Treatment of Advanced Disease (Stage IV)

8/7/2019 Treatment of Advanced Disease (Stage IV)

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PostgastrectomyPostgastrectomy ProblemsProblems



Dumping SyndromeDumping Syndrome

y Dumping is a phenomenon caused by the

destruction or bypass of the pyloric

sphincter.

y Clinically significant dumping occurs in 5

to 10% of patients after pyloroplasty,

pyloromyotomy, or distal gastrectomy,

and consists of a constellation of postprandial symptoms



y early dumping occurs about 15 to 30

minutes after a meal, the patient becomes

diaphoretic, weak, light-headed, and

tachycardic. These symptoms may beameliorated by recumbence or saline

infusion. Crampy abdominal pain is not

uncommon and diarrhea often follows.y thought to be the result of the abrupt

delivery of a hyperosmolar load into the

small bowel.



y late dumping which usually occurs later (2

to 3 hours following a meal), and is

relieved by the administration of sugar.

y A variety of hormonal aberrations have

been observed in early dumping,

including increased VIP, CCK,

neurotensin, peripheral hormone peptideYY, renin-angiotensin-aldosterone, and

decreased atrial natriuretic peptide. Late

dumping is associated with hypoglycemia

and h erinsulinemia.



medical therapymedical therapy

y consists of dietary management andsomatostatin analogue (octreotide).

y avoids liquids during meals.

y Avoid Hyperosmolar liquids (e.g., milk shakes)

y dietary fiber compounds at mealtime

y dietary manipulation fails, the patient is

started on octreotide, 100 g subcutaneouslytwice daily. This can be increased up to 500g twice daily if necessary.

y The -glucosidase inhibitor acarbose may beparticularly helpful in ameliorating the



SurgicalSurgical MxMx

yMost patients improve with time (months

and even years), dietary management, and

medication.

y takedown of gastrojejunostomy,

y interposition of a 10-cm reversed

intestinal segment between the stomach

and duodenum,y conversion of Billroth II to Billroth I

anastomosis, and

y conversion to Roux-en-Y anastomosis



DiarrheaDiarrhea

y Possible mechanisms include intestinal

dysmotility and accelerated transit, bile

acid malabsorption, rapid gastric

emptying, and bacterial overgrowth.

y The latter problem is facilitated by

decreased gastric acid secretion and (even

small) blind loops. Although bacterialovergrowth can be confirmed with the

hydrogen breath test, a simpler test is an

empirical trial of oral antibiotics.

y



Gastric stasisGastric stasis

y Gastric stasis following surgery on thestomach may be due to a problem withgastric motor function or be caused by anobstruction.

y The gastric motility abnormality may havebeen pre-existing and unrecognized by theoperating surgeon.

y Alternatively, it may be secondary to

deliberate or unintentional vagotomy, orresection of the dominant gastric pacemaker.

y An obstruction may be mechanical (e.g.,anastomotic stricture, efferent limb kink

from adhesions or constricting mesocolon, ora proximal small-bowel obstruction) or



y Once mechanical obstruction has been

ruled out, medical treatment is successful

in most cases of motor dysfunction

following previous gastric surgery.

y This consists of dietary modification and

promotility agents.

y Intermittent oral antibiotic therapy may behelpful in treating bacterial overgrowth,

with its attendant symptoms of bloating,

flatulence, and diarrhea.



y Billroth II anastomosis with Braun

enteroenterostomy may be preferable to

Roux-en-Y reconstruction. This latter

option may be associated with persistentemptying problems that will subsequently

require near-total or total gastrectomy, a

nutritionally unattractive option.y Gastroparesis following subtotal gastric

resection is best treated with near-total

(95%) or total gastric resection and Roux-

en-Y reconstruction. If total astrectom



Bile Reflux GastritisBile Reflux Gastritis

yMost patients who have undergoneablation or resection of the pylorus havebile in the stomach on endoscopic

examination, along with some degree of gross or microscopic gastricinflammation.

y it is generally accepted that a small subset

of patients have bile reflux gastritis, andpresent with nausea, bilious vomiting, andepigastric pain, and quantitative evidenceof excess enterogastric reflux.

y Curiousl , s m toms often develo



y differential diagnosis includes afferent or

efferent loop obstruction, gastric stasis,

and small-bowel obstruction.

y Plain abdominal x-rays, upper endoscopy,

upper GI series, abdominal CT scan, and

gastric emptying scans are helpful in

evaluating these possibilities.y Typically, enterogastric reflux is greatest

after Billroth II gastrectomy or

gastrojejunostomy, and least after



y Bile reflux gastritis after distal gastric

resection may be treated by one of the

following options:

1. Roux-en-Y gastrojejunostomy;

2. interposition of a 40-cm isoperistaltic

jejunal loop between the gastric remnant

and the duodenum (Henley loop); or3. Billroth II gastrojejunostomy with Braun

enteroenterostomy.



Roux SyndromeRoux Syndrome

y A subset of patients who have had distalgastrectomy and Roux-en-Ygastrojejunostomy will have great difficultywith gastric emptying in the absence of

mechanical obstruction.y These patients present with vomiting,

epigastric pain, and weight loss. This clinicalscenario has been labeled the Roux

syndrome.

y Endoscopy may show bezoar formation,dilation of the gastric remnant, and/ordilation of the Roux limb.

y An upper GI series confirms these findingsand may show delayed gastric emptying.



yMedical treatment consists of promotilityagents.

y Surgical treatment consists of paring

down the gastric remnant. If gastricmotility is severely disordered, 95%gastrectomy should be done.

y The Roux limb should be resected if it is

dilated and flaccid, unless doing so putsthe patient at risk for short bowelproblems. GI continuity may be re-established with another Roux, a BillrothII with Braun enteroenterostom , or an



GallstonesGallstones

y is thought to be secondary to vagaldenervation of the gallbladder with attendantgallbladder dysmotility.

y

Although prophylactic cholecystectomy isnot justified with most gastric surgery, itshould be considered if the gallbladderappears abnormal, especially if subsequent

cholecystectomy is likely to be difficult.y If preoperative evaluation reveals sludge or

gallstones, or if intraoperative evaluationreveals stones, cholecystectomy should be

done if it appears straightforward and the



Weight LossWeight Loss

y The causes of weight loss after gastricsurgery generally fall into one of twocategories: altered dietary intake or

malabsorption.y If a stool stain for fecal fat is negative, it

is likely that decreased caloric intake isthe cause.

y small stomach syndrome, postoperativegastroparesis, or self-imposed dietarymodification because of dumping and/ordiarrhea.

y



AnemiaAnemia

y Iron absorption takes place primarily in

the proximal GI tract, and is facilitated by

an acidic environment.

y Intrinsic factor, essential for the enteric

absorption of vitamin B12, is made by the

parietal cells of the stomach. Vitamin B12

bioavailability also is facilitated by anacidic environment.

y Pt should be monitored with periodic

determination of hematocrit, red blood



Bone DiseaseBone Disease

y Calcium absorption occurs primarily in theduodenum, which is bypassed withgastrojejunostomy.

y Fat malabsorption may occur because of

blind loop syndrome and bacterialovergrowth, or because of inefficient mixingof food and digestive enzymes. This cansignificantly affect the absorption of vitamin

D, a fat-soluble vitamin.y The problems usually manifest as pain

and/or fractures years after the indexoperation.

y Musculoskeletal symptoms should prompt astudy of bone density.



Treatment of Advanced DiseaseTreatment of Advanced Disease

(Stage IV)(Stage IV)



Palliative SystemicPalliative Systemic

ChemotherapyChemotherapy



Chemotherapy versus BestChemotherapy versus Best

Supportive CareSupportive Care

Regimen No. of Patients Median Survival (mo)

BSC 10 3

FEMTX 17 12

BSC 19 3

ETOPLF 10 10



SingleAgent ChemotherapySingleAgent Chemotherapy

FLUORINATED PYRIMIDINES

5-fluorouracil 21

UFT 28

S1 49 JCOG 9912Capecitabine 26 Korean trial

HEAVY METALS

Cisplatin 19

TAXANES

Paclitaxel 17

Docetaxel 19

CAMPTOTHECANS

Irinotecan hydrochloride 23



COMBINATIONCOMBINATION

CHEMOTHERAPYCHEMOTHERAPY� A meta-analysis that included trials

performed in patients with advanced

gastric cancer (predominantly using older

combination regimens) concluded thatfirst-line combination therapy was

associated with a modest but statistically

significant survival benefit whencompared to single agent therapy.

� The hazard ratio for death was 0.83 in



OlderOlder cisplatincisplatin--based regimensbased regimens

Study Drug

Dose

(mg/mL

Schedul

e (days)

No. of

PatientsRR (%)

Median

TTP/PF

S (mo)

Med

Survival

(mo)

2 Y

Survival

(%)

EORTC

(201)

C

F

100

1,000

1

1-5

127 20 4.1 7.2 ~10

COG (199)

CF

20800

1-51-5

105 36 7.3 3.9 7

Dank et

al. (202)

C

F

100

1,000

1

1-5

163 26 4.2 8.7 ~10

TAX325(200) CF 1001,000 11-5 224 25 3.7 8.6 9

REAL-2

(212)

E

C

F

50

60

200

1

1

Daily

289 41 6.2 9.9 ~15



SPIRITS trialSPIRITS trial

y significant benefit for combined S1 plus

cisplatin over S1 alone in terms of both

response rate (54 versus 31 percent) and

median survival (13 versus 11 months, p =0.04) in an Asian population.

y Rates of grade 3 or 4 neutropenia (40versus 11 percent), anemia (26 versus 4

percent), nausea (11 versus 1 percent),

and anorexia (30 versus 6 percent) were



FLAGS trialFLAGS trial

y which randomly assigned 1053 patients tocisplatin plus either 5-FU or S-1.

y Median overall survival (the primary

endpoint) was not significantly inferior withcisplatin/S-1 as compared to cisplatin/5-FU(8.6 versus 7.9 months) .

y Furthermore, cisplatin/S1 had a more

favorable side effect profile than cisplatin/5-FU (grade 3 or 4 neutropenia in 32 versus 64percent, stomatitis in 1 versus 14 percent,and hypokalemia in 4 versus 11 percent), and

fewer treatment-related deaths (2.5 versus



ECF and the REAL trialECF and the REAL trial

y The REAL trial was a landmark large

randomized trial reported in 2008 that

compared four different chemotherapy

regimens in 1002 patients with advancedgastric cancer.



ECF

Epirubicin 50 mg/m2 IV 1 Every 3 weeks

Cisplatin 60 mg/m2 IV 1

PVI 5-FU 200 mg/m2/Db 1

EOF


Oxaliplatin 130 mg/m2 IV 1

PVI 5-FU 200 mg/m2/Db 1

ECX


Cisplatin 60 mg/m2 IV 1

Capecitabine 625 mg/m2

/BD 1

EOX


Oxaliplatin 130 mg/m2 IV 1

Capecitabine 625 mg/m

2 BD1



ResultsResults

y the trial showed that outcomes werecomparable when capecitabine wassubstituted for infusional 5-FU in the ECFregimen.

y They also showed that outcomes werecomparable when oxaliplatin was substitutedfor cisplatin in the ECF regimen.

y

However, when the four groups wereconsidered separately, median survival inpatients treated with EOX was modestlylonger when compared to ECF (median 11.2

versus 9.9 months, hazard ratio 0.80, 95% CI



TaxaneTaxane based regimenbased regimen

DCFVan Cutsem, E;

2006

Docetaxel 75 mg/

m2 day 1

21 days

Cisplatin: 75 mg/m2

day 1

5-FU: 750mg/m2/day

continuous inf usion,days 1 through 5

Modified DCF Kelsen,D; 2009

Docetaxel: 40 mg/m2

day 1

14 days

LV: 400 mg/m2 day 1

5-FU: 400 mg/m2 IVbolus then 1000

mg/m2 per day, days

1 and 2 by IV

continuous inf usion

Cisplatin: 40 mg/m2

day 3



TAXTAX--325 trial325 trial

y Compared DCF (75/75/750) v/s

CF(100/1000)

y The group receiving docetaxel did

significantly better in terms of responserates (37 versus 25 percent), time to tumor

progression (TTP, 5.6 versus 3.7 months)

and two-year survival (18 versus 9percent).

y Although the incidence of grade 3 or 4

diarrhea (20 versus 8 percent) and



OxaliplatinOxaliplatin combinationscombinations

y A variety of different regimens have been

studied in phase II trials (FOLFOX, EOF,

XELOX [CAPOX]), all of which are

associated with response rates in the rangeof 40 to 67 percent, with median survival

durations between 8 and 15 months



FLO v/s FLPFLO v/s FLP

y a phase III trial comparing the FLO regimen(infusional 5-FU 2600 mg/m2 over 24 hours,leucovorin 200 mg/m2, and oxaliplatin 85 mg/m2,all drugs cycled every 14 days) versus FLP (5-FU

2000 mg/m2 over 24 hours plus leucovorin 200mg/m2 weekly and cisplatin 50 mg/m2 every 14days) in 220 patients with metastaticgastroesophageal adenocarcinoma.

y

There were no statistically significant differencesbetween the two arms in terms of median PFS (theprimary endpoint, 5.7 versus 3.9 months),response rate (35 versus 25 percent), or mediansurvival (10.7 versus 8.8 months).

y FLO was associated with significantly less nausea



BiologicAgentsBiologicAgents



TrastuzumabTrastuzumab

y Approx. 25% of the gastric cancer

overexpress Her2-type 2 EGFR.

y Her2 positivity more common in intestinal

type than diffuse type,(32 v/s 6%).



ToGAToGA trialtrial

y which compared standard chemotherapy (sixcourses of infusional 5-FU or capecitabine pluscisplatin) with and without trastuzumab (8 mg/kgloading dose, then 6 mg/kg every three weeksuntil disease progression) .

y The objective response rate was significantlyhigher with trastuzumab (47 versus 35 percent).

y At a median follow-up of 17.1 to 18.6 months,median overall survival (the primary endpoint)

was significantly better with trastuzumab (13.8versus 11.1 months). The

y toxicities in the two arms were comparable,except that a higher number of trastuzumab-treated patients had grade 3 or 4 diarrhea (9 versus

4 percent) and an asymptomatic decrease in left



BevacizumabBevacizumab

y In the global phase III AVAGAST trial,

in which 774 patients with previously

untreated locally advanced unresectable or

metastatic (98 percent) gastric or GEJcancer were randomly assigned to

capecitabine (1000 mg/m2 twice daily for

14 of every 21 days) plus cisplatin (80mg/m2 on day 1) with either bevacizumab

(7.5 mg/kg day 1) or placebo . Cycles

were repeated every three weeks for a

maximum of six cycles of cisplatin;



y In a preliminary report presented at the 2010ASCO meeting, there was no significantbenefit from bevacizumab in median overallsurvival (the primary endpoint, 12.1 versus

10.1 months, HR 0.87, 95% CI 0.73 to 1.03).y However, the use of bevacizumab

significantly improved both objectiveresponse rate (46 versus 37 percent) and

median progression-free survival (6.7 versus5.3 months, HR 0.80, 95% CI 0.68 to 0.93]).

y The incidence of venous and arterialthrombosis did not differ between the twogroups and although rates of hypertension

and bleeding were slightly higher, most of



OtherAgentsOtherAgents

y Cetuximab

y Gefitinib

y Erlotinib

y Sunitinib and

y sorafenib



SUMMARYAND SUMMARYAND

RECOMMENDATIONSRECOMMENDATIONSy First-line chemotherapy

y Despite a large number of randomized trials,there is no consensus as to the best agent or

regimen. In general, combinationchemotherapy regimens provide higherresponse rates than do single agents, but thistranslates into only modestly longerdurations of disease control and survival thatare measured in weeks to a few months.

y In randomized trials, the ECF or DCFcombinations have emerged as standard

regimens for first-line treatment. A major



y the addition of trastuzumab to

chemotherapy in patients with HER2-

positive tumors (as defined by 3+

immunohistochemical staining or FISHpositivity), as long as they do not have a

contraindication to trastuzumab (Grade

2B).y For elderly patients or those with a poor

performance status, we suggest

leucovorin-modulated 5-FU alone or

sin le a ent ca ecitabine Grade 2B .



y Response is assessed using a combination

of interval radiographic evaluation

(typically every two to three cycles),

serum tumor markers such ascarcinoembryonic antigen (CEA) (if

elevated at baseline), and clinical status of

the patient. Radiographic tumor responseis usually quantified using RECIST

(Response Evaluation Criteria In Solid

Tumors).

y While ersistentl risin levels of a serum



Second line chemotherapySecond line chemotherapy

y In general, clinical trials assessing the efficacy of avariety of second-line chemotherapy regimens afterfailure of the first-line regimen have shown thatresponse rates are lower than they are in previouslyuntreated patients, and toxicity rates tend to be higher.

y The criteria to select patients for second-linechemotherapy have not been established. In onestudy, five factors were identified that wereindependently associated with poor survival:performance status 2, hemoglobin 11.5 g/dL, serum

carcinoembryonic antigen (CEA) level >50 ng/mL,three or more metastatic sites, and time to progression6 months after the first-line regimen .

y A prognostic index was developed which dividedpatients into low- (no risk factors), intermediate- (oneor two risk factors) or high-risk (three or more risk factors) groups with different median survival



y Data from the REAL-2 trial suggest thatoutcomes are comparable if capecitabine issubstituted for infusional 5-FU, and whenoxaliplatin is substituted for cisplatin in theECF regimen. When both oxaliplatin andcapecitabine are substituted in the ECFregimen, outcomes may be better than withECF.

y While the use of capecitabine allows patientsto avoid infusion pumps and a central venouscatheter, the costs of capecitabine andoxaliplatin are significantly higher than with5 FU and cis latin and toxicit is not

Treatment of Advanced Disease (Stage IV)

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