Medical Oncology in Africa
Otis W. Brawley*
*This chapter should be referenced as: Brawley OW. Medical Oncology in Africa. In: Boyle P, Ngoma T, Sullivan R, Ndlovu N, Autier P, Stefan S, Fleming K and Brawley OW. The State of Oncology in Africa 2015. iPRI Scientific
Publication 4, iPRI, Lyon, France (2016).
C
ancer chemotherapy is a vital part of effective cancer treatment. In some diseases, among them Burkitt Lymphoma or Acute Lymphocytic Leukemia it is essential for cure. The medical oncologist uses a number of drugs to treat cancer. Often the patient will regularly receive three or four in combination over a period of months.Thirty-eight chemotherapeutic drugs and six hormones are
commonly used (Table 1) to treat the common treatable cancers with high population impact (Table 2). (Shulman et al, 2016; World Health Organization, 2015) These drugs have been judged essential for good care. Unfortunately many of these drugs are commonly not available to many cancer patients in Africa.
Table 1: Essential Medicines 19th edition WHO Model List
Cytotoxic and adjuvant medicines all-trans retinoid acid (ATRA) Capsule: 10 mg
− acute promyelocytic leukemia allopurinol Tablet: 100 mg; 300 mg asparaginase Powder for injection: 10 000 IU in vial
− acute lymphoblastic leukemia.
bendamustine
Injection: 45 mg/0.5 mL; 180 mg/2 mL
− chronic lymphocytic leukemia
− follicular lymphoma
bleomycin
Powder for injection: 15 mg (as sulfate) in vial
− Hodgkin lymphoma
− Kaposi’s Sarcoma
− ovarian germ cell tumour
− testicular germ cell tumour
The State of Oncology in Africa – 2015 Chapter 7 – Africa: Medical Oncology
Cytotoxic and adjuvant medicines dacarbazine Powder for injection: 100 mg in vial
− Hodgkin lymphoma dactinomycin
Powder for injection: 500 micrograms in vial
− gestational trophoblastic neoplasia
− rhabdomyosarcoma
− Wilms tumour daunorubicin
Powder for injection: 50 mg (hydrochloride) in vial
− acute myelogenous leukemia
Powder for injection: 10 mg; 50 mg (hydrochloride) in vial
− diffuse large B-cell lymphoma
Capsule: 100 mg Injection: 20 mg/ mL in 5 mL ampoule
− testicular germ cell tumour
fludarabine Powder for injection: 50 mg (phosphate) in vial; Tablet: 10 mg
− chronic lymphocytic leukemia.
fluorouracil
Injection: 50 mg/ mL in 5 mL ampoule
− early stage breast cancer
Injection: 3 mg/ mL in 10 mL ampoule. Tablet: 15 mg
− early stage colon cancer
Injection: 50 mg/5 mL; 150 mg/15 mL; 450 mg/45 mL; 600 mg/60 mL
− early stage breast cancer
Injection: 50 mg/50 mL; 100 mg/100 mL
− cervical cancer (as a radio-sensitizer)
− head and neck cancer (as a radio-sensitizer)
− nasopharyngeal cancer (as a radio-sensitizer)
− non-small cell lung cancer
− osteosarcoma
− ovarian germ cell tumour
− testicular germ cell tumour
cyclophosphamide
Powder for injection: 500 mg in vial. Tablet: 25 mg
− chronic lymphocytic leukemia
Powder for injection: 100 mg in vial
− acute myelogenous leukemia
− acute lymphoblastic leukemia
− acute promyelocytic leukemia
Cytotoxic and adjuvant medicines
paclitaxel
Powder for injection: 6 mg/ mL
− epithelial ovarian cancer procarbazine Capsule: 50 mg (as hydrochloride)
rituximab
Injection: 100 mg/10 mL in 10 mL vial; 500 mg/50 mL in 50 mL vial
− diffuse large B-cell lymphoma
− chronic lymphocytic leukemia
− follicular lymphoma tioguanine Solid oral dosage form: 40 mg
− acute lymphoblastic leukemia trastuzumab
Dose form:
− early stage HER2 positive breast cancer
− metastatic HER2 positive breast cancer
vinblastine
Powder for injection: 10 mg (sulfate) in vial
− Hodgkin lymphoma
− Kaposi’s Sarcoma
− Testicular germ cell tumour
− Ovarian germ cell tumour
vincristine
Powder for injection: 1 mg; 5 mg (sulfate) in vial
− diffuse large B-cell lymphoma
Injection: 120 micrograms/0.2 mL; 300 micrograms/0.5 mL; 480 micrograms/0.8 mL in pre-filled syringe 300 micrograms/mL in 1 mL vial, 480 mg/1.6 mL in 1.6 mL vial
− As primary prophylaxis in patients at high risk for developing febrile neutropenia associated with myelotoxic chemotherapy
− As secondary prophylaxis for patients who have experienced neutropenia following prior myelotoxic chemotherapy
− to facilitate administration of dose dense chemotherapy regimens gemcitabine
Powder for injection: 200 mg in vial, 1 g in vial
− epithelial ovarian cancer
− non-small cell lung cancer
hydroxycarbamide Solid oral dosage form: 200 mg; 250 mg; 300 mg; 400 mg; 500 mg; 1 g
− chronic myeloid leukemia.
ifosfamide
Powder for injection: 500 mg vial; 1-g vial; 2-g vial
− testicular germ cell tumour
Powder for injection: 50 mg (as sodium salt) in vial.
Tablet: 2.5 mg (as sodium salt)
− early stage breast cancer
Powder for injection: 50 mg, 100 mg in vial
− early stage colon cancer
− metastatic colorectal cancer
The State of Oncology in Africa – 2015 Chapter 7 – Africa: Medical Oncology
Pediatric Cancers Acute Lymphocytic Leukemia
Burkitt Lymphoma Osteosarcoma Retinoblastoma Rhabomyosarcoma
Wilms Tumor
Indeed, the effective treatment of many cancers is multi disciplinary, requiring surgery, radiation and cancer chemotherapy. These disciplines and especially cancer chemotherapy, require many other resources for support. Among them, are pathologic and laboratory analysis for diagnosis and receptor assay, radiologic imaging for staging and assessment of response, and supportive care services such as blood banking and nutrition counseling. Supportive care takes the form of drugs including anti-emetics and antibiotics. Some important support for chemotherapy is often not readily apparent. For example, pharmacists and pharmacy technicians are needed to prepare intravenous chemotherapy drugs. Specialized equipment is also needed, for example exhaust hoods are used so that drug preparation can be done safely and infusion lines and infusion pumps are needed for drug administration.
Drugs are often not available in low income and low middle income. A pharmaceutical company invests in a medicine based on its anticipated income. There is little financial incentive to seek approval to sell drugs in many low and middle-income countries. This is especially true in African countries where one dose of a chemotherapeutic can cost more than the average individual income. Availability can be limited due a number of factors beyond cost and profitability. These include issues with a country’s drug approval system, the logistics of importation and distribution and the lack of technology needed to support the use of the drug.
Some countries require an application for approval. This is a notoriously slow process in many African countries. It can often take three to four years after approval in the United States or European Union. Some countries will accept United States or European Union approval of the drug, but some require local review and a small number even require local clinical development. Local clinical development is a common requirement of the Japanese government but rare in Africa. It may become more necessary in Africa in the future as drugs become more personalized or tailored.
Drug importation is often laborious and expensive. The company often must pay the receiving country’s government inspection fees. Even after drug approval, there are often importation difficulties as the importer must document the chain of custody of the drug and that it has gone through Good Manufacturing Practice. Even with this, many countries do not have the infrastructure to guarantee the quality, efficacy and safety of medicines. In a 2015 survey of the 14 countries of the Southern African Development Community (Lesotho, Swaziland, Seychelles, DRC, Angola, Malawi, Mozambique, Zambia, Botswana, Mauritius, Namibia, South Africa, Tanzania, Zimbabwe), most National Medicine Registration Authorities were unable to perform full regulatory function (dossier evaluations and registration, GMP inspection)
There are other factors that cause pharmaceuticals to be hesitant to file application. In many instances the application has proprietary data. The pharmaceutical company may not have confidence that its intellectual property will remain confidential. Also, in many cases the unlicensed drug is already available on black or gray markets. (Caudron et al, 2008) Counterfeit drugs are a serious problem. (Gautam et al, 2009)
The American or European price of many cancer medicines is unaffordable for most Africans. In many countries the drug cost (not including cost Hormones and antihormones
anastrozole
Tablet: 1 mg
− early stage breast cancer
− metastatic breast cancer bicalutamide Tablet: 50 mg
− metastatic prostate cancer dexamethasone
Injection: 4 mg/ mL in 1 mL ampoule (as disodium phosphate salt) Oral liquid: 2 mg/5 mL [c]
− acute lymphoblastic leukemia leuprorelin
Dose form
− early stage breast cancer
− metastatic prostate cancer
hydrocortisone Powder for injection: 100 mg (as sodium succinate) in vial
− acute lymphoblastic leukemia
methylprednisolone Injection: 40 mg/ mL (as sodium succinate) in 1 mL single-dose vial and 5 mL multi-dose vials; 80 mg/ mL (as sodium succinate) in 1 mL single-dose vial
− acute lymphoblastic leukamia
Table 2: Priority Cancers for the 19th WHO Essential Medicines List
Adult Cancers Acute Myelogenous Leukemia Acute Promyelocytic Leukemia Breast Cancer, Early Stage Breast Cancer, Metastatic Cervical Cancer, Early Stage Chronic Lymphocytic Leukemia Chronic Myelogenous Leukemia Colon Cancer, Early Stage Colorectal Cancer, Metastatic
Epithelial Ovarian Cancer Follicular Lymphoma Gastrointestinal Stromal Tumor Gestation Trophoblastic Neoplasm
Head and Neck Cancer Hodgkin Lymphoma
Kaposi’s Sarcoma Nasopharyngeal Cancer Non-Small Cell Lung cancer
Ovarian Germ Cell Tumors Metastatic Prostate Cancer Rectal Cancer, Early Stage
The Essential Medicines List has had impact. (t Hoen et al, 2014) It has created pressure to push drug prices downward in some diseases. Several countries have used the EML and bulk or pooled procurement in order to negotiate a lower price for drug. To our knowledge, this has not happened for a cancer drug. Several years ago, Brazil did this with the manufacturers of hepatitis C drugs. Some African countries have bulk ordered anti-retroviral drugs.
Drug companies have also been involved in the effort to make drugs affordable in low and middle income countries. Some pharmaceutical houses have used equity pricing. They have reduced wholesale prices and varied margins, so that there are different retail prices in different countries and sometimes even a public and a private market price for the same drug within country. This can mean parallel importing for the public and the private markets and can create a public relations backlash.
Another approach is for a pharmaceutical company to voluntarily license a drug to a second manufacturer where production costs are lower. The second company can then make the drug, distribute and sell it cheaper in lower income countries. Roche partnered with Emcure, of India, as a second manufacturer of a lower priced Herceptin for sale in lower income countries.
Still other companies have established compassionate use or expanded access programs in which the drug is given away. The Gleevec International Patient Assistance Program is one example. Gleevec (imatinib) has been distributed directly to more than 35,000 patients to treat chronic myelog-enous leukemia, acute lymphocytic leukemia, and gastrointestinal stromal tumor in 80 countries. Novartis contracted with Axios International to qualify treatment centers and physicians and the Max Foundation to verify and screen patients for eligibility, do case management and provide patients with emotional support and education. This program has been very successful for distribution of an oral anticancer drug. It is unclear if it can be adapted to more complicated chemotherapy regimens that involve several drugs from several companies.
Even with all this activity, availability of the most essential and necessary drugs is limited in Africa. Of the nearly 600 drugs on the 2015 WHO list of essential medicines, 44 are used to treat cancer (38 chemotherapeutics and six hormones). They are listed in Table 1. The cancers considered treatable with these drugs are in Table 2. A most unsettling fact; among the 37 countries in the African region subscribing to the WHO Essential Medicines List, the median number of chemotherapeutics adapted for national formularies is 15. This means that a substantial number of cancer patients do not have legal, affordable access to very minimal anti-cancer therapies. Cancer can only be a treatable disease if the treatment is available. It is a shame that for many it is not treatable as the treatment is not available for logistical and monetary reasons.
References
Caudron JM, Ford N, Henkens M, Mace C, Kiddle-Monroe R, Pinel J.
Substandard medicines in resource-poor settings: a problem that can no longer be ignored. Trop Med Int Health. 2008;13(8):1062-72.
Doua JY, Van Geertruyden JP. Registering medicines for low-income countries: how suitable are the stringent review procedures of the World Health Organisation, the US Food and Drug Administration and the European Medicines Agency? Trop Med Int Health. 2014;19(1):23-36.
Gautam CS, Utreja A, Singal GL. Spurious and coun-terfeit drugs: a growing industry in the developing world. Postgrad Med J. 2009;85(1003):251-6.
Shulman LN, Wagner CM, Barr R, Lopes G, Longo G, Robertson J, et al. Proposing Essential Medicines to Treat Cancer: Methodologies, Processes, and Outcomes. J Clin Oncol. 2016;34(1):69-75.
t Hoen EF, Hogerzeil HV, Quick JD, Sillo HB. A quiet revolution in global public health: The World Health Organization’s Prequalification of Medicines Programme. J Public Health Policy. 2014;35(2):137-61.
Gross National Income per capita is a rough estimate of average annual income for a country’s citizens. It is used to classify countries as low income, lower middle income, upper middle income or high income. Most African countries are classified as low income or lower middle income.
A low income country has a Gross National Income per capita less than 1,025 USD and a lower middle income country has a has a GNI per capita up to 4,035 USD. A few are categorized as upper middle income (among them: Angola, 5,300 USD; Namibia, 5,820 USD; South Africa 6,800 USD).
(World Health Organization, 2016)
Country approval for sale of a drug does not mean all patients have access to medicine. It means a small number of wealthy patients will be able to pay for it in the private sector. Separate from approval, the country’s Ministry of Health must adopt the drug to a national formulary of medicines in order for it to be available in the public hospitals. Many Health Ministries consider drugs on the World Health Organization Essential Medicines List for inclusion on formularies for public hospitals.
The WHO publishes the Essential Medicines Lists in an effort to improve quality of care for a number of common diseases. Essential medicines, as defined by the WHO are “those drugs that satisfy the health care needs of the majority of the population; they should therefore be available at all times in adequate amounts and in appropriate dosage forms, at a price the community can afford.”
The list is updated every two years. The process of creating the list looks at the population impact of a disease as well as the efficacy of drugs on that disease. The cost and value of a drug is considered when evaluating it as is the support burden required to administer the drug. Preference is given to curative treatments and treatments that can provide palliation. An expensive adjuvant cancer therapy that increases median survival by three months and consumes many hospital resources is not weighted as high as a four-drug combination that can cure a disease.
In developing the cancer drugs for the list, the committee considers regulatory issues, supply chain management, quality assurance, training of personnel, service delivery. Cost and use scenarios are considered. Estrogen receptor testing is relatively simple and inexpensive. The drug tamoxifen and the SERMs are relatively inexpensive drugs that are quite effect in prolonging life. Erlotinib and Gefitinib for Non Small Cell Lung Cancer does prolong life, but were rejected because clinical effect is shorter, they are relatively expensive and there is a scarcity of laboratories capable of doing needed molecular essays.
Health Ministries can trust that a regulatory body has evaluated drugs on the WHO EML to assure efficacy, safety and value. (Doua et al, 2014) Inclusion on the list can provide some assurances replacing need for a formal country specific approval process. It is estimated that 90% of LMIC Health Ministries use the WHO EML to establish a national formulary and for public procurement. Factors in the decision to put a drug on a national formulary include the ability of the local health system to support use of the drug and the amount of resources the use of the drug would take from other clinical activities. In many countries drugs on the national formulary are provided at reduced cost or free of charge in public hospitals.
The EML lists the drug, its commonly used dose, and its formulation. In the case of cancer drugs, those on the EML are traceable to the type of cancer they are used to treat. Dose and schedule is important as it affects the volume estimates for national purchasing. Unfortunately, the limited number of registries and the very rough estimates of the number of cancer cases in Africa make purchase-planning difficulty.
While the EML is good for determining efficacy of a compound, most drugs on the EML are generic. The logistics of importation, storage and custody as well as assuring quality of the drug to be administered are still issues to be dealt with. (World Health Organization, 2016)
The State of Oncology in Africa – 2015 Chapter 8 – Africa: Palliative Care