Pertemuan 7

Kanker Otak, Kanker Pediatrik,

Radioterapi Paliatif
Sanggam Ramantisan,S.Si., M.Si.
Tumor otak primer
Pada pembahasan ini akan dibahas kanker otak ganas yaitu
tumor sel glial (glioma), meliputi glioma derajat rendah
(Astrositoma derajat I/II, Oligodendroglioma), glioma
derajat tinggi (Astrositoma Anaplastik [derajat III],
Glioblastoma [derajat IV], Anaplastik Oligodendroglioma).
Selanjutnya kanker otak lainnya seperti Meningioma, tumor
hipofisis dan Schwannoma.
Meningioma merupakan tumor jinak tersering. Berasal dari arachnoid cap cells
duramater dan umumnya tumbuh lambat. Lesi Meningioma umumnya memiliki
batas yang jelas, tapi dapat saja memberikan gambaran lesi yang difus, sebagai
contoh adalah meningioma yang tumbuh di sphenoid ridge dan disebut
meningioma en plaque. Meningioma dapat tumbuh intrakranial maupun pada
kanalis spinalis. Sistem tersering yang digunakan adalah menurut klasifikasi
WHO.
Yang termasuk WHO derajat I (umumnya jinak) antara lain meningotelia,
psamomatosa, sekretorik, fibroblastik, angiomatosa, limfoplasmosit,
transisional, mikrokistik, dan metaplastik. Yang termasuk WHO derajat II
(memiliki angka rekurensi yang tinggi, terutama bila tindakan reseksi tidak
berhasil mengangkat tumor secara total) antara lain clear-cell, chordoid, atipikal.
Tipe chordoid biasanya disertai dengan penyakit Castleman (kelainan proliferasi
limfoid). Yang termasuk WHO derajat III (anaplastik) adalah papiler (jarang dan
tersering pada anak-anak), rhabdoid dan anaplastik. Derajat III ini merupakan
meningioma malignan dengan angka invasi lokal yang tinggi, rekurensi tinggi,
dan metastasis.
Sinonim dari schwannoma adalah neurilemoma akustik, neurinoma akustik, atau
schwannoma vestibular. Neuroma akustik (AN) adalah tumor saraf
vestibulokohlearis (N. VIII) yang berasal dari selubung saraf sel Schwann. Sebagian
besar berasal dari bagian vestibuler dan kurang dari 5% berasal dari divisi kohlearis
(pendengaran). Biasanya schwannoma termasuk tumor jinak dan tumbuh lambat,
tapi dapat menimbulkan gejala efek desak ruang dan tekanan pada struktur lokal
yang akhirnya mengancam kehidupan. Pola pertumbuhan bervariasi dan sebagian
kecil dapat tumbuh cepat (2 kali lipat dalam 6 bulan). Dengan mempertimbangkan
kemungkinan yang ada, dapat dilakukan diagnosis dini sehingga dapat
meningkatkan pilihan terapi dan menurunkan angka kematian.
Di daerah cerebellopontine angle (CPA), tumor dapat tumbuh dengan diameter 4
cm dan pertumbuhan lambat memungkinkan peregangan tanpa mempengaruhi
fungsi. Namun tumor lain dalam kanalis auditoris interna, akan menimbulkan
gejala-gejala lebih awal dengan gangguan pendengaran (gejala umum yang
ditimbulkan) atau gangguan vestibuler. AN mewakili 6-10% dari kebanyakan tumor
intrakranial, tetapi merupakan bentuk tersering dari tumor CPA. Tumor-tumor
sporadik yang jumlahnya 95%, sementara yang berhubungan dengan
neurofibromatosis bilateral jumlahnya 4,5%
Tumor hipofisis biasanya jinak dan dapat disembuhkan. Tumor hipofisis
dapat menyebabkan masalah akibat produksi hormon yang berlebihan,
efek lokal dari tumor, dan produksi hormon yang inadekuat dari kelenjar
hipofisis yang tersisa.
Berdasarkan urutan frekuensinya, yang termasuk tumor hipofisis adalah:
adenoma non fungsional, prolaktinoma, tumor yang mensekresi GH
(growth hormone) yang berlebihan, tumor yang mensekresi ACTH
(adrenocorticotrophic hormone ) yang berlebihan, tumor yang
menghasilkan sekresi tiroid, dan tumor pensekresi LH/FSH (leutinising
hormone/follicle-stimulating hormone).
Manifestasi Klinis
Gejala yang timbul pada pasien dengan kanker otak tergantung
dari lokasi dan tingkat pertumbuhan tumor. Kombinasi gejala
yang sering ditemukan adalah peningkatan tekanan intrakranial
(sakit kepala hebat disertai muntah proyektil), defisit neurologis
yang progresif, kejang, penurunan fungsi kognitif.
Pada glioma derajat rendah gejala yang biasa ditemui adalah
kejang, sementara glioma derajat tinggi lebih sering
menimbulkan gejala defisit neurologis progresif dan tekanan
intrakranial meningkat.
Diagnostik
Anamnesis dan Pemeriksaan Fisik
Keluhan yang timbul dapat berupa sakit kepala, mual,
penurunan nafsu makan, muntah proyektil, kejang, defisit
neurologik (penglihatan ganda, strabismus, gangguan
keseimbangan, kelumpuhan ekstremitas gerak, dsb), perubahan
kepribadian, mood, mental, atau penurunan fungsi kognitif.
Pemeriksaan fisik yang perlu dilakukan mencakup pemeriksaan
status generalis dan lokalis, serta pemeriksaan
neurooftalmologi.
Diagnostik
Anamnesis dan Pemeriksaan Fisik
Keluhan yang timbul dapat berupa sakit kepala, mual,
penurunan nafsu makan, muntah proyektil, kejang, defisit
neurologik (penglihatan ganda, strabismus, gangguan
keseimbangan, kelumpuhan ekstremitas gerak, dsb), perubahan
kepribadian, mood, mental, atau penurunan fungsi kognitif.
Pemeriksaan fisik yang perlu dilakukan mencakup pemeriksaan
status generalis dan lokalis, serta pemeriksaan
neurooftalmologi.
Diagnostik
Pemeriksaan Fungsi Luhur
Gangguan kognitif dapat merupakan soft sign, gejala awal pada kanker
otak, khususnya pada tumor glioma derajat rendah, limfoma, atau
metastasis. Fungsi kognitif juga dapat mengalami gangguan baik melalui
mekanisme langsung akibat destruksi jaras kognitif oleh kanker otak,
maupun mekanisme tidak langsung akibat terapi, seperti operasi,
kemoterapi, atau radioterapi. Oleh karena itu, pemeriksaan fungsi luhur
berguna untuk menjelaskan kesesuaian gangguan klinis dengan fungsional
kanker otak, serta mengevaluasi pre- dan post tindakan (operasi,
radioterapi dan kemoterapi). Bagi keluarga, penilaian fungsi luhur akan
sangat membantu dalam merawat pasien dan melakukan pendekatan
berdasarkan hendaya yang ada.
Diagnostik
Pemeriksaan Penunjang
Pemeriksaan laboratorium terutama dilakukan untuk melihat keadaan
umum pasien dan kesiapannya untuk terapi yang akan dijalani (bedah,
radiasi, ataupun kemoterapi).
Pemeriksaan yang perlu dilakukan, yaitu: darah lengkap, hemostasis, LDH,
fungsi hati dan ginjal, gula darah, serologi hepatitis B dan C, dan elektrolit
lengkap.
 Lanjutan Pemeriksaan Penunjang
Pemeriksaan radiologis yang perlu dilakukan antara lain CT scan dengan kontras;
MRI dengan kontras, MRS, dan DWI; serta PET CT (atas indikasi).
Pemeriksaan radiologi standar adalah CT scan dan MRI dengan kontras. CT scan
berguna untuk melihat adanya tumor pada langkah awal penegakkan diagnosis dan
sangat baik untuk melihat kalsifikasi, lesi erosi/destruksi pada tulang tengkorak. MRI
dapat melihat gambaran jaringan lunak dengan lebih jelas dan sangat baik untuk
tumor infratentorial, namun mempunyai keterbatasan dalam hal menilai kalsifikasi.
Pemeriksaan fungsional MRI seperti MRS sangat baik untuk menentukan daerah
nekrosis dengan tumor yang masih viabel sehingga baik digunakan sebagai
penuntun biopsi serta untuk menyingkirkan diagnosis banding, demikian juga
pemeriksaan DWI. Pemeriksaan positron emission tomography (PET) dapat berguna
pascaterapi untuk membedakan antara tumor yang rekuren dan jaringan nekrosis
akibat radiasi.
Pemeriksaan sitologi dan flowcytometry cairan serebrospinal dapat dilakukan untuk
menegakkan diagnosis limfoma pada susunan saraf pusat, kecurigaan metastasis
leptomeningeal, atau penyebaran kraniospinal seperti ependimoma.
Penatalaksanaan
Tumor Otak Sekunder
Metastasis otak adalah tumor otak sekunder yang jumlahnya empat kali melebihi
jumlah tumor otak primer. Di Amerika Utara terdapat 98.000-170.000 kasus baru
metastasis otak per tahunnya. Angka ini akan terus bertambah dengan meningkatnya
populasi lanjut usia serta meningkatnya tatalaksana diagnostik yang lebih baik dan
kemajuan terapi mutakhir pada keganasan lokal dan sistemik. Tumor primer dapat
berasal dari kanker paru (50%), payudara (15-25%), melanoma (5-20%), kolorektal dan
ginjal. Sebanyak 15% paien metastasis otak tidak diketahui lokasi tumor primernya.
Lesi metastasis dapat tumbuh di parenkim otak (sekitar 75%) maupun di
leptomeningeal. Sebanyak 80% metastasis soliter berada di hemisfer serebri.Lokasi otak
dengan insidens tertinggi berada di posterior dari fissuraSylvii dekat pertemuan antara
lobus temporal, parietal dan oksipital. Banyak metastasis tumbuh di daerah perbatasan
antara substansia grisea dan alba. Sebanyak 16% metastasis soliter berada di
serebellum.
Panduan Radioterapi
Radioterapi merupakan salah satu modalitas penting
dalam tatalaksana kanker otak. Radioterapi dalam
tatalaksana kanker otak dapat diberikan sebagai
terapi kuratif definitif, ajuvan pascaoperasi, dan
paliatif.
Glioma Derajat Rendah (Derajat I dan II)
Volume tumor ditentukan dengan menggunakan imejing pre dan post-
operasi, menggunakan MRI (T2 dan FLAIR) untuk gross tumor volume
(GTV). Clinical target volume (CTV) = GTV ditambah margin 1-2 cm,
mendapatkan dosis 45-54 Gy dengan 1,8-2 Gy/fraksi.
Glioma Derajat Tinggi (Derajat III dan IV)
Volume tumor ditentukan menggunakan pencitraan pra- dan pascaoperasi,
menggunakan MRI (T1 dan FLAIR/T2) untuk GTV. CTV adalah GTV ditambah 2-3
cm untuk mencakup infiltrasi tumor yang subdiagnostik.
Dosis yang direkomendasikan adalah 60 Gy dengan 2 Gy/fraksi atau 59,4 Gy
dengan 1,8 Gy/fraksi, dosis yang sedikit lebih kecil seperti 55,8-59,4 Gy dengan
1,8 Gy/fraksi atau 57 Gy dengan 1,9 Gy/fraksi dapat dilakukan jika volume tumor
terlalu besar (gliomatosis) atau untuk astrositoma derajat III. Pada pasien
dengan KPS yang buruk atau pada pasien usia tua, hipofraksinasi yang
diakselerasi dapat dilakukan dengan tujuan menyelesaikan terapi dalam 2-4
minggu. Fraksinasi yang digunakan antara lain 34 Gy/10 fraksi, 40,5 Gy/15 fraksi,
50 Gy/20 fraksi.
Ependimoma
Volume tumor ditentukan dengan menggunakan pencitraan pra dan
pascaoperasi, menggunakan MRI (T1 dan FLAIR/T2) untuk GTV. CTV merupakan
area anatomis tempat tumor primer praoperasi ditambah dengan abnormalitas
signal yang ditemukan pada MRI post-operasi (CTV = GTV + 1-2 cm),
mendapatkan dosis 54-59,4 Gy dengan 1,8-2 Gy per fraksi.
CRANIOSPINAL : whole brain radiotherapy (WBRT) dan spinal (sampai dengan
bawah thecal sac) mendapatkan dosis 36 Gy/1,8 Gy per fraksi diikuti dengan
lapangan terbatas pada spinal sampai dengan 45 Gy. Lokasi primer di otak harus
mendapatkan dosis total 54-59,4 Gy dalam 1,8-2 Gy per fraksi.
Meningioma
Meningioma WHO derajat I diterapi dengan radiasi konformal terfraksinasi, dosis
45-54 Gy. Meningioma WHO derajat II yang diradiasi, terapi langsung pada gross
tumor (jika ada) atau pada tumor bed dengan margin 1-2 cm, dosis 54-60 Gy
dalam fraksi 1,8-2 Gy. Pertimbangkan pembatasan ekspansi margin pada
parenkim otak jika tidak ada bukti adanya invasi otak.
Meningioma WHO derajat III diterapi seperti tumor ganas, langsung pada gross
tumor (jika ada) dan surgical bed dengan margin 2-3 cm dan dosis 59,4 Gy dalam
1,8-2 Gy/fraksi.
Meningioma WHO derajat I juga dapat diterapi dengan SRS dosis 12- 16 Gy
dalam fraksi tunggal.
Metastasis Otak
Pada kasus metastasis otak, diberikan WBRT dengan dosis bervariasi
antara 20-40 Gy dalam 5-20 fraksi. Regimen standar adalah 30 Gy dalam
10 fraksi atau 37,5 Gy dalam 15 fraksi. Untuk pasien dengan performa
yang buruk, 20 Gy/5 fraksi merupakan pilihan yang baik untuk dapat
dipertimbangkan. Pada pemberian SRS, dosis marginal maksimal adalah
24, 18 atau 15 Gy sesuai dengan volume tumor yang direkomendasikan.
Referensi
http://kanker.kemkes.go.id/guidelines/PNPKOtak.pdf
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2644621/pdf/CO16-1-62.pdf
RADIOTERAPI PADA KANKER PEDIATRIK
 Central Nervous System Tumors in Children
 Wilms Tumor
 Rhabdomyosarcoma
 Neuroblastoma
 Ewing Tumor
 Central nervous system (CNS) tumors account for 20% to 25% of all
malignancies that occur in childhood.
 The etiology of pediatric CNS tumors remains largely unknown.
 Only 2% to 5% can be ascribed to a known genetic predisposition.
Included in this category are those seen in patients with
neurofibromatosis types 1 (NF-1) and 2 (NF-2), tuberous sclerosis,
nevoid basal cell (Gorlin’s) syndrome, familial adenomatous polyposis,
and Li-Fraumeni syndrome.
 An even smaller percentage can be attributed to ionizing radiation
used for diagnostic or therapeutic purposes. For the majority of
patients, no predisposing factors can be identified.
Radiotherapy for Pediatric CNS Tumors: General
Issues
 Radiotherapy is an essential component of treatment for many children with
CNS tumors. However, survivors are at significant risk for the development
of long-term sequelae, many of which, while usually multifactorial, are in
large part due to radiotherapy; many of the strategies used in the
management of children with CNS tumors over the past three decades have
been designed to reduce the risks associated with treatment.
 Recent developments in radiotherapy including improved targeting and new
technologies and techniques for treatment, as well as new treatment
modalities such as protons, all offer important opportunities for therapeutic
gain that will be discussed below and in each section of this chapter
 Long-Term Effects of Radiotherapy
The quality of survival of children with brain tumors may be compromised
by long-term sequelae. While some patients (e.g., patients with NF-1) may
be at particular risk and while some sequelae (e.g., neurologic deficits) are
more often due to the tumor and/or surgery, it is clear that radiotherapy is
directly, alone or modulated by other factors, responsible for many late
effects. A review by Kortmann et al. gives an excellent account of
radiation-related sequelae in children treated for low-grade glioma
including effects on brain parenchyma, neurologic deficits, neurocognitive
and behavioral effects, endocrine dysfunction, vasculopathy, and the
development of second tumors
Strategies that have been used to avoid or minimize the long-term effects of treatment
for pediatric brain tumors include the following:
 Avoidance of radiotherapy altogether (e.g., in patients with low-grade astrocytoma
for whom surgery alone may be a good option)
 Delay of radiotherapy for young children (i.e., those younger than age 3 to 8) by the
use of chemotherapy
 Use of daily anesthesia, improved immobilization techniques (e.g., rigid casts or a
stereotactic frame), and/or daily pretreatment image verification, all of which allow
the use of reduced safety margins
 Use of image-based treatment planning using computed tomography (CT)–MRI or
CT–MRI–functional imaging coregistration and better treatment-planning and
delivery techniques that result in greater sparing of normal brain and organs at risk
 Use of new radiation modalities (e.g., proton therapy that provides even greater
sparing of the surrounding normal brain and organs at risk)
 Use of reduced radiotherapy target volumes when it is shown safe to do so (e.g.,
tumor bed rather than whole posterior fossa for the boost in standard-risk
medulloblastoma)
 Reduction of radiotherapy dose (e.g., in young patients with standard-risk
medulloblastoma for whom in the North American studies the dose for craniospinal
irradiation has been reduced progressively from 35 to 36 Gy to 23.4 Gy and, in
current studies, to 18 Gy for children younger than 8)
 Use of smaller fraction sizes where appropriate (e.g., 1.5 Gy/day for patients
with radiosensitive tumors such as germinoma)
 Use of hyperfractionated radiotherapy (HFRT) (e.g., as in the current European
studies for standard-risk medulloblastoma)
Preparation for Radiotherapy
 The planning and delivery of radiotherapy for children with CNS tumors
are technically challenging and labor intensive for the entire
interprofessional team.
 The expertise of specialist personnel such as pediatric nurses and play
therapists can be pivotal in encouraging a young child to lie still for the
making of an immobilization device, for radiotherapy-planning procedures,
and for treatment itself.
 For children younger than age 4 or 5 years, daily anesthesia will almost
always be necessary, and this will require a skilled pediatric anesthetist
because anesthesia will be administered in an environment without all of the
support available in an operating room.
Radiotherapy Target Volumes and Treatment
Techniques
 Focal, Tumor or Tumor Bed Radiotherapy
For most tumor types, target volume definition is best accomplished using CT
simulation with CT–MRI image coregistration. For patients who have undergone
cerebrospinal fluid (CSF) diversion or surgical resection or in whom tumor
shrinkage has occurred with chemotherapy, it will be important to take into
account any anatomic shifts that may have taken place.
This will be more of an issue for tumors arising in some areas than others and
often adds significantly to the time required for contouring. The clinical target
volume (CTV) will be tumor type specific, while the planning target volume (PTV)
will be technique specific, ranging from 1 to 5 mm depending oan the type of
immobilization device used and whether daily pretreatment image verification is
to be performed.
 Whole-Ventricle Radiotherapy
Whole-ventricular irradiation is used most frequently in patients with
CNS germ cell tumors. Because subependymal spread is common,
the target volume logically would include the lateral, third, and
fourth ventricles with a margin of 1 to 1.5 cm. If lateral opposed
fields are used, the volume of brain spared will be small. Better
sparing can be achieved using intensity-modulated image-guided
radiotherapy
 Craniospinal Radiotherapy
The CTV for craniospinal radiotherapy has an irregular shape that
consists of the whole brain and spinal cord and their overlying
meninges.
In standard techniques, the lower borders of lateral whole-brain fields
are matched to the cephalad border of a posterior spine field, usually
with a moving junction between the brain and spine fields to minimize
the risk of underdose or overdose in the cervical spinal cord.
Compensators may be needed to achieve dose homogeneity
throughout the target volume.
Patient Positioning and Immobilization
 Patients have traditionally received craniospinal irradiation (CSI) in the
prone position, but modern technology allows safe treatment in the
supine position that in general is more comfortable and, if anesthesia is
required, allows better control of the airway. In either case,
immobilization is essential and involves the use of a head shell or full-
body immobilization. Careful attention to positioning at the time of
simulation is critical to minimize or even eliminate the risk of certain long-
term effects. For example, using neck extension together with careful
selection of the level for the junction of the brain and spine fields, it is
possible to avoid including the dentition in the exit from the superior
aspect of the spinal field and thus damage to developing teeth.
Target Volume Definition
 CT simulation is necessary to ensure adequate coverage of the CTV in the subfrontal
region at the cribriform plate. Traditionally, blocks have been used in the lateral fields
to shield not only the facial structures but also the lenses. However, in most children it is
impossible to adequately irradiate the cribriform plate and shield the lenses and
adequate PTV coverage should take precedence. CT simulation is helpful, too, in
identifying the lateral aspect of CTV for the spine field that includes the extensions of
the meninges along the nerve roots to the lateral aspects of the spinal ganglia. The
field will be narrower in the dorsal region to avoid unnecessary irradiation of the heart
and lungs and wider in the lumbar region, although here it is important to avoid an
excessively wide field that will result in unnecessary irradiation of the bone marrow
and gonads. The lower limit of the CTV for the spine field is best determined by MRI.
Traditionally, the lower border of the spine field was placed at the lower border of the
second sacral foramen, but it is well documented that the lower border of the thecal
sac can be as high as L5 or as low as S3.
Treatment Planning and Delivery
 There are many issues that need to be addressed in designing a CSI
technique. Many of the different solutions add further complexity.
Using modern tools for treatment planning and delivery, it is
possible to greatly simplify the technique and substantially reduce
planning and delivery times.
 In general, photons in the 6-10 MV range provide satisfactory
coverage of the PTV. A variation of dose along the spinal axis of
>10% will require the use of dose compensation that can be
achieved using multileaf collimation.
Radiation Dose and Dose-Fractionation
 Regimens The conventional daily fraction size for the treatment of most pediatric CNS
tumors is 1.8 Gy and the total dose typically on the order of 54 to 55.8 Gy.
 When treating a primary tumor of the spinal cord, it is conventional to use a lower total
dose (e.g., 50.4 Gy). It is also usual to use lower doses for children younger than age 3
years to reduce the risk of neurocognitive deficits.
 When treating radiosensitive tumors such as intracranial germinoma, radiotherapy may
be delivered using a lower dose per fraction (e.g., 1.5 Gy) and lower total doses of 30
to 45 Gy. Many pediatric brain tumors exhibit a dose–response relationship for tumor
control and in some cases local progression is not prevented by the use of a conventional
“CNS tolerance” radiation dose.
 When the target contains only a small volume of normal brain tissue, dose escalation
may be possible using newer treatment-planning and delivery techniques. HFRT may be
a useful strategy in situations where dose escalation cannot be achieved safely using
conventional fractionation.
 Wilms tumor (WT, nephroblastoma) is a highly curable childhood
neoplasm.
 The prognosis of children with WT has improved considerably
from a very high mortality rate at the beginning of the 20th
century to the current cure rate of >90%.
 The management of WT is a paradigm for successful
interdisciplinary treatment of solid tumors of childhood to
maximize cure rates and minimize treatment-related
complications.
Epidemiology
 WT is the most common malignant renal tumor of childhood. It occurs with an annual
incidence of 7 cases per million children <15 years of age. Approximately 500 new
cases are diagnosed each year in North America. The peak incidence is between 3
and 4 years of age. WT may arise as sporadic or hereditary tumors or in the setting
of specific genetic disorders.
 Most WTs are solitary lesions, multifocal within a single kidney in 12% and bilateral
in 7%.
 The clinical syndromes associated with WT include WAGR syndrome (WT, Aniridia,
Genitourinary malformations,mental Retardation), Denys-Drash syndrome
(pseudohermaphroditism, mesangial sclerosis, renal failure, and WT), and overgrowth
syndromes like Beckwith-Wiedemann syndrome (somatic gigantism, omphalocele,
macroglossia, genitourinary abnormalities, ear creases, hypoglycemia,
hemihypertrophy, and a predisposition to WT and other malignancies) and Simpson-
Golabi-Behmel syndrome
Diagnostic Work-Up
 Plain films of the abdomen may demonstrate calcifications, which occur in 60% to 70% of
neuroblastomas but in only 5% to 10% of WT.
 Excretory urography (intravenous pyelography) was once the mainstay of imaging in WT and
now has largely been replaced by ultrasonography and computed tomography (CT)
scanning.
 Ultrasonography is very useful because it is readily available and is cost-effective. A specific
advantage of ultrasonography is its ability to assess vessels for flow and tumor thrombus with
duplex and color Doppler. Routine use of Doppler sonography after abdominal CT scans was
not found to be useful in detecting cavoatrial thrombus in a Children’s Oncology Group
(COG) study.
 Abdominal CT scans can demonstrate gross extrarenal spread, lymph node involvement, liver
metastases, and the status of the opposite kidney
 Magnetic resonance imaging (MRI) has several advantages over CT scans, especially in
identifying renal origin and vascular extension of the tumor.
General Management
 The diagnosis of WT is usually made before surgery and confirmed at
surgery.
 A transverse transabdominal, transperitoneal incision is recommended for
adequate exposure and thorough abdominal exploration. The surgeon must
excise all tumors without spillage, if possible. Lymph node sampling from the
para-aortic, celiac, and iliac areas must be performed. The use of titanium
clips to identify residual tumor and margins of resection is also
recommended.
 Routine exploration of the contralateral kidney was mandated in the past,
but it is no longer recommended due to better imaging of the contralateral
kidney with CT and MRI scans. The chemotherapy and radiation therapy
(RT) regimens for WT in the COG protocols.
 Radiation Therapy Volume
 Parallel-opposed fields using 4 or 6 MV photons are preferred.
 The flank RT field is determined by the CT or MRI scan performed at diagnosis
before any chemotherapy is administered.
 The planning target volume is the tumor bed (outline of the kidney and associated
tumor on the initial CT or MRI) with a 1-cm margin.
 The medial border must cross the midline to include the entire width of the
vertebrae so as to minimize growth disturbances.
 When whole-abdomen RT is administered, the femoral heads and acetabulum
must be shielded .
 Whole-lung Irradiation (WLI) portals if the lungs and either the flank or whole
abdomen have to be treated simultaneously, it is preferable to include them in one
treatment portal.
 Rhabdomyosarcoma (RMS) is a highly malignant soft tissue
sarcoma that arises from unsegmented, undifferentiated
mesoderm or myotome-derived skeletal muscle.
 It may occur at any site in the body, but the most frequently
involved sites are the orbit, 9%; head and neck (excluding
parameningeal tumors), 7%; parameningeal, 25%; genitourinary
31%; extremity, 13%; trunk, 5%; retroperitoneum, 7%, and other
sites 3%.
 RMS is the most common of the childhood soft tissue sarcomas, with an annual
incidence of 4.4 per 1 million whites and 1.3 per 1 million blacks. The male-to-
female ratio is ∼1.5 to 1.0, and males may have slightly better overall survival.
 The great majority of patients are <10 years of age at the time of diagnosis, and
approximately 5% are <1 year of age. There are two peak age frequencies, at
ages 2 to 6 and in adolescence. Tumors in the younger age group are likely to be of
embryonal histology (or one of its subtypes). About 25% of patients are ≥10 years
at diagnosis and their tumors are more commonly of alveolar histology. Age has been
identified as an independent predictor of prognosis, with children <1 year and >10
years having inferior survival.
 Adults with RMS have been reported to have poor outcomes, although there is
evidence that when treated aggressively using pediatric-type protocols, the
prognosis may be similar to that of younger patients.
 The cause of RMS is unknown; however, it is associated with several
environmental exposures including paternal cigarette use, prenatal x-
ray exposure, and maternal recreational drug use.
 RMS is also associated with disorders in development, including
central nervous system, genitourinary, gastrointestinal, and
cardiovascular anomalies, and with congenital disorders including
congenital pulmonary cysts, Gorlin basal cell nevus syndrome, and
neurofibromatosis. In addition, RMS is the most frequently occurring
childhood cancer in families with Li-Fraumeni syndrome, and its
incidence is increased in children with neurofibromatosis type 1,
Beckwith-Wiedemann syndrome, and Costello syndrome.
Presentation
 Because RMS occurs in multiple primary sites, there are many site-
specific clinical signs and symptoms. It usually presents, however,
as an asymptomatic mass. When symptoms are present, they
relate to mass effect on associated organs and tissues.
 Tumors of the orbit may cause proptosis and ophthalmoplegia.

 Patients with parameningeal tumors often present with nasal,

aural, or sinus obstruction, cranial nerve palsy, and headache.
 Genitourinary tumors may cause hematuria, urinary obstruction, or
constipation.
General Management
 A multidisciplinary approach using surgery, irradiation, and
chemotherapy is important in the management of RMS; however,
the optimal sequence and specific application of each modality
continue to be investigated. Although the primary goal remains
long-term cure, improvement in therapeutic results necessitates
considerations of quality of life, with particular attention to
maximization of functional and cosmetic results.
Surgery
 Before the era of multidisciplinary therapy, surgical ablation resulted in a
long-term survival rate of approximately 20% of those patients able to
undergo resection. Certain primary sites represented exceptions to these data;
for example, approximately 50% of those with localized disease of the orbit
survived after orbital exenteration. However, with the introduction of effective
adjunctive treatment, preservation of function and appearance became major
goals.
 The concept of reasonable surgery has evolved. It involves removal of the bulk
of tumor with maximal conservation of anatomic structures, including
preservation of bladder, bowel, and sexual function in patients with tumors of
genitourinary origin; limb function in patients with extremity tumors; and vision,
voice, deglutition, and appearance in patients with head and neck tumors.
 Resection of RMS from normal surrounding tissues is often technically challenging. Only 20%
of tumors are located in sites where complete excision can readily be accomplished without
an undesirable loss of function or cosmesis. An additional 20% of patients have compromised
surgical procedures, leaving microscopic residual disease. Sixty percent of patients have
tumors amenable to biopsy only or present with metastatic disease and are not candidates
for primary resection. When the IRS surgical grouping system is used, patients with tumor
amenable to complete excision fare better than those who have subtotal resection or biopsy
alone.
 However, the tumors that are most accessible to surgical excision are small and noninvasive
and are confined to the organ or structure of origin. Assessment using a TNM system
demonstrates that prognosis is dictated by tumor size and invasiveness rather than by the
initial surgical approach. Furthermore, combined-modality therapy provides good local
control of the primary tumor, even after subtotal excision. For these reasons, the trend has
been toward lessaggressive surgical resection, with more reliance on radiation therapy and
chemotherapy to provide local control.
Chemotherapy
 Chemotherapy is necessary in all cases. Several drugs have
demonstrated single-agent activity measured as a percentage
response rate, including vincristine (59%), dactinomycin (24%),
cyclophosphamide (54%), cisplatin (15% to 21%), dacarbazine
(11%), mitomycin-C (36%), etoposide (15% to 21%), ifosfamide
(86%), irinotecan (23%), and topotecan (46%). 78–80 Agents with
known activity against central nervous system tumors, such as the
nitrosoureas and methotrexate, have not shown activity against RMS.
Radiation Therapy
 Adequate irradiation implies careful attention to volume and dose. It is
essential to evaluate the soft tissue extent of the primary lesion by CT
scan or magnetic resonance imaging. Because RMS tends to infiltrate
tissue planes widely, tumors often extend beyond a fascial
compartment and beyond the obvious visible margins. Careful
examination by a radiation oncologist at the time of initial diagnosis,
even if the treatment plan calls for neoadjuvant chemotherapy, is
essential to establish the appropriate tumor volume
 Treatment portals are designed to encompass the involved region at the time of presentation (before
chemotherapy) with margins that encompass surgical sites and biopsy tracts. A biopsy should be performed of
clinically suspicious lymph nodes, or they should be included in the radiation therapy portal.
 Prophylactic lymph node irradiation is not necessary in children with clinically negative findings who will be
receiving combination chemotherapy.
 The gross tumor volume is defined as the tumor as seen at the time of initial diagnosis. A clinical target volume
of 1 cm is added and can be modified to account for anatomic barriers to tumor spread (such as the bony orbit
in primary orbital tumors) or to account for regression of “pushing” the tumor border after chemotherapy, such
as may occur in large pelvic tumors that initially displace contents of the peritoneal cavity. The planning target
volume adds a patient-specific margin, which is typically about 5 mm. Many current treatment protocols use a
cone-down boost or simultaneous integrated boost to any gross posttreatment tumor volume after a microscopic
tumor dose has been delivered.
 Patients with tumors at parameningeal sites (middle ear, paranasal sinuses, nasopharynx, nasal cavity,
infratemporal fossa, and parapharyngeal area) have developed meningeal extension of tumor when
inadequate irradiation portals were used.
 Radiation therapy portals that cover the adjacent meninges in these patients can prevent meningeal relapse.
 Radiation is necessary to ensure local tumor control in patients who are unable to undergo complete
surgical resection.
 Local control of gross disease in most anatomic sites requires doses of 50 to 55 Gy.
 Data from the IRS-V D9602 study support a somewhat lesser dose of 45 Gy for gross tumor at orbital
sites, especially if cyclophosphamide is included in the systemic therapy regimen.
 In the IRS-IV study, investigators studied the efficacy of a higher radiation dose, 59.4 Gy, given in 1.1-
Gy fractions twice daily at 6-hour intervals for children with gross residual disease. This
hyperfractionated regimen was compared in a prospective, randomized fashion to a standard
radiotherapy regimen consisting of 50.4 Gy given as 1.8 Gy once daily. There was no difference in
locoregional disease control, failure-free survival, or overall survival between the two groups.
Therefore, the standard of care for group III RMS continues to be conventionally fractionated radiation
with chemotherapy.
 Ninety percent of patients with microscopic residual tumor achieve local control with 41.4 Gy, and the
D9602 study results suggest that 36 Gy may be adequate for microscopically positive margins that
are not associated with lymph node involvement. Investigators have been unable to generate a strict
dose– response curve but have observed an association with age that suggests that lower doses, often
given to infants and youngsters, are associated with higher relapse rates. They also suggest that local
tumor control is greater for tumors <5 cm in diameter than for larger lesions, supporting the adult
experience with soft tissue sarcomas.
 Neuroblastoma is an enigmatic malignant neoplasm. In its early stages
it can be readily cured with surgery or, in somecircumstances, can even
spontaneously regress or mature to a benign ganglioneuroma. In the
more common advanced stages, the disease is often fatal.
 The unique biology of neuroblastoma has attracted the interest of
many prominent scientists and is one of the first malignancies in which
molecularbiologic assays have influenced treatment and prognosis.
Epidemiology
 After brain tumors and leukemia, neuroblastoma is the thirdmost-
common malignancy diagnosed in children, with an annual incidence of
9 new cases per 1 million children in the United States. It is the most
common cancer diagnosed before the age of 12 months, accounting
for almost half of all cancers in infants. The median age at diagnosis is
2 years.
 The relatively good prognosis of infants diagnosed with early-stage
neuroblastoma prompted the initiation of infant-screening studies.
 Neuroblastoma, along with ganglioneuroma and ganglioneuroblastoma, may arise from any
site in the sympathetic nervous system. The most common sites of origin are the adrenal
medulla (30% to 40%) and paraspinal ganglia in the abdomen or pelvis (25%). Thoracic
(15%) and head and neck primary tumors (5%) are slightly more common in infants than in
older children.
 More than 70% of patients have metastatic disease at presentation. The most frequent
metastatic sites are lymph nodes, bone, bone marrow, skin (or subcutaneous tissues), and liver.
The lung and central nervous system are rare sites of involvement.
 Neuroblastoma has the highest spontaneous remission rate of any human neoplasm, usually
by maturation to ganglioneuroma. Microscopic neuroblastomas have been found in the
autopsy material of the adrenal glands of young infants at >40 times the expected rate. It
has been suggested that most potential neuroblastomas are never clinically manifested,
because of spontaneous regression. Despite these peculiarities, clinically obvious
neuroblastoma is frequently a progressive and relentless disease.
Clinical Presentation
 Pain is the most common presenting symptom. This frequently is caused by bone,
liver, or bone marrow metastases or local visceral invasion by the primary tumor.
Other constitutional symptoms may include weight loss, anorexia, malaise, and
fever. Respiratory distress may accompany massive hepatomegaly, especially in
infants with stage IV-S disease. Horner’s syndrome can accompany a primary
tumor originating in the neck. Spinal cord compression with paralysis of the lower
extremities can accompany the so-called dumbbell-shaped tumor that extends
from its origin along the sympathetic ganglia through the adjacent neural
foramina. Orbital metastases are not uncommon and can cause proptosis and
ecchymosis. Skin metastases may have a bluish tinge, giving the classic “blueberry
muffin” sign. When pressed, the release of catecholamine into the tissue causes
transient blanching of the adjacent skin. An unusual presentation of localized
neuroblastoma is the opsoclonus–myoclonus syndrome, manifested by truncal
ataxia and cerebellar encephalopathy. This syndrome typically indicates a
favorable prognosis from the tumor, but patients may have persistent neurologic
sequelae after successful tumor therapy.
Diagnostic WorkUp

 As in the case of any suspected malignant neoplasm in children, the diagnosis of

neuroblastoma must be established by pathologic evaluation.
 Tumor tissue may be obtained from the suspected primary tumor site or from involved
lymph nodes by excision (if the tumor is resectable) or incisional biopsy.
 Bone marrow aspirate and biopsy frequently show metastatic tumor deposits that can
establish the diagnosis. Pathologic evaluation of bone marrow is also a requirement for
staging of neuroblastoma.
 Characteristically, neuroblastoma in bone marrow appears in clumps and pseudorosettes.
The absence of pseudorosettes does not eliminate the possibility of neuroblastoma.
 Appropriate use of imaging studies assists in staging and in planning an
approach to therapy. X-ray studies demonstrate intrinsic speckled calcifications in
85% of neuroblastomas.
 Computed tomography (CT) of the abdomen with intravenous contrast is more
sensitive than intravenous pyelography and provides more information about
lymph-node or hepatic metastases as well as tumor resectability.
 Increasingly, high-quality magnetic resonance imaging (MRI) scans are replacing
the routine use of CT in evaluation of suspicious thoracic or abdominal masses in
children. Although MRI cannot demonstrate intratumoral calcifications, it allows
better evaluation of blood vessel encasement, intraspinal extension (dumbbell
tumors), diffuse hepatic replacement, and bone marrow involvement .
 Each of these findings improves staging accuracy and facilitates the decision-
making process regarding appropriate surgical interventions.
 Nuclear medicine scans are helpful in determining the extent of metastatic
disease.
 Because neuroblastoma has a predilection for bony metastases, a
radionuclide bone scan is a mandatory investigation. It is more sensitive than
a skeletal survey in detecting bone metastases Meta-iodobenzylguanidine
(MIBG) is concentrated by neurosecretory granules of both normal and
neoplastic tissues of neural crest origin and can be used to image primary
and metastatic sites of neuroblastoma. MIBG labeled with either 131I or
123I has a sensitivity of 85% to 90% and a specificity of almost 95% in
the detection of metastatic neuroblastoma.
General Management

 Because of the biologic heterogeneity of neuroblastoma, the following

treatment recommendations should be considered as guidelines. The
prognostic implications of a tumor’s biologic indices, such as MYCN
amplification and DNA index, may warrant more aggressive therapy in
young patients with otherwise a favorable stage
 Low-Risk Disease
Low-stage, resectable tumors (INSS stage 1, 2, or 3 with negative
nodes) have an excellent prognosis after complete gross surgical
excision. Adjuvant chemotherapy or irradiation has not improved the
outcome in children with completely resected tumors with favorable
biologic features. Positive surgical margins or microscopic residual
disease does not uniformly require more aggressive therapy. Patients
with MYCN amplification or low DNA index may require adjuvant
therapy and should be enrolled in clinical trials
 Intermediate-Risk Disease
Localy advanced and regionally metastatic tumors (INSS stage 2b to 3 with
positive lymph nodes) require more intensive therapy. Infants <1 year of
age should undergo complete resection of the primary tumor and receive
adjuvant chemotherapy. In unresectable cases, chemotherapy may be
administered initially, and surgery can be performed after response to
systemic treatment. In older children with lymph-node metastases, adjuvant
radiation therapy to the primary and regional lymph nodes has improved
the disease-free and overall survival rates. A prospective,randomized trial
of postoperative chemotherapy or chemotherapy plus regional irradiation
demonstrated 31% disease-free survival in children treated with
chemotherapy, compared with 58% in those who also received radiation
therapy.
 However, the value of radiation therapy in intermediate-risk patients is not
universally accepted. De Bernardi et al. failed to demonstrate a benefit
from the addition of radiotherapy in 29 children >1 year of age with
postoperative residual tumor or positive regional lymph nodes. Children in
that randomized study received two cycles of peptichemio with or without
radiation. Progression-free survival was 64% in the radiotherapy arm and
73% in the arm without radiotherapy.62 Coupled with the risk of late
effects from even moderate radiotherapy doses, this small trial provided an
argument that systematic radiation therapy, even for POG stage C patients,
may not be necessary. Current COG trials reflect this bias because the use
of radiation therapy is decreasing.
 High-Risk Disease
The majority of patients with neuroblastoma present with metastatic
disease. With the exception of infants with favorable disease confined
to the skin, bone marrow, or liver, the outcome is poor. Extremely
aggressive treatment regimens have been used in these patients to
prolong survival and achieve cure. Intensive high-dose chemotherapy
regimens appear to be superior to less intensive regimens. Active
drugs in advanced neuroblastoma include cyclophosphamide, cisplatin,
doxorubicin, etoposide, and teniposide
Radiation Therapy Techniques: Treatment Planning and
Field Design
 Significant reductions in irradiation-associated morbidity have accompanied
technological advances. The transition from orthovoltage to megavoltage x-
rays has decreased the risk of severe growth-related skeletal defects. CT-
assisted simulation and three-dimensional radiation-therapy treatment
planning have the potential to decrease the volume of normal tissues
irradiated and thereby decrease the incidence of late effects . As in Wilms’
tumor, the radiation oncologist must be aware of the increased risk of spinal
deformity or other skeletal anomalies if symmetric irradiation of the bone is
not administered. The clinician needs to balance the treatment of disease
and normal tissues to maximize tumor coverage while not sacrificing the
growing tissues.
 Radiation therapy portals to a primary tumor site should treat the gross
residual tumor remaining after chemotherapy with at least a 2-cm margin
from the tumor to the block edge. This margin usually ensures adequate
dosimetric coverage of the residual tumor, taking into account treatment-
related positional uncertainties and beam penumbra.
 Children who are not sedated may require more margin if they tend to shift
or move on the treatment table.
 Regional lymph-node sites should be covered if nodes were
radiographically or pathologically involved at any time during the disease
course.
 The appropriate radiation dose is debatable. Laboratory data suggest that
neuroblastoma is very radiosensitive and that neuroblasts exhibit very little
repair capacity between fractions. This makes hyperfractionated radiation
therapy an attractive option because comparable tumoricidal doses can be
achieved with minimization of the risk of late effects.
 However, despite irradiation doses that approach normal tissue tolerance in
the young, local recurrences after radiation therapy still occur. The
irradiation dose required to control gross disease may be age dependent.
In infants <1 year of age, a dose of 12 Gy appears sufficient for durable
local control. Tumors in children aged 12 to 48 months may require doses of
at least 25 Gy. Children >4 years of age frequently develop local failures
even with doses of > 25 Gy.
 Epidemiology
Ewing sarcoma family tumor (ESFT) is the second most common primary
tumor of bone in childhood, and also arises in soft tissues. ESFT is uncommon
before 8 years of age and after 25 years of age.1 In the European
Intergroup Cooperative Ewing Sarcoma Study group (EICESS), the median
age was 14 years, with 57% of the patients male and 43% female,
although a majority of the patients below 10 years of age were female.
The malignancy is rare in African Americans.2 In the EICESS, 24.7% of
lesions are located in the pelvis, 16.4% in the femur 16.7% below the knee,
12.1% in the ribs, 8.0% in the spine, and 4.8% in the humerus.
Clinical Presentation
 The most frequent presenting symptoms are pain and swelling. Pain
can wax and wane as the tumor progresses. Symptoms of systemic
disease occur at times, including low-grade fevers, malaise, and
weakness. ESFT patients exhibit a mean lag time of 146 days
between the onset of symptoms and diagnosis, the longest lag time of
any pediatric solid tumor. Both patients and physicians contribute to
this delay. Overall, patients with the EWS-FLI1 fusion have a similar
clinical presentation and prognosis to those with the less common EWS-
ERG fusion.
Diagnostic Workup
 In Ewing tumor of bone, plain films usually reveal a mottled or moth-eaten lesion.
Lytic and blastic areas may be present; lytic areas are more commonly seen.
Subperiosteal reactive new bone may be present, producing an “onion skin”
appearance.
 Like an osteosarcoma, Ewing tumors may produce spicules radiating from the
cortex of the involved bone, or expansion of the bone may produce a cystic-
appearing tumor. Occasionally, the tumor may appear to arise on the surface of
the bone, producing a saucerlike indentation of the surface.
 A magnetic resonance imaging (MRI) scan of the primary lesion will show the
extent of bone marrow involvement and soft-tissue invasion, whereas bone
destruction is best seen using computed tomography (CT). The radiographic
differential includes osteosarcoma, osteomyelitis, eosinophilic granuloma, primary
lymphoma of the bone, and even an occasional metastatic malignancy.
Radiotherapy Techniques
 For gross disease, standard treatment is a total dose of 55.8 Gy at 1.8 Gy per
day, with a field reduction at 45 Gy, although 36 Gy may be adequate for the
initial field.
 Local control at doses <40 Gy is significantly worse, even for small lesions. Twice-
a-day irradiation has been used in several trials. To treat ESFTs, radiation
oncologists at the University of Florida used 1.2 Gy twice a day to a total dose
of 50.4 Gy, 55.2 Gy, or 60 Gy, depending on the tumor response to induction
chemotherapy, and showed that late effects could be decreased while
maintaining good local control, even for large primary tumors.48,51 In CESS 86,
doses of 1.6 Gy twice a day to a total of 60 Gy were given, although not in a
continuous course. The Italian SE-91 trial also used 1.6 Gy twice a day to a total
of 60.8 Gy, but in a continuous course. The CESS 86 trial showed no advantage
for the accelerated hyperfractionated approach, but the early results of SE-91
are promising with regard to local control.52,56 Both of the latter regimens would
be theoretically expected to increase late effects.
 Three-dimensional treatment planning is essential.
 In the present open COG trial, the initial clinical target volume includes
the prechemotherapy tumor volume with a 1-cm margin, with at least a
0.5-cm addition for planned target volume .
 The boost is to the residual tumor volume at the time of radiotherapy
plus a 1-cm margin, with or without a 0.5-cm planned target volume
 PET-CT may be helpful for planning. Any initial bone or bone marrow
abnormalities in the primary bone should be included in gross tumor
volume. These margins are much tighter than in previous studies, and
only additional follow- up will show whether they will be adequate.
PALLIATIVE AND EMERGENCY
RADIOTHERAPY
Brain Metastasis
Brain metastasis is very common, with an annual incidence of approximately
170,000 to 200,000. The rising incidence of brain metastasis is most likely from a
combination of increasing survival from recent advances in systemic therapy and
a greater availability and use of magnetic resonance imaging (MRI). The most
common primary site is the lung followed by breast.
Metastatic brain tumors out number primary brain tumors by a factor of 10 to 1,
with autopsy series demonstrating a 10% to 30% incidence rate
Clinical Presentation, Diagnosis, and Prognosis

The majority of patients present with neurologic signs and symptoms Although
differential diagnoses such as an abscess or a stroke must be considered, new-
onset neurologic symptoms in a known cancer patient should always be
presumed to be from brain metastasis until proven otherwise. Given its ability to
image in multiple orientations and sequences, including superior resolution and
accuracy compared to computed tomography (CT), MRI has become the
standard of care for imaging of the central nervous system (CNS) in cancer
patients. MRI will frequently pick up smaller lesions not seen on CT scans, which
can have a significant effect on the patient’s prognosis and treatment course.
Full systemic workup (e.g., positron emission tomography [PET] and CT) should
be promptly initiated if brain metastasis is the presenting event. The incidence
of unknown primaries may subsequently decrease with th increasing popularity
of integrated PET-CT scans.
Whole-Brain Radiotherapy
WBRT continues to be the standard of care in patients with brain metastasis. In general,
WBRT should be given soon after the diagnosis of brain metastasis. There has never
been any evidence to suggest that delaying systemic chemotherapy for WBRT
compromises overall survival, especially when one considers that progression in the
brain frequently leads directly to the death of the patient.
There is still no agreement on the dose and fractionation schedule for WBRT, despite
numerous studies designed to determine the optimal delivery. Most of these studies
have been negative, and the overall survival has not improved appreciably over the past
25 to 30 years.
A total of 30 Gy in 10 fractions continues to be the standard for a vast majority of
patients. In chemotherapy refractory RPA class III patients, a shorter fractionation
scheme (e.g., 20 Gy in 5 fractions) should be considered.
Spinal Cord Compression
In the United States, more than 20,000 cases of metastatic spinal
cord compression (MSCC) are diagnosed annually, and it is
estimated to develop in approximately 5% to 14% of all cancer
patients. MSCC is a devastating complication of cancer. It is
considered a true medical emergency, and immediate intervention is
required. Even with aggressive therapy, results can often be
unsatisfactory. Although most patients with MSCC have limited
survival, up to one-third will survive beyond 1 year. Therefore,
aggressive therapy should always be considered to preserve or
improve the quality of life.
Pathophysiology
MSCC develops primarily in one of three ways: (a) continued growth
and expansion of vertebral bone metastasis into the epidural space;
(b) neural foramina extension by a paraspinal mass; or (c) destruction
of vertebral cortical bone, causing vertebral body collapse with
displacement of bony fragments into the epidural space.
Although complex, the most significant damage caused by MSCC
appears to be vascular in nature. Epidural tumor extension causes
epidural venous plexus compression, which leads to edema of the
spinal cord. This increase in vascular permeability and edema cause
increased pressure on the small arterioles. Capillary blood flow
diminishes as the disease progresses, leading to white matter
ischemia. Prolonged ischemia eventually results in white matter
infarction and permanent cord damage
Clinical Presentation, Diagnosis, and Prognosis

The vast majority of patients with MSCC have a cancer diagnosis

history. In a review by Fuller et al., of more than 1,000 patients with
MSCC, the most common tumor types are breast cancer (29%), lung
cancer (17%), and prostate cancer (14%). This reflects the high
natural incidence of these tumors. New on set back pain in cancer
patients needs to be taken seriously and worked up. Even without a
prior cancer diagnosis, MSCC should be suspected in anyone who
presents with progressively worsening back pain, incontinence, or
paraplegia, especially in the high-risk population such as longtime
smokers.
The most common level of the MSCC involvement is in the thoracic
spine (59% to 78%), followed by lumbar (16% to 33%) and cervical
spine (4% to 15%), while multiple levels are involved in up to half of
the patients.
Back pain is the most common presenting symptom (88% to 96%),
followed by weakness (76% to 86%), sensory deficits (51% to 80%),
and autonomic dysfunction (40% to 64%).
MRI is the standard modality for spine imaging. It has a very high
sensitivity (93%), specificity (97%), and accuracy (95%) in diagnosing
MSCC. Because patients can have synchronous, multifocal MSCC, an
MRI of the entire spine with and without contrast should be
promptly performed in anyone suspected of having MSCC. High-
resolution CT scan or CT myelogram of the spine should be
performed for those with contraindications to MRI.
Radiotherapy Palliative radiotherapy has been the standard
of care in the treatment of patients with MSCC. Although a
total of 30 Gy in 10 fractions is the most frequently
employed fractionation schedule, multiple fractionation
schemes have been reported, which undoubtedly reflects
the heterogeneity in the patient population and tumor
histology.
In one of the largest studies to date, Rades et al. reported a retrospective series
of 1,304 patients with MSCC. The patients were separated into five schedules: 8
Gy × 1 in 1 day (n = 261, group 1), 4 Gy × 5 in 1 week (n = 279, group 2), 3 Gy ×
10 in 2 weeks (n = 274, group 3), 2.5 Gy × 15 in 3 weeks (n = 233, group 4), and 2
Gy × 20 in 4 weeks (n = 257, group 5). All of the groups had similar
posttreatment ambulatory rates (63% to 74%) and motor function
improvements (26% to 31%). However, in-field recurrence rates were much
lower for the protracted schedules. The 2-year in-field recurrence rates for
groups 1, 2, 3, 4, and 5 were 24%, 26%, 14%, 9%, and 7% (P <.001), respectively.
They recommend that a single fraction of 8 Gy should be used in MSCC patients
with limited survival expectations, and that 30 Gy in 10 fractions should be used
for all other patients
Palliation of Bone Metastases
Metastatic disease to the bone is a common cause of pain and other significant
symptoms that are detrimental to quality of life. The exact incidence of bone
metastases is difficult to determine, but estimates are that >100,000 people in
the United States will develop osseous metastatic disease annually.The incidence
of bone metastases varies significantly, depending on the primary site, with
breast and prostate cancer accounting for up to 70% of patients with metastatic
disease. Bone metastases may be found in up to 85% of patients dying from
breast, prostate, or lung cancer. Other primary sites with a propensit for bone
metastases include thyroid, melanoma, and kidney. On the other hand,
gastrointestinal sites of primary malignancy give rise to bone metastasis in only
3% to 15% of patients with metastatic disease. Some hematologic malignancies,
including myeloma and lymphoma, can also cause significant pain and bone
destruction.
The ultimate prognosis for patients with bone metastases is poor, with median
survival typically measured in months rather than years. Overall survival
depends on the primary site and the presence or absence of visceral metastases.
Patients with bone metastases from lung cancer have short median survival
durations of 6 months. However, patients with bone metastases from breast or
prostate primary sites may have significantly longer survival times. In patients
with bone-only metastatic prostate or breast cancer, median survivals of 2 to 4
years have been reported.Whether the survival time is only a few months or
extends to multiple years, these patients will often require active treatment
because of pain, difficulty with ambulation and immobility, hypercalcemia,
pathologic fractures, neurologic deficits, anxiety, depression, spinal cord or
nerve root compression, fatigue, insomnia or sleep disturbances, and general
deterioration of quality of life.
The axial skeleton is the most common site of bone metastasis, with metastasis
most frequently occurring in the spine, pelvis, and ribs. The lumbar spine is the
most frequent site of bone metastasis. In the appendicular skeleton, the
proximal femurs are the most common site of metastatic disease, and humeral
lesions also occur frequently. The acral sites (feet and hands) are rarely involved.
Certain skeletal sites are associated with specific areas of bone metastases. For
example, scapular metastases are seen more frequently from renal primaries.
Involvement of the skull is more common with breast primaries. The distal
appendicular skeleton (tibia, fibula) and acral sites (especially the hands) are
more common with lung primaries, and involvement of the toes is seen more
commonly with genitourinary primaries .
The most common symptom of bone metastases is slowly progressive,
insidious pain that is fairly well localized. The pain may be worse at night.
Pain from the femur or acetabulum may worsen with weight bearing or
ambulation. In contrast, pain from the inferior ischium or sacrum may be
worse with sitting but less bothersome with ambulation. Although the
pain is frequently localized, pain may radiate to other areas. This is most
frequently seen with pain in the lower back, pelvis, or hips that may
radiate down the legs. Pain that radiates does not necessarily indicate
nerve impingement because radicular pain can also be caused by spasm of
muscles that originate or insert near the area of disease (e.g., pain in the
hip radiating to the knee).
Technetium-99m bone scintigraphy (nuclear medicine bone scan) is the best
method for screening patients at risk for bone metastasis and is useful to
evaluate the extent of metastatic disease in the bone. Bone scintigraphy is an
indicator of osteoblastic activity. Because multiple myeloma is frequently purely
osteolytic, bone scans are less useful for evaluating extent of disease in
myeloma. Bone scintigraphy is not specific for metastatic disease, and positive
findings must often be confirmed using other imaging studies. A confirmatory
study is especially important in a weight-bearing bone such as the proximal
femur. False-positive readings may be seen in areas of arthritis, trauma, or
Paget’s disease. In addition, the osteoblastic activity in healing bone after
treatment may give the appearance of progressive disease. False-negative
readings may occur in fastgrowing, highly aggressive tumors, especially if these
are mainly osteolytic.
Computed tomography (CT) scans are more sensitive than plain
radiographs and may be better able to localize the lesion within the
bone. However, CT scans are more expensive, more time-consuming,
and may not be useful as a screening tool for skeletal metastasis. The
CT may be useful in defining the extent of cortical destruction and
helping to assess the risk of a pathologic fracture.In addition, the CT
scan may be used to guide needle biopsies to obtain a tissue
diagnosis. CT scans have limited usefulness in detecting marrow
involvement but are much better than plain radiographs at
evaluating soft tissue extension of disease.
Magnetic resonance imaging (MRI) is better than plain radiography or nuclear
medicine bone scintigraphy at assessing the involvement of trabecular bone (red
marrow), especially in the vertebral bodies. The findings are typically best seen
on T1 contrast- enhanced images and short-tau inversion recovery (STIR)
images. Metastatic prostate cancer is visible as high-intensity lesions on the STIR
images and is visible prior to its appearance on bone scintigraphy. In addition,
MRI scans are useful in determining the involvement of neurovascular
structures. MRI scans are not useful as a screening tool for bone metastases.
However, MRI scans may be more sensitive than bone scintigraphy in the
vertebral body region. The sensitivity of MRI scanning has been reported as 91%
to 100%, compared with 62% to 85% for bone scintigraphy. In addition, MRI
images can help distinguish whether a vertebral body compression fracture is
from malignancy or from osteoporosis.
Positron emission tomography (PET) scanning evaluates areas of increased
metabolic activity, most commonly using the 18-fluorodeoxyglucose (FDG)
isotope. These scans are useful in detecting osteolytic bone metastases but are
less sensitive for osteoblastic metastases. In addition, precise determination of
the location of lesions is difficult with PET scans, but the use of simultaneous CT
scans allows for much better localization of the abnormal FDG uptake. PET scans
may be useful as a whole-body screening tool. Comparative studies have shown
PET scans to be more sensitive than Tc-99m scintigraphy or whole-body MRI
scans in detecting bone metastases.
There may be limitations in the sensitivity of PET scanning in certain areas such
as the skull, where the intense physiologic uptake from the adjacent brain
parenchyma may obscure small skull metastases.
Radiation therapy has been reported to be effective in palliating painful bone
metastases, with partial pain relief seen in 80% to 90% of patients and complete pain
relief in 50% of patients. These data are primarily from studies using physician
evaluation of pain. When patient evaluation of pain is used, pain improvement is seen
in 60% to 80% of patients and complete pain relief is seen in 15% to 40% of patients.The
response to treatment depends on a large number of factors, including sex, primary site
and histology, performance status, type of lesion (osteolytic vs. osteoblastic), location of
the metastases, weight-bearing vs. non–weight-bearing site, extent of disease, number
of painful sites, marital status, and level of pain prior to treatment.
The effectiveness of the treatment also depends on the goal: palliation of pain,
prevention of pathologicfracture, avoidance of future treatments, or local control of the
disease. The doses required and volumes treated may bequite different for each of
these goals. In addition to pain relief, other symptoms may be relieved by radiotherapy.
Patients who have improvement in pain after radiotherapy may also have improvement
in emotional functioning, decreased insomnia and decreased constipation, and overall
improvement in quality-of-life scores. Radiation therapy should be an integral part of
palliative treatment for bone metastases for treatment of pain and prevention of other
symptoms.
Local-field external-beam radiation therapy is typically used for palliation of a
few discrete areas of painful metastases. The first large randomized study
evaluating different dose an fractionation schemes was the Radiation Therapy
Oncology Group (RTOG) 74-02 trial. Patients with solitary bone metastases were
randomized to 40.5 Gy in 15 fractions versus 20 Gy in 5 fractions. Patients with
multiple painful metastases were allocated to one of four treatment schedules:
30 Gy in 10 fractions, 15 Gy in 5 fractions, 20 Gy in 5 fractions, or 25 Gy in 5
fractions. The initial analysis by Tong et al. in 1982 showed no statistically
significant difference in response rates between any of the treatment arms, with
complete responses in 49% to 61% of patients. These results were questioned
by Blitzer, who reanalyzed the data using different criteria for complete
response, which excluded patients who received repeat treatment, and defined
complete response as no pain and no analgesic usage.
There have been multiple randomized, prospective trials in the last 30 years
comparing shorter-course, lower–total-dose treatment to the more “standard”
longer-course, higher–dose
treatment. Several conclusions are clear from these studies:
1. Single-dose treatments of 8 Gy provide similar pain relief to longer-treatment
regimens (30 Gy in 10 fractions or 20 to 24 Gy in five to eight treatments).
2. The retreatment rates are higher after short-course treatment by a factor of
two to three.
3. Response rates are lower when scored by the patient instead of by the
treating physician.
4. Response rates are better when the initial pain scores are lower, that is, when
the patients are treated for moderate pain rather than severe pain.
5. There is no consistent dose–response relationship for palliation of bone
metastases.
Radiopharmaceuticals
The first radiopharmaceutical used for treatment of bone metastases was phosphorous-32 (P-32).
Treatment with P-32 for diffuse bone metastases was successful in giving subjective pain relief but
with unacceptable bone marrow toxicity. Other radioisotopes have been used for the palliation of
diffuse osseous metastases with a better therapeutic ratio than P-32. Strontium-89 (Sr-89) is
chemically similar to calcium and is deposited in the bone matrix, preferentially in sites of active
osteogenesis.
Sr-89 is a pure β-emitter with an energy of 1.4 MeV and a half-life of 50.6 days. Samarium-153 (Sm-
153) is primarily a β-emitter but also has a component of gamma emission, which is useful for
imaging purposes. The Sm-153 ethylenediaminetetra methylenephosphoric acid (EDTMP) is
concentrated in areas of high bone turnover, accumulating in areas of hydroxyapatite. The physical
half-life of Sr-153 is 46.3hours, but the biologic half-life is much shorter because about half of the
compound is excreted in the urine within 8 hours of injection. These two isotopes have been
evaluated in multiple prospective trials. There are other, newer isotopes that are being evaluated,
including rhenium-186, rhenium-188, and tin-117m. All of these isotopes accumulate in areas of
osteoblastic activity, especially in areas of increased uptake on bone scintigraphy; for this reason,
most of the patients entered on prospective trials have metastatic prostate cancer.
Radiopharmaceuticals
The primary advantages of Sm-153 compared with Sr-89 are reduced radiation
safety issues (because of the much shorter half-life) and the ability to image the
distribution of the Sm-153. Although there has not been a randomized
comparison of Sr-89 and Sm-153, there does not appear to be a significant
difference in the incidence, severity, onset, or duration of hematologic toxicity,
despite the short half-life of the Sm-153. Both radiopharmaceuticals appear
equally effective at palliating pain from bone metastasis. These
radiopharmaceuticals add to the growing armamentarium of therapies designed
to palliate pain and improve the quality of life of patients with bone metastasis
from cancer.
Superior vena caval
obstruction
Over 90 per cent of cases of superior vena caval obstruction (SVCO) have a malignant cause. Although
uncommon in patients with lung cancer, the commonest cause of SVCO is nevertheless small cell and non-
small cell lung cancer. Other malignant causes are lymphoma and metastasis from mesothelioma,
thymoma or any tumour that spreads to mediastinal lymph nodes.
The obstruction arises from compression of the SVC by tumour at the right main or upper lobe bronchus or
by large volume mediastinal lymphadenopathy. Symptoms may be severe when the obstruction is below
the entry of the azygous vein. The clinical features are neck swelling and distended veins over the chest.
There may be swelling of one or both arms, shortness of breath, hoarse voice and headaches.
The diagnosis is made on contrast-enhanced spiral or multi-slice CT scans, which can accurately identify
the site of occlusion or stenosis and the presence of intravascular thrombus. Impending SVCO may also be
diagnosed on CT scans. SVCO is no longer considered a radiotherapy emergency, as outcome is not related
to the duration of symptoms. Urgent action may be needed to prevent SVCO leading to airway obstruction
from laryngeal or bronchial oedema, or coma from cerebral oedema. Confirmation of histology is
important and can be obtained by biopsy of the primary tumour at bronchoscopy or mediastinoscopy, by
percutaneous CT-guided biopsy, or by biopsy of an involved cervical lymph node. Tumour markers such as
α-fetoprotein (AFP) and β-hCG for germ cell tumours, lactic dehydrogenase for lymphoma, and prostate-
specific antigen (PSA) for prostate cancer may be helpful.
Target volume definition
The GTV is defined on the
contrast-enhanced CT scans,
including any mediastinal
mass and the site of SVCO.
The CTV is chosen according
tumour type and patterns of
spread The CTV-PTV margin is
1–2 cm. The margin is
modified to spare normal lung
tissue if possible.
Dose fractionation
20 Gy in 5 daily fractions of 4 Gy given in 1 week.
30 Gy in 10 daily fractions of 3 Gy given in 2 weeks.

For some chemo-sensitive tumours, a single fraction of 4 Gy in conjunction with chemotherapy

may give adequate immediate palliation.
Haemorrhage
Bleeding from advanced tumours of the breast, bladder, bronchus and other
sites can be effectively palliated with radiotherapy. Simple arrangements such as
opposing anterior and posterior beams for treatment of the bronchus or
bladder, or small tangential beams for breast tumours, are used. The size is
chosen clinically as the smallest needed to palliate the bleeding effectively with
the fewest side effects, and may not include the whole tumour.
The following dose fractionations can be used:
Single 8 Gy fraction.
20 Gy in 5 daily fractions given in 1 week.
30 Gy in 5 fractions given in 6 weeks (6 Gy once weekly) can be used for patient
convenience where higher doses are needed.
SEKIAN DAN TERIM KASIH