Sentinel Lymph Node Biopsy in Colon Cancer

SENTINEL LYMPH NODE BIOPSY IN COLON CANCER

BY

SQN LDR (Dr.) K SHANKAR REDDY

SYNOPSIS FOR REGISTRATION OF SUBJECT FOR DISSERTATION

TO

RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES

BANGALORE, KARNATAKA

IN PARTIAL FULFILLMENT OF REGULATIONS FOR THE

AWARD OF

MASTER OF SURGERY

IN

GENERAL SURGERY

DEPARMENT OF SURGERY

COMMANDHOSPITAL (AIR FORCE), BANGALORE – 560 007

RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES

BANGALORE, KARNATAKA

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

SYNOPSIS

DISSERTATION TOPIC

SENTINEL LYMPH NODE BIOPSY IN COLON CANCER

By

SQN LDR (Dr.) K SHANKAR REDDY

PG student (General Surgery)

Command Hospital (Air Force),

Bangalore.

Course

2013-2016

RajivGandhiUniversity of Health Sciences, Bangalore,Karnataka

Annexure-A

1.Name of candidate : Sqn Ldr (Dr.) K Shankar Reddy

2. Name of Institution :Command Hospital (Air Force), Bangalore

3. Course of study and subject :M.S. (General Surgery)

4. Date of admission : July 2013

5. Title Of Topic : Sentinel Lymph node biopsy in colon cancer

.

6. Brief resume of intended work

Need for the study : APPENDIX ‘A’

Objective of study : APPENDIX ‘B’

Review of literature : APPENDIX ‘C’

7. Material and Methods : APPENDIX 'D'

Source of data : APPENDIX ‘D’

Method of collection of data : APPENDIX ‘D’

8. Does the study require any investigation

and interventions to be conducted

on patients or other animals? : YES/NO

Has ethical clearance been obtained

from your institution? : YES/NO

9. Patient Proforma : APPENDIX ‘E’

10. Statistical Analysis : APPENDIX ’F’

11. List Of References : APPENDIX ‘G’

12. Patient Consent Form : APPENDIX ‘H’

13. Study Information Sheet : APPENDIX ‘I’

14. Signature Of Candidate

15. Remarks of guideApilot study whichwill provide a road map for carrying out sentinel lymph node biopsy and guide adjuvant therapy protocols, with aim at improving survival in colon cancer.

16. Name and designations

GuideGp Capt (Dr.)NK Saidha

Senior Advisor, Oncosurgeon

Department of Surgery

Command Hospital (Air Force)

Bangalore

Signature

17. Head of the Department Col (Dr.) SC Dash

Professor & Head,

Department of Surgery

Command Hospital (Air Force)

Bangalore

Signature

18.Remarks of the chairman and principal

Signature

Appendix ‘A’

Need for the study

The presence oflymphnodemetastases remains the most reliable prognostic predictor and the gold indicator for adjuvant treatment in coloncancer. In spite of a potentially curative resection, 20 to 30% of colon cancer patients testing negative forlymphnodemetastases (i.e. pN0) will subsequently develop loco regional and/or systemic metastases within 5 years. The presence of occult nodal Isolated Tumor Cells (ITCs) and/or Micrometastases (MMs) at the time of resection predisposes these patients to high risk for disease recurrence. These pN0 (micro+) patients harboring occult micrometastases may benefit from adjuvant treatment.

The SLN procedure is a selective sampling technique that can be used to ultra-stage regional nodes. The SLNs are the first nodes to receive lymphatic drainage from a primary tumour and thus the most likely nodal site of metastasis. Mapping, dissection, and focused examination of SLNs can identify occult nodal metastases that may increase the risk of recurrence. The tumour status of the SLN does not change the extent of resection because en bloc resection of the primary colon cancer includes regional lymph nodes. However, results of SLN-based nodal ultra-staging can improve identification of candidates for adjuvant therapy of colon cancer, a treatment that is highly effective for metastatic disease but too toxic and expensive for routine use in node-negative colon cancer.

Appendix 'B'

Objectives of study

The Objectives of the present study are to

(i) Determine the sensitivity of the procedure in detecting sentinel lymph node(s)

(ii)Delineate the subset of pN0 patients with micrometastases pN0 (micro+), for consideration of adjuvant chemotherapy.

Appendix ‘C

Review of literature

Colorectal carcinoma is a common gastrointestinal malignancy and remains the second most common cause of cancer mortality. The 5-year survival rate is approx. 90% for patients with localized disease and approx 6% with regional disease as determined at diagnosis. There is a 25% incidence of disease recurrence in the absence of regional node involvement, suggesting that conventional pathology may fail to detect occult nodal metastases [1]. Adjuvant therapy improves survival in as many as one third of patients with stage III disease; however, there is no consistent evidence that adjuvant therapy improves survival in node-negative (stage I or II) disease [2]. Lymph node evaluation is essential for accurate staging and improves the selection of patients for adjuvant therapy.

Current techniques for nodal evaluation are inadequate for the detection of micrometastasis; more sensitive techniques, such as multilevel step sectioning and intraoperative sentinel lymph node mapping, have therefore been applied to solid malignancies [3]. The sentinel lymph node is the lymph node that has the highest probability of harboring metastatic tumor cells from a primary tumor; this concept has been validated in melanoma and breast cancers. Sentinel lymph node evaluation allows a focused examination for the detection of occult metastases not detected by conventional techniques [4]. In colorectal cancer, the assessment of sentinel lymph nodes using multilevel sectioning and cytokeratin immunohistochemistry detects micrometastasis in 23% of patients whose nodal specimens are tumor-free as determined by routine H&E staining [5]. Focused analysis of the sentinel lymph node can therefore provide a more efficient approach for the detection of micrometastases and improve patient management.

Considering that the lymph node status is still the clinicopathological prognostic factor that most influences the survival of these patients at diagnosis, the accuracy of this stage is critical for choosing the most effective treatment [6].

Patients with lymph nodes for cancer will present better survival after adjuvant chemotherapy.In this particular case, unlike breast cancer and melanoma, lymph node status in colorectal cancer does not change the programming or the radical surgery, but the prognosis and further treatment of these patients [7, 8].

The mechanism of improving the accuracy of the study lymph node is realized in that it is obtained for histopathologic analysis, smaller volume and more representative of lymph node tissue selected for detailed study and may be cross-sectioned and ultra-staged combined with the conventional methods of immunohistochemistry, thus providing the diagnosis of lymph node micrometastases, which potentially modifies the actual parameters of malignant colorectal disease stage [9, 10].

The detection of sentinel lymph node (SLN) is a relatively simple technique with a short learning curve apparently, can be performed using chromate-identification with blue dye or lymphoscintigraphy using tracer and measurement of radioactivity probe with manual intra-operative gamma probe.

Appendix ‘D’

Material and Methods

Source of Data

After approval from Institutional Ethics Committee for this study, it is proposed to conduct the study on 40 consecutive operable colon cancer patients at Command Hospital Air force Bangalore, a tertiary care hospital of Armed Forces.

Inclusion criteria:

Patients with endoscopic and histopathological diagnosis of adenocarcinoma of the colon planned for operation with curative intent.

Exclusion criteria:

Presence of synchronous lesions in the large intestine, malignant or inflammatory in nature, prior colorectal resection, and distant metastatic disease.

Method of collection of data

All patients will undergo standard surgical resection with adequate lymphadenectomy. The steps in identification of SLN are as follows:

1. 1 percent Isosulfan blue dye will be used for lymphatic mapping intraoperatively.
2. After laparotomy and mobilization of the tumor-bearing part of the colon, 1-3 ml of 1 percent Isosulfan blue dye will be injected into the subserosal layer immediately adjacent to the tumor in 4 portions.
3. The first to fourth blue-staining nodes within ten minutes of injection will be tagged with a suture as sentinel nodes.
4. The subsequent resection of the tumor will be performed as a standardized radical hemicolectomy (left or right) or transverse colon resection.
5. After resection of the specimen, the tagged lymph node(s) will be excised and separately processed to further examination as sentinel lymph nodes (SLN).
6. Thereafter, as many non-SLN lymph nodes as could be identified will be dissected from the specimen (aiming at a minimum of 12 lymph nodes as recommended by the UICC/AJCC).

These SLN lymph node will undergo stepwise sections of 250 μm distance each until sampled completely. At each level, at least 2 serial sections will be cut at 5 μm thicknesses and one of them separated for immunohistochemical staining. In case no tumor cells are found by H & E staining, at least 4 serial sections per lymph node will be stained by immunohistochemistry using pan-cytokeratin antibody.

Definitions:

Tumor cell deposits larger than >0.2 mm, but smaller than 2 mm in diameter will be classified as Micrometastases (MM).

Tumor cell clusters up to a diameter of 0.2 mm or single CK-positive cells will be classified as “Isolated Tumor Cells” (ITC) according the UICC/AJCC.

SLN detection rate:

Number of patients with successfully retrieved SLN X 100

Number of patients enrolled

To define the rate of “upstaging,” the proportion of patients will be calculated that was found to reveal micrometastases or isolated tumor cells in the SLN by step-sectioning and IHC, but were classified as pN0 by routine hematoxylin and eosin-staining.

Those patients upstaged based on sentinel lymph node examination will be considered for adjuvant chemotherapy.

Appendix ‘E’

Patient Proforma

Pt Name:………………….Age/Sex……………….Wt………..Sr. No………………………….

Diagnosis………………………………………..Surgery………………..………………………..

Clinical Presentation:

Socio-economic strata:Diet:

Co-morbidity

Clinical Examination

PallorLNEdemaNails

Mucus/Skin

HepatomegalySplenomegaly

Others

Investigations

HbTLCDLCPltPT-INRESR

PBS

MCVMCHMCHC

BilOT/PT/SAPTP/Alb

FBSBUN/CrTumor markers

Colonoscopy

USG Abdomen

CECT Abdomen:

Colonoscopic Bx:

Intra- operative findings:

SLN Biopsy report:

H&E staining report of other lymph nodes :

Appendix ‘F’

Statistical analysis

For statistical analysis the SLN detection rate will be calculated as follows:

SLN detection rate:

Number of patients with successfully retrieved SLN X 100

Number of patients enrolled

To define the rate of “upstaging,” the proportion of patients will be calculated that was found to reveal micrometastases or isolated tumor cells in the SLN by step-sectioning and IHC, but were classified as pN0 by routine hematoxylin and eosin-staining.

Appendix ‘G’

References

1. Nicastri DG, Doucette JT, Godfrey TE, Hughes SJ: Is occult lymph node disease in colorectal cancer patients clinically significant? A review of the relevant literature. J Mol Diagn 2007, 9:563-571.

2. Iddings D, Ahmad A, Elashoff D, Bilchik A: The prognostic effect of

micrometastases in previously staged lymph node negative (N0) colorectal carcinoma: a meta-analysis. Ann Surg Oncol 2006, 13:1386-1392.

3. Yun HR, Kim HC, Lee WY, Cho YB, Yun SH, Chun HK: The necessity of

chemotherapy in T3N0M0 colon cancer without risk factors. Am J Surg 2009, 198:354-358.

4. Saha S, Monson KM, Bilchik A, Beutler T, Dan AG, Schochet E, et al:

Comparative analysis of nodal upstaging between colon and rectal cancers by sentinel lymph node mapping: a prospective trial. Dis Colon Rectum 2004, 47:1767-1772.

5.Saha S, Seghal R, Patel M, Doan K, Dan A, Bilchik A, et al: A multicentre trial of sentinel lymph node mapping in colorectal cancer: prognostic implications for nodal staging and recurrence. Am J Surg 2006, 191:305-310.

6.Cahill RA, Bembenek A, Sirop S, Waterhouse DF, Schneider W, Leroy J, et al: Sentinel node biopsy for the individualization of surgical strategy for cure of early-stage colon cancer. Ann Surg Oncol 2009, 16:2170-2180.

7.Bembenek AE, Rosenberg R, Wagler E, Gretschel S, Sendler A, Siewert JR, et al: Sentinel lymph node biopsy in colon cancer: a prospective multicenter trial. Ann Surg 2007, 245:858-863.

8.Davies M, Arumugam PJ, Shah VI, Watkins A, Roger MA, Carr ND, et al: Theclinical significance of lymph node micrometastasis in stage I and stage II colorectal cancer. Clin Transl Oncol 2008, 10:175-179.

9Stojadinovic A, Nissan A, Protic M, Adair CF, Prus D, et al. Prospective randomized study comparing sentinel lymph node evaluation with standard pathologic evaluation for the staging of colon carcinoma: results from the United States Military Cancer Institute Clinical Trials Group Study GI-01. Ann Surg 2007; 245: 846-857

10.Bembenek AE, Rosenberg R, Wagler E, Gretschel S, Sendler A, et al.Sentinel lymph node biopsy in colon cancer: a prospective multicenter trial. Ann Surg 2007; 245: 858-863

Appendix ‘H’

COMMAND HOSPITAL AIRFORCE, BANGALORE 560007

CONSENT FORM

Patient’s name………………...…………Age…………….Rank…………………..

Unit………………………………………Ward……………….……………………

I hereby authorize the performance of the following procedures upon myself/my relative(name of the patient ……...…………….………………)

1. Sentinnel Lymph Node biopsy.

The kind of procedure to be performed has been fully explained to me and all my questions and doubts about the procedure have been cleared to my satisfaction. All the risks involved have been explained to me and I understand those risks and I accept them.

I understand that the procedure and the medication have their own advantages and disadvantages and each is associated with its own share of risks. I understand that all due care will be taken during the above said procedure.

I understand that though best efforts will be put into the present condition no guarantee of the outcome can be given.

I agree to cooperate fully with my doctor and to follow the instructions to best of my ability.

This consent to be of my own free act of will

Signature of Witness Signature of patient/NOK

Appendix ‘I’

Study Information Sheet for Patients/NOK

Title:Sentinel lymph node biopsy in colon cancer.

Investigator:Sqn Ldr (Dr) K Shankar Reddy

Dear Sir/Madam

You/your relation are suffering from colorectal cancer, whichis operable and requires surgical intervention. In this study we propose to do sentinel lymph node biopsy in addition to routine lymph node dissection. This is done to help detection of occult metastases.

We seek your consent to participate in this study.

Benefits of the study to the patient

You are likely to benefit by having better chances of detecting occult lymph nodes which will help in clinical decision making for consideration of adjuvant chemotherapy.

Potential Risks and discomforts

NIL: The procedure will be carried out during standard radical colectomy, as determined by clinical staging.

Alternative to participation:

Not applicable as no separate procedure is involved.

Confidentiality

All information that will be provided during the study will be kept confidential.

Contacts

If you have any further questions, any time during the course of the study you can contact the following :

Sqn Ldr (Dr) K Shankar Reddy

Resident

Dept. of Surgery

Command Hospital Air force

Bangalore 560007

Gp Capt (Dr) NKSaidha

Senior Advisor, Oncosurgeon

Dept. of Surgery

Command Hospital Air force

Bangalore 560007

CERTIFICATE FROM THE HEAD OF THE INSTITUTION

Permission is hereby accorded to the student Sqn Ldr (Dr) K Shankar Reddy, to undergo MS (General Surgery) course being conducted at Command Hospital (Air Force) Bangalore affiliated to the Rajiv Gandhi University of Health Sciences commencing from July 2013 under the guidance of Gp Capt (Dr.) NKSaidha (Senior Advisor, Oncosurgeon), Dept of Surgery, Command Hospital (Air Force) Bangalore.

Date:

Commandant and Principal

Command Hospital, Air Force

Bangalore - 560007

CERTIFICATE FROM ETHICAL COMMITTEE

1. The committee has examined the scope including the need, objectives, methods and human /animal interventions and the follow-up study to be carried out by Sqn Ldr (Dr) K Shankar Reddy, MS student (General Surgery) under guidance of GpCapt (Dr) NKSaidha, the title of which is Sentinel Lymph node biopsy in Colon Cancer.

2.The committee has no objections for undertaking this study at CommandHospital (Air Force) Bangalore.

(MS Prakash) (SC Dash) (H Sahni) (SKJha)

Brig Col Gp Capt Col

Prof & HOD Medicine Prof & HODSurgery OIC AFMRCOIC PG Cell Member Member MemberSecretary Member

(S Kiastha) (S Chaudary) (Mrs. Vasantha Kishore) (Dr V Sinha)

Wg Cdr Sqn Ldr Counsellor e- support Scientist ‘D’ Physiologist Rep of AFWWA OIC Legal Cell Member Member

MK Bedi

AIR CMDE

CHAIRMAN ETHICAL COMMITTEE

COMMAND HOSPITAL AIRFORCE

BANGALORE - 560007

CERTIFICATE OF ACCEPTANCE BY THE GUIDE

1. I, Gp Capt NK Saidha, hereby accept Sqn Ldr K Shankar Reddyas a candidate of MS (General Surgery ) course. The title of his dissertation is as follows:-

“Sentinel Lymph node biopsy in Colon Caner.”

2. He will be under my guidance during the period of his study and thesis work.

Date:Gp Capt(Dr.) NK Saidha

Senior Advisor & Oncosurgeon

Dept.ofSurgery

Command Hospital Air Force

Bangalore 560007