The real-world cost of systemic therapies for advanced head and neck cancers

Head and neck squamous cell cancers (HNSCC) are the seventh most common cancer by incidence accounting for 3% of global cancer mortality.[1] However, their distribution worldwide is quite heterogeneous with clustering in developing nations. For instance, the age-standardized rate (ASR) of cancers of the lip and oral cavity in males increase more than twofold from 3.9 cases per 100,000 population to 8.7 cases per 100,000 population from regions of high or very high human development index (HDI) to regions of medium to low HDI against a global ASR of 5.8 cases per 100,000.[2] In India, cancers of the lip and oral cavity account for 10% of all cancer cases in terms of both incidence and mortality, ranking second on both accounts. They are also the most common newly diagnosed cancer in males.[2] In low-middle-income countries (LMICs) and low-income countries (LICs), most HNSCCs (nearly 75%) present for treatment at a locally advanced or metastatic stage[3] due to logistical and financial limitations, which include a shortage of specialized oncology centers at the periphery and the subsequent need to travel large distances to obtain cancer care. Developing countries make up four-fifths of the world’s population and more than 90% of the worldwide disease burden, yet they represent a minor proportion of global income and net spend on health care.[4] India spends about 2% to 3% of its 3 trillion USD gross domestic product (GDP) on health care (out-of-pocket and public), which is significantly worse than the OECD (Organisation for Economic Co-operation and Development) average (8.8%) and even lower than some countries in sub-Saharan Africa.[5-7] According to a published report in 2016 by Credit Suisse, India is the second most disparate country in terms of wealth distribution whereby the top 1% of the population owns 58% of the total wealth.[8] Using data from the National Sample Survey Organization, the mean out-of-pocket expenditure in India was maximum for cancer, with the likelihood of incurring financial toxicity three times as high (odds ratio [OR] = 3.23; 95% confidence interval [CI]: 2.62-3.99). Distress health financing, defined as the need to borrow money or sell assets to meet health care expenses, was the highest for hospitalizations due to cancer (OR = 42.5%; 95% CI: 39.7-45.4). Catastrophic health expenditure on hospitalization, defined as the expenditure when the capacity to pay exceeds 10% of the fraction of consumption expenditure, also had the highest incidence for cancer (79%).[9] Systemic therapy in unresectable, metastatic, or recurrent HNSCC includes the use of monoclonal antibodies or conventional chemotherapeutic agents such as platinum, taxane, 5-fluorouracil, or methotrexate.[10] Conventional chemotherapy regimens, either alone or in combination, offer similar median overall survival (OS) of around six months, with differences only in terms of their response rates.[10,11] Targeted agents such as cetuximab, nivolumab, or pembrolizumab offer statistically significant but small absolute improvements in overall survival [Table 1].[12-14] However, the cost and the quality of this extension in life for the patient and their family members alike are not straightforward. Recently, Professor Vijay Patil et al. from the Tata Memorial Hospital, Mumbai, published the final results of the Metro-CIS study, which was keenly anticipated since the ASCO (American Society of Clinical Oncology) 2020 presentation.[15,16] Besides being a well-designed noninferiority trial, it is a socially relevant study, particularly in the context of LMICs and LICs, and reinforces the role of methotrexate in this subset of patients.Table 1: Approved targeted agents for unresectable, metastatic, or recurrent head and neck cancersUsing manufacturers’ maximum retail prices in the Indian market, we estimated that cetuximab, nivolumab, and pembrolizumab have an average cost per cycle between 2,000 U.S. dollars (USD) to 6,000 USD [Table 2]. For a period of 6 months (estimated median OS), the average monthly cost approximates between 2,000 USD and 8,000 USD. Methotrexate administered weekly, on the other hand, for the same intent garners an average monthly cost of approximately 12 USD (intravenous/intramuscular) or 2 USD (oral). Thus, the incremental cost advantage of methotrexate is nearly 1,000 times for cetuximab and 4,000 times for pembrolizumab at a slightly inferior overall survival.Table 2: Cost analysis of methotrexate versus other recommended agents for palliatively treated head and neck cancers (assuming 1 U.S. dollar [USD] = 75 Indian rupee [INR])The median overall survival reported in the Metro-CIS trial for oral methotrexate is 7.5 months. As per the reports in literature, the absolute median gain in OS is around 3 months for cetuximab (compared with platinum and 5-fluorouracil), and 2.5 months and 1 month for nivolumab and pembrolizumab, respectively.[12-14] The modest gain in OS should not be considered an isolated event, that is, it comes with an overwhelming economic insecurity. The widespread evidence of distress financing also implies that concurrently further generations of the patient are thrown into extreme poverty, which marks their economic status as “below the poverty line.” As per the World Poverty Clock, 50 million people in India currently live below the extreme poverty threshold of 1.90 USD, which is nearly 4% of its total population.[17] The minuscule gain in OS or progression free survival (PFS) thus comes at the sacrifice of education, and basic amenities of daily living such as food, clothing, or shelter for future generations. To put things into perspective, we are oncologists at the largest tertiary care academic university hospital in the most populous state of India catering to a population of 200 million, and we routinely see approximately 2000 patients with head and neck cancers every year. The majority of HNSCC patients at our center come from a financially distressed section of the society, and government-sponsored financial assistance is offered to patients with an annual income of less than INR 35,000 (USD 467), which constitutes more than four-fifths of our HNSCC population. This means that the incremental cost per month’s gain of median OS for the targeted agents is unacceptably high, and it is not feasible to maintain a patient at such a high cost-benefit ratio. Cost-effectiveness analyses in health care usually focuses on an incremental cost-effectiveness ratio (ICER) or on quality-adjusted life-years (QALYs), which can be further supplemented with the use of the five-dimensional EQ-5D instrument to assess the quality of life.[18] However, these analyses are not free from criticisms and are usually unable to account for differences in value perceptions, among people. These may be somewhat circumvented by high-quality economic modeling, which may then be used to take health care decisions.[19] The National Institute for Health and Care Excellence (NICE) in the United Kingdom issues guidelines and approves antineoplastic agents for use in their publicly funded health care system, the National Health Service (NHS), after proper evaluations for their cost-effectiveness.[20] As an example, the use of the anti-angiogenesis agent bevacizumab in metastatic colon cancer with oxaliplatin and either fluorouracil plus folinic acid or capecitabine was found to have an unacceptably higher ICER per QALY gained and is therefore not recommended by NICE for use in the NHS.[21] Reinforcing the aspect of financial disparity in LMICs/LICs, those who can afford these targeted agents for advanced HNSCC are a minority, and it may be absurd to prescribe a drug with a monthly cost of a few thousand dollars to an individual with an annual income of 500 USD. Additionally, in the setting of a limited health budget, the relocation of government funds toward the purchase of these agents will entail that other patients with relatively lower costs of cancer treatment are unfairly disadvantaged. As oncologists in developing countries, it is, therefore, our responsibility to balance financial toxicities with treatment-related toxicities. While most international guidelines originate from developed nations, they need to be taken with a grain of salt, and there is a profound and unmet need for local guidelines that focus not merely on the OS gained but also account for cost-effective analysis of such gains.