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ORIGINAL ARTICLE

Acta Medica Indonesiana - The Indonesian Journal of Internal Medicine

Influence of the Sorafenib Patients Assistance Program on Treatment Compliance and Overall Survival of Unresectable Hepatocellular Carcinoma Patients

Laurentius A. Lesmana1, Rino A. Gani1, Irsan Hasan1, Agus Waspodo2, Poernomo Boedi3, Melissa S. Luwia4, Adityawati Ganggaiswari4

1 Department of Internal Medicine, Faculty of Medicine, University of Indonesia - Cipto Mangunkusumo Hospital. Jl. Diponegoro no. 71, Jakarta Pusat 10430, Indonesia. Correspondence mail: llesmana.id@gmail.com.2 Dharmais National Cancer Center, Jakarta Indonesia.3 Department of Internal Medicine, Faculty of Medicine, University of Airlangga, Surabaya, Indonesia.4 Indonesian Cancer Foundation, Jakarta Indonesia.

ABSTRAKTujuan: mengevaluasi kepatuhan pengobatan dan kesintasan pasien-pasien yang menerima Sorafeniboral

di Indonesia. Metode: uji kohort prospektif. Pasien karsinoma hepatoseluler yang tidak dapat di reseksi lagi yang menerima Sorafenib pada program NexPAP antara Oktober 2008 dan September 2011. Sejarah kohort dari RSCM, antara 1998 – 2000 dipilih sebagai kelompok kontrol. Pasien pada kelompok kontrol menerima pengobatan simptomatik. Analisa kesintasan dilakukan dengan analisa kurva Kaplan-Meier dan tes log-rank. Perbedaan median kesintasan antara kelompok NexPAP dan kontrol diuji menggunakan analisis hazard cox regresi. Hasil: ada 48 pasien pada kelompok NexPAP dan 40 pasien pada kelompok kontrol. Kepatuhan pengobatan sangatbaik, tidak ada pasien yang berhenti dari studi. Secara umum, Sorafenib dapat di toleransi oleh pasien. Kejadian tidak diinginkan paling sering adalah reaksi kulit tangan dan kaki yang ringan atau sedang. Median kesintasan pada kelompok NexPAP adalah 49 minggu (95% IK 37.9–60.1) berbanding 20 minggu pada kelompok kontrol (95% IK 9.0–31.0). Analisis Regresi Cox memperlihatkan bahwa Sorafenib signifikan memperpanjang kesintasan dengan rasio hazard (HR) 0.339 (95% IK 0.196–0.584). Tidak ada perbedaan kesintasan antara pasien dengan Child Pugh kelas A dan kelas B baik pada kelompok NexPAP (median 49 berbanding 52 minggu; HR 1.1; 95% IK 0.5–2.3; p = 0.855) maupun kontrol (27 berbanding 20 minggu; HR 1.1; 95% IK 0,5–2.4; p=0.822). Kesimpulan: program bantuan Sorafenib bagi pasien karsinoma hepatoseluller memastikan kepatuhan pasien dan signifikan memperpanjang kesintasan dibandingkan kohort historis menerima pengobatan paliatif.

Kata kunci: kesintasan, karsinoma hepato seluler, Sorafenib, program bantuan pasien.

ABSTRACTAim: to evaluate treatment compliance and survival of patients receiving oral sorafenib in Indonesia.

Methods: a prospective cohort trial. Unresectable Hepatocelullar carcinoma patients receiving Sorafenib in NexPAP program were recruited between October 2008 and September 2011. A historical cohort from Cipto Mangunkusumo Hospital, between 1998 and 2000 was selected to serve as control group. Patients in the control group received symptomatic treatment. Survival analysis was done by the Kaplan-Meier survival curve analysis and the log-rank test. Median survival difference between the NexPAP and control group was tested using the Cox-regression hazard analysis. Results: There were 48 patients in the NexPAP group and 40 patients in the control group. Treatment compliance was very good; no patient with drew from the study. Sorafenib generally could be tolerated by the patients. The most common adverse events are mild or moderate hand and foot skin reaction and diarrhea. The median survival was 49 weeks in NexPAP group (95% CI 37.9-60.1) vs. 20 weeks

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in the control group (95% CI 9.0-31.0). Cox-regression analysis showed that sorafenib significantly prolonged overall survival with a hazard ratio (HR) of 0.339 (95% CI: 0.196-0.584). There was no survival difference between patients with Child-Pugh class A and class B in both NexPAP (median 49 vs. 52 weeks; HR 1.1; 95% CI 0.5-2.3; p=0.855) and control groups (27 vs. 20 weeks; HR 1.1; 95% CI 0.5-2.4; p=0.822). Conclusion: Sorafenib patient assistant program in unresectable hepatocellular carcinoma ensured compliance treatment and significantly prolonged overall survival over the historical cohort receiving palliative treatment.

Key words: survival, hepatocelullar carcinoma, Sorafenib, patient assistant program.

INTRODUCTIONBased on GLOBOCAN 2008 data ,

hepatocellular carcinoma (HCC) is the fifth most common cancer in men and the seventh in women and also the third cause of cancer-related death worldwide.1 The World Health Organization (WHO) has projected that the incidence of HCC in Indonesia is still increasing until 2030; partly due to the increasing liver cirrhosis cases caused by chronic hepatitis B virus infection.2 Epidemiology data in Indonesia are limited; however, several studies in Jakarta have shown a significant number of HCC patients each year.3-5

Many patients came with advanced stage at diagnosis; therefore, the prognosis is usually poor with a median survival of less than 1 year.6 Systemic chemotherapy with cytotoxic agents has little benefit for these patients.7 Sorafenib, an oral multikinase inhibitor, is now considered as the first line treatment in HCC patients who can no longer be treated with potentially more effective therapies, such as surgery or transarterial chemoembolization.8 Sorafenib acts by inhibiting signal transduction in tyrosine kinase and serine/threonine kinase pathways.9

Systemic treatment with oral targeted therapy may be life long and expensive. Financial reason may influence the patient’s compliance and jeopardize the patient’s survival especially those who were not covered by health insurance. To overcome this problem, Bayer HealthCare Pharmaceutical Indonesia and the Indonesian Cancer Foundation have established a special program called the Nexavar Patients Assistance Program (NexPAP). In this program, patients with unresectable HCC, who were decided by doctors to be suitable for oral sorafenib treatment will be given free drugs after they purchased sorafenib for three consecutive months. This scheme was given to eligible patients who do not have adequate financial support or insurance and have life expectancy of more than 12 weeks.

This study was aimed to evaluate treatment compliance and survival of patients receiving oral sorafenib in Indonesia.

METHODSNexPAP program was designed as a

prospective cohort trial to increase treatment compliance. Subjects were recruited between October 2008 and September 2011. Inclusion criteria were patients with unresectable HCC who have life expectancy of more than 12 weeks and have Child-Pugh Class A or B, and have been prescribed oral sorafenib by their physicians. Patients agreed to purchase sorafenib for three consecutive months, but were lack of health insurance or medical reimbursement support to continue treatment afterwards. Exclusion criteria were patients who discontinued treatment before purchasing Sorafenib of three consecutive months.Patients were treated until they did not show further benefit or underwent intolerable side effects of sorafenib.Survival analysis was done by comparing patients receiving Sorafenib to a historical cohort from CiptoMangunkusumo Hospital, Jakarta between 1998 and 2000.

Study Drug and DosagePatients receiving oral Sorafenib as prescribed

by their physician. Patients in the control group received symptomatic treatment. Seven (17.5%) patients in the control group also underwent transarterialembolization (TAE).

Survival AnalysisOverall survival (OS) for patients in the

NexPAP group was calculated from the first day they took sorafenib until they died or until they reached the end of the study. The OS for the control group was calculated from the first day of diagnosis until they died or reach the end of the study. Survival analysis was done by the Kaplan-Meier survival curve analysis and the log-rank test. Median survival difference between the

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NexPAP and control groups was tested using the Cox-regression hazard analysis. A p-value of less than 0.05 was considered significant. Analysis was done by using the SPSS statistical software version 17.0 (SPSS Inc., Chicago, Illinois, US).

RESULTS

Characteristics of the Study SubjectsThere were 48 patients in the NexPAP group

and 40 patients in the control group. NexPAP patients came from all of Indonesia region.Subjects were recruited from many centers throughout Indonesia but 54% of them came from Jakarta and West Java (Table 1). There was no significant different at baseline between both groups in terms of sex, age and Child-Pugh class (Table 2). BCLC staging for patients in NexPAP group were 6 (12.5%) stage B, 38 (79.2%) stage C, and 4 (8.3%) stage D. BCLC staging data for the control group were not available,but none of them had BCLC stage A because they all were found at least with one of the following clinical signs: tumor lesion >5 cm, had a macrovascular invasion or had an extrahepatic spread.All of the patients in NexPAP group received oral Sorafenib 400 mg a day.

treatment due to diarrhea but then resumed medication. Serious adverse events in patients receiving Sorafenib were hemorrhoid bleeding, tumor of the scalp and bloody streak in the saliva. Patient who had tumor of the scalp also experienced back pain and MRI examination shown suspect of bone metastases in lumbar region.

Survival AnalysisTwenty-eight patients (58.3%) in the NexPAP

group and 29 (72.5%) patients in the control group died during the study period. Kapplan Meier curve analyses showed significantly different survival between NexPAP and control groups (Figure 1). The median survival was 49 weeks (95% confidence interval [CI] 37.9-60.1) in NexPAP group vs. 20 weeks (95% CI 9.0-31.0) in the control group. Cox-regression analysis showed that sorafenib significantly prolonged overall survival with a hazard ratio (HR) of 0.339 (95% CI: 0.196-0.584). There was no survival difference between patients with Child-Pugh class A and class B in both NexPAP (median 49 vs. 52 weeks; HR 1.1; 95% CI 0.5-2.3; p=0.855) and control groups (27 vs. 20 weeks; HR 1.1; 95% CI 0.5-2.4; p=0.822) (Figure 2 and 3).

DISCUSSIONThis is the first study in Indonesia evaluating

HCC patients receiving Sorafenib. This program ensured that patients received adequate treatment and complied with it. However, NexPAP was first designed as a program for helping patient in getting access to Sorafenib, not a survival study; therefore, no control group receiving placebo was

Table 1. List of provincial origin of the NexPAP patients

Province No. of patients

North Sumatra 2

West Sumatra 1

Riau 1

Lampung 1

Jakarta 14

Bandung and West Java 12

Central Java 5

Surabaya and East Java 6

Kalimantan 2

Sulawesi 3

Irian 1

Table 2. Characteristics of the study subjects (n=88)

Variables NexPAP group (n=48)

Control (n=40)

Sex:

- Male 35 (72.9%) 30 (75.0%)

- Female 13 (27.1%) 10 (25.0%)

Age (years):

- mean + SD 58.3+11.08 56.7+13.71

- median 58 60

- range 21-79 29-82

Child-Pugh class

- A 19 (39.6%) 11 (27.5%)

- B 29 (60.4%) 29 (72.5%)

Treatment Evaluation and Adverse EventsSorafenib generally could be tolerated by

the patients. Treatment compliance was very good; no patient with drew from the study due to discontinued treatment for any reason. The most common adverse events are mild or moderate hand and foot skin reaction and diarrhea. There were two patients who temporarily discontinued

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established since the beginning. In the future, such study will unlikely to be done due to potential considerable ethical issue in giving placebo to this group of patients. Other limitations of this study include the incomplete patients’ characteristics such as etiology and staging.

Hepatocellular carcinoma patients generally have poor prognoses since the tumor remains refractory to many chemotherapeutic regimens.10 This current study showed that the historical cohort patients, when sorafenib was not been available, have significantly shorter survival than NexPAP patients. Kaplan-Meier curve analysis showed that the curve separation has occurred since the very beginning, suggesting that the effect of treatment has begun since the first week. In fact, the survival of patients in the NexPAP group may even be longer than the placebo, because the OS was calculated from the first day of sorafenib treatment, not the day of diagnosis as with the control group.

The first international phase-III trial, i.e. the SorafenibHCC Assessment Randomized Protocol (SHARP) has shown a significant survival benefit of sorafenib(n=299) over placebo (n=303). Oral sorafenib 400 mg twice daily increased OS by 44% compared to placebo group (46 vs. 34 weeks; HR 0.60; p=0.00058).11,12 Similar study in Asia on 226 HCC patients also supports this finding. The results showed that sorafenib significantly prolonged survival compared to placebo (6.5 vs. 4.2 months; HR 0.68; 95% CI 0.50-0.93; p=0.014).13 Since 2007, sorafenib was approved as the only systemic therapy for advanced HCC by the United States Food and Drug Administration, the European Medicine Agencies and also the Indonesian Drug and Food Agency.

Our study subjects did not show survival difference between Child-Pugh Class A and B. Many previous studies in patients receiving sorafenib have shown that those with Child-Pugh Class B have shorter survival than Class A.14-17 A recent study also showed a similar outcome in patients‘ overall survival but the time-to-progression was not significantly different between Child-Pugh Class A and B.18

CONCLUSIONThe Sorafenib patients assistance program

was established in Indonesia to ensure patients’ compliance with Sorafenib treatment for

Figure 1. Kaplan-Meier survival curves of NexPAP versus control groups. The difference was statistically significant (p<0.001 by log-rank test).

Figure 2. Kaplan-Meier survival curves of patients in the NexPAP group based on their Child-Pugh Class. The difference was not statistically significant (p=0.854 by log-rank test).

Figure 3. Kaplan-Meier survival curves of patients in control group based on their Child-Pugh Class. The difference was not statistically significant (p=0.819 by log-rank test).

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unresectable hepatocellular carcinoma. This compliance, in turn, showed significantly prolonged overall survival over the historical cohort of hepatocellular carcinoma patients receiving palliative treatment.

ACKNOWLEDGEMENTS We would like to thank all physicians who

contributed to patients in NexPAP. Analysis assistance was supported by a

grant from Bayer Health Care Pharmaceuticals Indonesia.

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