VOLUME 34 • NUMBER 1 • JANUARY 1, 2016

JOURNAL OF CLINICAL ONCOLOGY R E V I E W A R T I C L E

Proposing Essential Medicines to Treat Cancer:

Methodologies, Processes, and Outcomes
Lawrence N. Shulman, Claire M. Wagner, Ronald Barr, Gilberto Lopes, Giuseppe Longo, Jane Robertson,
Gilles Forte, Julie Torode, and Nicola Magrini

Lawrence N. Shulman and Claire M.

Wagner, Dana-Farber Cancer Institute; A B S T R A C T
Lawrence N. Shulman, Partners In
Health, Boston, MA; Claire M. Wagner Purpose
and Julie Torode, Union for International A great proportion of the world’s cancer burden resides in low- and middle-income countries
Cancer Control; Jane Robertson, Gilles where cancer care infrastructure is often weak or absent. Although treatment of cancer is
Forte, and Nicola Magrini, World Health
multidisciplinary, involving surgery, radiation, systemic therapies, pathology, radiology, and other
Organization, Geneva, Switzerland;
Ronald Barr, McMaster University,
specialties, selection of medicines that have impact and are affordable has been particularly
Hamilton, Ontario, Canada; Gilberto challenging in resource-constrained settings. In 2014, at the invitation of the WHO, the Union for
Lopes, Centro Paulista de Oncologia e International Cancer Control convened experts to develop an approach to propose essential cancer
Hcor Onco, São Paulo, Brazil; Gilberto medicines to be included in the WHO Model Essential Medicines Lists (EML) for Adults and for
Lopes, Johns Hopkins University,
Baltimore, MD; and Giuseppe Longo,
Children, as well as a resulting new list of cancer medicines.
Azienda Ospedaliero-Universitaria Methods
Policlinico di Modena, Modena, Italy. Experts identified 29 cancer types with potential for maximal treatment impact, on the basis of
Published online ahead of print at incidence and benefit of systemic therapies. More than 90 oncology experts from all continents
www.jco.org on November 17, 2015. drafted and reviewed disease-based documents outlining epidemiology, diagnostic needs, treat-
Supported by the Center for Global Health ment options, and benefits and toxicities.
of the National Cancer Institute, National
Institutes of Health. Results
Briefing documents were created for each disease, along with associated standard treatment
Authors’ disclosures of potential conflicts
of interest are found in the article online at
regimens, resulting in a list of 52 cancer medicines. A comprehensive application was submitted as a
www.jco.org. Author contributions are revision to the existing cancer medicines on the WHO Model Lists. In May 2015, the WHO
found at the end of this article. announced the addition of 16 medicines to the Adult EML and nine medicines to the Children’s EML.
Corresponding author: Lawrence N. Conclusion
Shulman, MD, Center for Global Cancer
The list of medications proposed, and the ability to link each recommended medicine to specific
Medicine, Abramson Cancer Center
University of Pennsylvania, 3400 Civic
diseases, should allow public officials to apply resources most effectively in developing and sup-
Center Blvd, Philadelphia, PA 19104; porting nascent or growing cancer treatment programs.
e-mail: [email protected].
edu.
J Clin Oncol 34:69-75. © 2015 by American Society of Clinical Oncology
© 2015 by American Society of Clinical
Oncology surgery, medical oncology, nursing oncology,
INTRODUCTION
0732-183X/16/3401w-69w/$20.00 radiology, and radiation oncology are all neces-
DOI: 10.1200/JCO.2015.61.8736
sary for optimal treatment. The public sector in
It is now well documented and widely recognized all countries must develop and nurture all of these
that the majority of the world’s cancer patients disciplines to best support cancer care at the same
reside in countries where options for treatment are time as they establish mechanisms for financing
limited, are sometimes only affordable by the and resource procurement. Each of these layers
wealthy, or do not exist at all.1,2 Substantial gains of service delivery is elaborate, and, although
have been made over the past four decades in more research is needed, there are a number
improving outcomes for patients with cancer, but of important articles delineating the process
these largely benefit patients living in high-income of overcoming such challenges in resource-
countries. An improved understanding of the constrained settings.6-14
biology of cancer that accompanies advances in When making decisions about establishing or
cancer surgery, radiation therapy, and systemic strengthening a national cancer program, policy
therapies has been responsible for this progress.3-5 makers must have knowledge of the number of
The creation of a cancer treatment program patients with each disease seen in their country and
is complex and multidisciplinary by nature. which types of cancer can be affected. This analysis
Tissue procurement, pathology capacity, cancer can be time consuming, and a disease-based

© 2015 by American Society of Clinical Oncology 69

 Shulman et al

decision-making platform is one way that countries have prioritized

Table 1. Diseases Included in the UICC Review and Proposal
medicines for procurement when resources are limited. Nonetheless,
among the many cancer medicines that have been developed over Type of Cancer
the years, there is wide variation in availability and access—a Adult Pediatric
variation that that carries its own implications and one that often Acute myelogenous leukemia and acute Acute lymphoblastic
follows the fault lines of cost rather than efficacy. promyelocytic leukemia (adult and leukemia
pediatric)
Many have begun calling for the narrowing of the gap between Chronic lymphocytic leukemia Burkitt’s lymphoma
the haves and the have-nots in global cancer medicine.15-23 Indeed, a Chronic myelogenous leukemia (adult and Ewing sarcoma
major development in this area recently was the invitation by the pediatric)
Diffuse large B-cell lymphoma Hodgkin lymphoma
WHO to the Union for International Cancer Control to review the Early-stage breast cancer Osteosarcoma
WHO Model List of Essential Medicines (EML), section 8.2, which Early-stage cervical cancer Retinoblastoma
recommends chemotherapeutic and hormonal agents for cancer Early-stage colon cancer Rhabdomyosarcoma
treatment. The result of this review has been two-fold: an application Early-stage rectal cancer Wilms tumor
Epithelial ovarian cancer
to the WHO Essential Medicines Secretariat in December 2014 as well Follicular lymphoma
as a proposed methodology for regular revisions over time. GI stromal tumor
The overarching objectives of this exercise were not only to Gestational trophoblastic neoplasia
develop a comprehensive proposal, but also to describe and document Locally advanced squamous carcinoma of the
head and neck
guiding principles for the prioritization of systemic therapies that Hodgkin lymphoma
are most essential for cancer treatment. This article is not meant Kaposi’s sarcoma
to diminish the importance of other components of cancer Metastatic breast cancer
Metastatic colorectal cancer
care—pathology, surgery, or radiation—but rather will focus on Metastatic prostate cancer
cancer medicines as one component of care. Similar analyses for Nasopharyngeal carcinoma
the other aspects of cancer care would be highly complementary. Non–small-cell lung cancer
Ovarian germ cell tumors (adult and pediatric)
Testicular germ cell tumors (adult and pediatric)
METHODS
Abbreviations: UICC, Union for International Cancer Control.

In January 2014, in response to the WHO invitation, the Union for

International Cancer Control convened a group of oncology experts to
review the existing pediatric and adult EMLs.24,25 Although more infor-
mation can be found on the WHO Web site and in the literature cited,26,27 Traditionally, pediatric cancers have been considered separately from
it is relevant to note here that applications for revisions to the Model List adult cancers in the WHO application process. Furthermore, disease-based
are accepted every 2 years (usually by agent, not by disease or disease recommendations already exist within the WHO for some childhood cancers.
category) and are deliberated on by a panel of invited experts in April of the Thus, for the pediatric cancers that were considered to be a high burden and/
given year. Full reviews of the cancer medicines on the WHO Model List or highly responsive to therapy, recommendations were made for revisions to
were conducted in 1984,28 1994,29 and, most recently, in 1999.30 the existing WHO Model List for Children and for additions to the Model
This review was part of the regular cycle of applications to the WHO List. Adult and pediatric diseases that were addressed are listed in Table 1.
Expert Committee. Between January 2014 and December 2014, more than 90 Incidence of disease is a major contributor to public health relevance,
individuals from all regions of the world contributed to the development of the together with other factors, such as age at diagnosis, cure rates, and potential
29 disease-based applications.31 A working group of expert clinicians from for long-term remission. The data presented in these sections are
around the world met at the WHO 1 month before submission to finalize the derived from global estimates and are not country specific. Incidence of
applications and identify the proposed medicines. As of the submission of this disease and age distribution is likely to vary geographically. Useful data
manuscript, the comprehensive proposal was under review by the WHO Expert sources include the International Agency for Research on Cancer, which
Committee for deliberation in April 2015, with publication of decisions planned maintains the GLOBOCAN database and includes national and regional
for the following month. data and projections.18 In addition, the Institute for Health Metrics and
Evaluation hosts a similar cancer data set: the Global Burden of Disease
Study.36 Although these repositories are a vital step toward our under-
Choice of Diseases to Address standing of cancer burden worldwide, it remains optimal for policy makers
An initial series of in-person and telephone meetings defined which types
to use national data, because regional projections may not be wholly
of cancer should be addressed. Choices were based on a combination of disease
reflective of cancer incidence or age distribution in a given country.
burden (ie, incidence and prevalence) and the potential impact of systemic
therapy (ie, medicines), mostly driven by impact rather than by disease burden.
Breast cancer is an example of a disease with a high incidence and a high Process for Development and Completion of the
potential impact of systemic therapies. In wealthy countries, more than 80% of Disease-Based Documents
patients with breast cancer are long-term survivors.32 Yet, estimates identify More than 90 oncology specialists from all continents participated in
breast cancer as the leading cause of cancer death in women worldwide, which the preparation of the disease-based documents. They were chosen on
burdens health systems already strapped by minimal resources.33 Non–small- the basis of their areas of expertise and on geographic location, to gather
cell lung cancer (NSCLC), conversely, is a high-incidence disease but one for a diversity of perspectives. A medical or pediatric oncologist who had
which systemic therapy has a much more modest impact on survival, so it is specialized knowledge of the disease was engaged to produce the first
included on the basis of disease burden.34 Chronic myeloid leukemia (CML) is draft of each disease-based document. He or she was asked to complete
a rare disease but one for which oral therapy dramatically affects survival, so it specific sections (Table 2) and could write these sections alone or
is included on the basis of the impact of systemic therapy.35 Diseases that were recruit colleagues to help. Other consultants completed additional
excluded from the analysis were based on low incidence, the lack of substantial sections and documents (also in Table 2). A central team worked
impact of systemic therapies, or both. on collating information to put the documents into a consistent

70 © 2015 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

 Proposing Essential Medicines to Treat Cancer

the following: whether there was potential for long-term remission;

Table 2. Disease-Based Documents whether the benefit was greater than a baseline benefit from surgery, as is
Section Writer the case with localized breast or colorectal cancer, versus a benefit entirely
from systemic agents, such as with lymphomas; and the requirement or
Executive summary Lead author(s)
Public health relevance Staff
not of sophisticated pathology testing, such as genomic mutation
Requirements for diagnosis, treatment, and monitoring Lead author(s) analyses. The following hypothetical scenarios serve as examples of these
Overview of regimens Lead author(s) different categories.
Review of benefits and harms (including systematic Lead author(s) Large magnitude of treatment impact with medicines alone in a low- to
reviews) and staff moderate-incidence disease. Diffuse large B-cell lymphoma is a disease that
Recommendations Lead author(s) is highly curable with medicines alone. Surgery offers no chance for cure
Additions proposed for section 8.2 of EML Lead author(s) (though biopsy is necessary to establish a diagnosis). Four old, relatively
Supplementary documents inexpensive medicines (ie, cyclophosphamide, doxorubicin, vincristine,
Medicine prices from MSH price indicator guide (2014) Staff
and prednisone [CHOP]), however, can cure approximately 55% of
Costing scenarios Staff
Regulatory information for recommended medicines Staff
patients.37 This represents an increase in the cure rate from 0% to 55%
Patent status for recommended medicines Staff with CHOP alone. A newer biologic agent, the humanized monoclonal
Granulocyte colony-stimulating factor Lead author(s) antibody rituximab, when added to CHOP, will increase the cure rate from
and staff 55% to greater than 70%.22 Thus, rituximab increases the cure rate more
than 15% from the cure rate of CHOP alone. Rituximab is much more
Abbreviations: EML, Model List of Essential Medicines; MSH, Management
Sciences for Health.
costly than the four chemotherapy agents in CHOP and is more difficult to
administer, so the improved cure rate comes with these costs. Our costing
scenarios revealed that the cost of medicines in the CHOP with rituximab
regimen are 30 times more expensive than CHOP, not including the
additional costs related to administration of the agent (approximately $200
format. Each disease-based document was then reviewed by at least two v $6,000 USD for six cycles of therapy).
additional disease specialists. On receiving each reviewed document, the central Clinically relevant magnitude in cure rate with systemic therapy over
team synthesized the views of the different reviewers and created a consensus surgery alone in a high-incidence disease. Early-stage breast cancer has a high
document. All disease-based documents were then, again, fully reviewed, cure rate in the developed world. Surgery is required for cure or long-term
evaluated, and discussed at an in-person meeting at the WHO headquarters in remission, with removal of the breast tumor and involved axillary lymph
Geneva, Switzerland, in November 2014. Final documents were produced and nodes. Without surgery, the chance for long-term remission is nil. A patient
submitted to the WHO in December 2014. The timeline for the work is shown with stage II, estrogen receptor–positive, HER2-negative disease may have a cure
in Table 3. It is important to note that there was enormous generosity and rate of 70% with surgery alone (depending on the specifics of stage and biologic
support by authors and reviewers, who received no compensation for the characteristics). Additional treatment with tamoxifen might increase the cure
many hours devoted to this endeavor, which we believe reflects the rate from 70% to 85%, therefore giving an incremental benefit of a 15% chance
groundswell of interest and commitment to global cancer medicine.16 for cure versus surgery alone. The addition of chemotherapy to tamoxifen might
increase the cure rate from 85% to 89%.38,39 Because this is a high-burden
Methodology to Evaluate Potential Impact of disease in all parts of the world, the absolute number of saved lives with the
Systemic Agents addition of tamoxifen and chemotherapy would be substantial. Although
The value of systemic agents was assessed by reviewing treatment out- not relevant to the recommendation for chemotherapy and tamoxifen, it is
comes, including all therapeutic options—radiation, surgery, and regimens of important to note that the medicines used to treat a woman with this disease
systemic agents—and determining the relative contribution of single systemic profile could cost as little as $300 for the entire course of chemotherapy and 5
agents and/or multidrug regimens in this context. Factors considered included years of tamoxifen.

Table 3. Timeline for Cancer Medicines Review

Date Process or Event
January-May 2014 Methodology and process determined by core group from the Dana-Farber Cancer Institute and UICC.
May 31, 2014 UICC held planning meeting with core group plus new contributors at the Annual Meeting of the American Society of
Clinical Oncology in Chicago, IL.
June-August 2014 A total of 22 adult cancers (including adult and pediatric cancers) as well as seven pediatric-specific cancers were included
in the 2014 review process. Authors and reviewers were identified for solicitation of disease-based briefings.
September-October Invited authors from all over the world prepared and submitted disease-based briefings (including regimens) for the adult
2014 and pediatric cancers.
October-November 2014 Peer reviewers from all over the world reviewed briefings, including the treatment regimens.
November 2014 Dana-Farber Cancer Institute and UICC group compiled final drafts of briefings and prepared supplementary documents
(eg, regulatory information, costing and price information, patent status, G-CSF briefing).
November 17-19, 2014 Cancer Medicines Working Group meeting held in Geneva, Switzerland, with more than a dozen participants from around
the world. Each cancer briefing was reviewed in detail, and all input was recorded in real time. Long-term solutions
were also discussed.
November-December Disease briefings were revised according to working group input and finalized for submission; 52 cancer medicines were
2014 recommended in the review, and 22 of those medicines were not yet included in the current WHO Model List.
December 15, 2014 Application submitted to the WHO Medicines Secretariat.
January 7, 2015 Application posted online on WHO Web site for public comment.
April 20-24, 2015 WHO to host 20th Expert Committee meeting for the selection of medicines to the 2015 Model List of Essential
Medicines.

Abbreviations: G-CSF, granulocyte colony-stimulating factor; UICC, Union for International Cancer Control.

www.jco.org © 2015 by American Society of Clinical Oncology 71

 Shulman et al

Large magnitude of palliative treatment impact in a low-incidence Stage IIB cervical cancer, for example, can be treated curatively with
disease. CML is an uncommon disease and one that affects people of all radiation and concurrent administration of cisplatin.51 Cisplatin alone is not
ages, including children. Imatinib, an oral tyrosine kinase inhibitor of the curative and in this circumstance likely works primarily as a radiation sensitizer.
BCR-ABL fusion protein, though not curative, offers a majority of patients Therefore, procuring cisplatin to treat patients with stage IIB cervical
long-term hematologic remission with acceptable toxicity and high quality of cancer, if radiation is not available, is likely not to have a long-term impact on
life—because many patients are young, productive life-years gained can be patients with this disease.
considerable. Though the incidence of CML is low, the prevalence becomes In regard to the use of systemic medicines, expertise in procurement,
substantial with long-term disease control and life-long treatment with storage, supply chains, preparation, and administration is required, as is
imatinib.20 Imatinib should only be administered to patients whose leukemia expertise in the monitoring of patients receiving these therapies. Capabilities
cells contain the BCR-ABL fusion protein; therefore, access to molecular for administration of parenteral medicines and necessary equipment, such as
testing is required. The disease can be controlled before testing results with infusion pumps and monitoring devices, are required for safe and effective
medications such as hydroxyurea. care. In addition, adequate blood product support is required for patients who
Low to marginal magnitude of palliative treatment impact and extension of receive intensive therapies, particularly those who have hematologic disorders,
life in a high-incidence disease. NSCLC is one of the more common diseases such as the acute leukemias.52 The requirements differ depending on the
worldwide and has a high mortality rate.18,19 Even in wealthy parts of the treatment; therefore, specific recommendations are made in each disease-
world, most patients with NSCLC eventually die as a result of their disease; in based document. Also, the contributors to this review who are clinical experts
the United States, the 5-year relative survival rate for NSCLC patients is working in low-income settings provided unique reflections and responses to
approximately 15%.40 Most patients present with metastatic disease—a the realities of cancer care delivery within the disease briefings.
disease that is never curable—and many patients who present with earlier-
stage, potentially curable disease will have disease recurrence and will not
survive.41 For patients who present with metastatic NSCLC, the average Choice of Regimens
survival without systemic therapy is approximately 6 months and increases Because each disease-based document was authored by one individual
to 10 to 12 months with doublet chemotherapy (eg, vinorelbine and or a small group and reviewed and critiqued by at least two others, a variety of
cisplatin).42 Despite the poor prognosis for most patients with NSCLC, recommendations were taken into consideration. The core team collated all
chemotherapy does improve overall survival and should be available to opinions, and, when necessary, obtained additional input from new experts;
patients in need.43 When patients have tumor progression after first-line the result represents as much of a consensus as was possible. In all cases, there
therapy, second-line chemotherapy offers only modest life extension44,45; was input from multiple continents, and this wide geographic representation
in the context of this work, we often have not recommended use of strengthened the process.
second-line chemotherapy. Some patients with NSCLC will have tar- Finally, a standard regimen and, for many, alternative regimens, were
getable somatic mutations in their tumors, such as mutations in the epi- agreed on for each disease. In the context of our application to the WHO, the
dermal growth factor receptor kinase region, or of anaplastic lymphoma word “standard” was applied after the regimen received its final review by the
kinase (ALK). In these instances, oral therapies can result in disease remis- working group in November 2014; it is the result of as much consensus as
sion or stabilization, sometimes with long-term palliation and modest could be achieved over the course of the 12-month review period. The disease-
toxicity. Overall survival can be significantly prolonged and sometimes based documents, we hope, will allow policy makers to have more information
doubled, though no patients are cured.46 In addition, the testing for these to support decision-making processes within a specific national context.
mutations currently is complex, not universally available, and expensive— Criteria for choice included efficacy as well as toxicity. Cost was not a
though some are due to come off patent and should be more affordable in primary consideration for regimens with high levels of efficacy but was
the near future. considered when benefit was marginal (as in NSCLC, for example).
Absolute and relative benefits were considered. As one example, a
medicine might reduce the rate of relapse and death from 12% to 9%,
Supportive Services which is a relative reduction of 25% but an absolute reduction of only 3%.
Administration of cancer medicines does not occur in isolation. A For both patients and the EML decision-making process, the absolute
number of essential services must be available. Pathology is key for almost any figures are those that are most useful and more informative.
cancer diagnosis. High-quality general histopathology contributes greatly as a Systematic reviews of diseases and treatment options were utilized
first step, though it is often challenging in limited-resource settings.12 Catego- and referred to when possible and are referenced in the application. Key
rization of tumors as squamous cell carcinoma versus adenocarcinoma, versus studies that provided strong support for use of one regimen versus another
lymphoma, is a critical first step but often insufficient. Immunohistochemistry were also cited within the briefings (generally, large phase III trials).
can be important as in breast cancer, in which estrogen receptor status governs
much of systemic therapy choices, as does HER2 status if trastuzumab or
similar medicines are available. Patients with suspected CML should have Cost
molecular confirmation of the BCR-ABL translocation before being pre- Ideally, cost would not be a consideration when a person’s well-being is
scribed imatinib, a costly medicine that will not be effective in patients whose concerned. However, even in wealthier countries such as the United States,
leukemia cells lack this mutation. Novel and effective targeted biologic agents cost now is becoming a major issue. For countries with relatively limited
now utilized in NSCLC treatment, such as crizotinib, are only effective in resources, cost is always a consideration. There is a wide spectrum of price for
patients whose tumors harbor specific mutations, such as ALK. Because only different medicines and, in some cases, the same medicine. Many of the older
a small percentage of patients with NSCLC will have somatic ALK mutations, cytotoxic agents can be obtained relatively inexpensively, whereas newer bio-
giving all patients with this disease a medicine such as crizotinib would be a logic agents can be extremely expensive.
poor use of resources and would add potential drug toxicity with no chance Because the purpose of this initiative was to determine the essential
for benefit. Not all settings will have the ability to perform all tests; therefore, cancer medicines in a way that could be useful to policy makers, cost was a
the procurement of drugs should be paired with the advancement of molecular factor that was not ignored. A complete financial analysis of all recom-
diagnostic capacity. mended medicines in the standard regimen was beyond the scope of this
Surgical resection of the primary tumor is required for potential cure work in the timeframe available. In addition, any costing data presented
of early-stage breast or colon cancer, for instance. Without the ability to referred only to the cost of the antineoplastic medicines and did not take into
perform safe and effective cancer surgery, adjuvant chemotherapy regi- consideration the cost of ancillary medications, such as antiemetics, or the
mens will be palliative and not potentially curative. Authors point readers cost of provision of care or other components of care, such as surgery or
to an important and burgeoning set of literature on global surgical oncol- radiation, all of which are important as well. This area of research has
ogy in limited-resource settings.47-50 received scant attention, and more investigation is highly needed,53-55 as

72 © 2015 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

 Proposing Essential Medicines to Treat Cancer

Table 4. List of Recommended Medicines for Included Diseases

Medicine Disease
Allopurinol Supportive care
Anastrozole* (class) Early-stage breast cancer, metastatic breast cancer
Arsenic trioxide* Acute promyelocytic leukemia
Asparaginase Acute lymphoblastic leukemia
ATRA* Acute promyelocytic leukemia
Bendamustine* Follicular lymphoma, chronic lymphocytic leukemia
Bicalutamide* Metastatic prostate cancer
Bleomycin Testicular germ cell tumor, ovarian germ cell tumor, Hodgkin lymphoma, Kaposi’s sarcoma
Calcium folinate Early-stage colon cancer, early-stage rectal cancer, gestational trophoblastic neoplasia, metastatic colorectal cancer
Capecitabine* Early-stage colon cancer, early-stage rectal cancer, metastatic colorectal cancer, metastatic breast cancer
Carboplatin Epithelial ovarian cancer, early-stage breast cancer, metastatic breast cancer, nasopharyngeal cancer, non–small-cell lung cancer,
ovarian germ cell tumor, osteosarcoma, retinoblastoma
Chlorambucil Chronic lymphocytic leukemia
Cisplatin* Epithelial ovarian cancer, early-stage cervical cancer, head and neck cancer, testicular germ cell tumor, ovarian germ cell tumor,
nasopharyngeal cancer, non–small-cell lung cancer, osteosarcoma
Cyclophosphamide Chronic lymphocytic leukemia, diffuse large B-cell lymphoma, early-stage breast cancer, metastatic breast cancer, gestational trophoblastic
neoplasia, Hodgkin lymphoma, follicular lymphoma, Burkitt’s lymphoma, rhabdomyosarcoma, Ewing sarcoma, acute lymphoblastic leukemia
Cytarabine Acute myelogenous leukemia, acute promyelocytic leukemia, acute lymphoblastic leukemia, Burkitt’s lymphoma
Dacarbazine Hodgkin lymphoma
Dactinomycin Gestational trophoblastic neoplasia, rhabdomyosarcoma, Ewing sarcoma, Wilms tumor
Dasatinib* Chronic myelogenous leukemia
Daunorubicin Acute myelogenous leukemia, acute promyelocytic leukemia, acute lymphoblastic leukemia
Dexamethasone Metastatic prostate cancer, ovarian germ cell tumor, acute lymphocytic leukemia
Diethylstilbesterol* Metastatic prostate cancer
Docetaxel Early-stage breast cancer, metastatic breast cancer, metastatic prostate cancer
Doxorubicin Epithelial ovarian cancer, diffuse large B-cell lymphoma, early-stage breast cancer, Hodgkin lymphoma, Kaposi’s sarcoma, follicular
lymphoma, metastatic breast cancer, osteosarcoma, Ewing sarcoma, acute lymphoblastic leukemia, Wilms tumor, Burkitt’s
lymphoma
Erlotinib* Non–small-cell lung cancer
Etoposide Epithelial ovarian cancer, testicular germ cell tumor, gestational trophoblastic neoplasia, Hodgkin lymphoma, non–small-cell lung
cancer, ovarian germ cell tumor, retinoblastoma, Ewing sarcoma, acute lymphoblastic leukemia, Burkitt’s lymphoma
Fludarabine* Chronic lymphocytic leukemia
Fluorouracil Early-stage breast cancer, early-stage colon cancer, early-stage rectal cancer, metastatic colorectal cancer, nasopharyngeal cancer
G-CSF* Supportive care
Gefitinib* Non–small-cell lung cancer
Gemcitabine* Epithelial ovarian cancer, non–small-cell lung cancer, metastatic breast cancer
Hydrocortisone Acute lymphoblastic leukemia
Hydroxycarbamide Chronic myeloid leukemia
Ifosfamide Testicular germ cell tumor, ovarian germ cell tumor, osteosarcoma, Rhabdomyosarcoma, Ewing sarcoma
Imatinib* Chronic myeloid leukemia, GI stromal tumor
Irinotecan* Metastatic colorectal cancer
Leuprolide* (class) Metastatic prostate cancer
Mercaptopurine Acute lymphoblastic leukemia, acute promyelocytic leukemia
Mesna Testicular germ cell tumor, ovarian germ cell tumor, osteosarcoma, rhabdomyosarcoma, Ewing sarcoma
Methotrexate Early-stage breast cancer, gestational trophoblastic neoplasia, osteosarcoma, acute lymphocytic leukemia, acute promyelocytic
leukemia
Methylprednisolone Acute lymphocytic leukemia
Nilotinib* Chronic myeloid leukemia
Oxaliplatin* Early-stage colon cancer, early-stage rectal cancer, metastatic colorectal cancer
Paclitaxel Epithelial ovarian cancer, early-stage breast cancer, metastatic breast cancer, Kaposi’s sarcoma, nasopharyngeal cancer, non–small-
cell lung cancer, ovarian germ cell tumor
Prednisolone Chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin lymphoma, follicular lymphoma, acute lymphoblastic leukemia,
Burkitt’s lymphoma
Procarbazine Hodgkin lymphoma
Rituximab* Diffuse large B-cell lymphoma, chronic lymphocytic leukemia, follicular lymphoma
Tamoxifen Early-stage breast cancer, metastatic breast cancer
Thioguanine Acute lymphoblastic leukemia
Trastuzumab* Early-stage breast cancer, metastatic breast cancer
Vinblastine Hodgkin lymphoma, Kaposi’s sarcoma
Vincristine Chronic lymphocytic leukemia, diffuse large B-cell lymphoma, gestational trophoblastic neoplasia, Hodgkin lymphoma, Kaposi’s sarcoma, follicular
lymphoma, retinoblastoma, rhabdomyosarcoma, Ewing sarcoma, acute lymphoblastic leukemia, Wilms tumor, Burkitt’s lymphoma
Vinorelbine* Non–small-cell lung cancer, metastatic breast cancer

Abbreviations: ATRA, all-trans-retinoic acid; G-CSF, granulocyte colony-stimulating factor.

*New medication.

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 Shulman et al

we learned and are still learning in the case of HIV/AIDS and tuberculosis In conclusion, a large and growing portion of the world’s patients
treatment cost analyses.56-58 with cancer live in low- and middle-income countries. Many of these
Although some of the medicines recommended for addition to the patients have cancers that are potentially curable or amenable to long-term
EML are currently under patent protection and are only sold at a high remission with surgery, radiation, and systemic therapies. As policy makers
price, there are some good examples of initiatives to expand the availability and program managers strategize to develop and scale-up cancer treatment
of such medicines to lower-income settings at an affordable price. To programs, it can be a challenging task to select systemic therapies that will
acknowledge that there is both a human rights imperative and a financial have a major impact on patients in a national setting. The work described
imperative to avail cancer medicines to patients with cancer worldwide, the in this article is an attempt to provide some relevant and applicable
authors believe inclusion on the WHO Model List as a critical step in the guidance that, we hope, results in improved outcomes for patients around
right direction to improve affordability, as was a widely held view for the world. The proposed list of recommended systemic therapies in the
antiretroviral therapy. In addition, some medicines currently under patent applications to WHO is provided in Table 4 along with the diseases for
will shortly come off of patent and are likely to be available at much lower which they are included. The authors believe this effort to be just one
prices (eg, gefitinib and imatinib). component of the major movement required, and happening, in global
cancer medicine as the world advances toward the dual aims of lowering
Generation of a Proposal to Include New Cancer Medicines cancer incidence and increasing access to cancer therapies.
on the WHO EML
Each disease-based document lists required medicines. The applica- Addendum
tion lists all proposed drugs together, including agents on the 2013 list and The World Health Organization Rules on EML. On May 8, 2015 (after
newly proposed agents. In the list of medicines, each agent refers back to the development of this manuscript), the WHO published its 2015 Model
diseases for which it is indicated. For example, a medicine such as cyclo- List of Essential Medicines for Adults, in which 16 of the 22 proposed new
phosphamide has 11 diseases listed next to it, whereas an asparaginase only cancer medicines were included, bringing the total of approved cancer
lists acute lymphocytic leukemia. We believe that this approach could be medicines to 46. The 2015 EML for Children included nine new medicines,
beneficial to all who use the EML. eight of which had been approved for adults but not yet children. These
Classes of medicines exist in parts of the WHO EML for many diseases. new medicines for adults and children affect treatment regimen options for
For cancer medicines, there are times when any medicine in a particular class 26 different types of cancer, of the 29 cancer types considered. Fur-
would be acceptable. One example is aromatase inhibitors as treatment for thermore, the WHO EMLs now include the disease-based regimens that
breast cancer, for which it was recommended that anastrozole be added to the are associated with each medicine, facilitating national formula devel-
EML; letrozole and exemestane were considered in the same class and can be opment, procurement decisions, and supply chains.
included on this basis. The platinum medicines, however, are examples of a The six medicines that were not approved were arsenic trioxide (acute
class of medicine for which interchange is not always permissible. Oxaliplatin is promyelocytic leukemia), dasatinib and nilotinib (CML), diethylstilbesterol
efficacious in colon cancer but not in lung or ovarian cancer, in which (prostate cancer), and erlotinib and gefitinib (NSCLC). The following limita-
carboplatin and cisplatin do have utility. Cisplatin is efficacious in combina- tions in the applications were observed that resulted in these medicines not
tion with radiation therapy for stage II cervical cancer, but carboplatin and being added to the 2015 list: the clinical impact of arsenic trioxide was not
oxaliplatin are not acceptable replacements. The medicines within a class that significant enough in treatment-naı̈ve patients, and the price of the drug was
are not interchangeable are listed specifically, and class inclusion is not im- extremely high; second-line CML therapy with nilotinib and dasatinib was not
plied. Thus, important recommendations were made to the WHO to separate supported because of inadequate data demonstrating impact beyond existing
the platinum medicines instead of listing them as a class. treatment options; diethylstilbesterol’s side effects are notably hazardous, and
The current and proposed list of medicines is shown in Table 4, together it had negligible to no advantage compared with alternative treatment options
with the diseases for which they are the proposed treatment. for prostate cancer; last, neither gefitinib nor erlotinib were included because
of relatively modest impact of therapy coupled with infrastructural complex-
Utility of the WHO EML for Governments and Ministries ities and financial considerations surrounding molecular testing for EGFR
of Health mutations in patients with NSCLC. In addition, although oxaliplatin was
Historically, the purpose of having a comprehensively updated WHO approved for early-stage colon cancer and metastatic colorectal cancer, its use
EML for cancer was to provide public officials guidance on purchase and was not approved for early stage rectal cancer.
procurement prioritization. It is the hope of the authors that a list that reflects
drugs used to treat diseases for which systemic therapy has a high impact
and/or diseases that are high burden will support national cancer programs.
In addition, our application details dosing and scheduling for each regimen,
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
which, if appended to the 2015 EML, could ease volume determination and
supply chain planning and strengthening.
Disclosures provided by the authors are available with this article at
www.jco.org.
Keeping the EML Current
Cancer medicine is evolving rapidly. Studies are being presented and
published that give us more accurate information about the optimal treatment
for a particular disease, and new medicines are frequently being approved by AUTHOR CONTRIBUTIONS
regulatory agencies. An EML for cancer medicines, thus, is also likely to need
regular review and revision. Organizations such as the National Comprehen- Conception and design: Lawrence N. Shulman, Claire M. Wagner, Julie
sive Cancer Network, which has developed treatment guidelines for many Torode, Nicola Magrini
cancers, has a formal process to review and update guidelines on an annual Financial support: Julie Torode
basis. We would propose that a similar process be put into place for the EML Administrative support: Lawrence N. Shulman, Julie Torode
for cancer, and we offer our support to the WHO and the Expert Committee Collection and assembly of data: Lawrence N. Shulman, Claire M.
on the selection and use of essential medicines and on potential mechanisms to Wagner, Gilberto Lopes, Julie Torode
do so. This new mechanism would be concerned with the addition of new Data analysis and interpretation: Lawrence N. Shulman, Claire M.
types of cancer for therapy consideration and, thus, medicine addition, possible Wagner, Gilberto Lopes, Jane Robertson, Julie Torode
deletion if a medicine is superseded by another, and additional lines of treatment Manuscript writing: All authors
for current and added disease types. Final approval of manuscript: All authors

74 © 2015 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

 Proposing Essential Medicines to Treat Cancer

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 Shulman et al

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Proposing Essential Medicines to Treat Cancer: Methodologies, Processes, and Outcomes
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.
Lawrence N. Shulman Expert Testimony: Sanofi
No relationship to disclose
Giuseppe Longo
Claire M. Wagner No relationship to disclose
No relationship to disclose
Jane Robertson
Ronald Barr No relationship to disclose
No relationship to disclose
Gilles Forte
Gilberto Lopes No relationship to disclose
Honoraria: AstraZeneca, Genentech, Merck Serono, Merck Sharp &
Dohme, Fresenius Kabi, Novartis Julie Torode
Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, Eli Lilly, No relationship to disclose
ImClone Systems Nicola Magrini
Research Funding: Eli Lilly, ImClone Systems, Pfizer, AstraZeneca, No relationship to disclose
Merck Sharp & Dohme, Eisai

© 2015 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY