A Study of Surgical Management of Intestinal Obstruction

A CLINICAL STUDY OF GASTRIC OUTLET OBSTRUCTION IN ADULTS

Synopsis of the Dissertation

Submitted toRAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA

In partial fulfillment of the regulations for the Award of Degree ofMASTER OF SURGERY-GENERAL SURGERY

Submitted by

Dr. M.S. SUSHRUTA, M.B.B.S.

Post Graduate in General Surgery

Under the guidance of

Dr. ABINASH HAZARIKA

MB.B.S., M.S.,

ASSOCIATE PROFESSOR

Department of General Surgery

SAH & R.C., B.G.NAGARA.

SRI ADICHUNCHANAGIRI INSTITUTE OF MEDICAL SCIENCES,

B.G.NAGARA, NAGAMANGALA TALUK, MANDYA DISTRICT

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1.NAME OF THE CANDIDATE AND ADDRESSDr. M.S. SUSHRUTA NO. 29, NEW KALPATARU BHAVAN,

A.I.M.S., B.G.NAGARA,

NAGAMANGALA TALUK,

MANDYA DISTRICT,

KARNATAKA - 571448.

2.NAME OF THE INSTITUTIONSRI ADICHUNCHANAGIRI INSTITUTE OF MEDICAL SCIENCES, B.G.NAGARA

3.COURSE OF THE STUDY & SUBJECTM.S. IN GENERAL SURGERY

4.DATE OF ADMISSION TO COURSE30th MAY 2011

5.TITLE OF THE TOPICA CLINICAL STUDY OF GASTRIC OUTLET OBSTRUCTION IN ADULTS

6.BRIEF RESUME OF THE INTENDED WORK

6.1 NEED FOR THE STUDY

6.2 REVIEW OF THE LITERATURE

6.3 OBJECTIVES OF THE STUDYAPPENDIX I

APPENDIX IA

APPENDIX IB

APPENDIX IC

7.

MATERIALS AND METHODS

7.1 SOURCE OF DATA

7.2 METHOD OF COLLECTION OF DATA-INCLUDING SAMPLING PROCEDURE IF ANY

7.3 DOES THE STUDY REQUIRE ANY INVESTIGATIONS OR INTERVENTIONS TO BE CONDUCTED ON PATIENTS OR OTHER ANIMALS; IF SO PLEASE DESCRIBE BRIEFLY

7.4 HAS ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR INSTITUTION FOR THE ABOVEAPPENDIX II

APPENDIX IIA

APPENDIX IIB

APPENDIX IIC

APPENDIX IID

8.

LIST OF REFERENCESAPPENDIX III

9.SIGNATURE OF THE CANDIDATE

10.REMARKS OF THE GUIDEThe proposed study is being done to understand the various factors responsible for Gastric Outlet Obstruction in the present scenario and the mode of management of patients with different etiology

11.NAME AND DESIGNATION OF {IN BLOCK LETTERS}

11.1 NAME & DESIGNATION OF GUIDEDr. ABINASH HAZARIKA MBBS, MSASSOCIATE PROFESSOR

DEPARTMENT OF GENERAL SURGERY,

A.I.M.S, B.G.NAGARA

11.2 SIGNATURE OF GUIDE

11.3 CO-GUIDE (IF ANY)No

11.4 HEAD OF DEPARTMENTDr. R. SRINATH MB.B.S., M.S.,

PROFESSOR AND HEAD

DEPARTMENT OF GENERAL SURGERY,

A.I.M.S, B.G.NAGARA.

11.2 SIGNATURE

1212.1 REMARKS OF THE CHAIRMAN & PRINCIPAL

The facilities required for the investigation will be made available by the collegeDr. SHIVARAMU. M.G., M.B.B.S., M.D.

PRINCIPAL,

AIMS, B.G. NAGARA.

12.2 SIGNATURE

APPENDIX - I

6. BRIEF RESUME OF INTENDED WORK

APPENDIX - IA6.1 NEED FOR THE STUDY:

Gastric outlet obstruction (GOO, also known as pyloric obstruction) is not a single entity; it is the clinical and pathophysiological consequence of any disease process that produces a mechanical impediment to gastric emptying. Intrinsic or extrinsic obstruction of the pyloric channel or duodenum is the usual pathophysiology of gastric outlet obstruction; the mechanism of obstruction depends upon the underlying etiology.

Clinical entities that can result in GOO generally are categorized into 2 well-defined groups of causesbenign and malignant. Until the late 1970s, benign disease was responsible for the majority of cases of GOO in adults, while malignancy accounted for only 10 to 39 percent of cases. By contrast, in recent decades, 50 to 80 percent cases have been attributable to malignancy.1 The incidence of gastric outlet obstruction has been reported to be less than 5% in patients with peptic ulcer disease which is the leading benign cause of the problem.

To understand and study the trends in the incidence of various factors responsible for gastric outlet obstruction in the present scenario.

To outline the rationale behind treatment of each patient with different etiology for gastric outlet obstruction.

APPENDIX - IIB

6.2 REVIEW OF LITERATURE

The stomach is a remarkable organ with important digestive, nutritional, and endocrine functions.2 During the fifth week of gestation the stomach arises as a dilatation in the tubular embryonic foregut2 Gastric outlet obstruction (GOO) is a clinical syndrome characterized by epigastric abdominal pain and postprandial vomiting due to mechanical obstruction.

The term gastric outlet obstruction is a misnomer since many cases are not due to isolated gastric pathology but rather involve duodenal or extraluminal disease.

Peptic ulcer disease, has historically been an important cause of GOO.

The predominant causes have changed substantively with the identification of Helicobacter pylori and the use of proton pump inhibitors.

The major causes of gastric outlet obstruction are peptic ulcer disease, ingestion of caustics, pyloric stenosis, pancreatic pseudocysts, and bezoars. Intrinsic or extrinsic obstruction of the pyloric channel or duodenum is the usual pathophysiology of gastric outlet obstruction; the mechanism of obstruction depends upon the underlying etiology. Peptic Ulcer Disease represents a spectrum of disease characterized by ulceration of the stomach or proximal duodenum due to an imbalance between acid secretion and mucosal defense mechanisms.3 Ulcers within the pyloric channel and first portion of the duodenum usually are responsible for outlet obstruction4.

Obstruction can occur in an acute setting secondary to acute inflammation and edema or, more commonly, in a chronic setting secondary to scarring and fibrosis3 Gastric outlet obstruction occurring due to peptic ulcer disease is more common in the younger age group below 40 years and obstruction occurring due to malignancy is more commonly encountered in the age group of 50-80 years. Generally, four types of gastric ulcer are described. 2 The most common, Johnson type I gastric ulcer, is typically located near the angularis incisura on the lesser curvature. These patients usually have normal or decreased acid secretion.2 Type II gastric ulcer is associated with active or quiescent duodenal ulcer disease, and Type III gastric ulcer is prepyloric. Both type II and type III gastric ulcers are associated with normal or increased gastric acid secretion.

Type IV gastric ulcers occur near the gastroesophageal junction, and acid secretion is normal or below normal.2 Patients with gastric outlet obstruction resulting from duodenal ulcer or incomplete obstruction typically present with symptoms of gastric retention, including early satiety, bloating or epigastric fullness, indigestion, anorexia, nausea, vomiting, epigastric pain, and weight loss. They are frequently malnourished and dehydrated and have a metabolic insufficiency. 4 Patients present with intermittent symptoms that progress until obstruction is complete. Vomiting is the cardinal symptom. Initially, patients may demonstrate better tolerance to liquids than solid food.

Upper GI endoscopy with biopsy is investigation of choice to differentiate between the benign and malignant causes.

Indications for elective operation for PUD include failure of medical therapy and inability to exclude malignancy.4 Peptic ulcer disease is now more commonly treated by antrectomy or distal gastrectomy followed by gastrojejunostomy.

Endoscopic balloon dilation has been used successfully in patients obstruction due to peptic ulcer disease. The use of balloon is preferred because it provides an even radial force, which has an advantage over the longitudinal shearing force associated with the use of conventional dilators.

Carcinoma stomach is the fourth-most common cancer worldwide. Its the second most common cause of death from cancer.6 The etiology of gastric cancer is complex and multifactorial, involving a combination of genetic, environmental, and infectious risk factors.

Gastric ulcers, adenamatous polyps and intestinal mataplasia have associated with a increased risk of carcinoma stomach.7 Dietary (nitroso compounds, high salt diet with low vegetables) and lifestyle factors (smoking and alcohol consumption).helicobacter pylori infection, especially certain genotypes (vasAs-1, vasAm1- and cagA-positive) remain an important risk factor.8 Men are more commonly affected than women, and the incidence increases with age.

As proposed by the Japanese Society of Gastro esophageal Endoscopy in 1962 is defined EARLY GASTRIC CANCER as adenocarcinoma limited to the gastric mucosa regardless of whether regional lymph nodes are involved or not (T1Nx)9 The Lauren classification system is most widely used and divides gastric cancers into two subtypes:10 Intestinal-type cancers (30%) are glandular and arise from the gastric mucosa

Diffuse-type cancers (70%) arise from the lamina propria and are associated with an invasive growth pattern with rapid submucosal spread.

Ninety-five percent of all malignant gastric neoplasms are adenocarcinomas. Other histologic types include squamous cell carcinoma, adenoacanthoma, carcinoid tumors, GI stromal tumors, and lymphoma. The Borrmann classification system was developed in 1926 and remains useful today for the description of endoscopic findings. The Borrmann system divides gastric carcinoma into five types depending on the lesion's macroscopic appearance.3a. Type 1, represents polypoid or fungating lesions;

b. Type 2, ulcerating lesions surrounded by elevated borders;

c. Type 3, ulcerating lesions with infiltration into the gastric wall;

d. Type 4, diffusely infiltrating lesions; and e. Type 5, lesions that do not fit into any of the other categories Presentation of gastric cancer generally involves nonspecific signs and symptoms such as epigastric abdominal pain, unexplained weight loss, nausea, vomiting, anorexia, early satiety, and fatigue. Gastric outlet obstruction is more typical of distal cancers. Perforation and upper GI bleeding are the presenting manifestations in a minority of patients (1% to 4%) Classic physical findings in gastric cancer represent metastatic and incurable disease and include the following:a. Cachexia.

b. Hepatosplenomegaly with ascites and jaundice.

c. Enlarged supraclavicular nodes (Virchow's node).

d. Fullness in the pelvic cul-de-sac (Blumer's shelf).

e. Enlarged ovaries on pelvic examination (Krukenberg's tumor).

f. Infiltration of the umbilicus (Sister Mary Joseph's node).

In the acute or chronic phase of obstruction, continuous vomiting may lead to dehydration and electrolyte abnormalities.

When obstruction persists, patients may develop significant and progressive gastric dilatation. The stomach eventually loses its contractility. Undigested food accumulates and may represent a constant risk for aspiration pneumonia. Abdominal pain is not frequent and usually relates to infiltration to the posterior bed-pancreas and celiac ganglia or due to the liver metastasis. Physical examination often demonstrates the presence of chronic dehydration and malnutrition. A dilated stomach may be appreciated as a tympanitic mass in the epigastric area and/or left upper quadrant.

Dehydration and electrolyte abnormalities can be demonstrated by routine laboratory examinations. Increases in BUN and creatinine are late features of dehydration. The result is a hyponatraemic hypokalemic hypochloremic metabolic alkalosis. Tissue diagnosis and anatomical localization of the primary tumuor are best obtained by upper gastrointestinal endoscopy.3 Despite new screening techniques like transabdominal and endoscopic ultrasound, computer tomography scan, magnetic resonance imaging and positron emission tomography scan, peritoneal tumuor spread and occult liver and lymph node metastasis are only intraoperatively in many patients.11 Gastrectomy is the most widely used approach for therapy of invasive gastric cancer. Distal subtotal gastrectomy with resection of adjacent lymph nodes appears to sufficient for lesions in the distal lower two thirds of the stomach.12 Complete surgical eradication of a tumuor with resection of adjacent lymph nodes represents the best chance of survival. Definitive treatment depends on the underlying etiology. Billroth was the first surgeon to successfully resect the distal stomach. The patient, Therese Heller, had distal gastric cancer, and continuity was re-established with a gastroduodenostomy (Billroth I) using interrupted silk suture2.

In 1885 Billroth performed a successful distal gastrectomy and gastrojejunostomy (Billroth II) for gastric cancer1 The draining lymph nodes basins for the stomach can be divided into 16 stations: stations 1-6 are perigastric, and the remaining 10 are located adjacent to major vessels, behind the pancreas, and along the aorta.13,14 A standard (D1) lymphadenectomy entails removal of perigastric nodes.

An extended (D2) resection includes removal of nodes along the left gastric, hepatic, splenic, and celiac arteries (stations 1-11)

D3 dissection is used by to describe a D2 lymphadectomy plus the removal of nodes within the porta hepatis and periaortic regions(stations 1-16).

Although the results of major trials attempting to answer this question have yielded confounding results, it is generally agreed on that, at high-volume centers, D2 lymphadenectomies that preserve the distal pancreas and spleen can be performed without increased morbidity, improve staging accuracy, and yield a survival advantage in patients with stage II and III gastric cancer.

Endoscopic mucosal resection or endoscopic Mucosal dissection can used as curative therapy for early gastric cancer.

Criteria for application of endoscopic mucosal resection in Early Gastric Cancer:

Maximum less than 2cm when lesion is slightly elevated and less than 1cm when lesion is flat or slightly depressed.

No evidence of multiple gastric cancers.

Intestinal type of gastric cancer.

Endoscopic mucosal dissection enables allows en bloc dissection of tumuor more than 2cm.

The epirubicin, cisplatin, infusion 5-FU (ECF) and docetaxel, cisplatin, infusional 5-FU (DCF) combinations have emerged as the standard regimens for first line treatment.

Recent advances include SEMS (Self Expanding Metallic Stents) for palliative care malignancy or benigm strictures.

APPENDIX - IC6.3 AIMS AND OBJECTIVES 1. To analyse the occurrence of benign, malignant and any other causes encountered as a cause of gastric outlet obstruction.

2. To analyse the various signs and symptoms of gastric outlet obstruction with reference to specific features of benign, malignant and any other causes.

3. To analyse the various modalities of investigations and treatment and their results.APPENDIX - II

7. MATERIALS AND METHODS

APPENDIX - IIA7.1 SOURCE OF DATA:

This study is conducted in the Department of General Surgery at Sri Adichunchanagiri Hospital and Research Centre, B.G.Nagara, Mandya district.

Sample size of a minimum of 50 patients fulfilling the inclusion criteria will be a part of this study conducted for a duration of 18 months.

Study design: Clinical study.APPENDIX - IIB

7.2 METHOD OF DATA COLLECTION:

Data will be collected from patients who are admitted in surgical wards of SAH & RC, with a provisional diagnosis of gastric outlet obstruction.

Clinical study will be through questionnaires and clinical examination.

All patients will undergo routine and special investigations.

Treatment modality will be planned once the definitive diagnosis of gastric outlet obstruction is arrived at.

Post operative observation of patients for any complication. Post operatively patients referred to onchocentres for chemotherapy. INCLUSION CRITERIA :1. All patients admitted to the surgery wards with a clinical diagnosis of gastric outlet obstruction.

2. Endoscopic evidence of gastric outlet obstruction.

3. Radiological evidence of gastric outlet obstruction.

4. Demonstration during surgery or at autopsy, gross narrowing of the gastric outlet.EXCLUSION CRITERIA

1. Children with gastric outlet obstruction will be excluded for which congenital causes may be: Congenital hypertrophic pyloric stenosis. Pyloric atresia, pyloric mucosal diaphragm. Duodenal atresia, stenosis. Malrotation, inomplete rotation.Annular pancreas, hypertrophic pancreatic tissue. Duplication of stomach, duodenum.

2. All pregnant women are excluded from the study.

3. Patient above 80 years of age who are not operated on.

4. Patients of coagulopathy and on anti-coagulant therapy. APPENDIX - IIC7.3 Does the study require any investigations or interventions to be conducted on patients or other animals; if so describe briefly:YES

INVESTIGATIONS:

1. Routine investigations

a. Haemoglobin percentageb. Total count

c. Differential count

d. Erythrocyte sedimentation ratee. Bleeding time

f. Clotting time

g. Urine for protein, sugar and microscopyh. Random blood sugar

i. Blood urea

j. Serum creatinine

k. Serum electrolytesl. HIV/ HbsAG

m. Blood grouping

n. Chest radiograph

o. Electrocardiogram

2. Specific investigations

a. Ultrasound abdomen and pelvis

b. Upper gastrointestinal endoscopy and biopsy

c. Liver function test

d. PT, aPTT, INR

e. CT Scan

INTERVENTION

1. Ulcers causing obstruction-Distal subtotal gastrectomy with gastrojejunostomy.

2. Distal tumors - by distal subtotal gastrectomy or total gastrectomy

3. Drainage procedure- Gastrojejunostomy.

4. Extent of lymphadenectomy25. (D1) lymphadenectomy- removal of perigastric nodes, (stations 3,4,5,6)

6. Extended (D2) resection - removal of nodes along the left gastric, hepatic, splenic, and celiac arteries.(stations 1,2,7,8,11)

7. D3 resection- D2 plus removal of nodes within porta hepatis and periaortic regions.(stations 9,10,12)

8. Palliative therapy given for non resectable tumuor where the tumuor has infiltrated to posterior stomach bed with liver or widespread metastasis, peritoneal deposits and ascitis where a anterior gastrojejunostomy or feeding jejunostomy is undertaken.

APPENDIX II D

7.4 PROFORMA APPLICATION FOR ETHICS COMMITTEE APPROVAL

SECTION A

aTitle of the studyA CLINICAL STUDY OF GASTRIC OUTLET OBSTRUCTION IN ADULTS

bPrinciple investigator

(Name and Designation)Dr. M.S. SUSHRUTA NO. 29, KALPATARU BHAVAN,

A.I.M.S., B.G.NAGARA,

NAGAMANGALA TALUK,

MANDYA DISTRICT,

KARNATAKA - 571448.

cCo-investigator

(Name and Designation)Dr. ABINASH HAZARIKA MBBS, MSASSOCIATE PROFESSOR

DEPARTMENT OF GENERAL SURGERY,

A.I.M.S, B.G.NAGARA

dName of the Collaborating

Department/InstitutionsDEPARTMENT OF GENERAL SURGERY, A.I.M.S., B.G.NAGARA

eWhether permission has been obtained from the heads of the collaborating departments & InstitutionYES

Section B

Summary of the ProjectAPPENDIX I

Section C

Objectives of the studyAPPENDIX IC

Section D

MethodologyAPPENDIX IIB

AWhere the proposed study will be undertakenSAH & RC, B.G.NAGARA

BDuration of the Project18 MONTHS

CNature of the subjects:

Does the study involve adult patients?

Does the study involve Children?

Does the study involve normal volunteers?

Does the study involve Psychiatric patients?

Does the study involve pregnant women?YES

NO

NO

NO

NO

DIf the study involves health volunteers

I. Will they be institute students?

II. Will they be institute employees?

III. Will they be Paid?

IV. If they are to be paid, how much per session? NO

NA

NA

NA

EIs the study a part of multi central trial?NO

FIf yes, who is the coordinator?

(Name and Designation)

Has the trial been approved by the ethics Committee of the other centers?

If the study involves the use of drugs please indicate whether.

I. The drug is marketed in India for the indication in which it will be used in the study.

II. The drug is marketed in India but not for the indication in which it will be used in the study

III. The drug is only used for experimental use in humans.

IV. Clearance of the drugs controller of India has been obtained for:

Use of the drug in healthy volunteers

Use of the drug in-patients for a new indication.

Phase one and two clinical trials

Experimental use in-patients and healthy volunteers.NO

NO

NA

NA

NA

NA

NA

NA

GHow do you propose to obtain the drug to be used in the study?

Gift from a drug company

Hospital supplies

Patients will be asked to purchase

Other sources (Explain)NA

HFunding (If any) for the project please state

None

Amount

Source

To whom payableNA

IDoes any agency have a vested interest in the out come of the Project? NO

JWill data relating to subjects /controls be stored in a computer?

NO

K Will the data analysis be done by

The researcher?

The funding agentYES

NO

LWill technical / nursing help be required form the staff of hospital.

If yes, will it interfere with their duties?

Will you recruit other staff for the duration of the study?

If Yes give details of

I. Designation

II. Qualification

III. Number

IV. Duration of EmploymentNO

NA

NA

NA

MWill informed consent be taken? If yes

Will it be written informed consent:

Will it be oral consent? Will it be taken from the subject themselves?

Will it be from the legal guardian? If no, give reason:NO

NA

NA

NA

NA

NDescribe design, Methodology and techniquesAPPENDIX II

Ethical clearance has been accorded.

Chairman,

P.G Training Cum-Research Institute,

A.I.M.S., B.G.Nagara.

Date :

PS : NA Not Applicable

APPENDIX IIILIST OF REFERENCES

1. http://emadicine.medscape.com/190621/Gastric outlet obstruction in adults treatment and management.

2. Brunucardi.C, Andersen K, Billiar.R, Dunn.L, Hunter.G, Pollock.E, Schwartz Principles of Surgery, Ninth edition;chapter 26, stomach: 907-935.

3. Townsend, Beauchamp, Evers, Mattox, Sabiston Textbook Of Surgery, The Biological Basis Of Modern Surgical Practice, Eighteenth edition; Volume 2, Section X, Chapter 47, Stomach :1236-1266

4. Williams SN, Bulstrode KJC, O Connell RP, Bailey And Loves Short Practice of Surgery; Stomach and Duodenum, 25 edition; Chapter 60: 1054-1057

5. Feldman M,Feildman S.L, Brandt L.J, Seisengers and Fordtrans Gastrointestinal and liver Diseases Pathophysiology Diagnosis and Management, Treatment Of Peptic Ulcer, Ninth Edition; volume I, Chapter 53:884-887.

6. Yu J, Xin F(2009); A study on the association of histological types and TNM stages, hepatogastroenterology 56:1219-1221.

7. Noyan T, Guducuoglu H, Ilhan M,(2009); A study of oxidative stress parameters in anti-helibacter pylorus immunoglobulin g positive and negative gastric cancer patients, Yonsei Med J 50:677-682

8. Shiyoma T, Fukuda S, Tanaka M, Nakaji M, Munakata A,(2000); Evaluation of the application of the gastric carcinoma risk index for intestinal type cancer in japanese patients infected with Helicobacter pylori, Virchows Arvh 436:585-587

9. .Rovielli F, Rossi S, Marelli D, Pedrazzani C, Corso G, Vindigni C, Morgagni C et al,(2006); Number of lymph node metastases and its prognostic significance in early gastric cancer: a multicentric Italian study. J Surg Oncol 94;275-280.

10. Klingensmith E, Chem E, Glasgow C, Goers A,The Washington Manual Of Surgery fifth edition chapter 9

11. Folli S, Dente M, DellAmore D, Gaudio M, Nanni O, Sargoni L, Via O , Early Gastric Cancer; prognostic factors in 223 patients, Br J Surg 82:952-956.

12. Muntean V, Mihailov A, Iancu C, Toganel R, Fabian O, Domsa I et al(2009); Staging laproscopy in gastric cancer. Accuracy and impact on therapy. J Gastrointestin Liver Dis 18:89-195

13. Topaloglu U, Dulundu E, Ozkan E,Kahayan N, Ozel Y (2009); Extended Lymphadenectomy for gastric cancer: a single center experience in Istanbul. Hepatogastroenterology 56:266-269.

14. Asoglu O, Karanlik H, Parlak M, Kecer M, Muslumanoglou M, Igci Yu J; Xin F(2009) A study on the association of histological types and TNM stages, hepatogastroenterology 56:1219-1221. A (2009); Metastatic lymph node ratio is a independent prognostic factor in gastric cancer, Hepatogastroenterology 56:908-913.

15. Van Custem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C et al (2006); Phase III study of docetaxel and cisplatin plus flurouracil compared with cisplatin and flurouracil as the first line therapy for advanced gastric cancer: a report of the V235 study group, J Clin Oncol24:4991-499716. Ajali JA, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A et al(2007), V-325 study group. Quality of life with docetaxel plus cisplatin compared with cisplatin and flurouracil from a phase III trial for advanced gastric or gastroesophageal adenocarcinoma: the V-325 Study Group. J Clin Oncol 25:3210-3216.PAGE 1