Professional Documents
Culture Documents
Ca colon stadium III memiliki modalitas kuratif yaitu operasi, yang juga merupakan satu-satunya
modal kuratif. Kemoterapi adjuvant juga merupakan tatalaksana standar bagi pasien dengan ca
colon stadium III.
Lesi yang terletak di caecum dan kolon sebeleh kanan
concluded that prospective studies are warranted, given the potential bias of those
results.[65]
Curative-intent resections of liver metastases have significantly improved long-term
survival, with acceptable postoperative morbidity, including in older patients. [66] A
study by Brouquet et al found that resection of colorectal liver metastases after a
second-line chemotherapy regimen was safe and provided a modest hope for
definitive cure, making this approach viable in patients with advanced colorectal liver
metastases.[67]
Hepatic arterial infusion (HAI) of chemotherapeutic agents such as floxuridine
(FUDR) is a consideration following partial hepatectomy. A study by House et al
found that adjuvant HAI-FUDR combined with modern systemic chemotherapy
resulted in improved survival compared with adjuvant chemotherapy alone. [68]
During the past decade, colonic stents have introduced an effective method of
palliation for obstruction in patients with unresectable liver metastasis. However, a
study by van Hooft et al found that colonic stenting has no decisive clinical
advantages compared with emergency surgery. Although it may be used as an
alternative treatment in undefined sets of patients, concerns about tumor spread
caused by perforations remains.[69]
Previous
Next
Ablation
Although resection is the only potentially curative treatment for patients with colon
metastases, other therapeutic options for those who are not surgical candidates,
include thermal ablation techniques. Cryotherapy uses probes to freeze tumors and
surrounding hepatic parenchyma. It requires laparotomy and can potentially have
significant morbidity, including liver cracking, thrombocytopenia, and disseminated
intravascular coagulation (DIC).
Radiofrequency ablation (RFA) uses probes that heat liver tumors and the surrounding
margin of tissue to create coagulation necrosis. RFA can be performed percutaneously,
laparoscopically, or through an open approach. Although RFA has minimal morbidity,
local recurrence is a significant problem and is correlated with tumor size.
Adjuvant Chemotherapy
The standard therapy for patients with stage III and some patients with stage II colon
cancer for the last two decades consisted of 5-fluorouracil in combination with
adjuncts such as levamisole and leucovorin. [2, 3, 4] This approach has been tested in
several large randomized trials and has been shown to reduce individual 5-year risk of
cancer recurrence and death by about 30%.
In an observational study of 1291 patients with stage III colon cancer, adjuvant
chemotherapy reduced the risk of distant recurrence after surgery by about half.
Elderly patients benefited to a similar degree as younger patients. [70, 71]
Overall, 56% of the study participants received adjuvant chemotherapy, 31%
developed distant metastases, and 37% were 75 years of age or older. In the total
population, the use of adjuvant chemotherapy was associated with a significantly
reduced risk of distant recurrence. In separate analyses of patients 75 years of age
and those 75 years of age, the effect of adjuvant chemotherapy on recurrence risk
was similar in both age groups, with hazard ratios of 0.50 and 0.57, respectively.[70, 71]
Two large randomized trials (MOSAIC and NASBP-C06) investigated the addition of
oxaliplatin to fluorouracil (FOLFOX4 and FLOX, respectively) and demonstrated a
significant improvement in 3-year disease-free survival for patients with stage III
colon cancer. The addition of irinotecan to fluorouracil in the same patient population
provided no benefit based on the results from two large randomized trials (CALGB
89803 and PETACC 3).
Another randomized study, XACT, demonstrated noninferiority of capecitabine
(Xeloda) compared with fluorouracil/leucovorin as adjuvant therapy for patients with
stage III colon cancer. A large trial comparing capecitabine plus oxaliplatin (XELOX)
versus FOLFOX has completed accrual, but survival data have not yet been reported.
Although information on results of adjuvant therapy in stage II and III colon cancer is
limited, analysis of a data set assembled by the Adjuvant Colon Cancer Endpoints
group showed that adjuvant chemotherapy provides a significant disease-free survival
benefit because it reduces the recurrence rate. The benefit was particularly evident
within the first 2 years of adjuvant therapy but some benefit extended to years 3-4. [72]
Adjuvant therapy in stage II colon cancer
The role of adjuvant chemotherapy for stage II colon cancer is controversial. Surgery
alone is usually curative for stage II colon cancer, but approximately 20-30% of these
patients develop tumor recurrence and ultimately die of metastatic disease. The
American Society of Clinical Oncology does not recommend the routine use of
adjuvant chemotherapy for patients with stage II colon cancer, and instead
recommends encouraging these patients to participate in clinical trials. [73]
A large European trial (QUASAR) demonstrated small but significant benefit (3.6%)
in terms of absolute 5-year survival rate for those patients who received
fluorouracil/leucovorin versus those in the control group. [49] In contrast, a study by
OConnor et al found that in Medicare patients with stage II colon cancer, with or
without poor prognostic features, overall survival was not substantially improved by
adjuvant chemotherapy.[74]
Ongoing adjuvant trials are investigating additional risk stratification of stage II colon
cancer based on clinicopathological and molecular markers. For example, the ECOG
5202 trial is comparing two forms of adjuvant therapy (oxaliplatin, leucovorin, and
fluorouracil with or without bevacizumab) in high-risk patients, with low-risk patients
undergoing observation only.
In this trial, high-risk patients are defined as those with microsatellite stability (MSS)
or low-frequency microsatellite instability (MSI-L) and loss of heterozygosity at 18q.
Low-risk patients are those with MSS or MSI-L and retention of 18q, or highfrequency MSI with or without loss of heterozygosity at 18q.
Chemotherapy for Metastatic Disease
Combination regimens provide improved efficacy and prolonged progression-free
survival (PFS) in patients with metastatic colon cancer. The advent of new classes of
active drugs and biologics for colorectal cancer has pushed the expected survival for
patients with metastatic disease from 12 months two decades ago to about 22 months
currently.
In a phase III multicenter trial in patients with advanced colorectal carcinoma
refractory to fluorouracil, overall survival did not significantly differ between patients
treated with fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) (n=246) compared
with irinotecan (n=245); however, FOLFOX 4 improved response rate (RR) and time
to progression (TTP) compared with irinotecan (P=0.0009 for each RR and TTP).
FOLFOX4 was associated with more neutropenia and paresthesias. [75]
Although many patients with colorectal cancer are elderly, exclusion of these patients
from randomized controlled trials has impeded the creation of evidence-based
guidelines for this population. A study by Seymour et al demonstrated that elderly and
frail patients with untreated metastatic colorectal cancer can participate in a
randomized controlled trial. Study patients, who were considered unfit for full-dose
A pooled analysis of cohorts of older patients (aged 65 years or older) from two
randomized clinical trials concluded that adding bevacizumab to fluorouracil-based
chemotherapy for first-line treatment of metastatic colorectal cancer improved OS and
PFS in older patients as it does in younger patients, without increased risks of
treatment in the older age group. Median OS improved from 14.3 months to 19.3
months with the addition of bevacizumab, while median PFS improved from 6.2
months to 9.2 months.[78]
Results from the randomized CAIRO3 trial appear to show that, compared with
observation, maintenance therapy with capecitabine (Xeloda) and bevacizumab
significantly delayed disease progression in 558 previously untreated patients with
stable (or better) metastatic colorectal cancer after six cycles of induction therapy with
capecitabine, oxaliplatin, and bevacizumab (CAPOX-B). [79, 80] Patients in both groups
were treated with CAPOX-B at first progression until second progression.
At a median follow-up of 48 months, CAPOX-B was restarted in 48% of those in the
maintenance treatment group and 61% of patients in the observation group. [79,
80]
Median second progression after randomization occurred at 11.7 months in the
maintenance group and 8.5 months in the observation group, and median first
progression after randomization occurred at 8.5 months in the maintenance group
compared with 4.1 months in the observation group. [80]
In a study by Tebbutt et al, bevacizumab was found to be associated with a modestly
increased risk of arterial thromboembolism (ATE). However, safety was not
significantly worse in older patients or those with a history of ATE or other vascular
risk factors.[81]
Despite its role in the therapy of metastatic colon cancer, bevacizumab did not
significantly prolong disease-free survival in patients with stage II and III colon
cancer, when added to adjuvant chemotherapy (mFOLFOX6) in a randomized trial
(NASBP C-08).[82]
Cetuximab
Cetuximab is a chimeric monoclonal antibody against EGFR that is approved for
treatment of KRAS mutationnegative (wild-type), EGFR-expressing, metastatic
colorectal cancer. Cetuximab may be used as monotherapy or in combination with
irinotecan (Camptosar) in patients with metastatic colorectal cancer refractory to
fluoropyrimidine and oxaliplatin therapy.[83] Additionally, cetuximab is approved as
combination therapy with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin). [84, 85]
KRAS mutations, which are present in about 40% of colon adenocarcinomas, affect
sensitivity to anti-EGFR treatment.[48] The addition of anti-EGFR antibody treatment
to standard chemotherapy regimens for patients with advanced colorectal cancer
improves progression-free survival for those with wild-type KRAS status, but not
those with mutant KRAS.[86]
The CRYSTAL trial, a large international trial exploring the benefit of adding
cetuximab to first-line chemotherapy with FOLFIRI, documented that only patients
with wild-type KRAS derived clinical benefit from cetuximab. In patients with
mutant KRAS, adding cetuximab to chemotherapy provided no clinical benefit and
resulted only in unnecessary toxicity.
Based on these results, testing for KRAS mutation was added to the cetuximab
indication by the European Medicines Agency (EMA). The US Food and Drug
Administration (FDA) approved the use of cetuximab in combination with FOLFIRI
for first-line treatment of patients with wild-type KRAS metastatic colorectal cancer,
as determined by FDA-approved tests, in July 2012.
Panitumumab
Panitumumab is a fully human monoclonal antibody against EGFR. This agent was
originally approved as monotherapy for patients with EGFR-expressing metastatic
colorectal cancer in whom combination chemotherapy with regimens containing
fluoropyrimidine, oxaliplatin, and irinotecan had failed or was not tolerated.
In May 2014, the FDA approved panitumumab for first-line treatment of patients with
wild-type KRAS (exon 2) metastatic colorectal carcinoma in combination with
fluorouracil, leucovorin, and oxaliplatin (FOLFOX4). [87] Approval was based on
results from the PRIME trial.[88]
The PRIME trial, a phase III study, showed that patients with wild-type KRAS tumors
achieved statistically significant improvement in PFS with panitumumab and
FOLFOX4 versus FOLFOX4 alone (9.6 versus 8.0 months, P=0.02) and a
nonsignificant improvement in OS versus FOLFOX4 alone (23.9 versus 19.7 months,
P =0.07). In contrast, patients with mutant KRAS had significantly reduced PFS with
panitumumab-FOLFOX4.[88]
Thus, panitumumab becomes an option, or an alternative to cetuximab, for patients
who have tumors with wild-type KRAS.[89, 90] However, Hecht et al reported that adding
panitumumab to bevacizumab and chemotherapy (oxaliplatin- and irinotecan-based)
as first-line treatment of metastatic colorectal cancer resulted in increased toxicity and
decreased PFS.[91]
Radiation Therapy
Although radiation therapy remains a standard modality for patients with rectal
cancer, it has only a limited role in colon cancer. Radiation therapy is not used in the
adjuvant setting, and in metastatic settings it is used only for palliative therapy in
selected metastatic sites such as bone or brain metastases.
Newer, more selective ways of administering radiation therapy, such as stereotactic
radiotherapy (CyberKnife) and tomotherapy, are currently being investigated. In the
future, these techniques may extend the indications for radiotherapy in the
management of colon cancer.
A prospective, multicenter, randomized phase III study by Hendlisz et al showed that
the addition of radioembolization with yttrium-90 significantly improved time to liver
progression and median time to tumor progression in patients with unresectable,
chemotherapy-refractory, liver-limited metastatic colorectal cancer. The study
compared treatment with fluorouracil alone with fluorouracil plus yttrium-90 resin,
which was injected into the hepatic artery.[98]
Deterrence/Prevention
Colorectal cancer prevention strategies fall into three categories:
Screening (see Workup)
Lifestyle measures
Pharmacologic prevention
Lifestyle measures
Abundant epidemiologic literature suggests an association of risk for developing
colorectal cancer with dietary habits, environmental exposures, and level of physical
activity. For example, a prospective cohort study in the general population of two
Danish cities concluded that if all participants had followed recommendations for five
lifestyle factors (physical activity, waist circumference, smoking, alcohol intake, and
diet), 23% of colorectal cancer cases might have been prevented. [99]
There is also evidence that diet and physical activity affect the risk for recurrence of
colon cancer. A prospective observational study involving patients with stage III colon
cancer from the CALGB 89803 adjuvant chemotherapy trial demonstrated adverse
effect with regards to risk for recurrence and increased mortality for patients
following a "Western" diet (high intake of red meat, refined grains, fat, and sweets)
versus a "prudent" diet (high intake of fruits and vegetables, poultry, and fish). [10]
In another observational study from the same cohort of patients, patients were
prospectively monitored and physical activity was recorded. The study concluded that
physical activity reduces the risk of recurrence and mortality in patients with resected
stage III colon cancer.[100]
Morikawa et al reported that in patients with colorectal cancer that tested negative for
cadherin-associated protein 1 (CTNNB1 or -catenin), high physical activity (18
metabolic equivalent task [MET] hours/week) after diagnosis was associated with
significantly better cancer-specific survival. No association between physical activity
and survival was seen in CTNNB1positive cases. [101]
In a study by Campbell et al, recreational physical activity before and after colorectal
cancer diagnosis was associated with lower mortality. These researchers determined
that 6 hours or more of sitting per day was associated with an increase in mortality
compared with sitting 3 hours or less per day. The findings suggest that increasing
physical activity helps reduce mortality in patients with colorectal cancer.[26]
Pharmacologic prevention
Pharmacologic prevention is based on the understanding of colorectal carcinogenesis
and the availability of pharmacologic agents that are effective yet minimally toxic.
The efficacy of these agents is usually first tested in high-risk populations.
Celecoxib (Celebrex), a selective cyclooxygenase-2 inhibitor, was first tested in
patients with familial adenomatous polyposis (FAP). Celecoxib was effective in
decreasing the number and size of polyps on serial colonoscopies, which was the
primary surrogate endpoint for this trial.[102] The drug was approved for FAP patients,
although it remains to be seen whether this intervention translates to reduced cancer
incidence and prolonged survival.
Enthusiasm for cyclooxygenase-2 inhibitors as chemopreventive agents has dampened
because of a high incidence of cardiovascular toxicity in trial patients, which led to
the removal of rofecoxib from the market. Other nonsteroidal anti-inflammatory drugs
(NSAIDs), such as sulindac and nonselective cyclooxygenase inhibitors, have been
tested in lower-risk populations.
Aspirin use has been shown to be effective in both primary prevention of colorectal
cancer (at doses of 300 mg or more daily for about 5 years [103] ) and secondary
prevention (at doses ranging from 81 to 325 mg daily[104] ) of colorectal adenomas. The
decrease in colon cancer risk with aspirin use may vary among population subgroups.
However, body mass index, physical activity, and plasma C-peptide levels were
shown to not have a significant impact on aspirins effect on colon cancer risk. [105]
Examination of questionnaire data collected from the Nurses Health Study and the
Health Professionals Follow-up Study showed regular aspirin use was associated with
lower risk of BRAF wild-type colorectal cancer (multivariable hazard ratio [HR],
0.73) but not with BRAF -mutated cancer risk (multivariable HR, 1.03). Status of
tumor PTGS2 expression or PIK3CA or KRAS mutation had no effect on this
association.[106]
A 2013 study showed that low-dose aspirin taken every other day lowers the risk for
colorectal cancer in middle-aged women. Nearly 40,000 women aged 45 and older
were randomized to low-dose aspirin (100 mg) or placebo every other day for roughly
10 years; 84% were followed for an additional 7 years after treatment ended. At
followup, colorectal cancer risk was lower in the aspirin group, mostly owing to a
reduction in proximal colon cancer; this reduction in risk emerged after 10 years. [107]
Some trials focused on combined inhibition of polyamine production and
cyclooxygenase inhibition. A report from a large randomized trial of a combination of
sulindac and dimethylformamine (DMFO), an inhibitor of ornithine decarboxylase
(ODC), described a dramatic effect of this combination in reducing polyp recurrence
in patients with prior history of colon polyps. Confirmatory trials are ongoing. [108]
Previous
Next
Consultations
Colorectal cancer, especially early stage disease, can be cured surgically. Following
diagnosis and staging, obtaining surgical consultation for the possibility of resection
may be appropriate. After surgery, the stage of the tumor may be advanced depending
on the operative findings (eg, lymph node involvement, palpable liver masses,
peritoneal spread).
In the care of patients with colorectal cancer and isolated liver metastases, consider
surgical consultation for possible resection. In some cases, resection of previously
unresectable liver metastases may become feasible after cytoreduction with
neoadjuvant chemotherapy. Therefore, ongoing involvement of the surgical oncologist
is very important in patient care, even if the tumor is not considered resectable at the
time of diagnosis. In patients with advanced disease, palliative surgery may be helpful
in cases of bleeding or obstruction.
Long-Term Monitoring
Pooled analysis from several large adjuvant trials showed that 85% of colon cancer
recurrences occur within 3 years after resection of primary tumor, with 95% occurring
within 5 years. Therefore, patients with resected colon cancer (stage II and III) should
undergo regular surveillance for at least 5 years following resection. [109] See Table 2
below.
Table 2. Surveillance recommendations for stage II and III colon cancer (Open Table
in a new window)
Parameter
History and
physical exam
CEA
Chest CT*
Colonoscopy**
Abdominal CT*
Organization
ESMO [JSMO](2013)
ASCO (2013)[109]
NCCN (2013)[111]
Every 3-6 mo for 3 y, then Every 3-6 mo for 3 y, then Every 3-6 mo for 2
every 6 -12 mo at 4 and 5 y every 6 mo to 5 y
y, then every 6 mo
to 5 y
Every 3-6 mo for 3 y, then Every 3 mo for 3 y*
Every 3-6 mo for 2
every 6 -12 mo at 4 and 5 y
y, then every 6 mo
to 5 y
Every 6-12 mo for first 3 y Every 1 y for 3 y
Every 1 y for 5 y
At y 1 after surgery, and
At 1 y, then every 5 y,
At 1 y, 3 y, and 5 y
every 3-5 y thereafter
dictated by the findings on if negative
the previous colonoscopy
Every 6-12 mo for first 3 y Every 1 y for 3 y
Every 1 y for 5 y;
scans to include
pelvis
[110]
* For patients at high risk for recurrence (eg, lymphatic or venous invasion, or poorly
differentiated tumors).
pembentukan abses.
5.
6.
Pembentukan abses
F.
Pencegahan
tertentu.
3.
betakarotin.
4.
5.
G.
Penatalaksanaan
1.
Penatalaksanaan medis
2.
Penatalaksanaan bedah
Penatalaksanaan Keperawatan
a)
b)
Meningkatkan kenyamanan.
c)
d)
Mencegah komplikasi.
e)
prognosis, dan
4.
kebutuhan pengobatan.
Penatalaksanaan Diet
a)
c)
berlebihan.
f)
teratur
H.
a)
Pemeriksaan penunjang
Endoskopi. Pemeriksaan endoskopi perlu dikerjakan, baik
antara lain adalah : foto dada dan foto kolon (barium enema).
Pemeriksaan dengan enema barium mungkin dapat
memperjelas keadaan tumor dan mengidentifikasikan
letaknya. Tes ini mungkin menggambarkan adanya kebuntuan
pada isi perut, dimana terjadi pengurangan ukuran tumor
pada lumen. Luka yang kecil kemungkinan tidak
teridentifikasi dengan tes ini. Enema barium secara umum
dilakukan setelah sigmoidoscopy dan colonoscopy.
Computer Tomografi (CT) membantu memperjelas adanya
massa dan luas dari penyakit. Chest X-ray dan liver scan
mungkin dapat menemukan tempat yang jauh yang sudah
metastasis.
Pemeriksaan foto dada berguna selain untuk melihat ada
tidaknya metastasis kanker pada paru juga bisa digunakan
untuk persiapan tindakan pembedahan. Pada foto kolon dapat
dapat terlihat suatu filling defect pada suatu tempat atau
suatu striktura.
c)
primer.
Perubahan yang
Memberi
Intervensi
Rasional
Perawat
Pasien lansia
Pasien akan
Intervensi
Rasional
bedah dan diulang setiap dua hari sekali pada luka abdomen
70% atau normal salin dengan cara swabbing dari arah dalam
keluar.
Antibiotic injeksi
Evaluasi
2.
3.
4.
a.
kalori.
b.
5.
a.
mual.
b.
6.
a.
b.
7.
diri pascaoperatif.
b.
8.
perineal.
a.
perawatan stoma.
9.
a.
b.
c.
Tidak demam.
d.
e.
f.
STUDI KASUS
PADA KANKER KOLON
Pengkajian
PENGKAJIAN KEPERAWATAN
Nama Perawat
: Ns. Cindra
Tanggal Pengkajian
: 05 Mei 2012
Jam Pengkajian
1.
: 08.00 WIB
Biodata :
Pasien
Nama
: Tn. A
Umur
: 35 th
Agama
: Islam
Pendidikan
: Sarjana
Pekerjaan
: PNS
Status Pernikahan
Alamat
: Menikah
Tanggal Masuk RS
Diagnosa Medis
: Ca. Colon
Penanggung Jawab
Nama
Agama
: Ny. B
: Islam
Pendidikan
: Sarjana
Pekerjaan
: PNS
Status Pernikahan
Alamat
: Menikah
: Istri
Keluhan utama :
3.
Riwayat Kesehatan :
a.
a.
Nutrisi
makanan cepat saji (sate & gulai). Klien tidak suka sayuran,
dan tidak memiliki pantangan terhadap makanan apapun. Klien
tidak pernah mengalami operasi gastrointestinal. Saat sakit,
klien hanya mengkonsumsi nasi lembek, sayuran hijau, buah
tapi jarang habis karena klien mual, tidak nafsu makan, &
klien tidak makan yang pedas & berminyak. Diet di rumah
sakit adalah diet rendah lemak hewani dan tinggi serat.
Kebutuhan pemenuhan nutrisi dibantu oleh keluarganya.
e.
Oksigenasi
Eliminasi fekal/bowel
h.
Eliminasi urin
Keadaan Umum
bagian bawah.
Hidung : Hidung klien simetris, tidak ada septum deviasi,
polip, epistaksis, gangguan indera pencium, atau secret.
Mulut : Mulut klien normal, dimana gigi klien normal, tidak
ada lubang, dan tidak ada gigi palsu. Bibir klien kering, tidak
stomatitis, dan tidak sianosis. Gusi klien berwarna merah,
lidah klien tampak kotor.
Telinga : telinga klien simetris, bersih, dan tidak ada
gangguan pendengaran.
Leher : leher klien normal, tidak ada pembesaran thyroid,
tidak ada kaku kuduk, tidak ada hematoma, tida ada lesi.
Tenggorokan klien normal, tidak ada nyeri tekan, tidak
hipremis, dan tidak ada pembesaran tonsil.
c.
tidak ada.
d.
peristaltik permenit.
e.
f.
Ekstremitas :
11,5
Ht/PVC
Hasil
Nilai Normal
12-18 g/dL
42
Leukosit
Trombosit
40-52%
7.000
Turun
Normal
4.000-10.000 /uL
253.000
Masa protrombin
13.0
Normal
150.000-450.000 /uL
11.0-17.0 detik
Radiologi :
Foto colon ( Barium Enema)
Colonoscopy
Interpretasi
Normal
Normal
7.
Terapi Medis
Bed rest
IVFD RL 20 tetes/menit
Th/oral :
Th/inj :
Kemoterapi
Leukovorin
Pembedahan / Laparaskopi
ANALISA DATA
Nama Klien
Umur
: Tn. A
: 35 tahun
Ruang Rawat
TGL/JAM
No. Register
Diagnosa Medis
: Paviliun Asri 3
DATA FOKUS
Alamat
PROBLEM
: 123
: Ca. Colon
: Kalirejo
ETIOLOGI
05/05/12
08.00 WIB
DS :
bergerak
-
DO :
-
akut
Nyeri
DS :
DO :
-
Nyeri akut
06/05/12
13.30 WIB
DS :
-
DO :
-
Suhu : 37,5 C
Risiko infeksi
06/05/12
15.00 WIB
DS
mandiri
DO :
-
DS :
-
pasca operasi
-
DO :
-
Pre Operasi
Nyeri akut b.d obstruksi tumor pada usus dengan
kemungkinan menekan organ yang lain
Post Operasi
1.
2.
pembedahan
3.
4.