolute benefit at different stages. mon hematological malignancies. Hematopoietic stem cell
Chemotherapy, along with locoregional therapy, is also an transplant (HSCT) either autologous or allogeneic is used
integral component of curative treatment of certain meta- for consolidation treatment as part of frontline therapy in
static solid tumors such as germ cell tumors, choriocarcino- certain high-risk hematological malignancies, for example,
ma, and neuroblastoma, which are highly chemo-sensitive. multiple myeloma (autologous HSCT), Philadelphia pos-
For most of the other solid tumors with advanced and met- itive acute lymphoblastic leukemia in adults (allogeneic
astatic disease, systemic chemotherapy and targeted agents HSCT), intermediate and high-risk acute myeloid leukemia
are used for palliative treatment. However, with the advent (allogeneic HSCT), and for salvage treatment of refractory/
of combination chemotherapy, targeted agents, monoclonal relapsed hematological cancers.

Annals of the National Academy of Medical Sciences (India) Vol. 55 No. 3/2019
 Cancer Therapy: A Brief Outline Kayal 141

Table 1 Common chemotherapy regimens used in hematological multidisciplinary tumor board consisting of surgeons, anes-
malignancies thetist, radiation oncologist, and medical oncology experts.
Further, the multidisciplinary team should also consist of
Disease Common chemotherapy regimens
nutritionist, physiotherapist, speech therapist, palliative care
Hodgkin’s ABVD (adriamycin, bleomycin, physicians, infection disease expert, psychosocial counsel-
lymphoma vinblastine, dacarbazine)
ors, and other specialists (endocrinologist, cardiologist, etc.,
Non-Hodgkin’s CHOP ± R (cyclophosphamide, doxorubicin, depending on the age, cancer, and treatment type) for guid-
lymphoma vincristine, prednisone) / Rituximab
ing supportive care during the course of treatment, rehabil-
Multiple VRD (bortezomib, lenalidomide, itation posttreatment, and for monitoring and management
myeloma dexamethasone)
of late side effects.
Acute myeloid 3+7 (daunorubicin and cytarabine) In metastatic solid tumors, for most of the common
leukemia malignancies of lung, breast, prostate, colorectal, renal,
Acute ATRA + ATO (all-trans-retinoic acid, ovary, etc., a multitude of treatment options are now avail-
promyelocytic arsenic trioxide) able for the first line and subsequent lines of therapy that
leukemia
have resulted in a significant increase in overall survival, up
Acute lym- Intensive multiagent chemotherapy (steroid, to 12 to 18 months on average over historical outcomes, in
phoblastic 6-MP, vincristine, daunorubicin L-asparagi-
particular patient subsets in these cancer subtypes. These
leukemia nase, cytarabine, cyclophosphamide, high
dose methotrexate) in induction and consol- treatment options include besides conventional cytotoxic
idation phase followed by maintenance with chemotherapy, targeted therapy related to the specific driver
6-MP and methotrexate genomic alteration, hormonal therapy for hormonally driv-
Chronic BR (bendamustine, rituximab) en cancers, drugs targeting the angiogenesis pathway and
lymphocytic tumor microenvironment, and immunotherapy targeting
leukemia the immune checkpoints involved in tumor cell to immune
Chronic Imatinib (BCR–ABL tyrosine kinase cell interactions. ►Table 2 outlines the common therapies
myeloid inhibitor) currently available for metastatic castrate-resistant pros-
leukemia tate cancer which can be ordered in numerous schedules for
sequential use. Current challenge in management of these
In solid tumors, depending on the stage, all the three metastatic solid tumors is in optimizing the right combina-
main modalities—surgery, radiotherapy, and chemothera- tion and sequencing of treatment. Another important clini-
py—are used in the frontline treatment. Further, hormonal cal challenge is in evaluating cost effectiveness of the newer
therapy, targeted agents are added to the protocol in certain drugs for palliative treatment and in identifying futility of
tumors depending on the biological characteristics and risk further treatment or when to stop further treatment for
group. We will discuss two tumors—breast carcinoma and patients with poor general condition and progressive disease.
neuroblastoma (common childhood tumor)—as prototype Other aspects of cancer care such as prevention, screen-
for multimodality treatment plan. ►Fig. 3 highlights the ing, early diagnosis, toxicity management, and rehabilitation
usual treatment modalities and course for breast carcinoma are important areas, but are beyond the scope of the current
and neuroblastoma. For stage II/III breast carcinoma, gen- review. Discussing the details on each cancer modality and
eral course of treatment includes neoadjuvant combination drug, and treatment for individual cancers, is also outside
chemotherapy (mainly with anthracyclines and taxanes) the space of this brief summary. Many comprehensive inter-
followed by surgery (either breast conservation or mastecto- national guidelines are available that summarizes the treat-
my depending on the baseline stage) and followed by radio- ment approach and algorithm for management of all com-
therapy (depending on type of surgery and baseline stage). mon malignancies and serve as useful resource.8,9 Finally, in
Hormonal therapy for a duration of 5 to 10 years is added clinical practice, treatment decisions require the expertise
for patients with estrogen or progesterone receptor positive and experience of the oncology team.
tumors and anti-Her 2 therapy (monoclonal antibody direct-
ed at the epidermal growth factor receptor Her 2) for Her
2 positive tumors. For a subset of very early stage, hormone
Treatment Adaptation: Based on Prognostic
receptor positive, Her 2 negative tumors, with low recur-
and Predictive Biomarkers
rence score by molecular tests treatment can be done by only Prognostic factor is defined as measurement taken at the
surgery followed by hormonal therapy without the need for time of diagnosis or treatment that is associated with the out-
radio- or chemotherapy. In high-risk metastatic neuroblas- come, determining a patient’s ability to fare in the absence of
toma, treatment is done with all modalities as combination treatment, for example, age of the patient, stage determined
chemotherapy, surgery, autologous HSCT, radiotherapy, and by tumor size, nodal involvement and distant spread, grade,
posttransplant maintenance treatment with differentiation cytogenetic or molecular profile, etc. Often a combination of
agent (isotretinoin) and immune modulators (anti-GD2 anti- clinical pathological and genetic changes are taken together
body and interleukin-2). Thus, majority of the malignan- to determine risk groups and based on the individual risk
cies require a multimodality treatment approach for cura- group treatment can be tailored—either intensified for
tive outcomes. Treatment decisions are generally taken in a high-risk group patients or de-intensified for low risk.

Annals of the National Academy of Medical Sciences (India) Vol. 55 No. 3/2019
142 Cancer Therapy: A Brief Outline Kayal

Fig. 3 Multimodality treatment approach for solid tumors, two prototype examples: (A) Breast carcinoma, depending on the clinical and
pathological factors, locoregional and systemic treatment are used to different extent and combination. (B) Neuroblastoma, for high-risk
patients all treatment modalities of combination chemotherapy, surgery, radiotherapy, autologous stem cell transplant, immunotherapy, and
differentiation agent are used in sequence.

Table 2 Treatment options for metastatic castrate resistant prostate cancer: clinical conundrum
Drug (chemotherapy, First line options Second line Third line Third line: Beyond and novel
hormonal therapy, options options agents
immunotherapy, radio-ligand
therapy)
Abiraterone Sipuleucel-T Abiraterone Cabazitaxel 177
Lu-PSMA therapy
Enzalutamide Pembrolizumab
Docetaxel Abiraterone Sipuleucel-T Radium 223 PARP (poly ADP ribose poly-
merase) inhibitors
Cabazitaxel VEGF inhibitors
Sipuleucel-T Enzalutamide Docetaxel Enzalutamide Src inhibitors
Radium 223 HSP90 inhibitors
177
Lu-PSMA therapy Docetaxel Enzalutamide Abiraterone AKT inhibitors
Pembrolizumab (for MSI high PI3 kinase inhibitors
tumors) Radium 223 MTOR inhibitors

Predictive factor is a measurement that predicts response either in the tumor genome or in germline deoxyribonucleic
or lack of response to a specific treatment. Some common acid involving the drug metabolizing pathways are known
examples include epidermal growth factor receptor (EGFR) that can affect responses to particular drugs.10,11 A plethora of
mutation in lung cancer that determines response to EGFR biomarkers have been studied in different diseases but clin-
inhibitor like gefitinib, Her2/neu amplification in breast ical utility has been established only for a handful of them.
cancer that determines response to anti-Her2 therapy like With growing understanding of cancer biology and disease
trastuzumab or lapatinib, and K-RAS/N-RAS mutations in pathogenesis, molecular classification is evolving for all can-
colorectal cancer which are a negative predictive factor for cer types which when clinically validated will help in further
response to EGFR monoclonal antibody such as cetuximab. prognostication and identification of predictive markers and
Several other biomarkers (mutations or polymorphism) thereby in personalizing cancer treatment.

Annals of the National Academy of Medical Sciences (India) Vol. 55 No. 3/2019
 Cancer Therapy: A Brief Outline Kayal 143

Clinical Endpoints Some of the additional challenges pertaining to

Treatment results in oncology are generally defined by resource-limited settings in the Indian context are wide
response rates, disease-free remission, morbidity or late disparity in the access to cancer treatment, delayed pre-
sequel of treatment, quality of life, and survival. In oth- sentation with higher disease burden, heterogeneity in
er words, a clinically relevant endpoint is a characteristic resources, available expertise and treatment cost and pay-
that reflects how a patient feels, functions, or survives. In ment structure across centers, poor social support system,
cancer patients, the risk for death from a specific neoplasm significant financial constraints as most of the treatment
is highest in the initial years after diagnosis; it decreases expenses are met out of pocket, poor understanding of the
progressively thereafter. To apply the word “cured,” the disease and its treatment course and consequently higher
time from the cancer diagnosis must be such that the treatment abandonment rates, restrictive access, nonavail-
patient’s risk of death does not, because of cancer, exceed ability or prohibitive cost of the latest anticancer drugs,
that of a sex- and age-matched general population.12,13 and very low rates of recruitment into well-designed clin-
However, in oncology, use of word “cure” is debatable in ical trials.
view of late and very late relapses in certain malignancies Besides development of newer generations of older
and the more commonly used terminology is long-term targeted agents, discovery of new drugs targeting single
survivor. For some of the early stage and good risk malig- molecular abnormality or pathway, and the expanding
nancies, for example, testicular germ cell tumor, thyroid field of immune checkpoint inhibitors, the following novel
cancer, Hodgkin’s lymphoma, childhood acute lympho- approaches to cancer treatment which have already been
blastic leukemia, and gestational trophoblastic neoplasm, studied in early phase clinical trials are making headway
5- and 10-year disease-free survival (that is the period into mainstream therapy. These include cellular immune
the disease remains in continuous clinical remission and therapy such as CAR-T cell (chimeric antigen receptor) ther-
without any recurrence) is close to 85 to 90% which may apy, anticancer vaccines, and new therapeutic approaches
be taken as functional “cure.” For other tumors, available based on genomic editing.15 Also, so far the approach to
treatment modalities have prolonged survival with a fairly cancer treatment had been reductionist, which is target-
better quality of life making many cancers a chronic dis- ing single molecular abnormality or cancer pathway that
ease. Ongoing translational research in cancer biology and have modestly improved outcomes, but to move toward
treatment may further help to improve their outcomes. potential cure, systems biology or multipronged approach
targeting several driver molecular pathways or cancer
hallmarks of etiopathogenesis simultaneously might be
Challenges and Future of Cancer Treatment
a promising therapeutic strategy.14 As mentioned above,
Cancer therapy is a continuously evolving field and every challenge for this approach is in optimizing the right com-
year there is considerable upsurge in new drug discovery bination or sequence, and in finding valid biomarkers;
and approvals, in drug repurposing and approval of newer however, with better comprehension of next-generation
indications for older drugs, in newer methods of drug precision oncology tools and data this should be attainable
delivery and optimized management of toxicities, in dis- in the near future. Further, to find answer to locally rele-
covery of new predictive biomarkers and new treatment vant clinical problems in the Indian context, well-designed
approaches, and also in technological advances in locore- clinical trials through multicenter collaboration at the
gional treatment modalities of surgery and radiotherapy. regional or national level is a pressing need that would be
However, there remain several challenges in the path to vital to improve outcomes close to that seen in the western
translational of all these new developments in practice of developed world.
real precision medicine and into clinically meaningful ben-
efit in cancer survival. Some of the important challenges
Conclusion
are dealing with tumor heterogeneity, handling drug
resistance either due to pharmacogenomics differences In this concise review, we have attempted to outline the
in drug metabolism and transport or more commonly due major modalities of treatment in oncology, their evolution
to acquired mutations/alterations in cancer genome or its in brief, recent advances and challenges, and multimodality
downstream pathway, finding of actionable alterations in approach to cancer management in clinical practice with
the tumor tissue or its microenvironment (currently drug- some common examples. Overall, treatment has to be evi-
gable genomic alterations represent only a small subset in dence- and value-based, cost effective, and guided by local
certain cancer types), and identification and validation of problems, expertise, and resources. We hope this would be
predictive markers of immune therapy. Also, the discon- a useful summary on cancer therapy for a new induct into
certing background of genomic variability creates issues oncology or for anybody who is keen on understanding the
regarding clinical interpretation, application, and vali- basic principles of cancer treatment, and encourage them to
dation of enormous and complex genomic data. Another read and explore further and contribute their bit to cancer
practical challenge is in finding the optimal combination management.
regimen, targeting several molecular alterations concur-
rently or in precise sequence, and validating them in clini- Conflict of Interest
cal trials for demonstrating final benefit in survival.14 None declared.

Annals of the National Academy of Medical Sciences (India) Vol. 55 No. 3/2019
144 Cancer Therapy: A Brief Outline Kayal

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