Kemoterapi Solid Malignan Tumor Pada Anak

1. Apa itu kemoterapi?

Chemotherapy is used to cure a small percentage of malignancies, as adjuvant therapy

to decrease the rate of relapse or improve the disease-free interval, and to palliate
symptoms in some patients with incurable malignancies. In addition, chemotherapy
may play a role as preoperative or "neoadjuvant" therapy to reduce the size and extent
of the primary tumor, thereby allowing complete excision at the time of surgery.

2. Apa itu tumor

 Klasifikasi tumor pada anak?

Tradionally, descriptive data on cancers occurring in people of all ages combined have
been presented with the diagnoses categorized according to the International
Classification of Deseases (ICD), in which cancers other than leukemia, lymphomas,
kaposi’s sarcoma, cutaneous melanoma, and mesothelioma are classified purely on the
basis of primary site. The malignant solid tumors of children are histologically very
diverse and a proportion consist of characteristic entities that rarely seen in adults.
Therefore, it is appropriate to group childhood cancers in a way which more fully takes
morphology into account, and standart classification have been devised with the
categories defined according to the codes for tophography and morphology in the
International Classification of Disease for Oncology (ICD-O). The current scheme is the
International Calssification of Childhood Cancer, Third Edition (ICCC-3), based on the
third edition of ICD-O. ICCC-3 contains 12 main diagnostic groups :

i. Leukemias, myeloproliferative diseases, and myelodysplastic diseases.

ii. Lymphomas and reticuloendothelial neoplasms
iii. CNS and miscellaneous intracranial and intraspinal neoplasms
iv. Neuroblastoma and other peripheral nervous cell tumors
v. Retinoblastoma
vi. Renal tumors
vii. Hepatic tumors
viii. Malignant bone tumors
ix. Soft tissue and other extraosseous sarcomas
x. Germ cell tumors, trophoblastic tumors, and neoplasms of gonads
xi. Other malignant epithelial neoplasms and malignant melanomas
xii. Other and unspecified malignant neoplasms
All of the groups except retinoblastoma are split into subgroups, and the most
heterogenous subgroups are in turn split into divisions. Most groups contain only
malignant neoplasms, but groups III and X also include nonmalignant intracranial and
intraspinal tumors since they are usually recorded by cancer registries.

Successive classification have been designed to have as much continuity as possible with
their predecessors, while recognizing advances in understanding of tumor pathology
and biology. Although the nomenclature of many groups and subgroups has changed
since the previous version of the classification, their contents are largely the same.

 Solid malignant tumor pada anak?

 Solid tumor?
 Tanda-tanda malignancy?

tidak ada subjek yang ahli bedah harus berkonsultasi dengan ahli patologi yang lebih
sering dari pertanyaan mengenai apakah benjolan atau tidak ganas. dalam bidang ini
penghakiman patolog adalah semua penting. biasanya mudah untuk memutuskan hal
ini. kadang-kadang sulit seperti itu untuk ahli bedah untuk tiba pada suatu diagnosis
klinis yang benar. fitur yang patolog harus mengarahkan perhatian sebagian histologis,
artinya susunan sel tumor dan hubungannya dengan tisue sekitarnya, dan sebagian
sitologis, yaitu, sifat te sel tumor, dan khususnya sifat inti dan Nukleolus. karakteristik
utama keganasan, umum maupun mikroskopis, tujuh jumlahnya.

Nuklir perubahan. inti sel kanker yang besar dan hyperchromatic, pewarnaan intens
dengan Hematoksilin. itu bervariasi banyak ukuran dan bentuk. kehadiran sejumlah
tokoh mitosis (satu atau dua dalam lima bidang highpower) dan mitosis atipikal
terutama adalah nilai, untuk degenerasi sayangnya dalam mesenchymal tumor jinak
seperti leiomyoma rahim menimbulkan banyak tampilan atipikal yang sama dari inti
sebagai terlihat dalam suatu sarkoma. harus diingat dan di lain cepat regenerasi sel

Anaplasia. This term, which was introduced by von Hansemann in 1893, signifies leak
of differentiation. The anaplasia may be histological cytological. When the cells of a
carcinoma of the stomach fail to form glands, the tumor exhibits anaplasia. The same is
true of an epidermoid carcinoma of the skin in which the cells fail to develop into
cornified epithelium. The more anaplastic the tumor, the more malignant is it likely to
be and the more radiosensitive.

Loss of polarity. Epithelial cells which are arranged in sheets show a normal alignment
with their neighbors. One of the early signs of the malignant change is a loss of this
normal polarity, so that the cells may present a jumbled arrangement in relation to the
surface and to one another.

These three features, nuclear changes, anaplasia, and loss of polarity, may all be seen
before invasion of the deeper tissue has occurred. This is called preinvasive carcinoma
or carcinoma in situ, a condition which is described later.

Infiltration. One of the most charactheristic features of malignancy is infiltration, as a

result of which tissue such as gastric epithelium is found out of place as in the muscular
or serous coats. A benign tumor grows by expansion, compressing the surrounding
tissue to form a capsule. To this rule the angioma is an exeption.

Recurrence. This is a clinical term which signifies that the tumor has reappeared after
removal or radiotherapy, and is easily explained on the basis of the survival of some of
the infiltrating cancer cells. This cells may remain dormant for many years and may
then begin to grow again. Recurrence, however, is not necessarily due to incomplete
removal. It may be due to the tumor having a wide field of origin.

Perhaps the best example is provided by the duct system of the breast. Whwn the
surgeon suspects a wide field of origin, he will plai his operation accordingly, although
in some cases no such planning is possible. As willis remarks, in case of multiple skin
cancer associated with xeroderma pigmentosum the only fully adequate surgery would
be flaying.

Metastases. The formation of secondary growths due to lymph or blood spread is the
hallmark of cancer. For reasons which are at present unknown malignant tumors vary
widely in their ability to metastasize. Some grow to a great size without ever spreading
to a distance, whereas others invide the lymphatic and blood vessels while yet too small
to be detected clinically.

Progressive growth. A malignant tumor will continue to grow unless adequately treated.
A benign tumor may attain a great size, but eventually growth will cease.
These seven features are the principal characteristics of malignancy.

 Epidemiology?

Leukemia formed the most frequent diagnostic group, about one third of the total
incidence. The most numerous solid neoplasms were CNS and other intracranial and
intraspinal tumors, accounting for just under a quarter of total cancer incidence. The
next most frequent diagnostic groups were, in descending order of incidence,
lymphomas, soft tissue sarcomas, neuroblastoma and other peripheral nervous cell
tumors, and renal tumors, each accounting for 6-9% of the total.

Overall, incidence in the first 5 years of life was about 1,7 times that at 5-14 years of
age. Boys were affected 1,2 times as often as girls.

The principal embryonal tumors, namely those of the CNS (including medulloblastoma
and other primitive neuroectodermal tumors), neuroblastoma, retinoblastoma,
nephroblastoma (wilm’s tumor) and hepatoblastoma, all had their highest incidence in
early childhood, and about 40% of the cumulative incidence of retinoblastoma and
hepatoblastoma were observed in the first year of life.

And more than two thirds of the cumulative childhood incidence of Hodgkin lymphoma
and osteosarcoma occurred at age 10-14. Most cancers of the liver, kidney, and eye were
characteristic childhood embryonal tumors. Rhabdomyosarcoma was the most common
type of childhood cancer in other genitor-urinary sites of both sexes.

3. kemoterapi solid malignant tumor pada anak?

Children’s cancer are rare and account for 15 of all malignancies. Within Europe this
represents some 12.000 new cases each year, with approximately 1.600 per year in the
UK, 1 in every 600 children under 15 years of age develop cancer. Although rare,
childhood cancer is the second commonest cause of death in children between 1-14 years
of age. These cancers are quite different from cancers affecting adults. Most adult
tumors are carcinomas and are usually classified by their site of origin, whereas
pediatric tumors occur in different parts of the body, look different under the
microscope, and are classified by histological subtypes.
Survival rates for childhood cancer have improved dramatically over the last 20 years,
such that approximately 70% of children can expect to become long term survivors.
This is reflected by the fact that today, 1 in 750 of the young adult population is now a
survivor of childhood cancer. Treatment used to achieve this success are surgery,
chemotherapy, and/or radiotherapy. Factor contributing to these improved survival
rates are : the development of dedicated pediatric oncology centers, advances in
surgical techniques, novel chemotherapy agents and regimens, targeted radiotherapy,
and improvements in supportive care.

Surgery was the mainstay of treatment of solid tumors in children before the advent of
effective chemotherapy. Cure could be obtained by surgery alone in the proportion of
children with localized disease, and good palliation obtained in many others, and the
surgeon was often the key clinician in the menegement of pediatric solid tumors.
However, very few tumors present as a purely localized surgical problem. The surgeon
becomes part of the larger team, needing to integrate surgical procedures with
chemotherapy and/or radiotherapy. Although improvements in radiotherapy and
surgery have reduced the late sequelae of curative therapy, chemotherapy now remain
the mainstay of treatment for most childhood cancer.

Although complete tumor resection is of paramount importance for cure, most pediatric
cancers are advanced at presentation (e.g, 55-60% sarcomas are high risk at
diagnosis,25% of bone tumors are metastatic at diagnosis, 90% of neuroblastoma
occurring after infancy are stage IV) and require systemic treatment. The prognosis for
malignant solid tumors has improved since the introduction of affective chemotherapy
capable of reducing the tumor volume and making previously unresectable. The
operation also becomes safer and easier after preoperative chemotherapy. Furthermore,
there is no delay in treating metastatic disease, which is detectable at diagnosis in a
significant proportion of patients.

Some disease, such as osteosarcoma, canot be cured except with surgery to remove the
local tumor, whereas in others such as lymphoma, biopsy followed by chemotherapy is
all that is needed. In others, such as ewing’s sarcoma and rhabdomyosarcoma, the best
treatment results may be obtained with systemic chemotherapy and a combination of
surgery and/or radiotherapy for local control. In Europe, since the early 1990s, the
concept of preoperative chemotherapy and delayed surgery for solid tumors of
childhood became standard clinical practice due to successful wilm’s tumor trials of the
SIOP (international society of pediatrics oncology)

In nearly all case of malignancy, diagnosis must be confirmed by biopsy of the primary
tumor. Traditionally, tumor material would be obtained by incisional or excisional
biopsy at open operation

Although the overall cure rate for childhood tumors is now around 70%, it is only by
increased understanding at the biological level that further progress will be made,
particularly in an appropriate risk stratification of current intensive treatments and in
the development of novel therapies. With increased survival rates for childhood cancer,
philosophy of treatment has changed over the years from “cure at any cost” to “cure at
least possible cost”.

Once the diagnosis has been confirmed, the extent of the tumor (size, position,
relationship to surrounding structures, appearance of lymph node) must be established.
Unfortunately, there is no single uniform staging approach for childhood malignancies
and the surgeon will need to be aware of the requirements for staging of each tumor
type according to the current protocols.

More extensive tissue sampling n biopsy is usually only needed at the time of devinitive
operation. This information will determine what type of further treatment is required
postoperatively.

Increasingly, the chemotherapy respone of the primary tumor in the postsurgical

specimen is used in deciding postoperative treatment for a number of malignant solid
tumor ( e.g, in osteosarcoma and ewing’s sarcoma <90% necrosis of the tumor is
considered a poor response and these patients are now randomized to receive more
intensive treatment to improve the chances of long term survival).

Although chemotherapy is needed for nearly all tumors in childhood and is often given
before definitive surgery, primary surgical excision is still indicated for a number of
malignancies.

Debulking of tumors are rarely indicated as primary surgical procedures, except for
some brain tumors. In particular, they confirm no advantage in the treatment of
lymphoma, which may present with widespread intraabdominal disease, although
surgery may be necessary if chemotherapy results) in complication such as perforation
or bleeding, or if the patient presents with intestinal obstruction. It is important that the
surgeon is then as conservative as possible in his approach, since the chance of complete
remission of disease following chemotherapy is high and surgery performed at any stage
in the disease does not lead to improve cure rates.

Insertion of central venous catheter is probably the single most frequent operation that
pediatric surgeons perform while caring for a child with malignancy. Centrally placed,
long term venous catheters are used for the administration of chemotherapy and
antibiotics and for blood sampling.

Furthermore, a surgeon also has a role in providing enteral access in patients

receiving intensive chemotherapy. Children with cancer often have associated cachexia,
with significant weight loss and malnutrition. The intensity and type of primary therapy
(chemotherapy, surgery, and/or radiotherapy) is associated with decline in the
nutritional status. Furthermore, patients receiving intensive chemoteraphy have
prolonged illness-mucositis, diarrhea, suboptimal dietary intake, and decreased
appetite-all are side effects of chemotherapy that contribute to further weight loss.
Numerous studies have demonstrated that a nutritionally repleted patient tolerates
therapy better and with fewer complications (6-8). In addition to providing nutritional
requirements, gastrotomy tubes can perform other functions. Clinical experience has
demonstrated that gastrotomy tubes are an effective way to deliver medications and to
provide hydration to children experiencing excessive emesis. The quality of life both the
child and family also appears to improve , as eating is a frequent source of conflict
between the child and parents,

In many cases of solid tumors, surgical excision of primary tumoris the preferred
local treatment since radiotherapy has a much greater risk of long-term sequelae. The
general principles of choice of local treatment are that surgical excision is the treatment
of choice where: (1) complete excision is possible and results in improved survival and
cure; (2) it will give functional and cosmetics results better than those obtained by other
treatment.

Surgeon may also be consulted to deal with complications related to other forms
of treatment: extravasation of chemotherapy agents causing tissue necrosis, typhilitis
(neutropenic entrecolitis), intestinal perforation, strictures or avascular necrosis, or
other damage due to late effects of radiotherapy.

Surgical decisions, as well as those concerning chemotherapy, radiotherapy, and

overall treatment strategies are best made after joint discussion, which is facilitated by a
formal system of consultations such as regular multidisciplinary oncology team meetings
(Tumor Board), as well as maintaining communication between the key team members
during the treatment.

Chemotherapy

The effective use of cancer chemotherapy requires a thorough understanding of

principles of neoblastic cell growth kinetics, basic pharmacologic mechanisms of drug action,
and pharmaco-kinetic and pharmaco-dynamic variability.

The aim of adjuvant chemotherapy is to prevent metastatic recurrence by eliminating

micrometastatic tumor deposits in the lungs, bone, bone marrow, or other sites at the time of
diagnosis. Adjuvant chemotherapy has been demonstrated to be efficacious for most of the
common pediatric cancers , including Wilm’s tumor, Ewing’s sarcoma, osteosarcoma, and
rhabdomyosarcoma. Adjuvant chemotherapy should be given as soon as possible after
definitive local therapy. A delay to allow for recovery from surgery or radiation therapy may
compromise the chance of curing the patient.

Increasingly, chemotherapy is now used in a neoadjuvant setting (before the definitive

treatment) in pediatric solid tumors as chemotherapy shrinks the tumor and the operation
becomes safer and easier. Neoadjuvant chemotherapy also provides earlier set treatment for
micrometastases.

For example, nitrogen mustard, alkylating agents, and gamma radiation are non cycle
specific, being effective at most phases of the cycle and in some cases including the G0
population. Phase specific agents include Vinblastine and Vincristine, which are active during
the mitotic phase; etoposide and tenoposide affective during the G2 premitotic phase; and
methotrexate, 6-mercaptopurine and cytosine arabinoside affective during the S-phase.
Agents that are cycle but not phase specific include 5-fluorouracil, acinomycin D, and
Doxorubicine.

Obat-obat yang specific pada fase siklus sel

 S phase dependent M phase dependent
Antimetabolites Vinca alkaloids*
 Cytarabine  Vinblastine
 Doxorubicin  Vincristine
 Fludarabine  Vinorelbine
 Gemcitabine
Podophyllotoxins
 Hydroxyurea
 Mercaptopurine  Etoposide
 Methotrexate  Teniposide
 Prednisolone Taxanes
 Procarbazine
 Thioguanine  Docetaxel
 Paclitaxel
G2 phase dependent
 Bleomycin
 Irinotecan
 Mitoxantrone
 Topotecan
G1 phase dependent
 Asparaginase
 corticosteroids
*have greatest effects in S phase and possibly late G2 phase; cell blockade or death; however,
occurs in early mitosis.

Hepatic artery infusion has been used to treat liver metastases, particularly from colonic
cancers in adults. Again, the usefulness of this approach is limited in children where systemic
therapy is needed for most tumors because of the pattern of tumor spread. It may have some
place in the treatment of hepatoblastoma.

For solid tumors, chemotherapy has two main goals- to eliminate overt metastases or
microscopic spread, and to destroy or reduce the primary tumor mass so that, with or without
further local treatment, complete response (CR) can be obtained. Without complete response,
cure will never be possible.
Klasifikasi dari agen sitotoksik yang umum dipakai

Agent Substanc Major clinical use Metabo Excretion Toxicities

type e name lism
Antimetab Methotre Leukemia, Hepatic Renal,50- BM,M,kidney,lung,
olites xate lymphoma,CNS, 90% liver,CNS
osteosarcoma excreted
unchanged;
biliary
5- Colorectal,liver Hepatic Renal BM,M,diarrhea
fluorour
acil
6- Leukemia, Hepatic Renal BM,liver
mercapt lymphoma ,
opu-rin allopuri
(6-MP) nol
inhibits
metabol
ism
6- Leukemia,lym- Hepatic Renal BM
thiogram phoma
ine (6-
TG)
Cytarabi Leukemia,lym- Hepatic Renal BM,M,cholestasis,N+
ne phoma,CNS V,
diarrhea,CNS,lung,co
njungtivitis
Alkylating Nitrogen Hodgkin’s disease Hepatic Biliary BM,N+V,alopecia.ster
agents mustard ility
Cycloph Leukemia,lym Hepatic Renal BM,cystitis,alopecia,l
os- Phoma,neuro ung,heart, sterility
phamid blastoma,rha
bdomyosarco
ma,ewing’s
sarcoma,germ cell
tumors
Ifosfami Neuroblastoma, Hepatic Renal BM, alopecia,
de sarcomas,leukemia, cystitis,
hodgkin’s disease encephalopathy,
kidney, sterility, heart
Melphal Hepatic Renal BM, M, alopecia,
an heart, sterility
Busulph Leukemia Hepatic Renal VOD, lung fibrosis,
an sterility, addisonian-
like state
BCNU Brain tumors, Hepatic Renal Late bone marrow
(Carmus lymphomas toxicity(up to 6/52),
tine) sterility, lung, heart
CCNU
 (Lomusti
ne)
Cisplatin Germ cell tumors, Renal N+V, renal, hearing
neuroblastoma, loss
sarcomas, CNS,
liver
Carbopla
tin
Vinca Vincristi Leukemia,lympho Hepatic Biliary Neurotoxicity, jaw
alkaloids ne ma,wilm’s tumor, Hepatic pain,constipation,inap
Vinblasti neuroblastoma, Biliary propriate ADH
ne rhabdomyosarcoma secretion, jaw
, ewing’s sarcoma, pain,mucositis
lymphoma
Vindesin Sarcomas Hepatic Biliary BM
e
Epipodo- Etopusid Leukemia, Renal BM, N+V,
phylotoxi e (VP16) lymphoma, neurotoxicity,leukemi
ns neuroblastoma, a,alopecia
Teniposi germ cell tumors
de
Doxorub Leukemia, Hepatic Biliary,rena BM, N+V, heart,
icin lymphoma, l mucositis, alopecia,
neuroblastoma, radiation recall
rhabdomyosarcoma
, ewing’s sarcoma,
wilm’s tumor
Daunoru Leukemia Hepatic Biliary, BM, N+V, heart,
bicin renal alopecia, radiation
recall
EpirubicLymphoma, Hepatic Biliary, BM, alopecia,heart
in sarcoma Hepatic renal BM, cholestasis
MitozantLymphoma,
rone leukemia
Actinom Wilm’s tumor, Renal BM, N+V, skin (with
ycin D ewing’s sarcoma, radiation), liver,
rhabdomyosarcoma alopecia
Miscellan Bleomyc Germ cell tumor, Hepatic Renal Lung fibrosis, lever,
eous in lymphoma pigmentation,
raynaud’s
phenomenon
Dacarba Sarcoma, hodgkin’s Hepatic Renal “flu” symptoms,liver
zine disease
Procarba Hodgkin,s disease Hepatic Renal Liver, “flu
zine “symptoms
L- Leukemia Reticuloend Hypersensitivity,
Asparagi otelial liver, CNS
nase system
Predniso Leukemia, Hepatic Renal Hypertension, blood
 lone lymphoma sugar diabetes,
cataracts, cushing’s,
oeteoporosis,
immunosuppression

Prinsip dalam memilih kombinasi regimen kemoterapi

 Drugs known to be active as single agents should be selected for use in combinations;
preferentialydrugs that induce complete remission should be included.
 Drugs with different mechanisms of action and with additive or synergistic cytotoxic
effects on the tumor shoul be combined.
 Drugs with different dose-limiting toxicities should be combined so that full or nearly
full therapeutic doses can be utilized.
 Drugs should be used at their optimal dose and schedule.
 Drugs should be given at consistent intervals, and the treatment-free time period
should be as short as possible to allow for recovery for the most sensitive normal
tissues.
 Drugs with different patterns of resistance should be used to minimize cross-
resistance

When combined with initial surgery—and in some instances with irradiation—chemotherapy

increases the cure rate in Wilms' tumor and increases the rate of long-term control and cure of
breast cancer, colon cancer, rectal cancer, and osteogenic sarcomas.

Patients with incurable tumors who desire aggressive treatment should be referred for
experimental protocol therapy. Tumor cell vaccines combined with immune adjuncts are
under investigation as specific immunotherapy for chemotherapy-resistant tumors

While most anticancer drugs are used systemically, there are selected indications for local or
regional administration. Regional administration involves direct infusion of active
chemotherapeutic agents into the tumor site (eg, intravesical therapy, intraperitoneal therapy,
hepatic artery infusion with or without embolization of the main blood supply of the tumor).
These treatments can result in palliation and prolonged survival.

Protocol yang umum digunakan pada solid malignan tumor

Tumor Current protocol Drugs Acronyms
Neuroblastoma (stage HR-NBL- Vincristine
IV) 1/ESIOP(induction) Cyclophosphamide RAPID
Etoposide COJEC
Cisplatin
Carbolatin
(myeloablative Busulphan
treatment) Melphalan Bu-Mel
or
Carboplatin
Etoposide CEM
Melphalan
Unresectable/refractory TVD protocol Topotecan TVD
Vincristine
Doxorubicine
Wilms’ SIOP WT 2002 Vincristine/ AV
Actinomicyn
Doxorubicin AVD

(high risk) Etoposide

Carboplatin
Cycophosphamide
Sarcoma EpSSG RMS-2005 Ifosfamide IVADO
for Vincristine
Rhabdomyosarcoma Actinomicyn
Doxorubicin

EpSSG-Non-
rhabdomyosarcoma Ifosfamide
Doxorubicine
Ewing’s EURO-EWING’S Vincristine VIDE
(induction) Ifosfamide
Doxorubicin
Etoposide

(consolidation) Cyclophosphamide VAC,VAI

Hepatoblastoma SIOPEL-3 Cisplatin PLADO
Germ cell GC3 (standard risk) Doxorubicin
SIOPEL-4 Cisplatin
(high risk) Doxorubicin
SIOPEL-3 Cisplatin
GC-3 Etoposide JEB
Osteosarcoma Carboplatin
Bleomycin
EURAMOS Methotrexate MAP
Hodgkin’s Adriamycin
CisPlatinum
Ifosfamide MAPIE
Etoposide
 Hodgkin 2000 Vincristine
Non Hodgkin’s Prednisolone OEPA
lymphoma Etoposide
Adriamycin

EURO-I B 02 Cyclophosphamide
Procarbazine COPP
Prednisolone COP
Medulloblastoma Vincristine COP
Daunorubicine COPADM
Asparaginase CYM
Cyclophosphamide
Methotrexate
SIOP PNET4 (avg Vincristine Packer
risk)
High grade glioma Cisplatin
CCNU (lomustine)
Cis Tem Cisplatin CISTEM
Low grade glioma Temozolomide
LGG-2 Vincristine VCE
Carboplatin
Etoposide

Kritea respon pada tumor solid :

 Complete response (CR) : complete disappearance of all visible disease
 Very good partial response (VGPR) : volume tumor berkurang lebih dari 90% tapi
kurang dari 100%
 Partial response (PR≥2/3) : volume tumor berkurang ≥66% tapi <89%.
 Minor partial response (PR<2/3) : volume tumor berkurang >33% tapi < 66%.
 Stable disease (SD): tidak ada criteria untuk PR atau PD (volume tumor berkurang
<33%)
 Progressive disease (PD): any increase of more than 40% in volume (or >25% in area)
of any measurable lesion, or appearance of new lesions.