Cost-effectiveness analysis of XELOX versus XELOX plus bevacizumab for metastatic colorectal cancer in a public hospital school

Colorectal cancer (CRC) is the third most common type of cancer among men and women in the world. In 2016, an estimated 95,270 new cases of colon cancer and 39,220 new cases of rectal cancer are expected to be diagnosed, and 49,190 people will die from CRC [1]. Although CRC is diagnosed at early stages in most cases, leading the possibility of curative surgical procedure, nearly 20% of patients suffer from metastatic disease at the moment of diagnosis [2] and, in this case, treatment is not considered curative.

Fluoropyrimidine 5-fluorouracil (5-FU) was the first drug to emerge as the drug of choice for metastatic colorectal cancer (mCRC). Later, in the 90 decade, two additional agents – irinotecan and oxaliplatin showed anticancer activity in mCRC [3].

Angiogenesis is a vital process for the progression of primary tumors and metastasis, and new therapeutic approaches for mCRC have focused on the inhibition of this process. Bevacizumab is a humanized recombinant monoclonal antibody which blocks the activity of all isoforms of vascular endothelial growth factor (VEGF), one of the main proangiogenic growth factors. The neutralization of VEGF biological activity reduces tumor vascularization and inhibits tumor growth [4].

Meta-analyses of randomized, clinical trials have demonstrated beneficial effects of the addition of bevacizumab to chemotherapy on patients’ clinical conditions. Such combination has significantly reduced the risk of disease progression and death in comparison with chemotherapy only [5–9].

One of the main drawbacks of new oncologic agents is their high cost when compared with conventional chemotherapy. The development, incorporation and use of new technologies in the context of healthcare systems, along with the sustainability of these systems, are inserted in social and economic contexts that reflect the continuous production and consumption of products. This process should be built based on health needs, public budgeting, responsibilities of the three levels of government (including social control), and on the principles of equity, universality and integrity of the Brazilian healthcare system. In light of this, the National Policies in Healthcare Technology Management aims to maximize the benefits obtained from the available resources, so as to guarantee the equal access of the population to effective and safe technologies [10].

The aim of the present study was to perform a cost-effectiveness analysis of bevacizumab plus XELOX and XELOX alone as the first-line therapy of mCRC patients from the perspective of a public hospital school in Brazil.

Costs were expressed in local currency (Brazilian real, BRL), and the outcomes were expressed in months of life gained (MLG).

Costs of oncology drugs have caused a considerable impact on Brazilian public budgeting, particularly due to development of biotechnology, which has sparked a revolution in cancer treatment. This has caused a drastic increase in treatment costs, without necessarily indicating the feasibility of public health system in incorporating these medications.

In Brazil, the National Commission for the Incorporation of Technologies (Comissão Nacional de Incorporação de Tecnologias no SUS, CONITEC), created by the law 12,401 on April 28th 2011, addresses therapeutic assistance and incorporation of health technology in the scope of the SUS. Its aim is to advise the Ministry of Health in the incorporation, exclusion or changes in health technologies, as well as in the development or updates of clinical protocols and therapeutic guidelines based on economic analysis studies [19].

Considering the available literature, this is the first study aimed to conduct an economic analysis comparing the costs of XELOX and XELOX plus bevacizumab from the perspective of the public health system.

This study has some limitations that should be considered. This model did not examine the possibility of patients move from a second-line therapy to a third-line therapy due to advanced stages of the disease. Because of diagnostic delay and limited access to an oncology center, patients may start treatment late. For this reason, we decided to include the state “supportive care”, as many patients cannot continue treatment or start a new line of treatment due to clinical conditions.

Tappenden et al. [20] estimated the cost-effectiveness of adding bevacizumab to 5FU, irinotecan and leucovorin in comparison with 5FU and leucovorin alone in patients with mCRC. The states of the model used by the authors were: (1) alive without disease progression; (2) alive with disease progression; and (3) death. Goldstein et al. [21] developed two Markov models to compare costs and effectiveness of bevacizumab in first-line and second-line therapies in the USA. In the first-line therapy, the authors compared FOLFOX with and without bevacizumab in patients recently diagnosed with mCRC and in disease progression. Both groups received FOLFIRI without bevacizumab and progressed to death. In the second-line therapy, FOLFIRI with and without bevacizumab were compared with subsequent progression to death, in patients who had experienced progression during first-line therapy with bevacizumab. Thus, the states were first-line therapy, second-line therapy and death.

The recent study of Franken et al. [22] evaluated the cost-effectiveness of capecitabine and bevacizumab (CAP-B) maintenance compared with the observational strategy following first-line capecitabine, oxaliplatin and bevacizumab (CAPOX-B) induction treatment for mCRC patients with stable disease or better after 6 cycles of treatment. CAP-B maintenance compared with observation resulted in an ICER of €175,452 per quality-adjusted life years (QALY) and €204,694 per life year (LY). Varying the difference in health-related quality of life between CAP-B maintenance and observation influenced the ICER most. For patients achieving complete or partial response on capecitabine, oxaliplatin and bevacizumab induction treatment, an ICER of €149,300 per QALY was calculated.

In Brazil, Carvalho et al. [23] evaluated cost-effectiveness of two treatment strategies in mCRC from the perspective of SUS before and after revision of the values covered by the system, available at the Authorization for Highly Complex Procedures (AHCP) table. The pre-review strategy included 5FU and leucovorin (first-line therapy) followed by irinotecan (second-line therapy). The post-review (with coverage values updated) strategy included FOLFOX (first-line therapy) followed by FOLFIRI (second-line therapy). After the second-line therapy, patients could experience a progress to supportive care and subsequent death, which is similar to our study.

In the present study, the costs of the strategies were estimated using the micro-costing method, aiming to obtain precise information of the real costs paid by the patients in a tertiary, public hospital that offers highly complex care. These estimates may be subject to variations, since the values included in the analysis, registered in the electronic database of this hospital in 2013, were resultant from public bidding. However, these variations were included in the sensitivity analysis.

Our findings showed that in XELOX and XELOX plus bevacizumab regimens, the greatest impact on total treatment cost was caused by medications. It is worth mentioning oral capecitabine, which is an available, effective, safe treatment option for mCRC, requires lower number of chemotherapy sessions and promotes better adaptation to the treatment proposed [24].

Due to reduced number of hospital beds, hospitalization for chemotherapy is often unavailable for SUS beneficiaries. Besides, there are not infusion pumps for these patients to receive chemotherapy at home. These factors contribute for delays in the treatment proposed [25].

In addition, the cost analysis revealed that the category that had the greatest impact on FOLFIRI regimen was the cost of administration (51.6%) rather than the cost of medications (33.3%). The use of infusion pumps would hence be an alternative strategy to reduce these costs and adjust them to the values covered by the SUS (AHCP table). Tampellini [26] compared the costs of the administration of FOLFIRI and FOLFOX regimens in ambulatorial setting using an infusion pump with the administration in the hospital setting. In a same time period and with the same resources, the infusion pump permitted treatment of at least five times more patients than the traditional treatment at the hospital.

In the study by Carvalho et al. [23], costs related to drugs, laboratory and radiology tests, medical fees, and hospitalization were obtained from the official prices regulated by the Ministry of Health. Other parameters, including the number of visits were obtained from an opinion survey of oncologists of public health centers. The cost estimated by the authors for a three-month treatment with FOLFIRI was 13,925 BRL, which was similar to that found in our study (12,984 BRL). We also included the costs of medications used for possible adverse effects from the treatment.

In an economic analysis conducted with head and neck squamous cell carcinoma patients, Brentani [27] used the SUS coverage values and pointed out the difficulty in obtaining data of costs, as well as the absence of indirect cost data in patients’ medical records.

According to the AHCP table, the reimbursement value of first-line palliative chemotherapy of colon and rectal adenocarcinoma (locoregionally advanced, metastatic or recurrent disease) was 2224 BRL per month. Today, 80% of services provided to cancer patients in Brazil were performed by the public health system [28]. Therapy drugs are not specified in the AHCP table, and treatment choice is a medical staff’s decision, based on local protocols and international scientific guidelines.

Due to the lack of Brazilian studies on this subject, data of treatment effectiveness were obtained from international studies. Also, data of quality of life were unavailable in most of these studies, and hence only PFS and OS data were used in the analysis, which make it difficult to compare our results with those of studies that used the QALY outcome.

The decision to incorporate a new technology into the public health system depends on how much the beneficiaries would be willing to pay for the additional benefit. We found an ICER of 21,231.43BRL per MLG, which would correspond to 254,777.16 BRL per life year gained. In the study by Carvalho et al. [23], the cost of the implementation of FOLFOX and FOLFIRI regimens was 78,188 BRL per life year gain and, hence, not cost-effective when compared with 5FU plus leucovorin. Nevertheless, the authors brought up for discussion the fact that the current Brazilian health system reimbursement model does not permit the incorporation of new regimen protocols in a cost-effective manner.

The ICER of bevacizumab could be improved by the use of an effective biomarker to identify those patients who are more likely to benefit from treatment. For example, KRAS mutation testing identifies which patients with mCRC would benefit more from treatments such as cetuximab or panitumumab, increasing the cost-effectiveness of these interventions [29].

Our findings make several contributions: first, the study presents real health care costs related to mCRC treatment in a large, public hospital that offers highly complex care, which could be used for the planning and elaboration of public health policies. Second, it brings up for discussion the necessity of the AHCP table revision to permit the incorporation of cost-effective biological medications in the SUS. Finally, the results of this economic analysis, performed by a modeling method, provide valuable information on how financial resources can be efficiently allocated in the analysis of new strategies for the treatment of the Brazilian public health system beneficiaries.

The cost-effective analysis of XELOX (strategy 1) and XELOX plus bevacizumab (strategy 2) as first-line treatment of mCRC patients from the perspective of a public hospital resulted in a ICER of 21,231.43 BRL per MLG, or 254,777.16 BRL per life year gained. Therefore, the SUS reimbursement values do not allow the inclusion of bevacizumab to the treatment of mCRC patients in a cost-effective manner.