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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
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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.
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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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tamoxifen after 2–3 years tamoxifen. Annals of Oncology, 21(3), pp. 498-505.
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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.
31
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)
32
• 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.
• Hackshaw, A., Baum, M., Fornander, T., Nordenskjold, B., Nicolucci, A., Monson, K.,et al, 2009.
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.
• Torre, L.A., Bray, F., Siegel, R.L., Ferlay, J., Lortet‐Tieulent, J. and Jemal, A., 2015. Global cancer
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
• Ang, K.K., 2008. Multidisciplinary management of locally advanced SCCHN: optimizing treatment
outcomes. The oncologist, 13(8), pp.899-910.
• Bernier, J., Domenge, C., Ozsahin, M., Matuszewska, K., Lefèbvre, J.L., Greiner, R.H.,et al, 2004.
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