Carcinoma prostate

Dr kiran pJunior resident radiotherapy

INCIDENCE

• Common in western world• One in six American men will be diagnosed

with prostate cancer during his lifetime• Europe, the annual incidence rates were 214

per 1000 men

DIAGNOSIS STAGING WORK UP

• DRE• PSA • TRUS • getting a histological confirmation of prostate

cancer

DIGITAL RECTAL EXAMINATION

• simple, cost effective method• Positive predictive value from 21% to 53%• Good staging method• sensitivity of 52% and specificity of 80%• MAY UNDER/OVER ESTIMATE

J URO 1999;161:835-9

PROSTATE SPECIFIC ANTIGEN

• The normal PSA are <4 ng/ml• threshold PSA level for detection of cancer is

4.0 ng/ml• BUT 25% will have a normal or low PSA• PSA <10 ng/ml - low risk of peri-prostatic

spread and metastases

PSA

• PSA >20 ng/ml-An increased risk of peri-prostatic spread, seminal vesicle involvement and distant metastases

• GENERAL RULES• PSA >10 ng/ml indicates capsularpenetration

in more than 50% patients • PSA >50 ng/ml – metastatic disease.

PSA

• prostate specific • Not cancer specific• BPH, prostatitis, tuberculosis etc• borderline zone of 4-10ng/ml

FREE TO TOTAL

• < 0.15 -a higher Gleason score ,poorer prognosis

• free to total PSA of <0.1 is most likely• higher percentages with BPH

JAMA 1998;279(19);1542-7

Prostate biopsy

• Extended biopsy is more preferable• cancer detection rate- 40%,• sextant biopsy -20% to 25%

REV UROLOGY 2007 SUMMER,9(3):93-98

BIOPSY

• Sextant biopsies -undersample most and miss many

• Extended biopsies increase detection rates decrease sampling error.

• Initial biopsies should include at least 12 cores from the peripheral zone.

• repeat biopsies - anterior apical biopsies or saturation approaches is recommended.

.REV URO 2007 SUMMER;9(3)::93 98

CT/MRI

• T1&T2-with probability of LN involvement>10%

• T3-T4

• DREsize, location, volume, local extension• TRUS/Endorectal coil MRIlocal extension• CT/ProstaScint Scanpre-op pelvic node

assessment• Bone Scanmets

Bone scan

• MRI superior?• Indication T1+PSA >20 T2+PSA>10 Gleason score >=8 T3&T4

Predictive models in Ca prostate

TREATMENT

• NATURAL HISTORY OF PROSTATE CANCER IS DIFFICULT TO PREDICT

• Men with similar stage ,glisson score,psa can have markedly different outcome

OUTCOME WITH SCREENING

J natl Cancer inst.2009 March 18;101(6)

high grade prostatic intraepithelialneoplasia (PIN)

• Not an indication for treatment

• careful follow-up, early re-biopsy to rule out invasive cancer

• No evidence at the present for early treatment

Invasive prostatic adenocarcinoma

• Localized prostate cancer (T1 – T3a N0)

• Locally advanced disease (T3b-T4 N0)

• Metastatic disease: Any T, N+ or Any T, Any N &distant metastasis (M+)

Localized prostate cancer (T1 – T3a N0)

• Low risk (cT1-T2a and Gleason score 2-6 and PSA< 10)

• Intermediate risk (cT2b-T2c or Gleason score = 7or PSA 10-20)

• • High Risk (cT3a or Gleason score 8-10 or PSA >

20)

LOW RISK

• Very low risk gleason score-2-6 T1c psa<10ng/ml fewer than 3prostate core biopsies positive <=50% cancer in each core psa density-<0.15ng/ml/gm• Low risk

Life expectancy -<5yr-any risk

• If asymptomatic –no further work up or treatment

Very low risk

• Life expectancy -<20yrs-AS• PSA -3MONTHLY• DRE-6MONTHLY• Repeat biopsy-yrly

Low risk

• cT1-T2a and Gleason score 2-6 and PSA< 1

• Life expectancy<10yr,>10yr

Life expectancy

<10 yrs

AS

>10 yrs

AS RADICAL RX

SX RT

EBRT

BRACHY

ACTIVE SURVEILLANCE(AS)

• Most men with good risk prostate cancer have indolent and slow growing disease

• risk posed by cancer can be assessed with some degree of certainty that delayed treatment will be as curative as immediate treatment.

• attempt to avoid over-treatment in the majority of patients

AS

• low-volume, low-grade carcinoma • elderly patients or medical comorbidities with

limited life expectancy comply for• regular follow up

AS

• PSA tests and a digital rectal examination every 3 months for 2 years

• repeat biopsy 6-12 months after the initial diagnosis and yearly when indicated

ASRADICAL RX

• PSA DT of < or = 3 years (based on a minimum of 3 determinations over 6 months) are offered radical intervention.

• re-biopsy score• tumor volume• stage progression • patient preference

urol oncol 2006 jan -feb 24(1) 46-50

AS

• PSA doubling time• re-biopsy score• , tumor volume• stage progression • patient preference.

Outcome

• AS- 85% would remain treatment-free at 5 years

• no patient died from prostate cancer.

solowey etal ..BJU INTRN 2008 JAN;101(2) 165-9

• 65% remained free of treatment at 8 years.

• The prostate cancer specific survival using this approach was 99.3% at 8 years

urol oncol 2006 jan -feb 24(1) 46-50

Radical prostatectomy

• RP -removal of the entire prostate gland between the urethra and the bladder, with resection of both seminal vesicles

• is recommended for the organ confined prostate cancer with life expectancy of >10 years

RP

• complete removal of cancer • accurate pathological staging and allows

better planning for adjuvant therapy.

RP VS AS

j natl cancer inst 2008 aug 20;100(16) 1144-1154

RP VS AS

j natl cancer inst 2008 aug 20;100(16) 1144-1154

RP VS AS

j natl cancer inst 2008 aug 20;100(16) 1144-1154

RP

• Retro pubic• Perineal• Retro pubic-common, enables simultaneous

pelvic lymph node assessment• Robotic assisted-more magnification –reduce

morbidity

RP

• Low risk• Intermediate-risk Prostate Cancer and a life

expectancy of more than 10 years.

• prognosis -excellent when the tmr is confined to the prostate based on pathological examination

Pelvic node dissection

• Cut of-6%

• The sensitivity- 87.9%• specificity- 54%• negative predictive values-97.3%• associated with the 6% cut off

int j radtn oncol biol phys 2012 jun;83(2) 624-9

Pelvic node dissection

• Importance-to determine adjuvant therapy

• Only ePLND

• removal of obturator, external iliac, and hypogastric lymph nodes

int j radtn oncol biol phys 2012 jun;83(2) 624-9

Pelvic node dissection

• No use <10 nodes• 28 nodesnodes

RP in high risk prostate

• no consensus regarding the optimal treatment of men with high-risk localized disease

• discouraged,because of increased risk of positive surgical margins and lymph node metastases and/or distant relapse

NAHT followed by RP

• THEOROTICAL ADVANTAGE

• potentially downstage locally advanced tumors,

• thus making them more amenable achieving negative margins at the time of surgical resection

cochrane database syst rev.2006 octo18;(4):CD006019

• NHT have shown a significant decrease • in positive surgical margins• and lymph node metastasis, • reductions in tumor size • PSA levels

BUT

• NO DIFFERENCE IN DESEASE FREE SURVIVAL• OVERALL SURVIVAL

NAHT followed by RP

• Cochrane review(level of evidence: 1a)

• NAHT before RP does not provide a significant OS advantage over prostatectomy alone

• NAHT before RP does not provide a significant advantage in disease-free survival over prostatectomy alone

cochrane database syst rev.2006 octo18;(4):CD006019

NAHT before RP does substantially improve

• local pathological variables such as organ-confined rates, pathological down staging, positive surgical margins and rate of lymph node involvement.

• NHT prior to prostatectomy is not recommended

COMPLICATIONS OF RP

• mortality rate is 0-1.5%

• urinary fistulas are seen in 1.2-4% of patients

• urinary incontinence persists after one year in 7.7%

• Less complications procedure is performed in a high-volume hospital and by a surgeon

• Erectile dysfunction used to occur in nearly all patients

• nerve-sparing techniques can be applied in early-stage disease

• nerve-sparing RP may have a higher chance of local disease recurrence

RDIOTHERAPY

• No direct RCT between surgery vs RT• Retrospective analysis not much of difference

between both modalities

• radical&palliative

• EBRT• EBRT+BT• BT

CONVENTIONAL EBRT

• Patient supine

• Hands over chest

• Immobilization –

• Four field BOX

• Shrinking field technique

• Superior border-L4-L5-to include the common iliac nodes

• Inferior border-1.5 -2cm below the junction of prostatic and membranous urethra –just below the ischial tuberosities

• Lateral margin-1-2 c from the lateral boney pelvis

• Anterior -pubic symphysis

• Posterior margin-S2-S3 junction to include the pelvic and presacral nodes+sparing posterior rectal wall

• Anterior -pubic symphysis

• Posterior margin-S2-S3 junction to include the pelvic and presacral nodes+sparing posterior rectal wall

Boost field

• Cystogram –• supine ,catheter insitu-20 ml of contrast+10ml

of air introduced into bladder• 20 ml of contrast into catheter balloon which

is pulled down to bladder base• AP film in simulator-2cm margin is given with

bladder base as center

DOSE

• Conventional-60 to 70gy/1.8-2gy per fraction

DOSE escalation

• Depends on risk• Low risk-a minimum dose of 70 - 74 Gy is

(external with / without brachytherapy)• Ideal-75-79 GY for low risk• Intermediate &high risk-can extent to 81GY.• (level of evidence : 2)

Intermediate risk

• minimum dose of 74 - 76 Gy is recommended for Int risk group(level of evidence : 2)

High risk

• minimum dose of 74 - 80 Gy is recommended for high risk group(level of evidence : 1a)

• meta-analysis of data obtained exclusively fromRCT’s provides evidence that high dose RT is superior to conventional dose RT in terms of preventing biochemical failure in low-, intermediate-, and high-risk

• high dose RT should be offered to all patients regardless of their risk status

int j Radiat Oncol Biol phys.2009 aug1;74(5):1405-18.

DOSE

• 70 and 80 Gy• Significant increase in the 5-year Biochemical

control rate• low-14% • Intermediate- 17.8%• high-risk-19.2% (Level of evidence :1a)

Prophylactic WPRT• RCT -NO benefit from prophylactic irradiation of the pelvic lymph

nodes in high-risk cases (46-50 Gy).

• risk of LN involvement of 15% to 35% -benefited the most from pelvic nodal RT

• less than 15% or

• more than 35%(higher distant metastasis) did not benefit from pelvicnodal RT

• (level of evidence 2b )

WPRT VS PORT

int j Radiat Oncol Biol Phys.2007.NOVEMBER 1;69(3)646-655

INTERSTETIAL BRACHYTHERAPY

• Permanent• Temporary

• Permanent-Ideal-are those with favorable risk prognostic features who have a high likelihood of organ-confined disease

• PSA levels 10ng/mL or less,

• Gleason scores less than 6-7,

• Clinical stages T1b- T2a

• prostate volume of < 50 cm3 and

• good International Prostatic Symptom Score (IPSS)

International Prostate Symptom Score

• International Prostate Symptom Score (IPSS) is an 8 question (7 symptom questions + 1 quality of life question)

IPSS result of 7 symptoms questions

Score Correlation[1]

0-7 Mildly symptomatic

8-19 Moderately symptomatic

20-35 Severely symptomatic

• not recommended for patients with locally advanced disease

EBRT+BRACHY

• intermediate and highrisk patients with localized prostate cancer

• I 125 seeds or Pd 103• EBRT-45 to 50 Gy - conventional / conformal

• low-dose-rate boost -dose 90-100 Gy for 103Pd implants

• 110 Gy for 125I implants

• HDR brachytherapy-trans-perineal placement of after-loading catheters in the prostate under ultrasound guidance.

• CT-based treatment planning• DOSE-4 to 6 Gy –each 24 to 36 hours using192Ir. Followed by EBRTdose of 45 to 50.4 Gy using conventional fractionation

HDR-advantage

• more easily optimize the delivery of RT to the prostate

• reducing the potential for under-dosage ,• reduces radiation exposure • radiobiologically more efficacious in terms of

tumor cell kill for patients with increased tumor bulk or adverse prognostic features.

.

EBRT vs EBRT+LDR vs EBRT+HDR

• EBRT+HDR - give better biochemical control& better overall survival as compared to external beam radiotherapy alone.

• biochemical control rates with LDR was comparable to that of HDR

• overall survival was better with HDR brachytherapy.

• (Level of evidence: 1a)

RADIOTHERAPY&ONCOLOGY(2009);VOLUME:93,ISSUE 2

POST OP RT

• Indication-positive surgical margins, seminal vesicle invasion and/or extracapsular extension

• recommended doses are 60-64Gy• (level of evidence:1)

radiother oncol.2008 jul88(1)

evidence

POST OP RT

• Immediate vs late• Immediate postoperative radiotherapy -well

tolerated, with• grade 3-4 urinary toxicity of less than 3.5%

without significant differences regarding the rate of incontinence and/or stricture of anastomosis.

• immediate post-operative radiotherapy -better

• five-year clinical or biological survival:• Immediate- 72.2% vs 51.8% (p < 0.0001)

Androgen deprivation therapy

• Clinically localized disease• Neo adjuvant/concomitant/adjuvant-prolongs

survival in radiation managed patients• When ever used cab should use• Indicated in all high risk + locally advanced +

metastatic disease(2-3 yrs)• Short term androgen deprivation in

intermediate risk (4-6 months)

Adverse effect

• Hot flushes • vasomotor instability• Osteoporosis• Obesity insulin resistance• Greater risk of DM, cardiac diseses

locally advance Prostate Cancer(T3b-T4)

• Neo-adjuvant hormone therapy followed by Radical radiation therapy

• Neo-adjuvant hormone therapy followed by Radical prostatectomy

• Hormonal therapy alone

• Watchful waiting - Elderly patients with limited life expectancy

Treatment of Metastatic Disease

• a) Metastatic nodal (N+) disease• b) Distant Metastatic (M+) disease

Metastatic nodal (N+) disease

Treatment Options include: Hormanet therapy Watchful waiting (WW) Surgery Radiation therapy

HORMONE THERAPY

• mainstay of treatment -of long term hormonal therapy

• local therapy- with radiation therapy preferred

Watchful waiting (WW)

• Elderly patients

Surgery

• Lymph node-positive (N+) disease will mostly be followed by systemic disease progression, and all patients with significant N+ disease will ultimately fail treatment.

RADIATION THERAPY

• INDICATION• pelvic lymph node involvement lower than the

iliac regional nodes,• younger than 80 years old • WHO performance status 0-1 and• no severe co-morbidity

• External beam irradiation plus immediate long-term hormonal manipulation-

• (level of evidence : 1b)

DISTANT METASTATIC DISEASE

• Immediate hormone therapy is indicated

• should be offered early to all patients

• BOTH symptomatic and asymptomatic

• (level of evidence:1).

• Response rate-85%• median duration of response of 18 months• median survival of 36 months.• median survival of 36 months• ranges between 28 and 53 months• >10 yrs-only 7%

osseous metastases:

• Surgical intervention-Decompressive surgery in spinal cord compression

• Pathological fracture of weight bearing bones in patients with reasonable life-expectancy

RADIATION THERAPY

• EBRT-for painful or unstable skeletal metastases

• DOSE -800 CGY –SINGLE fraction(Level of evidence: 1b)

• Fractionated RT for bone metastases may be considered-spinal cord compression

30/10 vs 800 single

• acute toxicity was more frequent in the 30-Gy arm

30/10-17% 8-Gy arm 10%Late toxicity-rare in both arms & is same 4%-in both arms

J Natl Cancer Inst.2005 jun 1;97(11)

• overall response• 8-Gy Complete -15% partial response - 50%• 30-Gy Complete- 18% Partial- 48% in the arm

Hemibody radiation

• Multiple symptomatic skeletal metastases• 8 Gy for UHBI& 6 Gy for LHBI

Systemic radionuclide therapy

• Strontium89 • Samarium153• improve bone pains in upto 70% patients

Bisphosphanates

• reduce bone pains • skeletal-related events including fractures• inhibit osteoclast-mediated bone resorption and osteoclast precursors effective-HRPCresponse rate of 70-80%

• reduce pain • provide total pain relief• Effect more important- HRPC• Decreases pathological fractures-10%• skeletal related events-11%• time to first skeletal-related event-prolonged• Toxicity-osteo necrosis jaw necrosis,

HORMONAL THERAPY

• Androgen deprivation- suppressing the secretion of testicular androgens –

surgical medical castration

• Anti-androgens -inhibiting the action of the circulating androgens at the level of their receptor in prostate cells

• When two modalities can be combined- complete (or maximal or total) androgen blockade (CAB).

b/l orchidectomy

• Simple&quickest way to achieve a castration level

• Usually- obtained in less than 12 hours• main drawback- negative psychological effect

Long acting LHRH agonist

• Currently the predominant forms of ADT• Synthetic analogues of LHRH• interfere with the hypothalamic-pituitary-

gonadal axis• initially stimulate pituitary LHRH receptors

• inducing a transient rise in LH and FSH release

• consequently elevate testosterone • testosterone surge or ‘flare up’ phenomenon• begins 2-3 days of first injection and lasts

through first week• comparable efficacy to orchiectomy (level of

evidence: 1a)• Currently standard of care in hormonal

therapy

• detrimental effects- flare phenomenon increased bone pain, acute bladder outlet obstruction,obstructive renal failure, spinal cord compression

• fatal cardiovascular events due to hyper-coagulation status

Anti androgens

• compete with testosterone and DHT for binding sites on their receptors in the prostate cell nucleus

• promoting apoptosis and inhibiting Prostate Cancer growth

• Steroidal& non steroidal• Both competes with androgen at receptor but

• steroidal anti-androgens additional progestational properties with central inhibition of the pituitary gland

• M1 patients, an improvement in OS with castration

• M0 patients no significant difference in OS

Intermittent Vs Continuous Androgen Deprivation

• long-term CAB- which stimulates prostate cell apoptosis

• fails to eliminate the entire malignant cell population

• after a variable period-tumor invariably relapse- averaging 24 months

• Androgenindependent state of growth

Androgen-independent progression

• begin early after the administration of HT• Coinciding with the cessation of androgen-

induced differentiation of stem cells• cyclical ADT can make a clone –still

sussceptable to ADT

Biochemical relapse after local therapy

• RP- undetectable within 3 weeks• Persistently elevated PSA- PSA-producing

tissue remains in the body• rapidly increasing PSA level- distant

metastases(first 2yrs)• slowly increasing-local reccurrence• two consecutive values of 0.2 ng/mL or

greater

• RARELY-undifferentiated tumors- local treatment failure and distant metastases-undetectable PSA levels

• 50%-50%-local failure-distant mets

RADIATION THERAPY

• PSA nadir of less than 0.5 ng/mL• Interval for nadir varying some times very

long-3yrs• biochemical failure-Rising PSA->2ng/ml-above

nadir psa• Three consecutive PSA rises• late and slowly rising PSA is a sign of local

failure

LOCAL RECCURRENCE

• prostatic biopsy demonstrating malignant cells18 months or longer after initial radiotherapy

• PLUS associated psa elvation• No mets detected-MRI,CT,BONE SCAN

HRPC-hormone refractory prostate cancer

• Serum castration levels of testosterone (< 50 ng/dL, or < 1.7 nmol/L)

• 3 consecutive rises of PSA, 1 week apart, resulting in two 50% increases over the nadir, with a PSA > 2 ng/mL

• PSA progression, despite secondary hormonal manipulations

management

• anti-androgen withdrawal• addition of ant androgens• anti-androgen replacement• estrogenic compounds,• adrenolytic agents

• 1/3 will respond to anti androgen withdrawal > 50% PSA decrease in 4 moths

• flutamide was replaced by bicalutamide and vice versa

• Aminoglutethimide, ketoconazole and corticosteroids-also have some role with –anti androgen therapy

• DES-20-80% response rate but more complication

Cytotoxic chemotherapy

• Docetaxel containing CT-progress within 6 to8 months

• So toxicity should balanced with benefit

ROLE OF RT

• Conventional-four field box f/b boost to prostate and seminal vessicle-but rectal and bladder toxicities more

• 3 Dimensional Conformal techniques.• Multi-leaf collimators to “shape” fields• Reduced toxicities but no selective “sparing”

possible

Intensity modulated Radiotherapy

• Multiple non-coplanar beams ->• Inverse planning -> different • intensities -> highly conformal dose• distribution with normal tissue• sparing.

Image Guided RT (IGRT)

• EPID, USG with Fiducial markers etc• Recently , CBCT-kV or MV , • Tomotherapy ,Cyberknife etc

Conformal RT

• 3DCRTIMRT boost /IMRT alone

Respiratory motion

• Superior –inferior-2.9+/-1.7• Anterior-posterior-1.6+/-1.1

• ABS :monotherapy :T1c-T2a, GS<7,PSA≤10• + EBRT : T≥2c, GS ≥7, PSA >10• C/I :metastases, gross seminal vesicle J• involvement, large T3 disease.

Permanent seed implants

• IODINE(I 125) & PALLADIUM (Pd 103 )• Preplanned Transperineal • Implantation (Seattle Method)• TRUS guided• Intra-operative Planning Techniques• TRUS guided needle placement f/b intra-op • CT/MRI >Contouring > optimization > seeds.• LDR DOSE• Monotherapy : I-125 144 Gy; Pd-103 125 Gy.• After 40–50 Gy EBRT: I-125 110 Gy; Pd-103 90 Gy.

HDR-BRACHY

• After loading catheters under trus guidence• I192• After EBRT-9.5 GY-two fractions• Monotherapy-9.5GY bid X 2 days 10.5 gy X 3

LDR BRACHYTHERAPYHDR BRACHYTHERAPY

RT in Combined Approach• Surgery + Adjuvant RT (Ind: ECE ,Margin+ or SVI)• SWOG 8794 : 431pts: Observation Vs. RT 60- 64Gy• 15yr OS:38->46%,bF:77->55%,LF:22%->8%.• QOL worse initially , later better.

• EORTC 22911 : 1005 pts : Obsn Vs. RT 60Gy• 5yr OS: No diff,bPFS:5374%,LRF: 15 5%,• No significant diff in toxicities-02

• Salvage RT after RP: beneficial if PSA-DT< 6-10month• LN-,lower pre-RT PSA,GS<8.• Increases Prostate cancer Specific Survival.•

• RT + short term HT (STHT)• 3-6 months of HT improves bPFS by 15-25% and CSS by 3-

8% Vs. No HT.• TTROG(Denha et al.2005),Crook et al.( 2004),RTOG

9413, Lavadiere et al• D’Amico et al and RTOG 8610 trials showed 10-15% OS

benefit.• RT + long term HT• For high risk patients, HT for >2-3 yrs improves OS by

10-15% ,CSS by 5% and DFS by 20-30% Vs. no HT or 4-6 month HT.

• (RTOG 8531,EORTC 22863,RTOG 9202,EORTC 22961)•

• PSA & DRE :every 6 months for 5yrs,then annually.• PSA FAILURE• Phoenix definition : current ASTRO/RTOG• EBRT with/without short term HT• - a rise by ≥2 ng/mL above the nadir PSA.

• PSA nadir : After RP : 3 weeks• EBRT:2-3yrs• Brachytherapy : 3-4 yrs• PSA bounce : transient PSA rises(<2ng/ml)• EBRT & Brachytherapy:20%• (9-14mnths)

Treatment related toxicities

• Late toxicities :• Urinary stricture : <4 %• If prior TURP/prostatectomy • 4-9 % stricture/stress incontinence• Post treatment Impotence :• Brachy (24%),EBRT + Brachy (40%),EBRT alone(45%), Nerve Sparing

RP(66%), Non Nerve sparing RP (75%).• Robinson JW et al. Int J Radiat Oncol Biol Phys

2002;54:1063-1068.• Perioperative complications : Obstructive symptoms (10%), Urinary

incontinence (1-3%),rectal injury (1-5%)

• Second cancers :(SEER, Tward 2008) No significant difference ,• RP Vs. EBRT

Future directions

• Dose escalation • 70.2 Gy Vs. 79.2Gy :T1b-T2b,High dose less likely to have

local failure , HR=.57, 10yr BF: 32.4% Vs. 16% in high dose. Zietman et al JCO 2010 Mar 1;28(7):1106-11

• Proton Therapy

• Molecular agents & New chemotherapy agents

• Immunotherapy Sipuleucel-T-relative reduction of 22% in the risk of death NEJM 2010 Jul 29;363(5):411-22

summery

• Role of Radiotherapy in Ca Prostate is time-tested.

• All stages and risk groups are benefitted with RT.

• In future , Radiobiology research , Molecular Pathways and Technological innovations are the keys to enhance the treatment.

Thank you