Comparison between the Swedish healthcare regions regarding the use of different cancer medications: - breast cancer, colorectal cancer and gastric cancer

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Comparison between the Swedish healthcare regions regarding the use of different cancer medications

- breast cancer, colorectal cancer and gastric cancer

Santa Bety

Degree Project in Social Pharmacy, 30 credits, Term 9

Examiner: Björn Wettermark

Division of Pharmacoepidemiology and Social Pharmacy Department of Pharmacy Faculty of Pharmacy Uppsala University, Autumn 2020

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Abstract

INTRODUCTION: Gastrointestinal cancers are one of the most fatal malignancies worldwide in both genders and all ages while breast cancer is the leading cause of cancer deaths in women internationally. Angiogenesis inhibitors and epidermal growth factor inhibitors are mainly used in colorectal and gastric cancer, while cyclin-dependent kinase inhibitors are mainly used in the treatment of breast cancer. However, studies of cost-

effectiveness are needed to assess whether the high prices for these drugs can be justified with better outcomes and to what extent the total expenditure is acceptable for the health care system. Regional comparisons are important for future advancement within the field.

PURPOSE: The aim with this study was to describe whether there were any differences regarding the use of selected cancer drugs in Sweden’s six healthcare regions from 2005 to 2020.

METHOD: This research was a descriptive-comparative study. The aggregate-level data used in this paper was provided by the Swedish eHealth Agency and included the

measurement total sales cost per 100,000 inhabitants of cyclin-dependent kinase inhibitors for both outpatient care as well as inpatient care. The angiogenesis inhibitors and epidermal growth factor receptor inhibitors were solely used in inpatient care. All data included both genders and all ages.

RESULTS: The majority of the cancer drugs studied in this paper had an uneven use and major differences were noted between the regions as regards the consumption of specifically bevacizumab and palbociclib in all the healthcare regions. Notable was the uptake of

bevacizumab with approximately a four-fold difference between the southeast healthcare region and the west healthcare region in the year 2020. Palbociclib demonstrated circa seven- fold difference in uptake in the year 2020 between the west healthcare region and the north healthcare region.

CONCLUSION: Broadly, we can conclude that there are regional differences in the use of angiogenesis inhibitors and epidermal growth factor inhibitors in the treatment of colorectal cancer and gastric cancer. Cyclin-dependent kinase inhibitors also demonstrate regional differences in the treatment of breast cancer in Sweden’s six healthcare regions. It is of interest to further study why the regional differences exist in Sweden.

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Populärvetenskaplig sammanfattning

Gastrointestinala cancerformer är en av de dödligaste maligniteterna runtom i världen i båda könen och i alla åldrar, medan bröstcancer är den främsta dödsorsaken på grund av cancer hos kvinnor internationellt. Angiogeneshämmare och epidermal tillväxtfaktorhämmare används huvudsakligen i kolorektalcancer och magcancer, medan cyklinberoende kinashämmare huvudsakligen används vid behandling av bröstcancer. Det är dock av stort behov att studera kostnadseffektiviteten för att bedöma om behandlingen har en bättre effekt än andra

behandlingar och om de höga priserna på läkemedlen kan accepteras i hälso- och sjukvården.

Regionala jämförelser är viktiga för att tillhandahålla jämlik och högkvalitativ vård och behandling för hela landet.

Syftet med denna studie var att analysera om det fanns några skillnader avseende

användningen av utvalda cancerläkemedel i Sveriges sex vårdsregioner från 2005 till 2020.

Denna forskning var en beskrivande-jämförande studie i syfte att analysera om det fanns stora skillnader i användningen av utvalda cancerläkemedel i Sverige från 2005 till 2020. Den aggregerade data som användes i denna uppsats tillhandahölls av e-hälsomyndigheten och inkluderade all försäljning av cyklinberoende kinashämmare till både öppenvård och slutenvård. Angiogeneshämmare och epidermal tillväxtfaktorreceptorhämmare användes enbart på sjukhus och inkluderade både kön och alla åldrar.

Majoriteten av de cancerläkemedel som studerades i denna uppsats hade en ojämn användning och stora skillnader noterades mellan regionerna vad gäller konsumtionen av specifikt bevacizumab och palbociclib i alla hälso- och sjukvårdsregioner. Anmärkningsvärt var upptagandet av bevacizumab med ungefär en fyrfaldig skillnad mellan den sydostliga vårdsregionen och den västra hälsovårdsregionen år 2020. Palbociclib visade cirka sjufaldig skillnad i upptag under 2020 mellan den västra sjukvårdsregionen och den norra sjukvården område.

I stort sett kan vi dra slutsatsen att det finns regionala skillnader i användningen av angiogeneshämmare och epidermal tillväxtfaktorreceptorhämmare vid behandling av

kolorektal cancer och magsäckscancer. Cyklinberoende kinashämmare visade också regionala skillnader i behandlingen av bröst cancer i Sveriges sex vårdsregioner. Det är av intresse att ytterligare studera varför de regionala skillnaderna finns i Sverige.

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Acknowledgements

To start, I would like to express my special gratitude and appreciation to my supervisor, Nils Wilking, who dedicated his time in engaging me and providing scientific feedback and encouragement throughout my degree project.

I would also like to express my deepest appreciation to Björn Wettermark for his contribution and constructive recommendations on this degree project.

My warmest thank you to Kelly Smith for her diligent proofreading, criticism and linguistic improvements on this paper.

Furthermore, I am grateful to my fiancé, my parents, my siblings and my friends for always being by my side and supporting me throughout all my educational, professional and personal pursuits.

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List of Abbreviations

AIP: Pharmacy wholesale price AUP: Pharmacy manufacturer price BC: Breast cancer

BCS: Breast-conserving surgery CDK: Cyclin-dependent kinase CRC: Colorectal cancer

CRT: Chemoradiotherapy CT: Computed tomography

ECF: Epirubicin + cisplastin + 5-Fu EGFR: Epidermal growth factor receptor EMA: European medicines agency EOX: Epirubicin + oxaliplatin + capecitabin

ER: Estrogen receptor

ESMO: European society for medical oncology

FAP: Familial adenomatous polyposis FDA: Food and Drug Administration FLOT: Fluorouracil plus leucovorin, oxaliplatin and docetaxel

FOLFIRI: 5-fluorouracil, folinic acid and irinotecan

GC: Gastric cancer

GI: Gastrointestinal cancer

GOF: Gastrointestinal oncological society H. pylori: Helicobacter pylori

HDGC: Hereditary diffuse gastric cancer IHE: Institute for Health Economics INN: Non-proprietary name

mBC: Metastatic breast cancer

MCBS: Magnitude of Clinical Benefit Scale

mCRC: Metastatic colorectal cancer mGC: Metastatic gastric cancer MRI: Magnetic resonance imaging

NICE: National Institute for Health & Care Excellence

NT: New therapies OS: Overall survival

PET: Positron emission tomography PFS: Progression-free survival PR: Progesterone receptor RB: Retinoblastoma SEK: Swedish krona

SKR: Sveriges Kommuner och Regioner T-DM1: Trastuzumab-emtansin

TLV: Tand- och Läkemedelsförmånsverket VEGF: Vascular endothelial growth factor QALY: Quality-adjusted life years

QoL: Quality of life

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1. Background

1.1 Gastrointestinal cancers – colorectal and gastric cancer

Gastrointestinal (GI) cancer is used as a collective term when defining a variety of cancer types that include the gastrointestinal tract and the digestive system. GI cancers

are one of the most fatal malignancies worldwide, due to its wide range that involves cancer from the esophagus to the rectum (1).

This paper will address gastric cancer (GC) and colorectal cancer (CRC) which are responsible for most cancer mortalities internationally. The incidence of developing these cancer types have shown to be related to differences in gender and age, although the reason for that is not yet fully established. Research has developed in the field of cancer but the actual cause of most GC and CRC is still not fully understood, therefore further research in different aspect within those fields are required for future improvements (1, 2).

1.2 Breast cancer

Breast cancer (BC) is most common and the leading cause of cancer death among women globally. Incidence of BC has increased over the years but the survival rate has also increased due to early detection of the cancer and the developed neo/adjuvant therapies.

Due to different histological types of breast cancer and molecular variations, it is of great need to study this cancer form in further detail (3, 4, 5).

1.3 Epidemiology

Various studies have established that race and geographic differences have an impact in developing CRC and GC. The incidence and reduced survival rate of CRC have shown to be more common in African-Americans compared to other ethnicities (e.g., Caucasians).

However, these dissimilarities can also be explained by socioeconomic status rather than racial differences (1).

GC is a major problem for Asian countries, especially Japan, Mongolia and the Republic of Korea (Eastern Asia), where the incidence rate and mortality for both genders exceed the remaining parts of Asia (6). Research suggests that there are associations between ethnicity and the incidence of GC and are demonstrated by nationalities with high-risk incidence of GC

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who migrated to a country with low-risk incidence of GC. It is assumed that the migrated individuals have a higher risk to develop GC compared to the native population (7).

Incidence of BC, according to studies, is not correlated to any specific country or income.

However, the incidence rate is higher in regions with higher income (e.g., North America) and the rate is lower in low-income regions such as Middle Africa and East Africa. The mortality rate is lower in countries with well-developed healthcare systems and higher incomes, while mortality rate is higher in countries with poor healthcare systems and lower incomes.

Studies have also proven that ethnicities have an impact in developing and surviving BC, where black women have a lower risk of developing BC but lower survival rate compared to white women (8).

1.4 Risk factors

Gastric cancer and colorectal cancer

GC is a combination of two subtypes: cardia GC, which is referred to the top part of the stomach that connects the esophagus, and non-cardia GC that involves the entire stomach.

The risk for developing gastric non-cardia cancer and gastric cardia cancer are associated with gender differences where it is proven that men have a higher incidence risk compared to women. Other risk factors that arise from these subtypes include higher ages, smoking status, family history and genetics, among other factors. Family, especially first-degree relatives (parents, children, siblings), are associated with increased risk of GC incidence (9).

Inherited syndrome of GC, called hereditary diffuse gastric cancer (HDGC), which by its name refers to a diffuse type of stomach cancer that is difficult to detect in its early stages, results in a mutation in the CDH1-gene. This mutation results in the deactivation of the protein E-cadherin, an important cell adhesion protein (9).

Despite all the risk similarities between the subtypes, there are also other risk factors that are associated with each group separately. Helicobacter pylori (H. pylori) is one of the main causes for the incidence of non-cardia GC, but not in cardia GC. Earlier studies have also demonstrated that low socioeconomic status contributes to higher incidence of non-cardia GC, followed by dietary factors such as high salt intake (9). A strong, hereditary family history of CRC is typically the main reason for higher incidence risk of CRC, especially in first-degree relatives (10). Familial adenomatous polyposis (FAP) syndrome is an inherited condition and

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results in CRC at an early age, as well as other gastrointestinal malignancies. FAP is caused by a mutated gene, called adenomatous polyposis coli gene (9). The risk for CRC arises with increasing age but also with family history of inflammatory bowel disease. Other risk factors which lead to increased risk of CRC are smoking, alcohol consumption and obesity, among other factors (10).

Breast cancer

According to previous studies, age, breast characteristics, early menarche or late menopause are nongenetic risk factors that increase the risk of developing BC. Other nongenetic factors such as socioeconomic status, long-term hormone use, tobacco and alcohol use, and nutrition are also correlated to increased incidence risk of BC but are factors that can be modified.

First-degree relatives are also associated with increased risk of BC incidence, where the mutations in different genes such as BRCA are very common in most women (8).

Overexpression or gene amplification of the tyrosine kinase receptor HER2 are associated with tumors due to BC (4, 11). Many breast cancers are estrogen receptor (ER)-positive (ER+) but also progesterone receptor (PR)-positive (PR+), which means that BC cells grows as a response to the estrogen and progesterone hormone (12). Another risk factor related to increased incidence of BC is the overactivation of cyclin-dependent kinase 4/6- (CDK 4/6) pathway. Inhibiting the CDK 4/6 pathway has been associated with activation of the retinoblastoma (Rb) tumor suppressor protein which regulates the cell cycle (13).

1.5 International (ESMO) and national guidelines (EMA) – Diagnostic methods

1.5.1 Gastric cancer

To set up a successful treatment strategy, it is of great importance to evaluate the tumor stage, localization and the appearance of the tumor. This can be done by gastroscopy, which is an endoscopic examination of the esophagus, duodenum and ventricle followed by biopsies taken from the tumor. It is also important to determine the patient’s medical history to establish the most efficient and relevant treatment. Radiological methods, such as computed tomography (CT) scan, positron emission tomography (PET)-CT and magnetic resonance imaging (MRI) are usually performed to determine if the cancer has metastasized to other organs (e.g., lymph nodes). These methods are also used to facilitate the choice of treatment for GC patients (14, 16).

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1.5.2 Colorectal cancer

Primarily, colonoscopy is used to determine the presence of a tumor followed by biopsies that ensure the finding. To determine the spread of the tumor in CRC, radiological methods (e.g., CT and MRI) are used and the results from the screening methods provide background on which treatment to use (15).

CT, FDG-PET-CT are used to establish if the cancer has metastasized to other organs, such as the liver, lungs or lymph nodes. If liver metastasis is detected, it is necessary to perform an MRI specifically for the liver as a follow-up to determine the stage of the tumor. The methods mentioned above make it possible to establish if the tumor has spread to other organs and gives a comprehensive view of the stage of the cancer. Despite that, these methods are

performed to assess whether the cancer is curative and a plan for treatment can be maintained.

Medical history and the appearance of the tumor should be taken in consideration when choosing the relevant treatment for the patient (16, 17).

1.5.3 Breast cancer

Regular screening with mammography has proven to minimize deaths related to BC by 20 – 25 percent and is recommended for women in the age group 40 – 74 years. However, the minimized death rate is not applied to women with hereditary BC, and therefore these patients should combine yearly mammography and other screening methods (e.g., ultrasound and MRI) from the age of 30. If the screening results demonstrate any suspected findings, certain diagnostic steps should be performed to determine the type of BC present. Initially, the doctor performs a clinical examination which includes palpation of the breasts and regional lymph nodes, such as the armpit, neck and under the collarbones. When a tumor is located, it is important to image the breasts with different methods such as bilateral mammography, ultrasound and MRI in some cases to assure the localization, size and if the tumor has metastasized. It is recommended to combine the imaging with tissue biopsy to ensure the presence of the tumor and to confirm metastasized tumor. The above steps are important to perform to be able to determine the most compatible and beneficial treatment for the patient (18, 19).

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1.6 International (ESMO/ASCO) and national guidelines (EMA) – Treatments

1.6.1 Treatment of gastric cancer

Primary treatment depends on the clinical stage of the tumor, where stages 0 – I only require resection of the stomach and surrounding lymph nodes, which can be done using laparoscopic or open surgery. Stages II – III require a combination treatment involving surgical removal of the stomach and surrounding lymph nodes, followed by oncological treatment, called

postoperative chemotherapy (e.g., fluorouracil + leucovorin, oxaliplatin and docetaxel

(FLOT)). Patients with stage IV GC cannot undergo surgery and therefore it is recommended to use a first-line treatment, which is a combination curative treatment that includes radiation therapy and chemotherapy treatment. Second-line treatment for stage IV GC patients, should include chemotherapy in combination with AI (e.g., ramucirumab) (14, 16).

1.6.2 Oncological treatments of gastric cancer

Surgery alone does not improve the survival rate in stages II – III GC patients, therefore applying oncological treatments are necessary. Oncological treatments include adjuvant and/or neoadjuvant chemotherapy, where neoadjuvant chemotherapy is given before surgery and adjuvant therapy is given after surgery. Adjuvant chemotherapies are epirubicin + oxaliplatin + capecitabin (EOX) and epirubicin + cisplastin + 5-Fu (ECF). ECF has established its use in Europe as the standard treatment in GC patients, while EOX has established its use as a standard oncological treatment in Sweden (14, 16).

Combination treatment with chemotherapy and radiation therapy, called adjuvant chemoradiotherapy, is another oncological treatment approach that has proven to have a positive impact on the survival rate of GC. It is the mechanism of adjuvant 5-Fu-based chemotherapy, and combined with radiation therapy, that has an increased survival rate.

Adjuvant chemotherapy, using fluoropyrimidine S1, has also proven to offer a significant increase in the rate of survival and is used in Sweden for palliative care of GC. Adjuvant S1 therapy is not recommended to be used in other cases than palliative care since additional research’s needs to be performed in the Western countries and increased total survival should be proved before establishing the adjuvant chemotherapy using S1 (14, 16).

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1.6.3 Treatment of colorectal cancer Rectal cancer

To determine whether to perform open or laparoscopic surgery, to give preoperative radiation therapy for a short period of time or to perform chemoradiotherapy (CRT) for a long period, depends on the MRI results and the risk of recurrence of the tumor (low, intermediate or high risk). Low risk indicates a minimal risk of recurrence due to early stage of rectal cancer and can be treated directly with surgery without the need of preoperative radiation. Moderate risk, however, has higher risk for relapse and therefore it is recommended to apply 5x5 Gy

radiation therapy followed by a surgical procedure to increase the odds of survival. High risk patients usually have an advanced rectal cancer, where it is required to have a reduced tumor size to be able to perform the surgery. It is recommended for the patient to postpone the surgery until fulfilling long treatment using CRT to minimize the tumor. CRT is also

recommended when the cancer has metastasized to other places than originated (15, 17, 20).

Colon cancer

It is recommended to perform a laparoscopic or open surgery to remove the tumor no matter the cancer stage. For early-stage colon cancer the cancer cells can be removed with a

colonoscopy or minimal invasive surgery when the tumor is larger. In more advanced cases, surrounding normal tissue and lymph nodes can also be dissected with the tumor (15, 17, 20).

1.6.4 Oncological treatments of colorectal cancer Rectal cancer

Neoadjuvant treatment with chemotherapy and radiation therapy is usually necessary before surgery with the goal to reduce as much as possible of the tumor. Radiation therapy, such as 5x5 Gy, is given before surgery and has proven to increase the chance of survival and has established its use in Sweden as well as the rest of Europe. Oncological treatments combined with surgery have demonstrated positive results in the recurrence of rectal cancer but not in metastatic cases. Adjuvant radiation therapy in combination with chemotherapy is another approach, but the actual efficacy of the combination is not yet fully studied (15, 17, 20).

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Colon cancer

Surgery are usually applied for patients with colon cancer without any preoperative treatments (e.g., chemotherapy and radiation therapy). In expectational cases, preoperative treatment can be performed before surgery for the purpose to minimize the size of the tumor. Adjuvant therapies (e.g., chemotherapy and radiation therapy) are usually applied after surgery to avoid recurrence of the tumor and as a symptom reliever in palliative patients (15, 17, 20).

1.6.5 Treatment of breast cancer

Breast cancer treatment choice is based on the size and location of the primary tumor, but also including other factors such as pathology results, if the cancer has metastasized and if the lymph nodes are affected. Surgery, such as breast-conserving surgery (BCS), is the preferred approaches for BC treatment. It is beneficial to combine the surgery with postoperative treatment (e.g., radiation therapy) in the early stages of BC to minimize the recurrence.

However, more advanced cancers should have a different and custom surgery approach including preoperative chemotherapy and/or antibody (HER2) therapy (18, 19).

1.6.6 Oncological treatments of breast cancer

Preoperative treatment is recommended before surgery for patients with locally advanced BC and HER2+ tumors as well as triple negative tumors (ER-/PgR-/HER2-). Patients can be treated for different lengths of time depending on factors like cancer stage, development and the patient’s general health condition. Patients with HER2+ cancer and remaining cancer cells after preoperative treatment are recommended to be given preoperative treatment for an additional 12 months which equals to 14 cycles of trastuzumab-emtansin (T-DM1). T-DM1 has proven to be efficient for the survival rate of BC. Postoperative radiation therapy has proven to be efficient against BC and minimize the risk of recurrence and increases the survival rate in all stages of BC (18, 19).

1.6.7 Epidermal growth factor-inhibitors in colorectal cancer

Developing metastatic colorectal cancer (mCRC) has been correlated to the activation of epidermal growth factor receptor- (EGFR) mediated pathway that activates further intracellular pathways. EGFR is a protein that is essential for cell differentiation,

proliferation, migration and angiogenesis: however, overexpression of EGFR in the body results in cancer cell growth (21).

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Cetuximab and panitumumab, called anti-EGFR, are monoclonal antibodies that target EGFR and blocks its signal activation. Cetuximab is approved as a single treatment, but due to the different mutation types involved in mCRC, anti-EGFR alone is not efficient and is therefore combined with chemotherapy to achieve the most efficient therapy. (22, 23).

1.6.8 Angiogenesis inhibitors in gastric cancer and colorectal cancer

The development of CRC and GC have been associated with the vascular endothelial growth factor (VEGF) family which include VEGF A to D. Angiogenesis inhibitors (AIs) such as bevacizumab, aflibercept and ramucirumab have shown to be effective in the treatment of CRC and ramucirumab also against GC by reducing the serum level of VEGF. High level of VEGF correlates with high mortality of CRC and GC, but inhibiting the signal that secrets from the interaction results in tumor reduction. A dimerization of two receptors occur when the VEGF A – D interact with their specific receptors (VEGFR-1, VEGFR-2, VEGFR-3) and results in initiated signal activation of different pathways. AIs, in general, acts by blocking diverse pathway activation that occurs due to the interaction between VEGF A, B, C or D with their specific receptors (24–26). In some clinical studies the AIs mentioned above increases the survival rate of advanced cases of CRC when combined with chemotherapy while most studies have not been able to demonstrate a survival benefit and regulatory approval have then been based on increased progression-free survival (PFS) (24–28).

The fully human monoclonal antibody, ramucirumab, target VEGFR-2, by binding to the receptor and blocking the interaction for VEGF. Ramucirumab has demonstrated an antitumor activity and, to date, is used to treat advanced cases of GC and CRC (13, 14).

Bevacizumab is an immunoglobulin G1-antibody that targets VEGF-A by inhibiting the signal of the interaction between the receptor and VEGF-A. The mechanism of bevacizumab has indicated prolonged survival rates for subgroups of mCRC and GC (26, 27). Aflibercept is a fused recombinant protein that blocks VEGF-A and VEGF-B activities separately by

inhibiting the VEGF to bind into their specific receptors. Aflibercept has shown to be

effective against advanced cases of CRC resulting in significantly increased survival rate (28).

The prescription and consumption of AIs, EGFR-inhibitors and CDK-inhibitors can vary depending on many factors, such as geographical areas, and the specific guidelines and recommendations applicable in that country. To ascertain whether there are any differences in the different Swedish healthcare regions, this research is focused on a descriptive-comparative

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study with the purpose to compare and examine the use of the above-mentioned medication consumption in the entire country. The amount of drugs used will be based on the price of the drug per milligram, which will be illustrated for all the medications mentioned earlier.

Moreover, to approach the national price comparison, the regions should be similar regarding their guidelines and evaluations regarding the drug use.

1.6.9 Cyclin-dependent kinase inhibitors in breast cancer

Studies have proven that changes in the D/CDK/Rb pathway, especially overexpression of cyclin D1 and minimized expression of Rb, are correlated to many cases of BC. The alternations in the pathway have been associated with particularly HER2+ BC.

Abemaciclib, palbociclib and ribociclib are all CDK-inhibitors, which inhibits the complex between CDK4/cyclin D1 that are responsible for phosphorylation and targets a protein called Rb tumor suppressor gene by inhibiting it. These drugs selectively target the CDK4 and CDK6 and inhibits the overactivation of these pathways and increases the expression of Rb.

Rb is essential for cell progression and by inhibiting the CDK4/CDK6, Rb will restore its properties and continue with cellular proliferation and replicating the DNA (29, 30).

1.7 EMA – National guidelines

Authorization for each specific indication of the drugs is based on the approval by the European Medicines Agency (EMA) and in the USA the Food and Drugs Administration (FDA) (31 – 38). National guidelines include recommendations and guidance for health care providers for a specific country. National guidelines facilitate the choice of the right treatment for every individual. Summarization of each medication, their ATC-code, International Non- proprietary Name (INN), brand name, authorization date and indication will be presented in table 1.

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Table 1. Overview of the cancer medication addressed in this study, including their ATC-code, INN, brand name, date of authorization and indication.

ATC-code INN/Chemical name Brand name Authorization year

(EMA) Cancer types

L01XC06 Cetuximab Erbitux 2006 Colorectal cancer; squamous cell carcinoma

L01XC08 Panitumumab Vectibix 2007 Colorectal cancer

L01XX44 Aflibercept Zaltrap 2013 Colorectal cancer

L01XC07

Bevacizumab Avastin

2007

2008 2011 2015

Breast cancer; colorectal cancer; non-small cell lung cancer

Renal cell cancer Ovarian cancer Cervical cancer

L01XC21

Ramucirumab Cyramza

2014 2015 2019 2020

Gastric cancer Colorectal cancer Hepatocellular carcinoma Non-small cell lung cancer L01XE50 Abemaciclib Verzenios 2018 Breast cancer (HR+, HER2-) L01XE33 Palbociclib Ibrance 2016 Breast cancer (HR+, HER2-) L01XE42 Ribociclib Kisqali 2017 Breast cancer (HR+, HER2-)

1.7.1 Indication and dose of AIs Bevacizumab

The EMA and FDA has approved the use of bevacizumab as a monoclonal antibody against mCRC, in combination with cytostatic chemotherapy medications that contains the substance fluoropyrimidine. Bevacizumab was earlier approved against metastatic breast cancer (mBC) by the FDA but was later withdrawn in the USA but is by date approved by EMA with the indication mBC in combination with paclitaxel. Bevacizumab is a solution that established its use as a cancer medicine and is administered directly into the vein as an infusion. Depending on cancer stage, the recommended dose varies between 5 – 15 milligrams per kilogram body weight and should be given every 2 – 3 weeks and given until no more clinical benefit is recorded during the treatment (31).

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Ramucirumab

Ramucirumab is also approved by the EMA and obtains the indications GC and CRC. It is recommended to use ramucirumab combined with paclitaxel for the indication GC after progression of the disease and already used chemotherapy that include fluoropyrimidine and platinum. Ramucirumab is also approved in GC patients after progression of GC when combination with paclitaxel is not relevant (32).

Ramucirumab is a concentrate solution that is given as an infusion. It is recommended to give ramucirumab as a 28-day cycle with 8 milligrams per kilogram body weight on day 1 and the same amount on day 15, in combination with paclitaxel for GC patients. It is recommended to administer 8 milligrams per kilogram body weight every 2 weeks combined with 5-

fluorouracil, folinic acid and irinotecan (FOLFIRI) against CRC (32).

Aflibercept

The protein aflibercept is approved for the indication mCRC when combined with FOLFIRI according to the EMA, when other treatments have failed to improve the cancer stage.

Aflibercept is given as an infusion with the recommended dose of 4 milligrams per kilogram body weight administered every 2 weeks until the patient shows no more clinical effective signs of the treatment (33).

1.7.2 Indication and dose of EGFR-inhibitors Cetuximab

Cetuximab has the therapeutic indication mCRC, however, it has to be combined with irinotecan-based chemotherapy and in combination with FOLFOX. Cetuximab is also approved as a monotherapy therapy if the patient cannot tolerate irinotecan or the patient has not responded well to other treatments (e.g., oxaliplatin and irinotecan therapies). Cetuximab is a solution given as an infusion with the initial dose of 12 milligrams per kilogram body weightand 7,5 milligrams per kilogram body weightonce a week. The treatment should be given until progression of the disease are shown (34).

Panitumumab

Panitumumab obtains the indication mCRC and best results are obtained when combined with FOLFOX or FOLFIRI. Panitumumab is the second-line choice when combined with

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FOLFIRI if the patient has already received chemotherapy that contains fluoropyrimidine.

Panitumumab can also be used as a single agent or in combination with chemotherapy.

Panitumumab is a solution and administered as an infusion once every two weeks with the dose of 6 milligrams per kilogram body weight (35).

1.7.3 Indication and dose of cyclin-dependent kinase inhibitors Abemaciclib

Abemaciclib is approved with the therapeutic indication hormone dependent mBC in

combination with endocrine based therapy. Abemaciclib tablets are given in combination with endocrine treatment (aromatase inhibitors or fulvestrant) until the patient shows

improvements or until unbearable side effects appear. The recommended dose for this indication is a daily dose of 150 milligrams twice a day (36).

Palbociclib

Palbociclib obtains the indication hormone dependent mBC when combined with aromatase inhibitors or fulvestrant to patients who have undergone endocrine treatment. Palbociclib are prepared as capsules with the recommended dose of 125 milligrams once a day for 21 days followed by a break for 7 days. The treatment cycle should continue until the patient shows clinical improvements or unbearable side effects occur (37).

Ribociclib

Ribociclib are indicated to treat hormone dependent mBC in combination with aromatase inhibitors or fulvestrant for patients who undergo or have undergone endocrine therapy.

Ribociclib has the pharmaceutical form as pills, with the dose 200 milligrams three times a day for 21 days and 7 days off treatment in order to have a 28-day cycle. The therapy should continue if the patient experiences clinical benefits (38).

1.7.4 EMA documentation – Clinical effect and safety of each medication

Documentation regarding clinical safety and efficacy of each drug and their combined agent(s) used for their intended indication are presented in table 2 and table 3. The studies performed on the drugs were compared to placebo and the results were calculated as median of progression free survival (PFS) and median of overall survival (OS) given in months. PFS and OS are endpoints to be considered in clinical trials when assessing new drug therapies.

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PFS refers to patients that after or during treatment did not experience new tumor growth or cancer spreading and OS can be referred to patient survival duration after/during cancer treatment until death (39).

As for aflibercept + FOLFIRI, bevacizumab + FOLFOX4/IFL and ramucirumab + FOLFIRI with the indication mCRC, they also had an increased median OS and PFS compared to placebo (40 – 42).

Ramucirumab + paclitaxel for the indication mGC demonstrated increased PFS and OS.

Cetuximab + FOLFIRI, panitumumab + FOLFOX4/FOLFIRI for the indication mCRC however provided different results (42 – 44).

Overall, the results for each study were satisfying and the EMA has, based on the performed and published studies on the clinical safety and efficacy of each drug, approved the drugs with their combined agent(s) for a specific indication.

Table 2. Overview of clinical safety and efficacy of drugs against CRC and GC based on EMAs’ documentation.

INN + combined agent Median OS

(months)

Median OS placebo (months)

Median PFS (months)

Median PFS placebo (months)

Aflibercept + FOLFIRI 13.50 12.06 6.90 4.67

Bevacizumab + FOLFOX4 21.2 19.9 9.4 8.0

Bevacizumab + IFL 20.3 15.6 10.6 6.2

Cetuximab + FOLFIRI *16.4; 28.4** *17.7; 20.2** *7.4; 11.4** *7.5; 8.4**

Panitumumab + FOLFOX4 *26.0; 15.6** *20.2; 19.2** *10.1; 7.3** *7.9; 8.7**

Panitumumab + FOLFIRI *16.2; 11.8** *13.9; 11.1** *6.4; 4.8** *4.6; 4.0**

Ramucirumab + Paclitaxel 9.6 7.4 4.4 2.9

Ramucirumab + FOLFIRI 13.3 11.7 5.7 4.5

PFS: progression-free survival | OS: overall survival | * Patients with wildtype-RAS mCRC | ** Patients with mutated-RAS mCRC

Breast cancer

Abemaciclib + aromatase inhibitor and bevacizumab + paclitaxel with the approved indication mBC had an increased PFS compared to placebo. The OS for abemaciclib + aromatase inhibitor could not be calculated. Abemaciclib/palbociclib + fulvestrant for the indication BC and mBC had an increased median PFS and median OS compared to placebo.

Ribociclib + fulvestrant demonstrated increased PFS but median OS could not be presented (45 – 47).

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Palbociclib/ribociclib + letrozole for the approved indication mBC showed increased PFS compared to placebo but OS could not be discussed due to poor evidence in the study.

Ribociclib + endocrine therapy for the indication mBC resulted in higher PFS compared to placebo, but OS could not be demonstrated due to poor evidence (45 – 47).

Table 3. Overview of clinical safety and efficacy of drugs against BC based on EMAs’ documentation.

INN + combined agent Median OS

(months)

Median OS placebo (months)

Median PFS (months)

Median PFS placebo (months)

Abemaciclib + aromatase inhibitor - - 28.18 14.76

Abemaciclib + Fulvestrant 46.7 37.3 16.4 9.3

Bevacizumab + Paclitaxel 26.5 24.8 11.3 5.8

Palbociclib + Letrozole - - 35.7 19.5

Palbociclib + Fulvestran 34.9 28.0 11.2 4.6

Ribociclib + Letrozole - - 25.3 16.0

Ribociclib + endocrine therapy - - 27.5 13.8

Ribociclib + Fulvestrant - - 20.6 12.8

PFS: progression-free survival | OS: overall survival

National and international recommendations regarding treatments, oncological approaches, doses and drugs used against CRC and GC are complementary to each other (14, 15).

Even though EGFR-inhibitors and AIs are recommended treatments according to guidelines, different research provides various health benefits and their actual efficiency have not been established yet: therefore, further studies should be developed to prove the health benefit when combining AIs and oncological treatments in CRC and GC (48).

Evidence regarding adjuvant treatment with bevacizumab in CRC stages II – III has been negative and it is not recommended to use bevacizumab in these stages. Cetuximab, however, showed significant improvement of OS when used in combination with preoperative CRT before surgery in CRC, but the proof was not enough to establish the clinical benefit of the combination (48).

Aflibercept also demonstrated improvements when combined with preoperative CRT, but the proof of benefit was not enough. Aflibercept combined with palliative cytostatic

chemotherapy showed significant improvement and medium health benefits for CRC patients but not in GC patients. Ramucirumab was also proven to have induced benefits when

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combined with palliative chemotherapy for GC and CRC patients, but other studies regarding its use in mCRC and GC have not yet been positive (48).

Breast cancer

Earlier studies have demonstrated that abemaciclib, palbociclib and ribociclib improves the progression-free survival rate in advanced cases of human epidermal growth factor receptor 2- positive (HER2+) and hormone receptor positive (HR+) BC when combined with endocrine treatment (e.g., aromatase inhibitors). It is recommended to administrate the CDK4/6

inhibitors as first-line treatment and also for patients who have been treated for metastatic BC.

The three different medications have proven to have almost similar effectiveness in treating mBC, and a close, acceptable tolerability and safety profile (49, 50).

1.8 Health economic evaluations

Health economic evaluations are of great importance when choosing the relevant treatment for a patient. The most beneficial treatment should be chosen but at the same time be cost- effective regarding resource distribution, for healthcare and society. Cost-benefit analysis can be measured in quality-adjusted life years (QALY), which are used to determine the quality of life (QoL) set in relation to the survival of the patient.

Population-based screening for CRC has been assessed as cost-effective through the perspective of the society and healthcare in older population (60 – 74 years) as well as younger population (50 – 69 years) (51).

Laparoscopic surgery and open surgery have proven to be equivalent regarding the cost- effectiveness in the long run. However, laparoscopic surgery in short-term appears to have higher cost-effectiveness compared to open surgery in both GC and CRC. Adjuvant combination therapy and surgery have proven to be more cost-saving when comparing to adjuvant monotherapy of either option (52).

In cases of recurrence of CRC where combination therapy is not appropriate, bevacizumab solely is used as a treatment. The treatment with bevacizumab is however not considered to be advantageous due to a high cost per QALY. EGFR (e.g., cetuximab combined with cytostatic

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chemotherapy) results in moderate cost per QALY and is therefore recommended as a treatment against mCRC (53).

Ramucirumab in combination with chemotherapy in the treatment of GC have shown to be cost-effective when compared to other combination treatments involving ramucirumab. The cost-effective analysis was measured based on the life quality of the patients in comparison to the pricing as well as cost per QALY (53). Ramucirumab in combination with aflibercept and FOLFIRI against mCRC have shown to be efficient, despite it being expensive. However, Ramucirumab has demonstrated that the benefits overweigh the risks and therefore it is found to be cost-effective (54).

Breast cancer

Abemaciclib in combination with aromatase inhibitors have proven to be the most effective treatment among the CDK-inhibitors, by demonstrating the highest QALY. However, the cost per QALY exceeds the benefits of the treatment and assumption of abemaciclib being cost- effective could not be established (55, 56).

Ribociclib combined with letrozole have proven to be more cost-effective when compared to palbociclib combined with letrozole. The results were obtained by measuring the health benefit and pricing of each treatment and was established by calculating QALY gained.

However, both treatments despite their increased PFS were considered to not be cost-effective when comparing the price per treatment to gained QALY (55, 56).

1.9 National guidelines – Swedish agencies

The New Therapies (NT) Council provides recommendations to different Swedish counties regarding the use of novel drugs. The NT council includes members with various of

competences, such as medical or pharmaceutical, as well as representatives with expertise in ethics and health economics. The NT Council take into consideration the ethical principal rather than the health economic evaluations. The ethical principle and priorities to be considered are the principle of human value, the principle of need and solidarity and cost- effectiveness (57, 58). However, the NT-council have not any recommendation at present that are applied for the medications discussed in this paper.

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1.9.1 The National Board of Health and Welfare recommendations

The National Board of Health and Welfare (Socialstyrelsen) is a Swedish government agency in charge of maintaining an equal high-quality treatment for the entire Swedish population.

The agency’s guidelines include medications approved before 2015 and therefore the newer medications (such as CDK-inhibitors and ramucirumab) do not obtain any recommendations from this particular agency (table 4). Their recommendations are based on a ranking system that goes from 1 – 10, with 1 considered to have the highest priority and 10 the lowest priority (59).

Table 4. The National Board of Health and Welfare recommendations per indication.

INN + combined agent Score Comments Indication

Aflibercept + FOLFIRI 9 Not recommended mCRC

Bevacizumab + chemotherapy 8 Not recommended mCRC

Bevacizumab + FOLFOX4 8 Not recommended mCRC

Bevacizumab + IFL 8 Not recommended mCRC

Cetuximab + FOLFIRI 5 Not recommended mCRC

Panitumumab + FOLFIRI 5 Not recommended mCRC

Comment explanation: not recommended to use

1.9.2 National guidelines recommendations

The National guidelines is a part of the organization SKR (Sveriges Kommuner och Regioner;

The Swedish Municipalities and Regions) that focuses on cancer treatments for Sweden. They provide guidance and recommendations regarding diagnostics and treatment, among other things. Their guidance and recommendations are not only based on regulatory approval by EMA but also on evaluations and recommendations by the NT group. Their recommendations apply to the entire country with the goal to obtain an equal care for all patients and also achieve regional cooperation (14, 15, 18).

The National guidelines uses GRADE as the evidence-grade system and is based on the strength of the provided scientific evidence, where four ++++ means very strong scientific evidence and one + means poor/not enough scientific evidence (table 5, table 6).

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Table 5. The National guidelines recommendations in the treatment of CRC and GC.

INN + combined agent GRADE Comments Indication

Aflibercept + FOLFIRI - Weak evidence mCRC

Bevacizumab + FOLFOX4 - Weak evidence mCRC

Cetuximab + FOLFIRI - Weak evidence mCRC

Panitumumab + FOLFOX4 - Weak evidence mCRC

Panitumumab + FOLFIRI - Weak evidence mCRC

Ramucirumab + Paclitaxel ++++ Evaluate treatment mGC

Weak evidence: not recommended to use | Evaluate treatment: recommended to use Table 6. The National guidelines recommendations in the treatment of BC.

INN + combined agent GRADE Comments Indication

Abemaciclib + aromatase inhibitor ++++ Increased PFS mBC

Abemaciclib + Fulvestrant ++++ Increased PFS BC

Bevacizumab + Paclitaxel ++++ Selected cases mBC

Palbociclib + Letrozole ++++ Recommended mBC

Palbociclib + Fulvestran ++++ Recommended mBC

Ribociclib + Letrozole ++++ Increased PFS mBC

Ribociclib + endocrine therapy ++++ Increased PFS mBC

Ribociclib + Fulvestrant ++++ Increased PFS mBC

Selected cases: recommended to use

1.9.3 Gastrointestinal Oncological Society recommendations

Gastrointestinal Oncological Society (GOFs) evaluates new GI cancer treatments based on earlier studies and focuses on health economic evaluation and risk-benefit analysis. GOF rates the drug depending on the clinical benefit and based on how strong the drugs clinical benefits have showed in earlier studies, where strong clinical effect is desired (60). GOFs

recommendations are independent and differs from other agencies (table 7).

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Table 7. GOFs recommendations per indication.

INN + combined agent Evidence for

clinical benefit Comments Indication

Aflibercept + FOLFIRI Moderate Increased OS and PFS, RR same mCRC Bevacizumab + chemotherapy Not enough Decreased OS and PFS, RR increased mCRC Bevacizumab + FOLFOX4 Not enough Vague results, increased PFS, OS same mCRC Bevacizumab + IFL Not enough Increased RR not optimal mCRC

Cetuximab + FOLFIRI Missing Small study population mCRC

Panitumumab + FOLFOX4 Moderate Increased RR mCRC

Panitumumab + mFOLFOX6 Moderate Increased OS and PFS mCRC

Panitumumab + FOLFIRI Moderate Increased PFS and OS mCRC

Ramucirumab + FOLFIRI Moderate Increased OS and PFS, RR same mCRC Ramucirumab + Paclitaxel Moderate Increased OS and PFS mGC OS = overall survival | PFS = progression free survival | RR = response rate

1.10 International guidelines – ESMO and NICE recommendations

The European Society for Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale (ESMO-MCBS) is a scale used to obtain an approximate assessment of the clinical benefits and is especially used when evaluating oncological treatments and for supporting customized recommendations for the medications. The scoring used for non-curative cancer indications goes from 1 – 5, with 5 being the highest possible score. Scores 4 and 5 are considered to have a substantial benefit but other factors should be taken into consideration (e.g., the price value). For curative indications, A is the highest score that can be obtained, but A and B are considered to have a benefit and should be further evaluated. ESMO’s scoring system is based on scientific evidence and earlier published studies. National Institute for Health and Care Excellence (NICE) in the UK, however, does not use a scale to evaluate the drugs, but bases their guidance on earlier studies and they either recommend or do not recommend the use of the drug. Both NICE and ESMO recommendations are important international guidelines that should be reviewed and taken into consideration when evaluating a novel drug but also older drugs on the market. NICE and ESMO recommendations are applied for Europe in its entirety to a different degree (61, 62) (table 9, table 10).

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Table 8. ESMO and NICE recommendations in the treatment of CRC and GC.

INN + combined agent ESMO-MCBS NICE Indication

Aflibercept + FOLFIRI 1 Not recommended mCRC

Bevacizumab + chemotherapy 1 Not recommended mCRC

Bevacizumab + FOLFOX4 3 Not recommended mCRC

Bevacizumab + IFL 3 Not recommended mCRC

Cetuximab + FOLFIRI 4 Recommended mCRC

Panitumumab + FOLFOX4 4 Recommended mCRC

Panitumumab + mFOLFOX6 3 Recommended mCRC

Panitumumab + FOLFIRI 3 Recommended mCRC

Ramucirumab + FOLFIRI 1 - mCRC

Ramucirumab + Paclitaxel 2 Not recommended mGC

Table 9. ESMO and NICE recommendations in the treatment of BC.

INN + combined agent ESMO-MCBS NICE Indication

Abemaciclib + aromatase inhibitor 3 Recommended mBC

Abemaciclib + Fulvestrant 4 Recommended BC

Bevacizumab + Paclitaxel 2 Not recommended mBC

Palbociclib + Letrozole 3 Recommended mBC

Palbociclib + Fulvestran 4 Recommended mBC

Ribociclib + Letrozole 3 Recommended mBC

Ribociclib + endocrine therapy 5 Recommended mBC

Ribociclib + Fulvestrant 4 Recommended mBC

Comment explanation - Not recommended: to use | Recommended: to use

1.11 Problem discussion

At present day, there is limited information about comparative studies between the Swedish healthcare regions regarding the use of AIs, EGFR-inhibitors and CDK-inhibitors in cancer patients. Comparative regional studies, especially drug utilization studies, are of great importance to apply with the purpose to benefit the healthcare facilities into providing an equal, effective and safe use of different medications. Further, those studies can introduce interesting discussion and promote further studies as regards improvements in areas such as consumption and prescription, focusing on medicinal and economical evaluations (63).

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2. Aims

The aim of this descriptive-comparison study was to describe whether there were differences regarding the use of specific CRC and GC medications and BC medications in Sweden from 2005 to 2020. The findings from this research can be applied to future research to highlight the factors that affect drug uptake and use, and to study why the use varies between these healthcare regions with the intention to help further advancements in the research of various cancer types.

3. Methods

This research was a descriptive-comparative cross-sectional study that is applied to describe the pattern in the use of AIs, EGFR-inhibitors and CDK-inhibitors between the different healthcare regions in Sweden. This research was based on Swedish aggregate-level sales data and therefore it was not necessary to apply for an ethical approval in order to be able to perform the study.

3.1 Obtaining publications

PubMed was used as a database to obtain publications by using inclusion and exclusion criteria to match our paper. In addition, information was obtained through different websites, such as EMA, ESMO, NICE and Janusinfo by manually searching for drugs of interest directly on the platform.

3.2 Data collection and study population

This study focuses on Swedish patients of both genders and all ages who were consulted inpatient and outpatient care for treatment of BC between 2016 – 2020. Swedish GI cancer patients of both genders and all ages who were hospitalized between 2005 – 2020 were also included in this paper.

Aggregate-level sales data for each Swedish healthcare region used for comparison was extracted from the Swedish eHealth Agency for 2005 to 2020 for selected medicines (ATC- codes; L01XC06, L01XC07, L01XC08, L01XC21, L01XX44, L01XE50, L01XE33, L01XE42) used for GC and BC. The Swedish aggregate-sale data was obtained through the statistical software “concise” by inserting the medication name in order to obtain information about sale pricing, amount of sold packages, to whom the medication was sold, and dose and

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indication, among other information. The agency facilitates tracking of drug consumption by storing all sales made by different bodies such as pharmacies or retailers to hospitals.

The provided data for the EGFR-inhibitors and AIs reflected the total sales of each

medication provided by the local healthcare facilities to different healthcare regions in the purpose to be used in hospitals. The data for CDK-inhibitors reflected the total sales of each medication that was provided from healthcare facility to both hospitals and pharmacies to be used for inpatient care as well as outpatient care facilities. The cost per medication sold for the outpatient care used the pharmacy price (AUP) as the measurement of expenditure. The cost per medication sold to hospitals for inpatient use or administrations in daycare was calculated as the wholesale price (AIP). That means that the pharmacy margins usually added on sales in outpatient care was not added. Pharmaceutical companies also offer discounts to the regions for the purchase to inpatient care of the drugs discussed in this paper. However, how much discount the regions get is usually not available to the public and is kept secret between the regions, the company and the Swedish reimbursement agency; The Dental and Pharmaceutical Benefits Agency (TLV).

To establish whether there were differences in drug utilization of selected cancer medications in Sweden, the obtained data for each region was illustrated in the form of tables and

diagrams by comparing the amount of drug use and cost per 100,000 inhabitants. To obtain the total sales cost for the year 2020, the total cost per 100,000 residents for the first six months of the year was multiplied by two to obtain the cost for the entire year (60).

The obtained results of the aggregate-sales data are presented as figures and text to give a better perception of regional differences regarding the use of AIs, EGFR-inhibitors and CDK- inhibitors in all six regional healthcare cancer centers in Sweden. Each drug will be presented as the total cost per 100,000 inhabitants in all the healthcare regions followed by a short description of the total cost, total cost per incidence and the total cost per mortality, which will be referred in the article as figures attached as appendices for more detailed results (A1 – A24).

Further, the total cost per 100,000 inhabitants of each group of medication and each

healthcare region separately will also be presented as bar charts and a short description will be included to assist with the key findings regarding the regional differences of the drug

consumption in all six healthcare regions.

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3.3 Fact about the six healthcare regions

The regional cancer centers and the regions they cover are presented in table 10, followed by number of inhabitants year 2005 and 2019.

Table 10. Six Regional Cancer Centers (RCC), their regions and population in the regions year 2005 and 2019.

Regional Cancer Centers (RCC)

Regions Population year

2005

Population year 2019

North healthcare

region Jämtland; Norrbotten; Västerbotten;

Västernorrland 880,156 897,986

Stockholm–Gotland

healthcare region Gotland; Stockholm 1,947,433 2,436,767

Southeast healthcare

region Jönköping; Kalmar; Östergötland 980,426 1,074,540

South healthcare region

Blekinge; Kronoberg; Skåne 1,641,537 1,905,826

Uppsala–Örebro

healthcare region Dalarna; Gävleborg; Södermanland;

Uppsala; Värmland; Västmanland; Örebro 1,926,811 2,119,665 West healthcare

region Halland; Västra Götaland 1,671,389 1,892,805

3.3.1 Cancer statistics year 2019 and 2005

Further, figure 1 – 6 represent new cases of each cancer group (GC/CRC/BC) per 100,000 inhabitants for year 2005 and 2019 for men (green) and women (purple).

Figure 1. New cases of GC/100,000 inhabitants for men and women year 2005.

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Figure 2. New cases of GC/100,000 inhabitants for men and women year 2019.

Figure 3. New cases of CRC/100,000 inhabitants for men and women year 2005.

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Figure 4. New cases of CRC/100,000 inhabitants for men and women year 2019.

Breast cancer

Figure 5. Number of new cases of BC/100,000 inhabitants for men and women year 2005.

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Figure 6. Number of new cases of GC/100,000 inhabitants for men and women year 2019.

4. Results

4.1 Regional differences of each medication separately 4.1.1 Aflibercept in the treatment of CRC

Aflibercept use as SEK used per 100,000 residents where the variation in cost between different healthcare regions can be explained by the increased use within some regions and is correlated with the total price of aflibercept in that specific region (figure 7). Although the use is equally distributed in the regions, some regions had a higher cost compared to others, which can be explained by the number of populations in that region. The cost of the use per 100,000 residents has decreased over the years in almost all the different regions, except the Stockholm-Gotland region which has slightly increased during 2019 – 2020. However, the difference in cost per 100,000 inhabitants in Sweden maintained a steady level during 2013 – 2020. The cost per 100,000 inhabitants in the entire country between 2013 – 2020 was 928,107 SEK.

Comparison between the Swedish healthcare regions regarding the use of different cancer medications: - breast cancer, colorectal cancer and gastric cancer

Abstract

Populärvetenskaplig sammanfattning

Acknowledgements

List of Abbreviations

Table of contents

1. Background

2. Aims

3. Methods

4. Results