i

i

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SCHOOL OF SURGICAL ONCOLOGY

FOR GENERAL SURGEONS XV

BUKU PROSIDING

WORKSHOP MODIFIED RADICAL MASTECTOMY,

CHEMOTHERAPY DAN SYMPOSIUM

BREAST CANCER

MANAGEMENT UPDATE

Editor

Dr. dr. I Wayan Sudarsa, SpB(K)Onk

14-15 September 2018

iii

KATALOG DALAM TERBITAN

SCHOOL OF SURGICAL ONCOLOGY FOR GENEERAL SURGEONS XV

BUKU PROSIDING

WORKSHOP MODIFIED RADICAL MASTECTOMY, CHEMOTHERAPY DAN

SYMPOSIUM BREAST CANCER MANAGEMENT UPDATE

ISBN :

978-602-294-340-2

Editor

Dr. dr. I Wayan Sudarsa, SpB(K)Onk

Penerbit

Udayana University Press

Universitas Udayana

Denpasar-Bali

Dicetak di

Denpasar, Bali, Indonesia

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Prologue

Om Swastyastu,

Praise be offered to the blessing from the Hyang Widhi Wasa almighty God for that had been

given to us so that this proceeding from the Workshop of Modified Radical Mastectomy,

Chemotherapy and Symposium of Breast Cancer Management Update, held on September 14th-15th

2018 at Grand Inna Bali Beach Hotel Sanur, Bali could be materialized.

The purpose of this workshop and symposium was to improve the ability of surgeons in

Modified Radical Mastectomy (MRM) operative techniques, and to update the surgeons regarding the

latest management of breast cancer.

This proceeding book contained a number of articles, which were presented at the symposium

such as “Operable Breast Cancer Technical Consideration”, “Role Of Aromatase Inhibitors In Breast

Cancer”, “{Treatment Continuum in HER2 Positive Breast Cancer Management”, “New Insight In

Management Of Chemotherapy Induced Neutropenia”, “The Role Of Goserelin Acetate In The

Management Of Pre-Menopausal Breast Cancer”, and “The Management of Difficult Cases of Head

and Neck Squamous Cell Carcinoma”.

We are grateful that our idea had received good response from colleague surgeons from

different parts of Indonesia, from Aceh to West Papua.

We conveyed our appreciation to all Participants, Faculty members, School of Medicine and

The University of Udayana for the success of this Workshop and Symposium.

Finally, we fully expect that this workshop would be of benefit for colleague surgeons, and improve

their competencies and ability to comprehensively treat cancers in general and specifically breast

cancer in the future.

Denpasar, 15th September 2018

Prof. DR. dr. I.B. Tjakra Wibawa Manuaba, MPH,Sp.B(K)Onk.

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Table of Contents

Table of Contents .................................................................................... v

Operable Breast Cancer Technical Consideration .................................. 1

Tjakra W. Manuaba

Role of Aromatase Inhibitors in Breast Cancer…………………...………14

I Ketut Widiana

Treatment Continuum in HER2 Positive Breast Cancer Management...33

Putu Anda Tusta Adiputra

New Insight In Management Of Chemotherapy Induced Neutropenia...45

Ni GAA Manik Yuniawaty Wetan

The Role Of Goserelin Acetate In The Management Of

Pre-Menopausal Breast Cancer……………………………………………57

I Nyoman Wawan Tirtha Yasa

Handling Difficult Cases of Head and Neck Squamous Cell Carcinoma..71

I Gede Budhi Setiawan

1

Operable Breast Cancer Technical Consideration

Tjakra W. Manuaba

Division of Surgical Oncology, Surgery Department, School of Medicine, Udayana University,

Denpasar, Bali, Indonesia

Introduction

Breast cancer was the most commonly diagnosed cancer among female in the United States.

it was affecting approximately 12% of women during their lifetimes, though it was much fewer in men

(less than 1%) (Freeman et al, 2018). In 2017, more than 250,000 women were expected to be

diagnosed with invasive breast cancer, and was estimated that approximately 40,000 would die from

disease (Fajdic et al, 2013). Being a woman with advancing age was the most significant risk factors

for developing breast cancer, and breast cancer screening was considered an essential part of

women's health care (Cao et al, 2013).

Screening is used to detect breast cancer and precancerous breast conditions at the earliest

and most treatable stages, before the signs and symptoms of disease appear (George et al, 2000).

Screening modalities include regular imaging followed by regular physical examination performed by

trained health care provider, hopefully would be able to detect breast at earlier and operable stages.

Breast self-examination, though was a proven to detect early breast cancer, but at least was expected

to down-stage breast cancer diagnosed. Imaging modalities may include mammography, sonography,

magnetic resonance imaging (MRI), and most recently, tomo-synthesis and contrast-

enhanced mammography (Emiroglu et al, 2015).

The high incidence of breast malignancy and it’s relatively easy detection at an early stage

(George et al, 2000). Early breast cancer followed by selective and effective surgical treatment,

radiation therapy, chemotherapy, hormonal and targeted therapy had yield a better overall survival of

breast cancer. Early breast cancer would give better chance for the surgeon to preserve the breast,

and breast oncoplasty (Emiroglu et al, 2015).

Developing technology had prompted a worldwide initiation of triple assessment for breast

cancer diagnosis. These will include clinical examination (anamnesis and physical examination),

radiological imaging (ultrasonography or mammography), and cytological (fine-needle aspiration

cytology [FNAC]), histopathology by Core Needle Biopsy or open incisional biopsy. It was noted that

core needle biopsy (CNB) was seen to gain more popularity. Tru-cut Needle biopsy was easy to

perform and would soon replace open biopsy, but the experience for surgeons and pathologists

needed in order to get the representative specimen and analyze a tiny piece of tumor tissue for

different pathology tests (Baker et al, 1992).

In the field of Oncology, the better understanding of tumor biology had discovered several

biomarkers, important to tumor carcinogenesis, development and metastasis (George et al, 2000).

Most biomarkers are detectable biomolecules derived from disease-related processes and are

associated with particular clinical outcomes or prognosis and on the other hand, they help predict

therapy responses. Based on these biomarkers the treatment of breast cancer can be personalized

(Baker et al, 1992).

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The most common biomarkers tested for breast cancer were Estrogen Receptor (ER),

Progesteron Receptor (PR), Her2/ Neu protein and Ki67. Test for biomarkers was by Immuno-Histo

Chemistry Staining (IHC), which would further divide breast cancer into 4 subtypes, Luminal A

(Hormonal Receptor +, Her2-, Ki67 -), Luminal B (Hormonal Receptor +, Her2 +, or ki67+), Her2 type

(Hormonal Receptor -, Her2+) and Triple Negative Breast Cancer (TNBC) or Basal Like Type

(Hormonal Receptor -, Her2-) (Emiroglu et al, 2015).

Types of Surgeries for breast Cancer were consequently affected by those subtypes, in term

the use of chemotherapy upfront, percentage of pathologically complete response after neoadjuvant

chemotherapy, and the availability of targeted therapy in breast cancer. “Surgery itself would not have

impact on breast cancer bad biology” (Baker et al, 1992).

Another influence on indication and surgical techniques was the hereditary breast cancer with

BRCA1 and BRCA2 positive patients.

History Of Surgery For Breast Cancer

Surgeries for breast cancer moved fast forward with the discovery of anesthesia, aseptic

technique and antibiotics, X ray (Freeman et al, 2018). One of the leader in breast cancer surgery was

Prof. William Halsted from John Hopkin, Baltimore, in the late eighties who develop a radical

technique for “mastectomy”, that was called as Halsted mastectomy. His technique was based of his

belief that breast cancer was a local and regional disease, and that cancer cells spread centrifugally

(Fajdic et al, 2013).

His technique was to remove the whole breast, pectoral major and minor and removes the

whole three level of axillary lymph nodes.

At the same year, Willy Meyer from New York, introduced more or less the same surgical techniques.

Besides of his radical techniques, nevertheless most of his patients died of distant metastasis,

although they might have a better disease-free survival (DFS). Their surgical techniques were the

standard surgery for breast cancer in those time (Cao et al, 2013).

With a belief that breast cancer was a loco-regional disease, the surgery of breast cancer was even

expanded to “supra-radical and extended radical mastectomy”, pioneered by Margotini and Iverson in

the early ninetieth century. Less radical surgery was started when Mc Whirter around 1950, showed

that “simple Mastectomy” followed by radiation in the axilla yield the same results as the more radical

surgeries of the breast (Emiroglu et al, 2015).

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Figure 1. Photo of Rober McWhirter, pioneer of more conservative surgery of breast

cancer “Simple Mastectomy”, and he added external radiation therapy for the axilla

Understanding the morbidity of removing pectoral muscles (mayor and minor), Patey-Dyson in

the 40ties, introduced the “Modified Radical Mastectomy” by preserving mayor pectoral muscle, but

cutting minor pectoral muscle to have a better access to level III axillary lymph nodes. Patey’s theory

was “it is impossible to get clearance of axillary lymph-nodes without cutting minor pectoral muscle

(Baker et al, 1992).

Auchincloss and Madden in later year, showed that by preserving mayor and minor pectoral

muscles had the same results as Patey’s technique and by special maneuver, the axillary lymph-

nodes could be completely dissected (Guidubaldo et al, 2004).

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Figure 2. The picture of William Halsted at John Hopkin, Baltimore

In the majority of early breast cancer, axillary lymph-nodes were turned out negative

(Guidubaldo et al, 2004). This discovery was used by surgeons in the late nineties and early twenties

to select patient with early disease for more conservative surgeries including “Breast Conserving

Surgeries”, “Axillary Lymph-Node Mapping” and “Sentinel Lymph-Nodes Biopsy or Dissection

(SLND)”, and followed by “External Radiation Therapy” (Guilano, early twenties) (Hunt et al, 2018).

Technology for Sentinel Lymph-Node retrieving using “dye material” with or without “radio-

isotop material agent” had reached their maturation phase and had been standard of Breast

Conserving Surgery. Minimal lymph node metastasis (2 lymph-nodes or less or micro-metastasis)

could avoid dissection (Hunt et al, 2018).

It had been proven that DFS or OS of “Breast Conserving Surgery/ BCS” had been

comparable to more radical surgeries. The problem that BCS, although it looked simple in technique,

but it required experience maturation, technology sophistication that no easy to find in developing

countries (Hunt et al, 2018).

Oncoplasty or breast reconstruction after cancer surgeries had been an important requirement

and demanded by most patients. Different techniques from local flap, distant flaps (Latissimus dorsi

flap, TRAM flap, Lateral chest perforator flap, etc), micro-surgical techniques (gluteal, TRAM,

Latissimus Dorsi, etc) and implants had been expanding a great deal at present (Emiroglu et al, 2015).

The development of “molecular biology”, and special staining technique (“Immuno-Histo

Chemistry/ IHC Staining)”, that confirming the subtypes of breast cancer into 4 big subtypes and each

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of them was still a heterogenic disease. The surgeries of breast cancer evolved further taking the

subtypes as the strong consideration of choosing different surgical techniques (Baker et al, 1992).

The understanding of molecular biology of breast cancer was also the foundation of selecting

and combining different systemic therapy, starting from hormonal therapy in Luminal Types,

chemotherapy in Triple Negative Breast Cancer/ Basal Like Breast Cancer and Targeted therapy for

Her2 Type Breast Cancer (Freeman et al, 2018).

High Lights In Breast Cancer

There were a couple of development and discoveries in the history of breast cancer before

coming to our present situation. The Mass Screening was more widely practiced worldwide by using

mammography, Ultra-sonography and MRI, had yield and increasing rate of early non-palpable or

DCIS discovered, and this would reduce the mortality of breast cancer by 30%. The situation was not

the case of developing countries in which screening was more individual, and depending on the

primary physician orientation on cancers (George et al, 2000).

The diagnosis of breast cancer was based on “triple diagnosis”, which was clinical, imaging

(USG, Mammography, MRI) and Biopsy. The Biopsy Techniques were also evolved, with open biopsy

as old standard, and developing to Fine Needle Aspiration Biopsy/ FNA or Core Needle Biopsy. What

was important that we could send enough specimen to pathologists for them to examine not only the

histopathology but also the expression different tumor or biologic markers (George et al, 2000).

Molecular Biology of Breast Cancer was one the most extensively studied in oncology. The

heterogeneity, the micro-environment, the metastasis, subtypes, prognosis, predicting response to

systemic therapy. In early breast cancer, it was important to find patients with poorer prognosis and

high risk of recurrence so that optimal systemic therapy could be given. AS couple of “Genes Profiling

Analysis” were available in the market such as “OncotypeDx” “mammaprint”, “PAM50”, etc. Better

understanding of Breast Cancer Molecular Biology had influenced the surgical techniques chosen, and

that types of surgeries would not have impact on “poor or good tumor biology (Fajdic et al, 2013).

Familial or Hereditary Breast Cancer was another high light that had to know and understand.

The BRCA1 or BRCA 2 mutation, the ATM gene mutation, Fanconi Anemia syndrome, Cowden, Lynch

were among them, but the BRCA1 and BRCA2 were the discovered in about 40% of those familial

breast cancer (Emiroglu et al, 2015).

The intensive surveillance, chemo-prevention, and prophylactic mastectomy were the policy

for early diagnosis and prevention. Risk calculation was used to interpret the risk of developing breast

cancer in those known with hereditary gene mutation.

Modified Radical Mastectomy/ Operative Technique (Auchincloss and Madden)

Before arrive to surgical decision, management ladder of cancer treatment should be strictly

followed those were:

- Pathological diagnosis

- Stages of Cancer

- Performance Status (Karnofsky, ECOGS, UICC)

- Treatment Planning

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- Treatment Implementation

- Evaluation of the whole processes

The most important thing in cancer management was a “good planning”

The mastering the anatomy of the breast was important for surgeons performing mastectomy.

What structures should be preserved in order to minimalize morbidity. The lymphatic drainage, levels

of lymph-nodes in the axilla would help surgeons in the axillary dissection (Guidubaldo et al, 2004)

Figure 3. The neuro-vascular-lymphatic structures of the chest and the breast

Copied from Baker & Niederhuber, 1992.

Figure 4. Deeper structures of chest and the axilla

Copied from Baker & Niederhuber

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Figure 5. Picture of Halsted Mastectomy. Please notice the mayor pectoral muscle was cut and

removed

Figure 6. Removal of mayor pectoral muscle along the para-sternal

The reason of choosing this technique/MRM over other techniques was the fact that majority

of breast cancer diagnosed in Indonesia were at advanced stages of III or IV (70-80%). The less

radical or preservative breast surgeries were not applicable and was not the primary choice or gold

standard surgical techniques (Hammond et al, 2009). MRM was the gold standard and had to be

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mastered by “general surgeons” through-out the country, so that good loco-regional control could be

achieved and followed by Radiation or Systemic Therapy accordingly (Klimberg et al, 2010).

The surgical techniques was begun with choosing the incision techniques which depending on

primary tumor location. A couple of common incisions recommended were “Stewart”, “OOR”, “Willy

Meyer”, “Halsted Tear Drop” Flaps were raised caudally at level of sub-mammary fold and cranially up

to 2nd intercostal space, medially to parasternal line and laterally to “:mid axillary line”. The flaps

continued until reaching the pectoral fascia, which would be cut and removed with the mastectomy

surgical specimen (Klimberg et al, 2010).

The next step would depend on surgeon’s preference or experience, the common approach is

in the lateral by finding the “lateral margin of Latissimus Dorsi muscle” released it and carefully looked

for “a.v.n thoraco-dorsalis” and preserved (Klimberg et al, 2010).

Figure 7. Skin flapping cranially and caudally until mayor pectoral muscle was exposed. Notice the

thickness of flaps and area of mastectomy.

Copied from Baker & Niederhuber, 1992

Figure 8. Mastectomy, removing pectoral fascia, starting from cranio-medial.

Copied from Baker& Niederhuber, 1992

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A.v.n. thoraco-dorsalis were preserved and followed carefully up to their origin. Mastectomy

was started from “cranio-medial” excised the whole breast tissue and the skin on top. Special caution

was identifying “perforator vessels” cabang dari a. mammaria interna in the medial part of the breast

and tied them (Klimberg et al. 2010).

Laterally, the breast was excised over serratus muscle all the way to already prepared

latissimus dorsi muscle and a.v,n thoraco-dorsalis. Breast specimen was dissected up toward axillary

space removing lymph-nodes encountered at level I and II. If neccessary level III lymph-nodes could

be approach by pulling up frontward minor and mayor pectoralis muscle (Rao et al, 2010).

Other structures should be found and preserved were axillary vein, long thoracic nerve,

“medial pectoralis nerve-muscular bundle”, and sometime inter-costo-brachial nerve (Rao et al, 2010).

Figure 9. Axillary Lymph-Nodes Dissection/ ALND

Copied from Baker & Niederhuber, 1992

Figure 10. Finishing Auchincloss & Madden Modified Radical Mastectomy

Copied from Baker & Niederhuber, 1992

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Post op irrigation of operative field with “warm sterile aquabidest” was an important step

before closing up the wound. The use of aquabidest for cleansing the operative field was to prevent

local recurrences. Different fluid formula had been tried in the past (Fajdic et al, 2013).

Bleeding should be managed, and two vacuumed “Redon” drain be inserted in the medial and

lateral part of surgical bed (Freeman et al, 2018).

Patient must be encouraged to move early, especially the operated part to prevent post-

operative stiffness and increased “ROM” of shoulder joint. The drain removed one by one when fluid

production was less than 30 cc (Klimberg et al, 2011).

Antibiotic was not necessary for primary mastectomy, but must be considered in post

chemotherapy (Neo-Adjuvant) patients because of immune-compromised situation. There were

complications of Modified Radical Mastectomy that had to understand and overcome those. The

specific complications of MRM, were the damage on the supposed preserved structures, which could

be avoided after mastering the technique (Rao et al, 2010).

Active bleeding or huge hematoma required for the surgeon to reopen and looked for the

bleeding. Flap necrosis, could be minimal or marginal but could be massive or complete, and flapping

raising would need a meticulous technique and experience of surgeons (Singh et al, 2018).

Accumulation of fluid or seroma was quite common in MRM/ Axillary Lymph-Nodes Dissection

(ALND), the delayed removal of the drain, increased risk of infection. The removal of the drain would

depend on the amount of fluid production, the present of impending infection, and pain. The sutures

should be removed in about 10-14 days depending on the tension of the wound (Zurida et al, 2011).

Follow Up after “MRM”

Once the drain was removed patient was followed up every week for fluid accumulation.

Repeated aspiration of the fluid must conduct with caution to prevent infection. Lymphangitis or

cellulitis could happen after aspiration, and hence should be protected by prophylactic antibiotic. When

the would settle down, the patient was prepared for adjuvant therapy depending on treatment planning

chosen (Rao et al, 2010).

Adjuvant Radiation Therapy was usually not necessary in MRM, unless there were certain

condition such as advanced stage (T4), close surgical margin, the present of LNN metastasis in more

than 3. Oncologic follow up, would be routinely conducted, started with every month for six months,

every 3 months and later six months. Oncologic Imaging was performed every six months depending

on subtype and aggressiveness of breast cancer being followed (Zurida et al, 2011).

Conclusions

Looking at present situation in developing countries, including Indonesia, Breast Cancer

patients came at advanced stages in seeking professional help. Seventy percent was at stage III or IV

that surgeries upfront was usually not possible. Neo-adjuvant therapy was necessary to downsize the

cancer so that surgery can be performed oncologically.

Ninety percent of breast cancer surgery would be performed by general surgeons, that quality

of surgical techniques became important indicator for long DFS and OS.

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Mastering the MRM technique, and competencies in giving chemotherapy either as neo-

adjuvant or adjuvant setting would help treating breast cancer patient to the best level, that DFS and

OS would be improved a great deal.

References

• Baker R.R., Niederhuber J., 1992. The Operative Management of Breast Disease. W.B. Saunders

Co. Philadelphia.

• Breach, N., Rovere, G.Q.D., Benson, J.R. and Nava, M., 2004. Oncoplastic and Reconstructive

Surgery of the Breast.

• Cao, J.Q., Olson, R.A. and Tyldesley, S.K., 2013. Comparison of recurrence and survival rates

after breast-conserving therapy and mastectomy in young women with breast cancer. Current

Oncology, 20(6), p.e593.

• Emiroğlu, M., Sert, İ. and İnal, A., 2015. The Role of Oncoplastic Breast Surgery in Breast Cancer

Treatment. The journal of breast health, 11(1), p.1.

• Fajdic, J., Djurovic, D., Gotovac, N. and Hrgovic, Z., 2013. Criteria and procedures for breast

conserving surgery. Acta Informatica Medica, 21(1), p.16.

• Freeman, M.D., Gopman, J.M. and Salzberg, C.A., 2018. The evolution of mastectomy surgical

technique: from mutilation to medicine. Gland surgery, 7(3), p.308.

• George H. Sakorafas, Adelais G. Tsi. Axillary Lymph Node Dissection in Breast Cancer: Current

Status and Controversies, Alternative Strategies and Future Perspectives. Acta Oncologica. 2000

Jan;39(4):455–66.

• Hammond, D.C., 2009. Breast augmentation. Atlas of aesthetic breast surgery, 4, pp.39-81.

• Hunt K.K., Kronowitz S.J., 2018. “Mastectomy and Breast Reconstruction. In Morita S.Y., Bach

C.M., Klimberg V.S., Pawlik T.M., Posner M.C., Tanabe K.K., Textbook of Complex Surgical

Oncology. McGrawHill Education. New York. VI. Breast. 76:1270-1281

• Klimberg, V.S., 2010. Atlas of Breast Surgical Techniques. Elsevier Health Sciences, Sec.III.15:

184-201

• Klimberg, V.S., 2010. Atlas of Breast Surgical Techniques. Elsevier Health Sciences, Sec.VI.

69:1172-1182

• Kuerer, H.M., 2010. Modified Radical Mastectomy for Avoiding Skin Necrosi. Breast surgical

oncology. Kuerer st, pp.64:693-704.

• Zurrida, S., Bassi, F., Arnone, P., Martella, S., Del Castillo, A., Ribeiro Martini, R., Semenkiw, M.E.

and Caldarella, P., 2011. The changing face of mastectomy (from mutilation to aid to breast

reconstruction). International journal of surgical oncology, 2011.

12

Role Of Aromatase Inhibitors In Breast Cancer

I Ketut Widiana

Division of Surgical Oncology, Surgery Department, Faculty of Medicine, Udayana University,

Denpasar, Bali, Indonesia

Introduction

Breast cancer, a genetically and clinically heterogeneous disease that originates from the

mammary epithelial cells, remains the leading cause of cancer deaths among females worldwide with

about one in eight women (12 %) developing breast cancer in her lifetime. A woman's risk for breast

cancer is linked to her reproductive history and her lifetime hormonal exposure. The levels of estrogen

in blood and tissue are associated with breast cancer carcinogenesis. Estrogen signaling is a key

regulator of postnatal development of mammary gland, breast carcinogenesis, and progression when

estrogen signaling pathways become dysregulated (Zhou et al, 2014).

Estrogens are known to be important in the growth of breast cancers in both pre and

postmenopausal women. As the number of breast cancer patients increases with age, the majority of

breast cancer patients are postmenopausal women. Although estrogens are no longer made in the

ovaries after menopause, peripheral tissues produce sufficient concentrations to stimulate tumor

growth. As aromatase catalyzes the final and rate-limiting step in the biosynthesis of estrogen,

inhibitors of this enzyme are effective targeted therapy for breast cancer. Three aromatase inhibitors

(AIs) are now FDA approved and have been shown to be more effective than the antiestrogen

tamoxifen and are well tolerated (Carpenter et al, 2005).

Primarily, the role of the aromatase inhibitors has been investigated in postmenopausal

women with breast cancer, although it is also now being assessed in premenopausal patients

following ovarian ablation/suppression. Aromatase inhibitors markedly suppress endogenous

estrogens without directly interacting with estrogen receptors, and thus have a different mechanism

of action to the antiestrogen, tamoxifen. The inhibitors may be divided into subgroups according to

their structure (steroidal and nonsteroidal), and there appears to be a lack of cross-resistance

between the classes of aromatase inhibitors enabling them to be used sequentially and potentially

to prolong endocrine hormone therapy (Chumsri et al, 2011).

Epidemiology

Almost 1.4 million women were diagnosed with breast cancer worldwide in 2008 and

approximately 459,000 deaths were recorded. Incidence rates were much higher in more developed

countries compared to less developed countries (71.7/100,000 and 29.3/100,000 respectively,

adjusted to the World 2000 Standard Population) whereas the corresponding mortality rates were

17.1/100,000 and 11.8/100,000. Five-year relative survival estimates range from 12% in parts of Africa

to almost 90% in the United States, Australia and Canada, with the differential linked to a combination

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of early detection, access to treatment services and cultural barriers. Observed improvements in

breast cancer survival in more developed parts of the world over recent decades have been attributed

to the introduction of population-based screening using mammography and the systemic use of

adjuvant therapies (Youlden et al, 2012).

Figure 1. Ten Leading Cancer Types for Estimated New Cancer Cases and Deaths By Sex, United

States, 2011.

Approximately 230,480 new cases of invasive breast cancer and 39,520 breast cancer deaths

are expected to occur among US women in 2011. Breast cancer incidence rates were stable among

all racial/ethnic groups from 2004 to 2008. Breast cancer death rates have been declining since the

early 1990s for all women except American Indians/Alaska Natives, among whom rates have

remained stable. Disparities in breast cancer death rates are evident by state, socioeconomic status,

and race/ethnicity. While significant declines in mortality rates were observed for 36 states and the

District of Columbia over the past 10 years, rates for 14 states remained level. Analyses by county-

level poverty rates showed that the decrease in mortality rates began later and was slower among

women residing in poor areas. As a result, the highest breast cancer death rates shifted from the

affluent areas to the poor areas in the early 1990s. Screening rates continue to be lower in poor

women compared with non-poor women, despite much progress in increasing mammography

utilization. In 2008, 51.4% of poor women had undergone a screening mammogram in the past 2

years compared with 72.8% of non-poor women (DeSantis et al, 2011).

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Figure 2. Incidence rates in ASEAN.

Figure 3. Mortality rates in ASEAN.

Figure 4. Ages and menstruations status in patient with breast cancer.

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Figure 5. Epidemiology Based on Subtypes of Breast Cancer.

Treatment Recommendations for Breast cancer

The 2013 St. Gallen Consensus Conference on early breast cancer provided mostly evidence-

based, globally valid treatment recommendations for breast cancer care, with a broad spectrum of

acceptable clinical practice. This report summarizes the results of the 2013 international panel voting

procedures with regard to loco-regional and endocrine treatment, chemotherapy, targeted therapy as

well as adjuvant bisphosphonate use (Harbeck et al, 2013).

Intrinsic subtype Clinico-pathologic definition Type of therapy

Luminal A Luminal A

- ER and/or PgR positive

- HER2 negative

- Ki-67 low (<14%)

Endocrine alone

Luminal B Luminal B (HER2 negative)

- ER and/or PgR positive

- HER2 negative

- Ki-67 high

Luminal B (HER2 positive)

- ER and/or PgR positive

- Any Ki-67

- HER2 over-expressed or

amplified

Endocrine ± cytotoxic

therapy

Cytotoxic + anti HER2

+ endocrine therapy

Erb-B2

overexpression

HER2 positive (non luminal)

- HER2 over-expressed or

amplified

- ER and PgR absent

Cytotoxic + anti HER2

20,14%

12,17%

22,60%

21,52%

23,57%Her2

Luminal A

Luminal B

Luminal-Her2

TNBC

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Basal like Triple negative (ductal)

- ER andPgR absent

- HER2 negative

Cytotoxic

Special histological

types

- Endocrine

responsive

- Endocrine

nonresponsive

Endocrine therapy

Cytotoxic

Table 1. Therapy recommendations for early breast cancer

Hormone Receptor-Positive (HR+) Breast Cancer

A cancer is called estrogen-receptor-positive (or ER+) if it has receptors for estrogen. This

suggests that the cancer cells, like normal breast cells, may receive signals from estrogen that could

promote their growth. The cancer is progesterone-receptor-positive (PR+) if it has progesterone

receptors. Again, this means that the cancer cells may receive signals from progesterone that could

promote their growth. Roughly two out of every three breast cancers test positive for hormone

receptors (Dunnwald et al, 2007).

Staining of ER+ breast cancer nuclei

by immunohistochemistry (IHC)4

(A) (B)

Figure 6. (A). Strong nuclear staining indicating widespread expression of ER (Allred score = 8), (B).

Weak nuclear staining indicating low to moderate expression of ER (Allred score = 4).

Approximately 70% of human breast tumors express hormone receptors (HRs), comprising

the estrogen receptor (ER) and/or progesterone receptor (PR). The ER is the primary transcription

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factor driving oncogenesis in HR-positive (HR+) breast cancers; it is both a target of, and predictor of

response to, anti-estrogen therapy (Lim et al, 2012).

Estrogen and estrogen receptors (ERs) are critical regulators of breast epithelial cell

proliferation, differentiation, and apoptosis. Compromised signaling vis-à-vis the estrogen receptor is

believed to be a major contributing factor in the malignancy of breast cells. Targeting the ER signaling

pathway has been a focal point in the development of breast cancer therapy. Although approximately

75 % of breast cancer patients are classified as luminal type (ER+), which predicts for response to

endocrine-based therapy; however, innate or acquired resistance to endocrine-based drugs remains a

serious challenge. The complexity of regulation for estrogen signaling coupled with the crosstalk of

other oncogenic signaling pathways is a reason for endocrine therapy resistance (Zhou at al, 2014).

Table 2. Changes of HR During the Course of Disease (Maroun et al, 2010).

Estrogen as A Key Hormone in Breast Cancer Development

Estrogen, a steroid hormone, has an essential role in the development and maintenance of

female secondary sexual characters. It plays a crucial role in the pathogenesis and progression of

breast cancer. The biological effects of estrogen, such as growth stimulation and differentiation of

normal mammary tissue, is mediated primarily through high-affinity binding to ERs. ERs are nuclear

receptor proteins that have an estrogen-binding domain and a DNA-binding domain. There are two

types of ERs: ERα and ERβ. The ERα gene is localized on chromosome 6q25.1. Estrogen-bound ERα

acts like a transcription factor, which binds to estrogen response element (ERE) upstream of the target

genes. The ERα is closely associated with breast cancer biology, especially in the deve lopment of

tumors. ERβ gene is located on chromosome 14q22-24. ERβ regulates genes that function as tumor

suppressors (Surekha et al, 2007).

Estrogens are considered to play a major role in promoting the proliferation of both the normal

and the neoplastic breast epithelium. Their role as breast carcinogens has long been suspected and

recently confirmed by epidemiological studies. Three major mechanisms are postulated to be involved

in their carcinogenic effects: stimulation of cellular proliferation through their receptor-mediated

hormonal activity, direct genotoxic effects by increasing mutation rates through a cytochrome P450-

mediated metabolic activation, and induction of aneuploidy (Russo et al, 2006).

18

Figure 7. Estrogen Structure.

Beneficial effects of estrogen Harmful effects of estrogen

Programming the breast and uterus for sexual

reproduction

The most serious problem arises from the ability

of estrogen to promote the proliferation of cells in

the breast and uterus.

Controlling cholesterol production in ways that

limit the build up of plaque in the coronary arteries

Although this ability to stimulate cell proliferation

is one of estrogen’s normal roles

Preserving bone strength by helping to maintain

the proper balance between bone buildup and

breakdown.

It can also increase a woman’s chance of

developing breast or uterine cancer.

Table 3. The Beneficial and Harmful Effects of Estrogen.

Estrogen Metabolism

Estrogen synthesis takes place primarily in the ovary (especially membrana granulose and

luteinized granulosa cells) in premenopausal women and primarily in peripheral tissues in

postmenopausal women. The aromatization of androgens into estrogens is the most important source

of estrogens in the breast tissue. Some active estrogens are also formed from circulating estrone

sulfate or 17β-estradiol sulfate as the result of de-conjugation by sulfatase. Local release of

biologically active estrogens from conjugates and their further metabolism prolong the effect of

estrogen on peripheral tissues. In addition, concentration of conjugating enzymes in some peripheral

tissues is low, which may result in the accumulation of active (unconjugated) metabolites and an

increased effect of estrogens on the target tissue (Yaghjyan et al, 2011).

19

Figure 8. Estrogen Receptors Trigger Gene Activation.

Estrogen metabolism in the peripheral tissues and that in the liver are different. In peripheral

tissues, including the breast, 4-hydroxylation of estrogens is the dominant pathway of estrogen

metabolism. Some of the intermediate metabolites in this pathway interact with the estrogen receptor

at a reduced dissociation rate compared to estradiol resulting in a longer effect. Semiquinones and

quinones formed as the result of 4-hydroxylation of estrogens have DNA-damaging properties realized

through non-receptor-mediated mechanisms. The metabolites formed through 2-hydroxylation of

estrogens, on the other hand, have much weaker hormonal potency than estradiol; they are rapidly

metabolized and suspected to be strong inhibitors of tumor cell proliferation and angiogenesis. Small

amounts of estrogens are metabolized through 16α-hydroxylation to 16α-hydroxyestrone (16α-OHE1)

which induces genotoxic DNA damage. Ratios of estrogen metabolites with different biological

properties in tissues can differ from their ratios in the blood (Yaghjyan et al, 2011).

20

Figure 9. Estrogen-Receptors-Signaling-Pathway.

Aromatase Inhibitors

Aromatase inhibitors (AIs) are a class of compounds that inhibit the synthesis of estrogens

from androgens. Third-generation nonsteroidal inhibitors (anastrozole and letrozole) and the steroidal

inactivator exemestane induce >98% inhibition of whole-body aromatisation and have been shown to

outperform tamoxifen as adjuvant therapy in postmenopausal women with early breast cancer.

Additionally, due to the lack of estrogenic activity, a potential advantage of their use in this setting

might be the lack of adverse uterine effects (Bertelli et al, 2009).

Aromatase inhibitors work by blocking the enzyme aromatase, which turns the

hormone androgen into small amounts of estrogen in the body. This means that less estrogen is

available to stimulate the growth of hormone-receptor-positive breast cancer cells(Smith et al, 2003).

21

There are three aromatase inhibitors:

• Arimidex (chemical name: anastrozole)

• Aromasin (chemical name: exemestane)

• Femara (chemical name: letrozole)

IES Trial – Aromasin registrational trial: Strength of the Switching Strategy

Tamoxifen Followed by Aromatase Inhibitors Trials (Switch Strategy)

Breast cancer is estrogen-dependent in many cases, and reducing the estrogen levels by

means of ovariectomy can cause regression of established disease, especially if the tumor is rich in

estrogen receptors. The selective estrogen-receptor modulator tamoxifen blocks the action of estrogen

by binding to one of the activating regions of the estrogen receptor. When given to women with

estrogen-receptor–positive breast cancer for five years after surgery, tamoxifen reduces the risk of

recurrence by 47 percent and the risk of death by 26 percent. The risk–benefit ratio of using tamoxifen

for longer than five years remains unclear, and trials addressing this question are ongoing.

International guidelines recommend that patients should not receive adjuvant tamoxifen therapy for

more than five years outside the context of a clinical trial (Coombes et al, 2004).

Alternative endocrine therapy is often effective after disease has relapsed despite tamoxifen

treatment, since at that point, estrogen receptors are still present in most patients. Several trials have

confirmed the superiority of aromatase inhibitors over progestins in this setting. Aromatase is an

enzyme that catalyzes the conversion of androgens to estrogens. There are two classes of third-

generation oral aromatase inhibitors: irreversible steroidal inactivators, exemplified by

exemestane, and reversible nonsteroidal inhibitors, such as anastrozole and letrozole (Coombes et al,

2004).

Exemestane inhibits aromatization in vivo by about 98 percent. It is superior to megestrol

acetate with respect to time to progression in advanced breast cancer and has antitumor effects in

patients who have no response to third-generation nonsteroidal aromatase inhibitors. Preliminary

results show that exemestane is superior to tamoxifen as first-line therapy for metastatic disease.

Theoretically, exemestane should not cause endometrial thickening or endometrial cancer, which are

occasionally observed after tamoxifen therapy (Coombes et al, 2004).

22

Figure 10. Intergroup Exemestane Study (IES) Trial Design.

The Intergroup Exemestane Study (IES) was designed to investigate whether exemestane,

when given to postmenopausal women who remained free of recurrence after receiving adjuvant

tamoxifen therapy for two to three years for primary breast cancer, could prolong disease-free survival,

as compared with continued tamoxifen therapy (Coombes et al, 2004).

Figure 11. Disease Free survival Between Exemestane and Tamoxifen.

23

Figure 12. Overall Survival Between Exemestane and Tamoxifen.

Reversal of Skeletal Effects of Endocrine Treatments in The IES

The adjuvant use of aromatase inhibitors in breast cancer is associated with adverse effects

on bone health (Coleman et al,2010).

Figure 13. Percentage change from baseline in lumbar spine and total hip BMD between treatment

groups.

Bone mineral density events associated with exemestane were short term and reversible,

following treatment withdrawal.

Mean BMD returned to pretreatment values 1 year post treatment.

Decrease in BMD seen with exemestane was partially reveresed following treatment

withdrawal.

While patients taking exemestane experienced fractures during the study, these rates fell after

treatment withdrawal and did not differ significantly from tamoxifen (p=0.12).

24

Long-term Endometrial Effects in IES in The Two Arms

Tamoxifen, for many years the ‘gold-standard’ endocrine treatment of breast cancer, is

associated with an increased incidence of uterine abnormalities such as endometrial hyperplasia,

polyps, cysts and fibroids and an increased risk of uterine cancer and sarcoma (Bertelli et al, 2009).

The relationship between ET and the presence of endometrial pathological abnormality varies, but

most investigators agree that endometrial thickening has low specificity and low positive predictive

value for histological abnormalities in tamoxifen-treated patients. This effect is mainly due to

tamoxifen-induced subepithelial stromal proliferation, entrapping gland lumens leading to cystic

changes (Bertelli et al, 2009).

Figure 14. Long-term Endometrial Effects in IES in The Two Arms

Exemestane associated with a significantly lower incidence of abnormal endometrial thickness

(ET) vs tamoxifen after 2 years of treatment (36% vs 62%, p=0.004), with a significant benefit

seen after just 6 months (p=0.01).

Switched patients experienced a rapid decrease of ET in the first 6 months (p=0.003).

25

Figure 15. Mean change from baseline TOI scores within treatment groups. Error bars denote 95%

Cls. Between treatment group : positive mean change in QoL favours exemestane. Within treatment

group : positive mean change in QoL indicates improvement from baseline. Mean (s.d) baseline TOI

scores are exemestane = 73.1 (10.9); Tamoxifen = 72.1 (11.5).

• Both the groups showed gradual improvement in overall QoL and lessening of total endocrine

symptoms post treatment compared with baseline (P<0.002).

• No evidence of any between-group differences in Trial Outcome Index.

• Vasomotor complaints remained high on treatment.

• Vaginal discharge was more frequent (P<0.01) with tamoxifen up to 24 months from baseline.

• In both the groups, post-treatment libido did not recover to baseline levels.

Conclusion:

Clinical benefits of switching to exemestane are accompanied by good overall QoL. Although

some symptoms persist, the majority of endocrine symptoms improve after treatment completion

(Derks et al, 2012).

26

Toxicity of AIs vs Tamoxifen

Table 4. Toxicity effect of AIs vs Tamoxifen

Conclusion :

The Intergroup Exemestane Study established that the protective effect of switching to

exemestane compared with continuing on tamoxifen on risk of relapse or death was maintained

for at least 5 years post-treatment and was associated with a continuing beneficial impact on

overall survival (Dent et al, 2011).

NCCN Guidelines - Hormone Receptor Positive Breast Cancer

Postmenopausal women

• Tamoxifen for 2–3 years then switch to an AI to complete 5 years or for 5 years (switch).

• AI for 2–3 years then tamoxifen to complete 5 years.

• Tamoxifen for 4.5–6 years then consider AI for 5 years, or continue tamoxifen for a total of

10 years.

• Tamoxifen for up to 10 years is an option if contraindication or intolerance to AI or if

patient declines AI.

• Note: the optimal duration of AI therapy is uncertain.

Postmenopausal advanced ER+ breast cancer

• Prior endocrine therapy <1 year: follow-up endocrine therapy.

• No prior endocrine therapy <1 year: AI, SERM, or selective ER downregulator.

Visceral crisis

• Consider initial chemotherapy

Summary

• Subtype of breast cancer is mandatory to identify.

• Immunohistochemical markers are often used to classify breast cancer into subtypes that

are biologically distinct and behave differently.

• Aromatase inhibitorsare superior to tamoxifen as adjuvant therapy for breast cancer and

have now replaced tamoxifen as first line therapy in a number of treatment regimens for

postmenopausal breast cancer patients.

• Exemestane in women at high risk of breast cancer demonstrated a 65% reduction of

new breast cancers.

27

• Switching from tamoxifen to exemestane significantly reserves endometrial thickening

associated with continued tamoxifen.

• The protective effect of switching to exemestane was associated with a continuing

beneficial impact on overall survival.

References

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• Smith, I.E. and Dowsett, M., 2003. Aromatase inhibitors in breast cancer. New England Journal of

Medicine, 348(24), pp. 2431-2442.

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polymorphism of estrogen receptor-α gene in breast cancer. Indian journal of human

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29

Treatment Continuum in HER2 Positive Breast Cancer Management

Putu Anda Tusta Adiputra

Divisi Bedah Onkologi, Departemen Ilmu Bedah Fakultas Kedokteran Universitas Udayana, RSUP

Sanglah Denpasar

HER2 diekspresikan pada 25% kanker payudara. Pada jaringan payudara normal reseptor

HER2 diekspresikan sekitar 25.000 sampai 50.000. Sedangkan pada jaringan tumor overekspresi ini

bisa mencapai 10-100x ekspresi normal sekitar 2 juta reseptor.

Gambar 1. Ekspresi reseptor HER2 pada sel normal (kiri), overekspresi HER2 (tengah), pembelahan

sel berlebihan (kanan)

Ekspresi berlebihan dari HER2 berhubungan dengan prognosis yang buruk pada kanker

payudara. HER2 menurunkan harapan hiduppada EBC (early breast cancer) dan MBC (metastatic

brast cancer).

Gambar 2. Grafik survival pasien EBC dan MBC dengan HER2

Pemeriksaan HER2 wajib dilakukan pada pasien dengan kanker payudara. Pemeriksaan

menggunakan cairan buffer normal formalin untuk fiksasi jaringan dengan waktu fiksasi 6-72 jam.

Kriteria penilaian HER2 berdasarkan ASCO/CAP 2013 yaitu :

• HER2 +3 : pewarnaan penuh dan kuat disekeliling membran sel yang ditemukan pada >10%

sel tumor.

30

• HER2 +2 : pewarnaan tidak penuh dan lemah/moderat disekeliling membran sel yang

ditemukan pada >10% sel tumor atau pewarnaan penuh dan kuat disekeliling membran sel

tumor pada ≤ 10% sel tumor.

• HER2 +1 : pewarnaan tidak penuh dan samar/hampir tidak terlihat disekeliling membran sel

tumor pada >10% sel tumor.

• HER2 0 : tidak ditemukan pewarnaan pewarnaan atau tidak penuh dan samar/hampir tidak

terlihat disekeliling membran sel tumor pada ≤ 10% sel tumor.

Gambar 3. Rekomendasi ASCO dan CAP untuk pemeriksaan HER2 dan terapi kanker payudara

Penanganan spesimen yang optimal dan fiksasi penting pada pemeriksaan HER2.

Rekomendasi cairan fiksasi adalah 10% neutral buffered formalin(10%NBP). Dengan volume optimal

10x dari volume jaringan yang diperiksa. Tidak disarankan untuk menunda fiksasi jaringan dengan

formalin sampai lebih dari 1 jam. Waktu memfiksasi < 1 jam. Penundaan waktu fiksasi menyebabkan

hasil yang tidak valid dari reseptor HER2 maupun analisis HER2.

Gambar 4. Definisi HER2 positif pada kanker payudara

Trastuzumab direkomendasikan pada pasien EBC dan MBC dengan HER2 (+) terdapat

rekomendasi dari beberapa penelitian pada pemberian trastuzumab.

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Tabel 1. Trastuzumab pada pasien dengan Early Breast Cancer dengan HER2 (+)

Tabel 2. Trastuzumab pada pasien dengan Metastatic Breast Cancer dengan HER2 (+)

Gambar 5. Kemajuan penelitian pada kanker dengan HER2 dengan terapi Trastuzumab dalam 15

tahun terakhir.

Terdapat beberapa pilihan agen anti-HER2 yang dapat dikombinasi dengan kemoterapi, terapi

hormonal, agen anti HER2 lain, maupun pemakainan agen HER2 saja tanpa dikombinasi.

• Lini pertama :

• Docetaxel + trastuzumab + pertuzumab (CLEOPATRA)

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• Kemoterapi + trastuzumab + pertuzumab (PERUSE)

• Kemoterapi + trastuzumab

▪ Paclitaxel/Docetaxel + trastuzumab

▪ Paclitaxel + Lapatinib

▪ Vinorelbine + trastuzumab

▪ Capecitabine + trastuzumab

• (Aromatase Inhibitor + Trastuzumab/lapatinib)

• Lini Kedua :

• T-DM1 (EMILIA)

• Vinorelbine + trastuzumab + everolimus

• Capecitabine + lapatinib

• Kemoterapi + trastuzumab (TBP)

• Trastuzumab + lapatinib pada HR (-) / +ET pada HR (+)

• Lini Ketiga :

• T-DM1 (TH3RESA)

• Kemoterapi + terapi anti HER2

• Vinorelbine + trastuzumab + everolimus (BOLERO-3)

• Trastuzumab + lapatinib pada HR (-)/+ ET pada HR(+)

• Trastuzumab

Trastuzumab merupakan terapi anti HER2 yang pertama kali disetujui untuk terapi kanker

payudara. Trastuzumab merupakan antibodi monoklonal pada manusia, 95% pada manusia 5% pada

sejenis tikus. Memiliki afinitas dan spesifisitas yang tinggi yang berikatan dengan bagian ekstraseluler

dari HER2 dengan berbagai mekanisme. Trastuzumab memiliki empat mekanisme kerja yaitu:

1. Aktivasi ADCC

2. Mecegah pembentukan p95HER2

3. Menghambat proliferasi sel

4. Hambatan pada HER2-regulated angiogenesis

Hipersensitivitas terhadap trastuzumab atau komponen lain dalam produk terebut merupakan

kontraindikasi pemberian transtuzumab. Diperlukan perhatian khusus dalam pemberian trastuzumab.

Pemberian obat harus dalam pengawasan dokter yang berpengalaman. Perlu diperhatikan pemberian

obat pada pasien dengan gagal jantung simtomatik, riwayat hipertensi, riwayat penyakit jantung

koroner. Pasien dengan fraksi ejeksi jantung kiri (LVEF) ≤ 55% pada EBC. Fungsi jantung harus

dimonitor dengan baik selama pengobatan. Jika LVEF turun 10 poin dari baseline dan dibawah 50%,

pemberian trastuzumab harus ditunda dan diperiksa ulang setelah 3 minggu. Jika LVEF tidak

membaik pertimbangkan penghentian pemakaian obat tersebut. Trastuzumab diketahui tidak memiliki

interaksi dengan obat lain pada manusia.

Dosis pemberian trastuzumab berdasarkan berapa lama interval pemberiannya. Dosis

mingguan trastuzumab yaitu 4mg/kgBB sebagai dosis awal yang diberikan secara intravena selama

90 menit, dilanjutkan 2 mg/kgBB pada minggu berikutnya, jika dosis sebelumnya bisa ditoleransi

dengan baik dapat diberikan selama 30 menit. Dosis 3 mingguan yaitu 8 mg/kgBB sebagai dosis awal,

dilanjutkan 6mg/kgBB setiap 3 minggu secara intravena selama 90 menit. Jika dosis sebelumnya bisa

33

ditoleransi dengan baik dapat diberikan selama 30 menit. Jika pasien melewatkan dosis trastuzumab

selama lebih dari 1 minggu, maka diperlukan pemberian dengan dosis 8 mg/kgBB, dilanjutkaan 6

mg/kgBB 3 minggu setelah dosis tersebut. Simpanlah vial obat pada suhu 2oC – 8oC, dan jangan

digunakan jika sudah melewati masa kadaluwarsa. Trastuzumab bertahan selama 28 hari dalam

lemari es dengan suhu 2oC – 8oC dilarutkan dengan bacteriostatic water for injection untuk 440 mg

vial dari trastuzumab. Jika menggunakan cairan steril, larutan hanya bertahan 24 jam. Larutan infus

(NaCl0.9%) yang mengandung trastuzumab secara kimiawi stabil selama 24 jam. Menggunakan spuit

steril suntikkan 20cc cairan bakteriostatik kedalam vial transtuzumab, campur perlahan, jangan

dikocok. Jangan menggunakan cairan dekstrosa 5% karena dapat menyebabkan agregasi protein.

Trastuzumab tidak boleh dicampur atau dilarutkan dengan obat lain.

Pemberian trastuzumab secara subkutan merupakan metode pemberian inovatif. Formula

terbaru trastuzumab dikembangkan menggunakan rekombinan hyaluronidase manusia

memungkinkan pemberian secara subkutan. Pemberian 600 mg trastuzumab secara subkutan telah

disetujui, dan tidak ditemukan perbedaan dengan pemberian intravena berdasarkan pathological

complete response dan konsentrasi serum pada HannaH study. Pemberian secara subkutan memiliki

beberapa keuntungan yaitu waktu pemberian yang lebih cepat yaitu 2-5 menit, rata-rata 10 kali lebih

cepat daripada pemberian secara intravena. Waktu persiapan yang sedikit, tidak memerlukan

pelarutan, kantong infus, tidak memerlukan penghitungan berdasarkan berat badan. 91.5% pasien

memilih pemberian secara subkutan karena lebih hemat waktu dan kurangnya rasa nyeri. Efikasi dan

toleransi yang sama dibandingkan dengan pemberian secara intravena.

Pemberian secara subkutan lebih dipertimbangkan karena memiliki efikasi, farmakokinetik

dan keamanan yang sama dengan intravena, yang ditemukan dalam berbagai penelitian klinis dengan

agen lain seperti bortezomin dan alemtuzumab. Pemberian secara subkutan juga cepat dan lebih

nyaman, tidak memerlukan akses vena sentral, dan berpotensi meningkatkan kepuasan pasien,

menjadi pilihan dan mengurangi beban dalam pengobatan. Dari sudut pandang tenaga kesehatan,

pemberian subkutan juga mengurangi waktu kunjungan, mengurangi durasi masuknya obat dan

kesalahan dalam pemberian dosis karena subkutan memakai dosis tetap.

Pemberian secara subkutan dalam volume yang cukup besar dihambat oleh struktur dan

fisiologi dari lapisan subkutan. Lapisan subkutan terdiri dari serat hyaluronan dan kolagen, yang

membatasi pemberian subkutan 1-2 ml. Hyaluronan dapat dihancurkan secara alami oleh enzim

hyaluronidase. Recombinant human hyaluronidase (rHuPH2O) menyebabkan degradasi hyaluronan

sementara dan lokal, menyebabkan peningkatan area penyebaran secara lokal, yang memungkinkan

pemberian cairan dalam jumlah besar.

34

Gambar 6. Mekanisme kerja rHuPH20 pada pemberian trastuzumab subkutan

Tabel 3. Berbagai penelitian pemberian trastuzumab subkutan pada HER2 dan EBC

Gambar 7. Desain Penelitian pada HANNAH Trial

35

Pada Hannah Trial, pemberian secara subkutan tidak lebih rendah dibandingkan pemberian

trastuzumab secara intravena. Efikasi dosis tetap trastuzumab dihitung dengan pCR (second co-

primary endpoint). Total pCR dan EFS dibandingkan dengan kesluruhan berat trastuzumab intravena

dan subgrup nya.

Gambar 8. Desain Penelitian SafeHer. Penelitian global mengenai keamanan trastuzumab subkutan

yang diberikan selama 1 tahun pada pasien dengan EBC positif HER2

Tabel 4. Demgrafi pasien yang secara umum seimbang

Tabel 5. Analisis Primer SafeHer : Karakteristik tumor yang secara umum seimbang

36

Berdasarkan data dari penelitian SafeHer menunjukkan keamanan dan toleransi pemberian

trastuumab subkutan sebagai terapi ajuvan baik diberikan secara bersamaan maupun bergantian

dengan kemoterapi pada pasien EBC yang positif HER2. Hasil penelitian konsisten menunjukkan

keamanan pemberian trastuzumab dan diperkuat dengan keamanan pemberian dosisi tetap pada

berbagai subgrup pasien. Rasio putus pengobatan sangat rendah pada pemberian subkutan ini.

Gambar 9. Desain Penelitian PrefHer. Penelitian Global, multisenter, randomised, two-cohort,

penelitian dua lengan untuk mengetahui pilihan pasien terhadap trastuzumab intravena atau subkutan

sebagai terapi ajuvan pada kanker payudara

Gambar 10. Tabel hasil penelitian PrefHer, pasien lebih memilih trastuzumab subkutan dibandingan

intravena

Tabel 6. Tingkat kepuasan pada tenaga kesehatan profesional

37

Kesimpulan dari penelitian PrefHer yaitu pemberian secara intravena dapat menimbulkan

berbagai tantangan dan masalah bagi pasien maupun tenaga kesehatan profesional. Perubahan

pemberian trastuzumab dari metode intravena menjadi subkutan dapat mengurangi penurunan pada

waktu pengobatan pada pasien dan tenaga kesehatan profesional. Sehingga sumber daya medis

yang diperlukan menurun, perhatian terhadap pasien meningkat, serta efisiensi staf dan senter

kesehatan meningkat dengan pemberian trastuzumab subkutan ini. Evolusi pengobatan kanker

memerlukan peningkatan efisiensi pengobatan dan kualitas hidup pasien, dan pemberian secara

subkutan merupakan salah satu dari solusi dalam hal tersebut.

Trastuzumab subkutan vial :

1. Trastuzumab subkutan vial mengandung trastuzumab 600 mg ditambah rHuPH2O 2000

unit/ml dalam 5 ml vial.

2. Tidak memerlukan dosis awalan

3. Steril, cairan tidak berwarna

4. Pemberian secara subkutan dengan spuit sesuai dengan prosedur lokal

5. Pemberian yang pendek kurang dari 5 menit

6. Diberikan selama 1 tahun pada pasien EBC dengan positif HER2 (setiap 3 minggu untuk 18

siklus)

7. Diberikan hingga perkembangan penyakit pada pasien MBC dengan positif HER2

Gambar 11. Trastuzumab subkutan vial

Dosis dan cara pemberian trastuzumab subkutan :

1. Larutan 600 mg/5 ml tidak dilarutkan lagi

2. Trastuzumab subkutan harus diberikan dalam waktu 5 menit pada lapisan subkutis pada

paha

3. Lokasi injeksi harus bergantian antara paha kanan dan kiri

4. Injeksi yang baru harus diberikan dengan jarak 2.5 cm dari lokasi injeksi sebelumnya dan

tidak boleh pada area yang kemerahan, lecet, nyeri atau keras

5. Selama pengobatan dengan trastuzumab subkutan, pemberian obat lain dengan metode

subkutan harus diberikan pada lokasi yang berbeda

38

Referensi

• Slamon, et al. (1987). Science. Human Breast Cancer: Correlation of Relapse and Survival

with Amplification of the HER-2/neu Oncogene, 235, 177-182.

• Pauletti, et al. (2000). J. Clin. Oncol. Assessment of Methods for Tissue-Based Detection of

the HER-2/neu Alteration in Human Breast Cancer: A Direct Comparison of Fluorescence In

Situ Hybridization and Immunohistochemistry, 18, 3651-3644.

• Bilous, M., et al. (2003). Mod. Pathol. Current Perspectives on HER2 Testing: A Review of

National Testing Guidelines, 16, 173-182.

• Wolf, Antonio, C., et al. (2013). J. of Clin. Oncol. Recommendations for Human Epidermal

Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical

Oncology/College of American Pathologists Clinical Practice Guideline Update, 31, 3997-4013

• Khoury T et al. 2009. Delay to formalin fixation effect on breast biomarkers. Mod

Pathol;22(11):1457-67.

• Cardoso, F., et al. (2014). Annals of Oncol. ESO-ESMO 2nd international consensus

guidelines for advanced breast cancer (ABC2), 00:1-18.

• National Comprehensive Cancer Network Breast cancer version 3 2015

• BPOM. 2014. Product Information. trastuzumab Intravenous (IV). 15 Jan 2014pp: 1-26

• Pivot X, et al. Poster presentation at the 37th ESMO 2012 (Abstract 272P).

• Ismael G, et al. Lancet Oncol 2012; 13:869–878.

• Jackisch C, Oral presentation at the 8th EBCC 2012 (Abstract 1BA).

• SafeHER/PrefHER Time and Motion Study. ESMO 2013.

• Perez-Garcia J, et al. Lancet Oncol 2012; 13(9): 850–851. 6. De Cock, et al. St Gallen 2013

(Poster 209).

• Pivot X, Poster presented at St Gallen Breast Cancer Conference, 2013 (Poster 207)

• Jackisch C, et al. Poster presentation at the 37th ESMO 2012 (Poster 271P).

39

New Insight In Management Of Chemotherapy Induced Neutropenia

Ni GAA Manik Yuniawaty Wetan

Division of Surgical Oncology, Surgery Department, Faculty of Medicine, Udayana University,

Denpasar, Bali, Indonesia

Introduction

Treatment-associated neutropenia continues to represent the most common dose-limiting

toxicity of cancer chemotherapy. It often leads to fever and infection, prompting hospitalization and

occasionally resulting in serious morbidity, and even mortality, despite modern broad-spectrum

antibiotic treatment and supportive care. Neutropenia and its complications may also lead to

chemotherapy dose reductions, treatment delays, or early treatment termination, compromising

disease control and the potential for cure. NCCN Clinical Practice Guidelines in Oncology recommend

administration of primary prophylaxis with a myeloid growth factor in patients receiving regimens

associated with a high risk for febrile neutropenia, and consideration of prophylaxis in patients

receiving lower-risk regimens who have other risk factors that might place them at higher risk for

febrile neutropenia(Dinan et al, 2015).

G-CSF was licensed in 1991 by the United States Food and Drug Administration (FDA) for

use in patients undergoing cytotoxic treatment. Like all CSFs available today, it is administered

subcutaneously and was approved for decreasing the incidence of FN and reducing the duration of

neutropenia and fever following myeloablative chemotherapy. Two different G-CSF preparations are

available: non-glycosylated G-CSF filgrastim (Neupogen®; Amgen, Thousand Oaks, CA) and

glycosylated G-CSF lenograstim (Granocyte®; Chugai, Utsunomiya, Japan)(Vehreschild et al, 2014).

Definition of febrile neutropenia

Febrile neutropenia (FN) is defined as an oral temperature of >38.3°C or two consecutive

readings of >38.0°C for 2 h and an absolute neutrophil count (ANC) of <0.5 × 109/l, or expected to fall

below 0.5 × 109/l(Klastersky et al, 2016).

Incidence, morbidity, mortality and microorganisms

Despite major advances in prevention and treatment, FN remains one of the most frequent

and serious complications of cancer chemotherapy (ChT). It is a major cause of morbidity, healthcare

resource use and compromised treatment efficacy resulting from delays and dose reductions of ChT.

Mortality from FN has diminished steadily, but remains significant. There is a clear relationship

between the severity of neutro-paenia (which directly influences the incidence of FN) and the intensity

of ChT. Currently, the different regimens are classified as producing a high risk (>20%), an

intermediate risk (10%– 20%) or a low risk (<10%) of FN. In the case of FN, prognosis is worst in

patients with proven bacteraemia, with mortality rates of 18% in Gram-negative and 5% in Gram-

positive bacteraemia(Klastersky et al, 2016).

40

Characteristics Score

Burden of illness : no or mild symptoms 5

Burden of illness : moderate symptoms 3

Burden of illness : severe symptoms 0

No hypotension (systolic BP>90 mmHg) 5

No chronic obstructive pulmonary disease 4

Solid tumor/lymphoma with no previous fungal

infection

4

No dehydration 3

Outpatient status (at onset of fever) 3

Age <60 years 2

Patients with scores ≥21 are at low risk of complications. Points attributed to the variable

‘burden of illness’ are not cumulative. The maximum theoretical score is therefore 26.

Table 1. MASCC febrile neutropaenia risk index.

The Incidence of neutropenia based on type of cancer

Diagram 1. The incidence of neutropenia based on type of cancer (Crawford et al, 2004).

Chemotherapy-induced neutropenia

Chemotherapy-induced neutropenia occurs most commonly in the first cycle of treatment.

Older patients, patients with multiple co-morbidities, and those receiving more myelotoxic drugs are

prone to develop neutropenia and its complications (Dale et al, 2009).

Neutropenia may result in fever and neutropenia, or febrile neutropenia (FN), often

necessitating hospitalization for evaluation and empiric broad-spectrum antibiotics. Neutropenia and

its complications, including febrile neutropenia, are major dose-limiting toxicities of systemic cancer

chemotherapy. A systematic review of the literature showed that age, performance status, nutritional

status, chemotherapy dose intensity, and low baseline blood cell counts were associated with the risk

of severe and febrile neutropenia or reduced chemotherapy dose intensity in multivariate analysis in

two or more studies (Lyman et al, 2005).

41

Figure 1. The course of neutropenia and its complication.

Initial assessment and investigations

A detailed history should be taken including the nature of the ChT given, prior prophylactic

antibiotics, concomitant steroid use, recent surgical procedures and the presence of allergies. To

guide therapy, it is important to check the clinical record for past positive microbiology, in particular

previous presence of antibiotic-resistant organisms or bacteraemia.

1. Note the presence of indwelling I.V. catheters

2. Symptoms or signs suggesting an infection

Focus : Respiratory system

Gastrointestinal

Tract skin

Perineal/genitourinary

Discharges Oropharynx

Central nervous system

3. Knowledge of previous positive microbiology result by checking clinical records

4. Routine investigations :

Urgent blood testing to assess bone marrow, renal and liver function

Coagulation screen

C-reactive protein

Blood cultures (minimum of two sets) including cultures from indwelling I.V. catheter

Urinalysis and culture

Sputum microscopy and culture

Stool microscopy and culture

Skin lesion (aspirate/biopsy/swab)

42

Chest radiograph

5. Further investigations (profound/prolonger neutropenia/following allografts)

High-resolution chest CT (if pyrexial despite 72 h of appropriate antibiotics)

Bronchoalveolar lavage

I.V. : intravenous , C.T. : computed tomography

Urinalysis, sputum and stool cultures only in case of suspected focus of infection at these sites.

Table 2. Initial assessment and investigations.

An initial assessment (Table 2) of circulatory and respiratory function, with vigorous

resuscitation where necessary, should be followed by careful examination for potential foci of infection.

Signs and symptoms of infection in neutropaenic patients can be minimal, particularly in those

receiving corticosteroids, or in elderly patients who often may present with a confusional state

(Klastersky et al, 2016).

Initial management of febrile neutropenia

The vast majority of FN cases, as managed according to the al-gorithm set out in Figure 2,

respond promptly to empirical therapy, suffering no major complications(Klastersky et al, 2016).

Figure 2. Initial management of febrile neutropaenia. ANC, absolute neu-trophil count; MASCC,

Multinational Association of Supportive Care in Cancer.

NCCN 2018 Alogrithm for use of preventive G-CSF Support

Figure 3. NCCN Guidelines 2018

43

EORTC and ASCO G-CSF Guidelines-Based FN Risk Assessment

Filgrastim, lenograstim and pegfilgrastim have clinical efficacy and we recommend the use of

any of these agents, according to current administration guidelines, to prevent FN and FN-related

complications, where indicated. Filgrastim biosimilars are now also a treatment option in Europe.

Recommendation grade: A (Aapro et al, 2010).

Figure 4. Patient assessment algorithm to decide primary prophylactic G-CSF usage. FN, febrile

neutropenia; G-CSF, granulocyte colony-stimulating factor. Primary prophylaxis: start G-CSF in first

cycle 24-72 hours after end of the first chemotherapy and continue through all cycles (when

appropriate as per cycle reassessment). Secondary prophylaxis: start G-CSF if a neutropenic event

was observed in the previous cycle.

The use of G-CSF (Lenogastrim) in the Fields of Haematology and Oncology

Overview

Lenograstim is the glycosylated recombinant form of human granulocyte colony stimulating

factor (rHuG-CSF). The drug supports the differentiation of neutrophil-committed colony-forming cells

and increases absolute neutrophil counts (ANC) in a dose-dependent manner. The drug is used to

reduce the risk of life-threatening infection in patients with neutropenia, particularly after cytotoxic

chemotherapy. Lenograstim accelerates neutrophil recovery significantly after chemotherapy, with

beneficial effects on clinical end-points such as incidence of laboratory confirmed infection and length

of hospital stay. Characteristic of Lenogastrim are having weight of molecular 20,000 Da, consist of

174 amino acids and 2 disulphide bonds (Dale, 2002).

44

Figure 5. The role of G-CSF in hematopetic tissue

Function of G-CSF Lenograstim on Bone Marrow and Neutrophil Granulocytes

1. Promotes the proliferation and differentiation of precursor cells to neutrophil granulocytes

2. Increased release of mature granulocytes

3. G-CSF is important for chemotaxis, phagocytosis and superoxide production in neutrophils

4. Releases haematopoetic progenitor cell (CD 34+ cells) into the peripheral blood

Glycosylation of G-CSF is important for its function and stability, for example as :

• Greater specific activity

• Greater stability in the event of variations of the pH-value and temperature

• Protection against proteolysis and aggregation

Glycosylated G-CSF (Lenograstim) VS Non-Glycosylated G-CSF ( Filgastrim)

As in vivo :

• Filgrastim alters the morphology and chemotaxis of neutrophils whereas they remain

unchanged under Lenograstim

• The receptor affinity of glycosylated G-CSF is approximately 3 times higher than that of non-

glycosylated G-CSF

As in vitro :

• The stability of the G-CSF molecule is increased

• Lenograstim stimulates the formation of neutrophil colonies at a dosage only of that of

Filgrastim

• Lenograstim achieves the maximum stimulation of neutrophil colony formation at only half the

concentration of Filgrastim

Glycosylation leads to a significantly greater amount of specific activity with Lenograstim, in fact

1µg Filgrasti =100.000 IU compared to 1 µg Lenograstim= 127.760 IU

45

Lenogastrim uses :

1. Reduction of chemotherapy-induced neutropenia

• Dosage: 150 µg/m² day

2. Reduction of duration of neutropenia after BMT

• Dosage: 150 µg/m² day

3. Mobilisation of blood stem cells in the peripheral bloodstream

• Dosage for autologous mobilisation : 150 µg/m²/day

• Dosage for healthy donors : 10 µg/kg/day

Lenogastrim advantages over Non G-CSF :

- Glycosylated G-CSF is more stable than non-glycosylated G-CSF under the physiological

conditions according to time of incubation (at 370C)

- Glycosylated G-CSF is more stable than non-glycosylated G-CSF under the physiological

conditions according to pH influence.

- Glycosylated G-CSF reveals 50% more specific activity in bone marrow assay and 26 %

greater activity in assay cell lines than non-glycosylated G-CSF in the conclusion form.

46

- Lenograstim is significantly more effective in stimulating growth of

CFU-GM (Colony-Forming Unit Granulocyte Macrophage) in the colony assay in the

conclusion form.

- Lenograstim already stimulated the formation of neutrophil colonies at significantly lower

concentrations than Filgrastim in the conclusion form.

- Immunophenotypically, in vivo G-CSF-primed granulocytes were more mature in the

Lenograstim than in the Filgrastim and to lesser extent in the Pegfilgrastim groups in the

conclusion form.

47

Lenogastrim as prophylaxis → have specific effect to reduce :

• Incidence of febrile neutropenia

• Number of documented infections

• Length of hospitalisation of patients

• Dose of i.v. antibiotics

• Mortality due to infections

Summary

• Febrile Neutropenia is the most common found side effect in chemotherapy management, that

increase in elderly & prolong duration of neutropenia.

• NCCN & EORTC/ASCO put the same risk evaluation on the G-CSF usage.

• GEICAM 9805 proved that using G-CSF:

– Reduce incidence of infection & febrile neutropenia.

– Reduce non-hematological toxicities.

• The primary-prophylactic use of G-CSF in myelotoxic chemotherapy reduces the rate of

documented infections by approx. 40 %.

• The secondary-prophylactic use of G-CSF is recommended in the case of neutropenia <500/µl

induced in previous chemotherapy cycles, especially in the case of additional individual risk

factors.

• In a systematic review, primary prophylaxis with G-CSF in patients’ chemotherapy, proven

reduce in: Episodes of Febrile Neutropenia Infection related mortality, Early mortality.

• The average treatment duration with G-CSF is 5-6 days/cycle.

•

References

• Aapro, M.S., Bohlius, J., Cameron, D.A., Dal Lago, L., Donnelly, J.P., Kearney, N.,et al, 2011.

2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce

the incidence of chemotherapy-induced febrile neutropenia in adult patients with

lymphoproliferative disorders and solid tumours. European journal of cancer, 47(1), pp.8-32.

• Crawford, J., Dale, D.C. and Lyman, G.H., 2004. Chemotherapy‐induced neutropenia: risks,

consequences, and new directions for its management. Cancer, 100(2), pp.228-237.

• Crawford, J., Becker, P.S., Armitage, J.O., Blayney, D.W., Chavez, J., Curtin, P.,et al, 2017.

Myeloid growth factors, version 2.2018, NCCN clinical practice guidelines in oncology. Journal of

the National Comprehensive Cancer Network, 15(12), pp.1520-1541.

• Dale, D.C., 2002. Colony-stimulating factors for the management of neutropenia in cancer

patients. Drugs, 62(1), pp.1-15.

• Dale, D.C., 2009. Advances in the treatment of neutropenia. Current opinion in supportive and

palliative care, 3(3), p.207.

• Dinan, M.A., Hirsch, B.R. and Lyman, G.H., 2015. Management of chemotherapy-induced

neutropenia: measuring quality, cost, and value. Journal of the National Comprehensive Cancer

Network, 13(1), pp.e1-e7.

48

• Klastersky, J., De Naurois, J., Rolston, K., Rapoport, B., Maschmeyer, G., Aapro, M.,et al, 2016.

Management of febrile neutropaenia: ESMO clinical practice guidelines. Annals of Oncology,

27(suppl_5), pp.v111-v118.

• Lyman, G.H., Lyman, C.H., Agboola, O. and Anc Study Group, 2005. Risk models for predicting

chemotherapy-induced neutropenia. The oncologist, 10(6), pp.427-437.

• Vehreschild, J.J., Böhme, A., Cornely, O.A., Kahl, C., Karthaus, M., Kreuzer, K.A.,et al, 2014.

Prophylaxis of infectious complications with colony-stimulating factors in adult cancer patients

undergoing chemotherapy—evidence-based guidelines from the Infectious Diseases Working

Party AGIHO of the German Society for Haematology and Medical Oncology (DGHO). Annals of

oncology, 25(9), pp.1709-1718.

49

The Role Of Goserelin Acetate In The Management Of

Pre-Menopausal Breast Cancer

I Nyoman Wawan Tirtha Yasa

Surgical Oncologist, Surgery Department, Sanjiwani General Hospital, Gianyar, Bali, Indonesia

Introduction

Breast cancer is among the leading causes of cancer-related mortality and the most common

cancer in women worldwide. Significant improvements in survival have been achieved with the

widespread use of adjuvant therapies in early-stage breast cancer (EBC) (ie, breast cancer that has

not spread beyond the breast or the axillary lymph nodes). However, approximately 25% of the cases

occur in premenopausal women, including 12% in women between the ages of 20 and 44 years. For

this subgroup of patients at reproductive age, the use of adjuvant chemotherapy with curative intent is

associated with a risk of ovarian dysfunction, permanent or transient amenorrhea, infertility, and

symptoms of menopause with a premature onset. In addition to complications that include

osteoporosis, loss of libido, increased cardiovascular risk, and atrophic vaginitis, early ovarian

dysfunction may adversely affect quality of life and result in a significant psychosocial burden. Based

on this concept, several uncontrolled trials have been conducted to evaluate the activity of luteinizing

hormone–releasing hormone analogs and/or gonadotropin-releasing hormone agonists (GnRHa) in

preventing the loss of ovarian function due to exposure to cytotoxic agents (Munhoz et al, 2016).

Epidemiology

Breast cancer is the most common malignancy in women in the United States and is second

only to lung cancer as a cause of cancer death. The American Cancer Society estimates that 255,180

Americans will be diagnosed with breast cancer and 41,070 will die of the disease in the United States

in 2017 (Gradishar et al, 2017).

Based on GLOBOCAN estimates, about 14.1 million new cancer cases and 8.2 million deaths

occurred in 2012 worldwide. Over the years, the burden has shifted to less developed countries, which

currently account for about 57% of cases and 65% of cancer deaths worldwide. Lung cancer is the

leading cause of cancer death among males in both more and less developed countries, and has

surpassed breast cancer as the leading cause of cancer death among females in more developed

countries; breast cancer remains the leading cause of cancer death among females in less developed

countries (Torre et al, 2015).

50

Figure 1. Estimated Age-Standarised Incidence and Mortality Rates; Both Sexes in Indonesia.

Premenopausal Women with Hormone Receptor Positive Breast Cancer

Premenopausal women with hormone receptor positive (HR+) and human epidermal growth

factor receptor-2-negative (HER2-) advanced breast cancer (aBC) often present with aggressive tumor

types that lead to poor prognosis, high rates of recurrence, and mortality (Dalal et al, 2018).

Figure 2. Breast cancer with HR + premenopausal/perimenopausal.

About 70% of invasive breast cancers are hormone receptor (HR) positive. The mainstay of

treatment for all women with HR positive breast cancer is endocrine therapy either after chemotherapy

or as endocrine therapy alone. The decision to recommend chemotherapy in HR positive breast

cancer is multifactorial. Factors such as presence of HER2/neu overexpression, lymph node

involvement, and genomic tests such as Oncotype DX (Genomic Health, Redwood City, CA) play a

role in decisions to recommend chemotherapy in HR positive breast cancer. Whether or not

51

chemotherapy is recommended, all patients with HR positive breast cancer are recommended to have

adjuvant endocrine therapy (Gemignani et al, 2017).

Figure 3. NCCN Guidelines Version 3. 2017 for Premenopausal Breast Cancer.

Figure 4. NCCN Panel Recommends Tamoxifen Treatment With or Without Ovarian Suppression

(LHRH agonist) or Ablation.

The NCCN Guidelines for Breast Cancer recommend the following adjuvant endocrine therapy

options for women with early stage breast cancer who are postmenopausal at diagnosis: (1) an AI as

initial adjuvant therapy for 5 years (category 1), with consideration of an additional 5 years on AI

therapy based on data from the recent MA17.R trial; (2) an AI for 2 to 3 years (category 1) followed by

tamoxifen to complete 5 years of endocrine therapy (category 1); (3) tamoxifen for 2 to 3 years

followed by one of the following options: an AI to complete 5 years of adjuvant endocrine therapy

(category 1) or 5 years of AI therapy (category 2B); or (4) tamoxifen for 4.5 to 6 years followed by 5

years of an AI (category 1), or consideration of tamoxifen for up to 10 years. In postmenopausal

women, the use of tamoxifen alone for 5 years (category 1) or up to 10 years is limited to those who

decline or have a contraindication to AIs (Benson et al, 2017).

For women who were premenopausal at diagnosis, the NCCN Guidelines for Breast Cancer

recommend 5 years of tamoxifen (category 1) with or without ovarian suppression (category 1), or

ovarian suppression plus an AI for 5 years (category 1). Women who are premenopausal at diagnosis

52

and who become amenorrheic with chemotherapy may have continued estrogen production from the

ovaries without menses. Serial assessment of circulating luteinizing hormone, follicle-stimulating

hormone, and estradiol to assure a true postmenopausal status is mandatory if this subset of women

is to be considered for therapy with an AI (Benson et al, 2017).

After 5 years of initial endocrine therapy, for women who are postmenopausal at that time

(including those who have become postmenopausal during the 5 years of tamoxifen therapy), the

NCCN panel recommends considering extended therapy with an AI for up to 5 years (category 1) or

considering tamoxifen for an additional 5 years. For those who remain premenopausal after the initial

5 years of tamoxifen, the panel recommends considering continuing up to 10 years of tamoxifen

therapy (Benson et al, 2017).

Ovarian Suppression with LHRH Agonist (Zoladex® - Goserelin)

Goserelin acetate was first approved by the US Food and Drug Administration (FDA) on

January 1996 for the treatment of localized prostate cancer in combination with flutamide and radiation

therapy or as palliative treatment in advanced prostate cancer. It is commercialized under the brand

name zoladex by Astra Zeneca, and it is now also approved to be used as palliative treatment in

premenopausal and perimenopausal women who suffer from advanced breast cancer. The approval

of the drug was based on controlled studies that revealed the capacities of goserelin acetate similar to

hormone suppression drugs (Gordon et al, 2017).

Early ovarian failure is an important and potentially devastating long-term toxic effect of

chemotherapy. Manifestations include menopausal symptoms, osteoporosis, and infertility. Concerns

about fertility may influence treatment choices for young women with breast cancer despite the known

survival benefit of adjuvant chemotherapy (Moore et al, 2015).

Both the estrogen receptor (ER) and progesterone receptor (PR) play important roles in

progression of breast cancer in hormone receptor-positive patients. Thus, anti-estrogen therapy has

become an important strategy for treatment of hormone receptor-positive breast cancer. Before

menopause, up to 90% of hormones are produced by the ovary in breast cancer patients. Thus,

ovarian ablation has become an important part of endocrine therapy and has been widely accepted in

treatment of breast cancer since 1896. However, with the development of adjuvant therapy for breast

cancer, there has been less emphasis on ovarian ablation. With the introduction of medical ovarian

ablation using luteinizing hormone releasing hormone-agonists (LHRH-agonists), ovarian ablation with

LHRH-agonists has attracted increasing attention due to its ability to reversibly suppress estrogen

secretion by the ovary (Zhou et al, 2015).

53

Figure 5. Zoladex® Mechanism of Action.

Treatment with ovarian ablation using goserelin was recommended by the clinician but was to

be according to patients’ decision. Patients who underwent LHRH-agonist therapy received a

subcutaneous depot injection of goserelin (Zoladex, AstraZeneca, London, UK) at 3.6 mg once every

month (four weeks) for at least two years according to the recommendation of the European Society

for Medical Oncology (ESMO) and The Adjuvant Breast Cancer Ovarian Ablation or Suppression Trial

(Cardoso et al, 2018).

Figure 6. Zoladex® 3.6 mg suppresses serum oestradiol to postmenopausal level by the 8th day.

Zoladex® plus Tamoxifen Provide Additional Benefit in Reducing Death & Recurrence

Luteinizing hormone-releasing hormone (LH-RH) agonists are effective adjuvant therapy for

premenopausal women with endocrine-responsive breast cancer. Tamoxifen, the most firmly

established adjuvant therapy, has been used as a standard adjuvant therapy for pre- and

postmenopausal women with early breast cancer. A meta-analysis of 4 randomized clinical trials

showed that the combination of tamoxifen plus LH-RH agonist was superior to LH-RH agonist alone

in providing a significant survival benefit. The St Gallen international expert consensus on the

primary therapy of early breast cancer has recommended 5 years of tamoxifen alone or in

54

combination with 5 years of ovarian suppression as a standard adjuvant therapy for premenopausal

breast cancer patients (Del Mastro et al, 2016).

Figure 7. Breast Cancer Recurrence.

Figure 8. Death Due to Breast Cancer.

The overview of LHRH agonists, based on an average follow-up of 6.8 years, reported data on

recurrence, death due to breast cancer. The main conclusions were that LHRH agonists had an effect

on reducing the risk of these events similar to that for chemotherapy (such as FEC or CMF), and could

be used as an effective treatment in women with ER-positive tumors, either alone or in combination

with chemotherapy or tamoxifen (Hackshaw et al, 2009).

Side Effect

Treatment Received

Goserelin Alone

(n = 154)

Gosereline Plus Tamoxifen

(n = 160)

Symptoms % (n) % (n)

Hot Flushes 74 (114) 72 (115)

Vaginal Discharge 13 (20) 18 (27)

Vaginal soreness 18 (27) 18 (29)

Adverse effect on sexual activity 15 (23) 10 (16)

Table 1. Zoladex®+Tamoxifen is well tolerated and has no additional safety issues.

55

Zoladex® achieve similar survival to oophorectomy

Goserelin and ovariectomy resulted in similar FFS and OS. We can rule out a moderate

advantage for ovariectomy. Goserelin was safe and well tolerated (Taylor et al, 1998).

Figure 9. Zoladex® Achieves similar survival to oophorectomy in premenopausal patients with

advanced breast cancer.

Zoladex® Associated with Chance of Pregnancy

The majority of young premenopausal women diagnosed with early-stage breast cancer are

candidates to receive a systemic treatment that includes chemotherapy. Chemotherapy may cause

acute and chronic side-effects, including premature ovarian failure (Lambertini et al, 2015).

Pregnancy after breast cancer is safe even in patients with endocrine-sensitive disease. With

a rising trend of delaying childbearing, more breast cancer patients are diagnosed without having

completed their families and thus, it is vital to provide reliable fertility preservation methods for these

young women. Recently, the 2015 St Gallen International Expert Consensus panel and the National

Comprehensive Cancer Network (NCCN) guidelines have been updated to acknowledge the role of

luteinizing hormone-releasing hormone agonists (LHRHa) in preventing chemotherapy-induced POF

of hormone receptor-negative breast cancer (Lambertini et al, 2015).

Figure 10. Zoladex® associated with a low risk of long term chemotherapy-induced amenorrhoea and

a high chance of pregnancy.

56

In conclusion, temporary ovarian suppression with LHRHa during chemotherapy is associated

with a reduced risk of chemotherapy-induced POF and seems to increase the pregnancy rate in young

breast cancer patients, with no apparent negative impact on patients' prognosis. The use of LHRHa

during chemotherapy might be considered as an option for women interested in preserving their

ovarian function, thus reducing the chance of developing the negative consequences of early

menopause, and might also play a role in increasing the likelihood of becoming pregnant after

cessation of chemotherapy (Lambertini et al, 2015).

Goserelin versus Cyclophosphamide, Methotrexate, and Fluorouracil as Adjuvant Therapy in

Premenopausal Patients with Node-Positive Breast Cancer (Jonat et al, 2002).

• Zoladex was directly compared with CMF chemotherapy in pre-or peri-menopausal patients

with node positive breast cancer.

• Patients had node-positive stage II operable invasive breast cancer with no evidence of

metastatic disease; and had not received previous systemic therapy.

Figure 11. Goserelin offers an effective, well-tolerated alternative to CMF in premenopausal patients

with ER-positive and node-positive early breast cancer.

Zoladex ® is as Effective as CMF Chemotherapy

(A) (B)

Figure 12. (A) Disease-free survival was equivalent between Zoladex and CMF, HR=1.05; 95% CI:

0.88–1.24; P= 0.597, (B) Overall survival with Zoladex was non-inferior to CMF, HR=0.94; 95% CI:

0.75-1.18; P= 0.622.

57

Zoladex ® Shows Significant Improvement in QoL and Menses Generally Returned

Goserelin offers improved overall QoL during the first 6 months of therapy compared with

CMF chemotherapy in premenopausal and perimenopausal patients with early breast cancer. Coupled

with equivalent efficacy in estrogen receptor-positive patients, these data support the use of goserelin

as an alternative to CMF in premenopausal and perimenopausal patients with estrogen receptor-

positive, node-positive early breast cancer (De Haes et al, 2003).

Figure 13. Zoladex was associated with significant improvement in QoL vs CMF at 3 and 6 months.

Figure 14. Only 22.6% of patients who received Zoladex remained amenorrhoeic 1 year after

completing therapy.

Zoladex administration is quick and simple:

• Injected subcutaneously into the anterior abdominal wall every 28 days.

• Does not require mixing (ready to use).

• Has a short administration time

• Has no potential for mixing errors

58

• No need to change the needle for administration.

• The ‘ZOLADEX Safe System’ needle is siliconized and includes an automatic safety shield

that helps to prevent needle stick injuries.

• 'ZOLADEX Safe System' was designed to eliminate accidental needle-stick injury and

exposure to blood.

Figure 15. Packaging of Zoladex.

Summary

• NCCN guidelines recommends ovarian suppression (LHRH agonist) for premenopausal

breast cancer.

• Zoladex® plus Tamoxifen is provide additional benefit in reducing death & recurrence; well

tolerated and has no additional safety issues.

• Zoladex® achieve similar survival to oophorectomy.

• Zoladex® associated with a low risk of long term chemotherapy-induced amenorrhoea and a

high chance of pregnancy.

• Zoladex® is as effective as CMF chemotherapy and shows significant improvement in quality

of life.

• Zoladex Safe System® is the only depot LHRHa to be presented in a ready to use syringe and

more preferable rather than Leuproprelin.

References

• Benson, A.B., D'Angelica, M.I., Abbott, D.E., Abrams, T.A., Alberts, S.R., Anaya, D.A., et al, 2017.

NCCN guidelines insights: hepatobiliary cancers, version 1.2017. Journal of the National

Comprehensive Cancer Network, 15(5), pp.563-573.

• Cardoso, F., Senkus, E., Costa, A., Papadopoulos, E., Aapro, M., André, F., et al, 2018. 4th ESO–

ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4). Annals of

Oncology, 29(8), pp.1634-1657.

• Dalal, A.A., Gauthier, G., Gagnon-Sanschagrin, P., Burne, R., Guerin, A., Niravath, P., et al, 2018.

Treatment and Monitoring Patterns Among Premenopausal Women with HR+/HER2− Advanced

Breast Cancer. Advances in therapy, 35(9), pp.1356-1367.

• De Haes, H., Olschewski, M., Kaufmann, M., Schumacher, M., Jonat, W. and Sauerbrei, W., 2003.

Quality of life in Goserelin-treated versus Cyclophosphamide+ Methotrexate+ Fluorouracil–treated

premenopausal and perimenopausal patients with node-positive, early breast cancer: The Zoladex

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Early Breast Cancer Research Association Trialists Group. Journal of Clinical Oncology, 21(24),

pp.4510-4516.

• Del Mastro, L., Rossi, G., Lambertini, M., Poggio, F. and Pronzato, P., 2016. New insights on the

role of luteinizing hormone releasing hormone agonists in premenopausal early breast cancer

patients. Cancer treatment reviews, 42, pp.18-23.

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premenopausal women with hormone receptor positive breast cancer. Gynecologic

oncology, 147(1), pp.153-157.

• Gordon, J., Fischer-Cartlidge, E. and Barton-Burke, M., 2017. The Big 3: An Updated Overview of

Colorectal, Breast, and Prostate Cancers. Nursing Clinics, 52(1), pp.27-52.

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NCCN guidelines insights: breast cancer, version 1.2017. Journal of the National Comprehensive

Cancer Network, 15(4), pp.433-451.

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Long-term effectiveness of adjuvant goserelin in premenopausal women with early breast cancer.

Journal of The National Cancer Institute, 101(5): 341–349.

• Jonat, W., Kaufmann, M., Sauerbrei, W., Blamey, R., Cuzick, J., Namer, M.,et al, 2002. Goserelin

versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal

patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association

Study. Journal of Clinical Oncology, 20(24), pp.4628-4635.

• Lambertini, M., Ceppi, M., Poggio, F., Peccatori, F.A., Azim Jr, H.A.,et al, 2015. Ovarian

suppression using luteinizing hormone-releasing hormone agonists during chemotherapy to

preserve ovarian function and fertility of breast cancer patients: a meta-analysis of randomized

studies. Annals of Oncology, 26(12), pp.2408-2419.

• Moore, H.C., Unger, J.M., Phillips, K.A., Boyle, F., Hitre, E., Porter, D., et al, 2015. Goserelin for

ovarian protection during breast-cancer adjuvant chemotherapy. New England Journal of

Medicine, 372(10), pp.923-932.

• Munhoz, R.R., Pereira, A.A., Sasse, A.D., Hoff, P.M., Traina, T.A., Hudis, C.A.,et al, 2016.

Gonadotropin-releasing hormone agonists for ovarian function preservation in premenopausal

women undergoing chemotherapy for early-stage breast cancer: a systematic review and meta-

analysis. JAMA oncology, 2(1), pp.65-73.

• Taylor, C.W., Green, S., Dalton, W.S., Martino, S., Rector, D., Ingle, J.N.,et al, 1998. Multicenter

randomized clinical trial of goserelin versus surgical ovariectomy in premenopausal patients with

receptor-positive metastatic breast cancer: an intergroup study. Journal of Clinical

Oncology, 16(3), pp.994-999.

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statistics, 2012. CA: a cancer journal for clinicians, 65(2), pp.87-108.

• Zhou, J., Wu, S.G., Wang, J.J., Sun, J.Y., Li, F.Y., Lin, Q.,et al, 2015. Ovarian ablation using

goserelin improves survival of premenopausal patients with stage II/III hormone receptor-positive

breast cancer without chemotherapy-induced amenorrhea. Cancer research and treatment: official

journal of Korean Cancer Association, 47(1), p.55.

Handling Difficult Cases of Head and Neck Squamous Cell Carcinoma

I Gede Budhi Setiawan

Divisi Bedah Onkologi, Departemen Ilmu Bedah Fakultas Kedokteran Universitas Udayana, RSUP

Sanglah Denpasar

Kanker kepala leher merupakan kelompok kanker yang meliputi tumor pada beberapa area

diatas tulang leher. Kanker kepala leher memiliki tiga subdivisi mayor meliputi kanker nasofaringeal,

kanker laringeal, kanker regio oral (Choong et al, 2008).

Secara epidemiologi, kanker kepala leher merupakan kanker nomor lima terbanyak didunia.

Sebanyak 650.00 kasus baru di dunia pertahun dengan jumlah kematian mencapai 350.000 kasus. Di

Asia, terdapat 368.000 kasus baru pertahunnya dengan kematian pada 223.000 kasus. Di Indonesia

sendiri terdapat 25.485 kasus baru pertahunnya (Sturgis et al, 2002).

Manajemen pengobatan kanker sel skuamosa pada kepala leher/Head and Neck Squamous

Cell Ca (HNSCC) harus mempertimbangkan berbagai faktor meliputi indeks terapi, prognosis pasien,

guidelines dan evidence, ketahanan pengobatan, luaran jangka panjang dan kualitas hidup, potensi

penemuan terapi terbaru (Kowalski, 2002). Diperlukan tim multidisiplin untuk mengoptimalkan luaran

pada pasien dengan HNSCC. Tim multidisiplin ini meliputi ahli bedah, onkologi medis, speech

pathologist, dokter gigi, radiologi onkologi, ahli bedah maksilofasial, radiologis, spesialis nyeri, ahli

gizi, spesialis kesehatan jiwa, fisioterapis, perawat yang terlatih dan pekerja sosial (Choong et al,

2008).

Tujuan terapi pada locally advanced HNSCC meliputi penyembuhan, kontrol lokoregional,

memperpanjang harapan hidup, meningkatkan kualitas hidup, preservasi organ (Vermoken et al,

2010). Tujuan terapi pada pasien dengan reccurent/Metastatic HNSCC meliputi menstabilkan

penyakit, mengecilkan tumor, mencegah gejala yang berkaitan dengan kanker, memperpanjang

harapan hidup, mengontrol gejala, dan meningkatkan kualitas hidup (Galloway et al, 2014).

Gambar 1. Proporsi HNSCC yang mengalami relaps atau metastasis (Lefebvre, 2005).

Pertimbangan pilihan terapi pada HNSCC berdasarkan pada riwayat pasien dan riwayan

pengobatan, serta faktor yang berhubungan dengan tumor. Riwayat pasien dan pengobatan meliputi

waktu kekambuhan, disfungsi organ akibat penyakti/terapi sebelumnya, radioterapi sebelumnya

(dosis, tipe, waktu terapi terakhir, permukaan, volume), kemoterapi sebelumnya, komorbid, dan

performance status. Sedangkan faktor pada tumor yang mempengaruhi meliputi lokasi tumor,

stadium, histologi, volume dan resektabilitas (Galloway et al, 2014).

61

Gambar 2. Berbagai Gambaran Klinis HNSCC

Manajemen HNSCC meliputi pembedahan, radioterapi, kemoterapi, serta molecular targeting

therapy. Pembedahan meliputi eksisi luas dengan margin bebas tumor dan rekonstruksi (bisa segera

atau ditunda). Akibat yang ditimbulkan dari pembedahan mayor pada kepala dan leher meliputi

morbiditas pasien yang berat, gangguan fungsi baik fisik, psikologis maupun nutrisi, gangguan

kosmetik dan perubahan kualitas hidup pasien (Reich et al, 2014).

62

Gambar 3. Eksisi luas dengan rekonstruksi pada HNSCC

63

Tabel 1. Strategi pengobatan pada locally Advanced HNSC (Ang, 2008).

Berdasarkan penelitian Bonner fase 3 menyebutkan bahwa cetuximab dengan radioterapi

terapi efektif pada pasien dengan locally Advanced HNSC. Dari penelitian tersebut sejumlah 424

pasien dengan 211 pasien mendapatkan cetuximab dan radioterapi, serta 213 mendapatkan

radioterapi saja. Sebanyak 50% terjadi kontrol lokoregional dengan cetuximab ditambah radioterapi

dalam 3 tahun. Ditambahkannya cetuximab pada pasien yang mendapatkan radioterapi meningkatkan

median kontrol lokoregional secara signifikan dari 14.9 menjadi 24.4 bulan. Selain itu jugan

meningkatkan angka harapan hidup 5 tahun. Selain itu pemberian Cetuximab dengan radioterapi tidak

menyebabkan eksaserbasi toksisitas pasien grade 3-4 dengan locally advanced HNSCC, kecuali

untuk acne like rash, dan reaksi infus. Kombinasi ini juga sangat baik dalam memperpanjang harapa

hidup dan optimalisasi kualitas hidup pasien pada locally advanced HNSCC (Booner et al, 2010).

Gambar 4. Skema Penelitian “Bonner” Fase 3 (Booner et al, 2010).

64

Gambar 5. Toksisitas grade 3-4 pada pemberian cetuximab dengan radioterapi (Booner et al, 2010).

Tabel 2. Perbedaan kualitas hidup, harapan hidup dan toksisitas pada radioterapi dan radioterapi +

cetuximab (Curran et al, 2007)

Pedoman manajemen pada recurrent HNSCC berdasarkan pada NCCN guidelines bertujuan

untuk memperpanjang ketahanan hidup, mengontrol gejala, dan mempertahankan kualitas hidup

(Pfster et al, 2015).

Gambar 6. Terapi lini pertama pada recurrent/metastatic HNSCC berdasarkan NCCN

guidelines (Pfster et al, 2015).

65

Gambar 7. Pedoman terapi pada recurrent locoregional HNSCC berdasarkan NCCN guidelines

(Pfster et al, 2015).

Gambar 8. Pedoman terapi lini pertama dan lini kedua pada recurrent/metastatic HNSCC

berdasarkan NCCN guidelines (Pfster et al, 2015).

Gambar 9. Algoritme terapi lini pertama pada recurrent/metastatic HNSCC (Pfster et al,

2015).

66

Tabel 3. Efikasi regimen kemoterapi lini pertama R/M HNSCC(Soo, et al, 2005).

Gambar 10. Overall survival pada R/M HNSCC dengan kemoterapi (Cooper et al, 2004).

Kemoterapi*

(n=220)

Cetuximab +

Kemoterapi*

(n=222)

p-value

Median OS1 (bulan)

7.4 10.1

0.04

HR 0.80 (0.64–0.99)

Median PFS1 (bulan) 3.3 5.6 <0.001

ORR1 (%) 20 36 <0.001

CR2 (%) 0.9 6.8

Disease control1 (%) 60 81 <0.001

Tabel 4. Efikasi cetuximab + kemoterapi dilanjutkan dosis pemeliharaan cetuximab (Vermorken et al,

2009).

67

Dari penelitian EXTREME fase III menunjukkan efikasi cetuximab dengan kemoterapi pada

pasien dengan R/M HNSCC. Terjadi penurunan resiko kematian 20% dibandingkan dengan

pemberian kemoterapi saja, terjadi pemanjangan progression free survival dan overall survival

dibandingkan dengan pemberian kemoterapi saja. Terjadi peningkatan overall response rate hampir

dua kali lipat dibandingkan dengan pemberian kemoterapi saja (Tanvetyanon et al, 2009).

Gambar 11. Grafik overall survival selama 3 tahun dengan cetuximab dan kemoterapi diikuti dengan

dosisi pemeliharaan cetuximab hingga berkembangnya penyakit (Vermorken et al, 2009).

Gambar 12. Grafik survival outcomes dengan cetuximab dan kemoterapi diikuti dengan dosis

pemeliharaan cetuximab hingga berkembangnya penyakit (Vermorken et al, 2009).

68

Gambar 13. Grafik efek toksisitas pemberian cetuximab pada kemoterapi (Vermorken et al, 2009)

Premedikasi pada cetuximab harus diberikan sebelum pemberian dosis awal cetuximab.

Premedikasi direkomendasikan sebelum pemberian cetuximab (Lee et al, 2007). Premedikasi

diberikan bersamaan dengan anti alergi meliputi antihistamin dan kortikosteroid seperti antagonis H1

(dipenhidramin 50mg) secara intravena 30-60 menit sebelum pemberian cetuximab dan dexametason

2 ampul (Machiels et al, 2014).

Kesimpulan

Masalah kesehatan pada kepala dan leher meningkat dengan mortalitas yang semakin

meningkat. Umumnya pasien datang pada stadium lanjut yang menurunkan kualitas hidup pasien.

Tujuan terapi pada pasien umumnya untuk mengendalikan gejala dan meningkatkan kualitas hidup

pasien. Respon terhadap terapi sistemik memiliki efek yang besar terhadap ketahanan hidup pasien.

Target terapi merupakan kunci untuk memaksimalkan efikasi tanpa memperburuk toksisitas pada

pasien (Machtay et al, 2008).

Pemberian cetuximab pada kemoterapi standard pada kanker kepala leher memperpanjang

progression free survival dan overall survival. Dan pemberian cetuximab dan radioterapi

meningkatkan kontrol lokoregional dan ketahanan 5 tahun pada penelitian fase III LA HNSCC.

(Mendenhall et al, 2008). International Guidelines menyarankan pemberian cetuximab dan radioterapi

pada pasien dengan locally advaced HNSCC dan penambahan cetuximab untuk terapi lini pertama

dan kedua pada R/M HNSCC (Pfster et al, 2015).

Referensi

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