5. • Physical Examination
(Digital rectal and Bimanual
palpation before and after
TURBT) –
1. Anterior vaginal wall in
women and the prostate in
men may reveal findings
that suggest local
extension of bladder
cancer.
2. Extravesical involvement
Sn 46% and Sp 82%
3. Size of tumor Sn of 93%,
Sp 43%
4. Lesions near trigone and
post bladder wall cannot
be palpated
A comparison between clinical
and pathologic staging in patients
with bladder cancer.
Et al Mehrsai A
6. • CBC, Urine analysis, PSA,
Biochemical profile , BUN ,
S.creatinine
• Urine Cytology Sn 40-60% ,
Sp 98% “second morning”
voided urine collected over
three consecutive days
1. Sensitivity decreases in
low grade as they shed less
and are similar to normal
cells
2. It should complement
cystoscopy findings
3. Cannot replace
Cystoscopy
4. Newer markers to identify
proteins NMP,FDP ,
hyaluronic acid etc
7. • Cystoscopy with bladder mapping-
• Tumor description (size and shape
site, number and appearance and
mucosal abnormalities)
1. Fluorescence scopy is more
efficient (5-ALA) that
accumulates in neoplastic cells
2. C/I in Acute infection and urethral
stricture
3. Disadvantage - It cannot detect
flat tumors efficiently
• The pathological report should
specify tumour location, tumour
grade, depth of tumour invasion,
presence of CIS, and whether the
detrusor muscle is present in the
specimen.
Illustrative bladder map
8. If patient is diagnosed to have bladder tumor he
needs to be investigated further for staging
9. • TURBT deep to detrusor
muscle ( As absence is
associated with higher
chances of residue ) under
anaesthesia (1)
1. Cold cup biopsy of
suspicious area
2. When diffuse CIS is
present, prostatic
urtethra contains
neoplastic cells in upto
25%
3. Sufficient resection to
evaluate muscle invasion
4. Comments regarding
residual, and muscle
invasion (HPR) is
important 1. Herr, H.W., et al. BJU Int, 2008. 102:
1242.
10. Carcinoma In Situ
• Carcinoma in situ can present as a velvet-
like, reddish area indistinguishable from
inflammation, or it may not be visible at all.
• In 128 men with T1G3 BC, the incidence
of CIS in the prostatic urethra was 11.7%
• The risk of prostatic urethra- or duct
involvement is higher if the tumour is
located on the trigone or bladder
• Photodynamic diagnosis is performed
using violet light after intravesical
instillation of ALA
• Without any treatment, approximately 54%
of patients with CIS progress to muscle-
invasive disease
1. Palou et al.
12. • All imaging to be performed
before TURBT , to avoid
post surgical edema
• CT urography detect
papillary tumours in the
urinary tract, which can be
seen as filling defects or
indicated by hydronephrosis
• CT abdomen and pelvis to
evaluate extravesical
involvement and lymph
nodal involvement
13. • MRI to distinguish superficial/invasive and
intravesical/extravesical Sn -0.92 , Sp 0.80–90.
Kobayashi S et al Eur Radiol. 2011;21:2178–2186
• PET CT in bladder cancer for pelvic node metastasis
Lodde M,et al . BJU Int. 2010;106:658–663
• PET CT in bladder cancer for primary evaluation
PET/CT and MRI in Bladder CancerKirsten Bouchelouche
Lymph node Sensitivity Specificity
PET CT 57% 33%
CT 100% 100%
Primary Sensitivity Specificity
PET CT 85% 25%
CT 77% 50%
14. Metastatic Work up
• 25% of cases with tumours invading the muscular layer and in
about 50% extending into the perivesical tissue present with
metastatic disease (PET/CT and MRI in Bladder Cancer Kirsten Bouchelouche )
• Chest X ray to rule out lung mets- Sn 52% . EAU 2016
recommends CT to diagnose pulmonary metastases.
• Bone scan for muscle invading disease, raised Alkaline
Phosphatase , Bone pain
• Renal Ultrasonography-can detect renal masses,
hydronephrosis, and bladder intraluminal masses
17. Regional lymph nodes (N)
Regional lymph nodes include both primary and secondary drainage regions. All other nodes above
the aortic bifurcation are considered distant lymph nodes.
NX Lymph nodes cannot be assessed
N0 No lymph node metastasis
N1 Single regional lymph node metastasis in the true pelvis (hypogastric,
obturator, external iliac, or presacral lymph node)
N2 Multiple regional lymph node metastasis in the true pelvis (hypogastric,
obturator, external iliac, or presacral lymph node metastasis)
N3 Lymph node metastasis to the common iliac lymph nodes
Distant metastasis (M)
MO No distant metastasis
M1 Distant metastasis
AJCC Cancer Staging Handbook, Seventh Edition (2010)
18. STAGE GROUPING
0a Ta N0 M0
0is Tis N0 M0
I T1 N0 M0
II T2a,b N0 M0
III T3a,b N0 M0
T4a N0 M0
IV T4b N0 M0
ANY T N1,2,3 M0
ANY T ANY N M1
AJCC Cancer Staging Handbook, Seventh Edition (2010)
20. •Transitional Cell Carcinoma (TCC) 90%
•Squamous cell Carcinoma- 5%
more common in middle east
Schistosomiasis
Chronic catheterization
•Adenocarcinoma – urachal 0.5%-2%
•Small cell Carcinoma Rare
21. HISTOLOGIC GRADE
• World Health Organization (WHO) has recommended
changing bladder cancer grading to only two
categories:
1) Low grade. Grade 1 is well differentiated and grade
2 is moderately well differentiated
2) High grade Grade 3 is poorly differentiated and
grade 4 is undifferentiated.
AJCC Cancer Staging Handbook, Seventh Edition (2010)
22. Non–Muscle-Invasive Disease (Superficial tumor)
•Occur at the level of the bladder mucosa
•Include carcinoma in situ (cis; Tis),
•Papillary lesions (Ta), and
•Invasion of(but not through) the lamina propria (T1).
Muscle-Invasive Disease
•T2, T3, and T4 tumors
• That penetrate the muscularis propria
• Are more aggressive and have a strong tendency to
metastasize
25. • Upto 80 % of them present with NMIBC
• If residue consider for re TURBT and perform a second
TURBT within 2-6 weeks after initial resection.
Post TURBT
alone
Residue Complete
Response
Progression
to MIBC
Recurrence
53% 47% 15% 70%
26. • After CR risk stratify the patient as below
• Millán-Rodríguez F 2000;164:680–4. [PubMed]
Risk Groups Constitutes Recurrence
at median
of 40
months
Progressio
n at
median of
40 months
Mortality
Low risk Grade 1 stage Ta
disease and a single
Grade 1 stage T1 tumor
37% 0% 0%
Intermediate
Risk
Multiple grade 1 stage
T1 tumors, grade 2
stage Ta disease and a
single grade 2 stage T1
tumor
45% 1.8% 0.73%
High Risk Multiple grade 2 stage
T1 tumors, grade 3
stages Ta and T1
disease and any stage
disease associated with
CIS
54% 15% 9.5%
27. EORTC calculator
• Adjuvant therapy post TURBT is decided by 2 factors
1. Probability of disease progression
2. Probability of recurrence
And these factors depend on
1. Type
2. Stage
3. Grade
4. Multi centric disease
5. Size
6. Presence of CIS
32. A single, immediate, post-operative intravesical
instillation of chemotherapy
• Indication – Low , Intermediate
• Initiated within 24 hours after resection
• MOA – Act by the destruction of circulating
tumor cells resulting from TURB, and by an
ablative effect (chemo-resection) on residual
tumor cells at the resection site and on small
overlooked tumors
• C/I- Bladder perforation
33. Evidence
• MMC, doxorubicin, and epirubicin showed
benefit
Sylvester RJ, Oosterlinck W, van der Meijden AP. J Urol. 2004;171:2186–90. quiz 2435.
Arms Number of
patients
Recurrence rate
Intravesical
chemotherapy
750 48.4%
Placebo/None 750 36.7%
34. Adjuvant instillation of intravesical
chemotherapy
• Indication-
1. Intermediate-risk disease 1-2 out of 4 risk factors (multiple
tumors, size >3 cm, early recurrence <1 year, or frequent
recurrences >1 per year)
2. No previous intravesical therapy
• Contraindication
1. Bladder perforation
• Treatment duration – Maximum of 1 year
Kamat AM et al.. J Urol. 2014;192:305–15.
36. METHOD OF ADMINISTRATION
OF MITOMYCIN
• 40mg of Mitomycin c in 20cc distill water can be instilled via
a small tri lumen catheter.
• Patients are recommended to limit fluid intake for 8-12 hours,
and no fluid for 4 hours before treatment
• The patient should lie prone for 15 minutes and then be
allowed to move freely to bathe all parts of the bladder
mucosa. The drug should to remain in the patient’s bladder
for at least 1 hour (to a maximum of 2 hours).
• Avoid direct skin contact during and after urinating as it may
cause skin rash and irritation.
• Following completion of the treatment, the Mitomycin should
be drained from the patient’s bladder, by attaching a catheter
drainage bag, allowing the Mitomycin to drain into the sealed
bag.
NCCN 2016
37. Intravesical Immunotherapy/BCG
1. Indication - high-risk tumors , Aggressive intermediate.
Below is a trial comparing BCG and MMC.
Benefit of
Chemo
immunotherap
y vs
Chemotherapy
alone
RR 95% CI P value
Risk of
recurrence
0.75 0.61-0.92 P = 0.006
Risk of
progression
0.45 0.25-0.81 P = 0.007
Houghton BB. BJU Int. 2013;111:977–83
38. Duration of treatment – EORTC
recommendation
• In all patients either 1-year full-dose BCG
treatment
• (induction plus 3-weekly instillations at 3,6
and 12 months), or instillations of
chemotherapy for a maximum of 1 year for
intermediate risk
• BCG is given at full dose, 3 years’
maintenance (three-weeky instillations 3, 6,
12, 18, 24, 30 and 36 months) for high risk
39. INTRAVESICAL BCG
1. Initiated 3-4 wks after resection
2.Contraindicated/With hold
• bacteriuria,
• Traumatic catheterisation
• gross hematuria,
• local symptoms,
• systemic symptoms
40. BCG administration procedure
• 120mg BCG in 50cc sterile normal saline can be instilled
via a small catheter.
• Patients are recommended to limit fluid intake for 8-12
hours, and to have no fluid intake for 4 hours before
treatment.
• For maximum effect the solution should be instilled when
the bladder is completely empty and remain in direct
bladder contact for 2 hours.
• Avoid direct skin contact during and after urinating as it
may cause skin rash and irritation.
• Advised to sit while urinating and to empty the bladder
completely.
• Thorough cleansing of genital area and hands is advised.
NCCN 2016
41. • Adverse effects from BCG are generally mild and
and 60-80% of them present with these symptoms
• Burning micturition
• urgency.
• frequency.
• Fever
• Skin rash.
Reduction of Side Effects of Intravesical Therapy with Bacille Calmette-Guérin by Pentoxifylline?—
An In Vitro Approach A. Böhle1,
42. Role of RT in High risk Superficial
Bladder Cancer
• No randomized studies
• Dutch South Eastern Bladder Cancer Group
had
• Treatment appeared to be as effective as
intravesical BCG / Mitomycin
• Currently phase 2 evaluated T1 for TURBT
followed by CTRT.
Sample Size Stage Dose
121 T1G3 50/25#
43. Radical Cystectomy NMIBC
• Indication
1. BCG Refractory tumors
2. The benefits and risks of immediate and
delayed RC should be discussed with patients
3. In patients in whom RC is performed at the
time of pathological NMIBC, the 5-year
disease-free survival rate exceeds 80%(1)
Stein, J.P., et al. J Clin Oncol, 2001. 19: 666.
44. Surveillence
Risk group Surveillence
Low Risk (grade 1 stage Ta disease and a
single grade 1 stage T1 tumor)
3 months after resection . If Negative 9 month
later , then annually
Intermediate Risk(multiple grade 1 stage T1
tumors, grade 2 stage Ta disease and a single
grade 2 stage T1 tumor)
3 monthly- for 2yrs
6 monthly for 5 yrs
High Risk(multiple grade 2 stage T1 tumors,
grade 3 stages Ta and T1 disease and any
stage disease associated with CIS)
3 monthly- for 2yrs
6 monthly for 5 yrs
46. Muscle-Invasive Disease
• Upto 30% of total Bladder Ca
•T2, T3, and T4 tumors
• That penetrate the muscularis propria
• Are more aggressive and have a strong
tendency to metastasize
47. Controversy
• Radical cystectomy with pelvic
lymphadenectomy is considered gold standard
• No evidence comparing it with ChemoRT
(bladder preservation)
• New advancements in neoadjuvant and
adjuvant chemotherapy, radiation therapy and
bladder-preservation protocols should
encourage bladder preservation
• UK SPARE had poor recruitment
48.
49.
50. Neoadjuvant chemotherapy
• Radical cystectomy provides 5-year survival in about 50% .
• To improve these results ,NACT has been used since the
1980s
• Most common regimens used for neoadjuvant chemotherapy
is three 28-day cycles of MVAC as follows:
methotrexate (30 mg/m2 on days 1, 15, and 22),
vinblastine (3 mg/m2 on days 2, 15, and 22),
doxorubicin (30 mg/m2 on day 2), and
cisplatin (70 mg/m2 on day 2).
• GC (gemcitabine/cisplatin)
Stein JP 2006 Aug;24(3):296-304.
David KA Urol 2007 Aug;178(2):451-4.
51. Advantages
• Chemotherapy is delivered,
when the burden of
micrometastatic disease is
expected to be low.
• Tolerability of
chemotherapy are expected
to be better pre-cystectomy.
• Favorable pathological
status, by achieving pT0,
pN0 and negative surgical
margins.
Disadvantages
• Delayed cystectomy might
compromise the outcome in
patients not sensitive to. There
are no trials indicating that
delayed surgery, due to NAC,
has a negative impact on
survival.
• Neoadjuvant chemotherapy
does not seem to affect the
outcome of surgical morbidity.
In one randomized trial the
same distribution of grade 3-4
postoperative complications
was seen in both trial arms[1]
Sternberg CN):1644-52[1]
52. European Association of Urology 2016
Recommendations
• Neoadjuvant chemotherapy is recommended
for T2-T4a, cN0M0 bladder cancer and should
always be cisplatin-based combination therapy.
• NACT is not recommended in patients who are
ineligible for cisplatin-based combination
chemotherapy.
53. Pre-operative radiotherapy in muscle-
invasive bladder cancer
Recommendations of European Association of
Urology
1. Pre-operative radiotherapy is not
recommended to improve survival
2. Pre-operative radiotherapy for operable
MIBC can result in tumour down-staging
after 4-6 weeks.
Huncharek M Res 1998 May;18(3b):1931-4.
54. Cystectomy
1. Indications
• MIBC T2-T4a, N0-Nx, M0
• high-risk and recurrent superficial tumours
• BCG-resistant Tis, T1G3
• extensive papillary disease that cannot be
controlled primary therapy
• Salvage cystectomy if bladder preservation fails
• In patients with inoperable locally advanced
tumours (T4b), primary radical cystectomy is a
palliative option.[1]
1. Nagele U World J Urol 2007 Aug;25(4):401-5.
55. • In men, standard RC includes removal of the bladder,
prostate, seminal vesicles, distal ureters, and regional
lymph nodes. Prostate-sparing cystectomy is an
option in a subset of carefully selected patients with
without involvement of the prostatic urethra and
without prostate cancer. This procedure is
oncologically safe [1]
• In women, standard RC includes removal of the
bladder, entire urethra and adjacent vagina, uterus,
distal ureters, and regional lymph nodes [2].
• Orthotopic bladder cannot be offered for N2
disease[3]
1. Mertens, J Urol, 2014. 191: 1250.
2. Stenzl, A., et al. Series, 2005. 3: 138
3. Lebret, T., et al. Eur Urol, 2002. 42: 344.
56. European Association of Urology 2016
Recommendations
• Offer sexual-preserving techniques to Male/
female patients motivated to preserve their sexual
function since the majority will benefit.
• Select patients based on:
1. Organ-confined disease;
2. Absence of tumor in bladder neck or urethra.
3. Do not offer pelvic organ-preserving radical
cystectomy for Male /female patients as standard
therapy for MIBC.
57. Lymph node dissection
• The extent of LND has not been
established to date. Standard
lymphadenectomy in BC patients
involves removal of nodal tissue cranially
up to the common iliac bifurcation, with
the ureter being the medial border, and
including the internal iliac, presacral,
obturator fossa and external iliac nodes
[1]
• No difference in outcome was reported
between extended and super-extended
LND in the two high-volume-centre
studies identified [2]
1.Simone, G., et al. J Urol, 2013. 20: 390.
2. Liu JJ J Urol 2011 May;185
58. Multimodality bladder-preserving
treatment
• Combines TURBT, chemotherapy and
radiation
• Radiosensitising chemotherapy, cisplatin [1] or
mitomycin C plus 5-fluorouracil can be used
[2]
• With MMT 5-year
• CSS 50-82%[1,2]
• OS 36-74%[3,4]
1. Milosevic, M., et al. 2007. 69: 80.
2.James, N.D., et al N Engl J Med. 2012. 366: 1477
3 Hoskin, P.J., et al. J Clin Oncol, 2010. 28: 4912.
4. Kaufman, D.S., et al. Urology, 2009. 73: 833.
59. Adjuvant chemotherapy
Adjuvant cisplatin-based combination
chemotherapy to patients with pT3/4 and/or pN+
disease if no neoadjuvant chemotherapy has been
given[1,2,3]
1.Cohen, S.M., et al..Oncologist, 2006. 11: 630
2. Sylvester, R., et al. Ann Oncol, 2000. 11: 851.
3. David, K.A., et al.. J Urol, 2007. 178: 451.
61. External Beam Irradiation
• The standard protocol for radical EBRT as well
as combined modality therapy.
• It uses a four field iso-centric technique for
both initial and boost field.
• It consists of shaped anterior , posterior , right
and left lateral fields
• Induction and boost treatment fields will be
discussed further
62. Simulation
1. Instruct patient to void urine
2. Insert Foley's catheter
3. Measure post void residual urine and replace with
equal volume of bladder contrast + Additional
25mL contrast + 15mL of air.
• Contrast defines the inner walls of bladder
• Air aids visualization of anterior bladder on lateral
simulation film
• Contrast amount should not be less than post void
residue
4. AP/PA and Lateral radiographs are taken or CT
simulation is done
63.
64. Induction Field
1. During first phase of treatment, bladder is treated
along with 2 cm margin.
2. If using radiograph , contrast lines only inner
wall hence another 5-10mm is added.
3. In men prostate is included and in women
proximal 2 cm of urethra is included .
4. Limit the amount of small bowel irradiated.
65. Break to evaluate
1. After induction treatment or after a dose of 39-
42Gy, repeat cystoscopy is done .
2. If CR/Ta/Tis then they are advised to continue
boost.
3. If the stage is more than T1 ,then advise
cystectomy.
66. Boost Field
1. Tumor alone with 2 cm margin .
2. Tumor is delineated using information from
bladder map during TURBT/Cystoscopy and
CT/MRI
3. Another alternate is to treat the whole bladder and
exclude the nodal volume
4. If tumor is in trigone or PL walls of bladder only
lateral fields can be used for boost
67. Dose
1. Total dose of 65Gy(1.8-2Gy fractions, 5 days
per week) together with chemo and max
TURBT.
2. 40-45Gy is Induction dose
3. The tumor is then boost to full dose (15-20Gy)
4. In invasive cancer ,if there is complete
response then local recurrence is limited to 15-
18% implying that dose is adequate in
responders
68. Partial bladder treatment
1. Rationale – High dose (upto 80 Gy) can be given if
1/3 of bladder is spared .
2. Indications
• <5cm in size
• Unifocal disease
• Without extensive Tis
• No significant difference between arms
Arms Dose/# 5 yr Local
control
Partial bladder
irradiation
57.5/20 58%
Whole bladder
irradiation
52.5/20 59%
69. Treatment margins in Conformal
radiotherapy
1. CTV to PTV margin , an isotropic 2 cm margin in
all 3 dimensions.
2. As the greatest degree of bladder wall positional
change occurred in cranial direction and least in
antero-inferior direction , limited by pubic
symphysis.
3. Anisotropic margin of 1.6cm anteriorly and
posteriorly , 1.4cm laterally , 3cm superiorly , 1.4cm
inferiorly has been recommended by Graham
4. Daily imaging
5. Fuducial based matching
70. 3D-CRT
Patient position and immobilization
• The patient should be planned and treated in the same position; supine with
arms on their chest. Knee and ankle immobilization should be used to
ensure patient positioning is reproducible.
• The rectum should be empty of flatus and faeces. The use of daily micro-
enemas may be considered.
• Patients will be asked to empty their bladder 15 minutes prior to scan.
• Whilst breathing normally, the patient should have a CT scan performed
with 3–5-mm slice spacing.
• Upper Extent -ischial tuberosities
• Lower Extent -3 cm above the dome of the bladder or bottom of L5
(whichever is higher)
• Reference radio-opaque tattoos should be made at the base of the abdomen
and over each hip.
71. Volume Delineation
• The GTV should integrate information from the staging CT
or MRI as well as the diagnostic TURBT . MRI/CT fusion
may be helpful, where available.
• CTV constitutes the entire bladder
• A standard approach is to define the PTV as the whole
bladder identified by its non-involved outer bladder wall
with a 1.5-cm margin plus extravesical extent of tumour
with a 2-cm margin
• All planning and treatment should be carried out with the
bladder empty to minimize the risk of geographical miss
and to keep the treated volumes as small aspossible.
Patients with significant residual volumes post voiding
should be considered for planning and treatment with a
catheter in situ , although this is likely to increase urinary
toxicity.
75. Altered Fractionation
• In T2-T4 tumors unsuited for cystectomy
Numb
er of
patien
ts
Dose Survival
at 5 yrs
Local
control
Clinical
complete
response
Hyperfractio
nation
84 1 Gy three times a
day to a dose of
84Gy
27% 12% 59%
Conventiona
l
84 2Gy everyday to a
dose of 64Gy
18% 7% 36%
76. Palliative Radiotherapy
• Palliative bladder irradiation is used in the
treatment of bleeding from a primary tumor or
a metastatic lesion to the bladder that cannot
be controlled cystoscopically.
• Symptomatic improvement can be achieved in
60-70% of patients
• Schedules used: 30 Gy in 10 fractions
21 Gy in 3 fractions
77. Brachytherapy
• Indications:
- A solitary transitional cell carcinoma
- Diameter less than 5 cm
- Muscle invasion but with no extension through
the bladder wall
• Contraindications: tumor extending to
perivesical fat and adjacent structures,
multifocal, lymph node involvement.
78. • Initially preoperative EBRT of 3 x 3.5 Gy
fractions for T1 tumors and 20 x 2 Gy for T2
tumors is delivered
• Partial Cystectomy with routine iliac
lymphadenectomy is performed.
• Hollow Nylon tubes are placed
intraoperatively for afterloading with Iridium
sources
79.
80.
81.
82. • Acute postoperative complications like
thromboses, infections, delayed wound healing
and fistula formation were seen in 19.5-30% of
the cases.
• Late complications: 25-39% were reported
In the first year hematuria, stone formation, chronic
cystitis were observed
Symptomatic ulceration or fistula formation needing
treatment or ureter stenosis with hydronephrosis
is rare (1-6%)
Chronic radiocystitis (0.6%)
85. Risk group classification
Risk of recurrence at
1 year
Risk of progression at
1 year
Adjuvant therapy
Low Risk (grade 1
stage Ta disease and a
single grade 1 stage
T1 tumor)
15% 0.2% Not required
Intermediate
Risk(multiple grade 1
stage T1 tumors,
grade 2 stage Ta
disease and a single
grade 2 stage T1
tumor)
38% 5% Required
High Risk(multiple
grade 2 stage T1
61% 17% Required
86. • Ta, G1 have 100 % recurrence rates at 5 yrs , but do not
invade or metastasize – Hence TUR alone maybe sufficient
Tumor Frequency of recurrence
Ta(G2,G3) 20% No indication
T1 (50% are G3) 50% Indication for Adjuvant
therapy
T1 with CIS 80% Indication for Adjuvant
therapy
Progression rate at
12months
Overall survival at 5
yrs
TURBT alone 63%
TURBT 88%
87. Risk group classification
Risk of recurrence at
1 year
Risk of progression at
1 year
Surveillence
Low Risk (grade 1
stage Ta disease and a
single grade 1 stage
T1 tumor)
15% 0.2% 3 months after
resection . If Negative
9 month later , then
annually
Intermediate
Risk(multiple grade 1
stage T1 tumors,
grade 2 stage Ta
disease and a single
grade 2 stage T1
tumor)
38% 5% 3 monthly- for 2yrs
6 monthly for 5 yrs
High Risk(multiple
grade 2 stage T1
61% 17% 3 monthly- for 2yrs
6 monthly for 5 yrs