TITLE: Protocol GOG #123, ARichard J. Farrell, COL, MC Chief, Pharmacy Service Patricia J. Basta,...

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ARM? .941116.014

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TITLE: Protocol GOG #123, "A Randomized Comparison of Radiation Therapy and Adjuvant Hysterectomy versus Radiation Therapy and Weekly Cisplatin and Adjuvant Hysterectomy in Patients with Bulky Stage IB Carcinoma of the Cervix"

INVESTIGATOR: Mark E. Potter, LTC, Medical Corps

LOCATION OF STUDY: Madigan Army Medical Center

EXPECTED START DATE: October 1992

ANTICIPATED COMPLETION DATE: October 1997

EXPECTED NUMBER OF SUBJECTS: 5

TYPE OF SUBJECTS: Adult females

SOURCE OF SUBJECTS: GYN Oncology service

CHEMOTHERAPEUTIC AGENTS: Cisplatin

OBJECTIVES: To evaluate the addition of weekly chemotherapy with Cisplatin during radiation therapy to patients with bulky Stage IB carcinoma of the cervix . MEDICAL APPLICATION: Patients experience an increase in pelvic control with hysterectomy following radiation therapy in the treatment of bulky cervical tumors confined to the cervix. This investigation will evaluate whether the addition of Cisplatin chemotherapy to this treatment plan will increase both pelvic and systemic control of the tumor, without the addition of significant toxicity.

STATUS: GOG has recently completed a study comparing radiation therapy and radiation therapy followed by hysterectomy in the treatment of patients with bulky IB cervical carcinomas. Preliminary evaluation of this data reveals an increase in local control of the tumor if not a survival advantage. Maturity of this data is not yet available to define unequivocally whether radiation therapy followed by hysterectomy is superior to radiation therapy only. Numerous studies have demonstrated improved pelvic control in patients with advanced cervical carcinoma when chemotherapy utilizing a variety of agents is added to radiation therapy. It is not known whether the addition of both surgery and chemotherapy will improve the survival of patients with bulky cervical carcinoma.

SUMMARY: This study randomizes patients to two different treatment regimens. Both regimens include radiation therapy followed by hysterectomy. One arm, however, will receive Cisplatin chemotherapy given on a weekly basis throughout the course of the external radiation therapy and a l s o once with the intracavitary treatment utilized. Radiation therapy will be administered over a standard four to five like period of time with at least one

. I

CONTINUED:

application of brachy therapy (local radiation . Radiation will be administered utilizing tandem and ovoids. The hysterectomy will be performed in a three to s i x week window after completion of radiation therapy. Patients will t h e n be followed every three months for two years and e v e r y six months for an additional three years. Subsequently, they will be seen o n a yearly basis.

RATIONALE: See pages 1-2 of the protocol.

EXPERIMENTAL DESIGN: See pages 3-20 of the protocol.

TITLE: GOG 123, "A Randomized Comparison of Radiation Therapy and Adjuvant Hysterectomy Versus Radiation Therapy and Weekly Cisplatin and Adjuvant Hysterectomy in Patients with Bulky Stage IB Carcinoma of the Cervix. ''

IMPACT STATEMENT

PATIENTS: 5

PATHOLOGY :

RADIOLOGY: N/A

Representive s l ides from each positive s i t e

PHARMACY: Weekly Cisplatin @ 4 0 mg/m2 not to exceed 70mg (not to exceed 6 cycles) approximate 1/2 of patients

NURSING: 6 one day hosptial stays in addition to standard of care approximately 1/2 of patients

RADIATION ONCOLOGY: Standard of care

CLINICAL INVESTIGATION: Standard

APPROVALS :

Richard J. Farrell, COL, MC Chief, Pharmacy Service

Patricia J. Basta, COL, AN Chief, Dept. of Nursing

Rahul Dewan, MAJ, MC C, Radiation Oncology Service

James Kelly, GOL, MC a i e f , Anatomic Pathology

TITLE: GOG 123, "A Randomized Comparison of Radiation Therapy and Adjuvant Hysterectomy Versus Radiation Therapy and Weekly Cisplatin and Adjuvant Hysterectomy in Patients with Bulky Stage IB Carcinoma of the Cervix.

IMPACT STATEMENT

PATIENTS: 5

PATHOLOGY:

RADIOLOGY: N/A

Representive slides from each positive si te

PKARMACY: Weekly Cisplatin @ 4 0 mg/m2 not to exceed 70mg ( n o t to exceed 6 cycles) approximate 1/2 of patients




APPROVALS :



p-+Y--l- Rahul Dewan, MAJ, MC C, Radiation Oncology Service

James Kelly, WL, MC Chief, Anatomic Pathology

TITLE: GOG 123, "A Randomized Comparison of Radiation Therapy and Adjuvant Hysterectomy Versus Radiation Therapy and Weekly Cisplatin and Adjuvant Hysterectomy in Patients with Bulky Stage IB Carcinoma of the Cervix."

IMPACT STATEMENT

PATIENTS: 5

PATHOLOGY :

RADIOLOGY: N/A

PHARMACY: Weekly Cisplatin @ 40 mg/m2 not to exceed 70mg (not to exceed 6 cycles) approximate 1/2 of patients

Represent ive slides from each p s i t ive s i t e




APPROVALS:



Rahul Dewan, MAJ, MC C, Radiation Oncology Service

COhV c James Kelly, O L , MC Qlief, Anatomic Pathology v a t 12c-c

TITLE OF PROJECT: GOG 12 I "A Randomized Comparison of Rat iation Therapy and Adjuvant Hysterectomy Versus Radiation Therapy and Weekly Cisplatin and Adjuvant Hysterectomy in Patients with Bulky Stage IB Carcinoma of the Cervix."

1.

2 .

3 .

4 .

5.

6.

PERSONNEL - List only the cost of additional personnel NONE would have to be hired - only in very rare instances would funds be approved for extra personnel.

EQUIPMENT - Itemize NONE $ 000

CONSUMABLE SUPPLIES - Itemize: See pharmacy impact.

REPRINTS : NONE $ 0 0 0

TRAVEL - travel to perform the protocol or to present results is considered a part of the protocol costs; however, the Department of Clinical Investigation has no funds with which to fund travel. This would have to come from departmental funds or for presentation, the DCCS has a limited amount of funding f o r travel.

MODIFICATION OF FACILITIES $ 000

7 . TOTAL $

APPROVE-

FOR THE COMMANDER:

,L e-- DAN C. MOORE, M.D.

- , ~

MEDCEN Approving Official

PROTOCOL TITLE: GOG ' 123, "A= Randomized Comparison of Radiation Therapy and Adjuvht Hysterectomy Versus Radiation Therapy and Weekly Cisplatin and Adjuvant Hysterectomy in Patients with Bulky Stage IB Carcinoma of the Cervix."

INVESTIGATOR'S STATEMENT

I agree to conduct this study as written and in accordance with the policies set forth in AR 40-38, paragraph 2-1Oc as listed below:

(1) Prepare a protocol following the policies and procedures in this

( 2 ) Prepare and maintain adequate records on: regulation.

(a) Receipt, storage, use, and disposition of all investigational drugs issued to the investigator by the pharmacy and investigational devices issued to the investigator by the activity responsible for storing them.

important to the study. (b) Case histories that record all observations and other data

( c ) Volunteer informed consent documents.

Investigation Program, RCS MED-300(RI), as determined by the approving authority and regulatory agencies.

( 4 ) I'repare and file an investigator sponsored IND (Investigational New Drug) or IDE (Investigational Device Exemption) as appropriate.

(5) Promptly notify the approving official through the medical monitor and the Human Use Committee of adverse effects caused by the clinical investigation. Report serious and unexpected adverse experiences involving the use of investigational drugs or devices to the sponsor or the FDA in accordance with AR 40-7. Ensure that the clinical investigation has been approved by the proper review committee(s) before starting, changing, or extending the investigation.

( 8 ) Ensure that all subjects or their representatives, including subjects used as controls, are fully informed of the nature of the investigation to include potential risks to the subject.

( 9 ) Ensure that investigational drug6 or devices are administered only to subjects under the investigator's personal supervision or that of a previously approved associate investigator.

cannot complete the clinical investigation for reasons such as permanent change of station or retirement.

(11) Apprise the Human Use Committee of any investigator's noncompliance with the clinical investigation.

(12) Seek Human Use Committee approval for other investigators to participate in the clinical investigation.

(13) Ensure that studies involving attitude or opinion surveys are approved in accordance with AR 600-46.

( 3 ) Prepare progress reports, including annual reports (Clinical

(6)

( 7 )

(10) Ensure that a new principal investigator (PI) is appointed if the PI

, . # -;?./& pt f c,

signature of%incipal Investigator Date

I have reviewed this protocol with the investigators for: a. scientific merit b. experimental design c. expenditure of money and manhours

rds in the use of human subjects

d with my full support and approval.

l . y L s \ Sigrwtdkd' of Departmentkhief Date

Enclosure 5

GYNECOLOGIC ONCOLOGY GRGUP ADMINISTRATIVE OFF1 CE 1234 MARKET STREET SUITE 1945 PHILADELPHIA, PA 19107 215-854-0770 FAX 215-854-0716

loberl C. Park, M.D. ;?airman

John R. Kellner Ad mini sr ra 1 ive Director

PROTOCOL GOG r '123

A R A N D O M I Z E D C O M P A R I S O N O F R A D I A T I O N T H E R A P Y 6 A D J U V A N T H Y S T E R E C T O M Y V E R S U S R A D I A T I O N T H E R A P Y AND WEEKLY C I S P L A T I N AND A D J U V A N T H Y S T E R E C T O N Y

IN P A T I E N T S WITH BULKY S T A G E I B C A R C I N O M A O F T H E C E R V I X

( P t i R S E 111)

( P O I N T S - 6 )

STUDY C H A I RMAK

HENRY B. K E Y S , M . D . ALBANY M E D I C A L C O L L E G E

O F UNION U N I V E R S I T Y D E P A R T M E N T OF R f i D I A T I O N O I C O L O G Y

A L B A N Y , NEW YORK 12208 47 NEN S C O T L A N D A V E N U E (14-809)

(516) 445-5807

S T U D Y CO-Cf iAIRMfiN

D E E O R A E G E R S E L L , M.D. DEPAiiTPIEtiT O F P A T H O L O G Y WSti i NGTON UN I V E ES I T Y S C H O O L OF K E D I C I N E 4911 BA2,NES H O S P I T A L P L A Z A ST. LOUIS, NISSOURI 63110 ( 3 1 4 ) 352-0115

F R E D E R i C E STEHMAN, @.El. D E P A R T b E N T O F OB/GYK I N D I A N F . lX1 V E i i S I T Y M E D I C A L C E N T E R 926 K E S T M I C H I G A R S T R E E T IXD;AN4"OLIS, I N D I A N A 46202 ( 3 2 7 ) Z74-2654

S A R A H L I N C O L N , l'8.D. RUSE-PRESBYTERIAK ST. L U K E ' S M E D I C A L C E N T E R 1753 k'. C O N G R E S Z PARKWAY C H I C A G O , I L 60612 ( 3 1 2 ) 942-5904

N U R S E COh'TACT

L O K R A I t t E D E N N I S , R . N . D E P A R T M E N T OF O B / G Y N . D I V I S I O N OF GYN ONCOLOGY ALGANY M E D I C A L C O L L E G E

OF U N I O N U N I V E R S I T Y 47 NE14 S C O T L A N D AVENUE A,L?F\NY, FIY 12206 (5:s) 445-5025

OPEfi TO PATIENT EI.:TP,\: FEBRLIGR'I' 2 4 , 1992 RE\ ' ISED I-iA2CH S i , i C 9 2

R E V I S E D J U L Y 2 , 1902 R E V I S E D S E P T E M B E R 11, 19Ci

A PROGRAM OF THE At4ERICCG COLLEGE OF O a S T E i R I C l A N S A R D GYNECOLOGISTS

GOG #123

S C H E M A

BULKY STAGE I - B 1 SQUAMOUS CELL CARCINOMA ADENOCARCINOMA OR ADENOSQUAMOUS CARCINOMA

EXTERNAL RADIATION, INTRACAVITARY RADIATION PLUS EXTRAFASCIAL HYSTERECTOMY

7

EXTERNAL RADIATION, PRETREATMENT STAGING INTRACAVITY RADIATION

WEEKLY CISPLATIN :: PLUS

P EXTRAFASCIAL HYSTERECTOMY 0 S E ?

- I T I V E i FNA OR SURGICAL STAGING

b I

P 0 S I T I v E

OTHER STUDY

7500 PT A 5500 PT E

:: ONE WEEK ECjUAiS ONE CdURSE

I

1 Def ined i n s e c t i o n 3.11

GOG #123

TABLE OF CONTENTS

PAGE

1.0 OBJECTIVES

2.0 BACKGROUND AND RATIONALE

3.0 PATIENT ELIGIBILITY AND EXCLUSIONS

3.1 Eligible Patients 3.2 Ineligible Patients

4.0 STUDY MODALITIES

5.0 TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE

6.0 TREATMENT MODIFICATIONS

7.0 STUDY PARAMETERS

8.0 EVALUATION CRITERIA

9.0 DURATION OF STUDY

10.0 STUDY MONITORING AND REPORTING PROCEDURES

11.0 STATISTICAL CONSIDERATIONS

12.0 BI8LIOGRAPHY

APPENDIX I - GOG COMMOR TOXICITY CRITERIA APPENDIX I1 - GOG PERFORMANCE SCALE APPENDIX 111 - CLINICAL STAGING (FIGO) APPENDIX IV - PARA-AORTIC NODE SAMPLING PROCEDURE APPENDIX V - EXTRAFASCIAL HYSTERECTOMY PROCEDURE APPENDIX V I - PERCUTANEOUS FINE NEEDLE ASPIRATION APPENDIX VI1 - FAST FACT SHEET

3

3 3

5

10

13

15

15

16

19

2 1

SUGGESTED PATIENT INFORMATION/INFORMED CONSENT

-1- GOG #123

1.0

2.0

OEJECTIVES

1.1 To determine i f weekly c i s p l a t i n infus ion improves l o c a l reg iona l con t ro l and su rv iva l when added t o r a d i a t i o n therapy p lus e x t r a f a s c i a l hysterectomy.

To determine the r e l a t i v e t o x i c i t i e s of t hese two t r ea tmen t arms. 1.2

BACKGROUND AND RATIONALE

Tumor volume i s one of t he most important prognos t ic f a c t o r s i n a l l h u m a n mal ignancies and c e r t a i n l y ce rv ica l carcinoma i s no excep t ion . [ l ] The c l i n i c a l s t ag ing system used by the M . D . Anderson Hospi ta l i n Houston, Texas f o r c e r v i c a l carcinoma, in f a c t , i s based on the combination of e x t e n t of tumor spread and s i z e of tumor.[Z] Within each of t h e FIG0 S tages of d i sease l a r g e r and more ex tens ive tumors c a r r y a h ighe r f a i l u r e r a t e and a r e more d i f f i c u l t t o t r e a t w i t h whatever modal i ty i s used. I n Stage IB ce rv ica l carcinoma l a r g e r o r bulky tumors, inc luding those descr ibed a s "ba r re l shaped", a r e demonstrably more d i f f i c u l t t o cure with primary su rg ica l t reatment . [3] The use of r a d i a t i o n therapy f o r S tage I B carcinoma of t h e ce rv ix i s gene ra l ly e f f e c t i v e but has a poorer t r a c k record i n providing c e n t r a l d i sease cont ro l w i t h i n t h e primary s i t e i t s e l f . T h u s t h e r e has developed cons iderable l i t e r a t u r e suppor t ing t h e concept of adjuvant hysterectomy a f t e r r a d i a t i o n therapy i n l a r g e c e r v i c a l carcinomas.[4] t e s t e d in c u r r e n t GOG Protocol # 7 1 i n a randomized Comparison w i t h s t a n d a r d r a d i a t i o n therapy alone.[5]

The r o l e . of t h i s ad juvant hysterectomy approach i s being

Pre l iminary da t a from Protocol 8 7 1 i n d i c a t e s a f a i r l y probable outcome o f increased loca l con t ro l in t h e combined r ad ia t ion /ad juvan t hysterectomy t r ea tmen t arm with unce r t a in e f f e c t on surv iva l a t t h i s point . [5]

There i s accumulating experience w i t h t he use o f r a d i a t i o n i n combination with c i s p l a t i n a lone o r c i s p l a t i n and o t h e r drug combinations. Protocol #85 compares r a d i a t i o n p l u s Hydroxyurea vs. r a d i a t i o n p l u s c i sp la t in /5FU in fus ion therapy f o r l o c a l l y advanced c e r v i c a l carcinoma.[6] This protocol has demonstrated accep tab le t o x i c i t y f o r t h i s combination t r ea tmen t apprczcn and a t l e a s t a sugges t ion of more rap id tumor response with unce r t a in e f f e c t on u l t ima te l o c a l tumor c o n t r o l . Another approach t h a t h a s been used by a number o f i n v e s t i g a t o r s a t Roswell Park,[7] Un ive r s i ty o f Minnesota,[8] and Albany Medical College,[9] i nc ludes the use of weekly c i s p l a t i n in fus ion w i t h convent ional f r a c t i o n a t e d r a d i a t i o n therapy in ex tens ive d i s e a s e . Again both publ ished r e p o r t s and unpublished exper ience have ind ica t ed good t o l e r a n c e and response in p a t i e n t s with

metas tases have experienced n o r e l a p s e s in e i t h e r t h e i r pe lv i c d i s e a s e or i n t he p a r a - a o r t i c a r e a s . [ 9 3

Current GOG

. c e r v i c a l carcinoma. GOG p a t i e n t s w i t h p o s i t i v e p a r a - a o r t i c nodal

- 2 - GOG #123

I n t h i s s tudy we t o compare the add i t ion of weekly c i s p l a t i n infus ion with the c u r r e n t apparent b e t t e r arm o f Protocol 4'71: r a d i a t i o n therapy plus ad juvant hysterectomy i n p a t i e n t s with bulky Stage IB carcinoma of the c e r v i x . e f f e c t a s the s i n g l e most e f f e c t i v e drug c u r r e n t l y a v a i l a b l e f o r use in squamous c e l l carcinoma of the cerv ix and i t s demonstrated r a d i a t i o n s e n s i t i z i n g e f f e c t . The use of a weekly program during e x t e r n a l a n d i n t r a c a v i t a r y r a d i a t i o n therapy should accentua te i t s r a d i a t i o n s e n s i t i z i n g e f f e c t s and may be respons ib le fo r the h i g h r a t e of l oca l con t ro l seen i n r e l a t i v e l y small numbers of p a t i e n t s t r e a t e d t h u s f a r .

The r a t i o n a l e f o r t he use of c i s p l a t i n i s the combination of i t s

3.0

- 3- GOG # i 2 3

PATIEKT ELIGIBILITY AND EXCLUSIONS

3 . 1 E l i g i b l e P a t i e n t s

3.11 P a t i e n t s with pr imary, prev ious ly un t r ea t ed , h i s t o l o g i c a l l y confirmed invas ive squamous c e l l carcinoma, adenocarcinoma, o r adenosquamous carcinoma of t h e u t e r i n e ce rv ix S tage IB who have l a r g e bulky l e s i o n s a s fo l lows:

3.111 Lesions 2 4 cm 3.112 Barrel shaped l e s i o n s

3.12 Pe lv i c and/or pa ra -ao r t i c lymph nodes must be r a d i o g r a p h i c a l l y o r s u r g i c a l l y nega t ive . I f CT scan o r lym hangiogram i s p o s i t i v e o r susp ic ious , f i n e needle a s p i r a t i o n (FNA P cytology o r h i s t o l o g i c a l confirmation of pe lv i c and/or pa ra -ao r t i c nodes must be nega t ive .

3.13 P a t i e n t s with adequate bone marrow funct ion: WBC equal t o o r g r e a t e r than 3,000 per m l ; p l a t e l e t s equal t o o r g r e a t e r than 100,000 pc: ml.

3.14 P a t i e n t s with adequate renal func t ion : c r e a t i n e equal t o o r ' l e s s than 2 . 0 mg pe rcen t .

3 .15 P a t i e n t s with adequate hepa t i c func t ion : b i l i r u b i n , a n d SGOT equal t o o r l e s s than two times normal.

3.16 P a t i e n t s who have met t h e pre-en t ry requirements s p e c i f i e d in Sec t ion 7.0.

3.17 P a t i e n t s who have signed a n approved informed consen t .

3.18 P a t i e n t s must be en tered wi th in e i g h t weeks o f d i a g n o s i s .

3.2 I n e l i g i b l e P a t i e n t s

3 .21 P a t i e n t s w i t h r e c u r r e n t carcinoma o f t he u t e r i n e c e r v i x r ega rd le s s o f previous t r ea tmen t , o r cancers o t h e r t h a n squamous c e l l , adeno-squamous o r adenocarcinoma.

3.22 P a t i e n t s who have n o t been o r cannot be adequate ly c l i n i c a l l y s taged .

3.23 P a t i e n t s who had any previous pe lv i c r a d i a t i o n o r have rece ived systemic chemotherapy.

3.24 P a t i e n t s whose circumstances wi l l not permit completion o f t he s tudy o r r equ i r ed f o l 1 ow-up.

3.25 P a t i e n t s with GOG performance s t a t u s of grade 4.

3.26 P a t i e n t s w i t h p rev ious o r concomitznt o t h e r mzl ignancies except non-me1 anoma s k i n cance r s .

-4- 6;)" 7 A - J

3 .27 P a t i e n t s with his tc l -og-icdl ly confirmed malignancy o u t s i d e of t r i e cerv ix .

3.28 P a t i e n t s w i t h previous p a r t i a l or t o t a l hysterectomy.

3 .29 P a t i e n t s who a r e deemed medically inoperable .

4.0 STUDY MODALITIES

A l l e l i g i b l e p a t i e n t s w i l l undergo c l i n i c a l s tag ing as permi t ted by the FIG0 r u l e s (Appendix 1 1 1 ) . I t wi l l be opt ional f o r p a t i e n t s t o undergo pre-randomization su rg ica l s tag ing t o include e x t r a p e r i t o n e a l sampling of pe lv ic a n d / o r pa ra -ao r t i c lymph nodes (Surgical Procedures Nanual , Appendix I V ) .

4.1 Pre-opera t ive C l in i ca l Staging

P a t i e n t s wi l l have a ches t x-ray a n d a n abdominal p e l v i c CT scan w i t h in t ravenous c o n t r a s t . I V P a n d lymphangiogram a r e o p t i o n a l . Pe lv ic examination i s requi red . Cystoscopy a n d sigmoidoscopy a r e t o be performed when c l i n i c a l l y ind ica t ed .

4 . 2 Surgical Procedures

4.21 Surg ica l Staging

E x t r a pe r i tonea l pe lv ic a n d / o r pa ra -ao r t i c node sampling- i s op t iona l ( s e e schema). These p a t i e n t s can be s taged i n a manner s i m i l a r t o t h a t performed f o r Stage IIB - I V c e r v i c a l carcinoma. Pe lv ic nodes below the mid common i l i a c area need n o t be sampled.

4.22 Ex t ra fa sc i a l hysterectomy, adnexectorny and intra-abdominal exp lo ra t ion w i l l be performed 3 t o 6 weeks fo l lowing completion o f the r a d i a t i o n therapy. The su rg ica l procedure i s ou t l ined i n Appendix V.

Revised 9 /11/92

-6 -

4.33 R a d i a t i o n Zwrces

R a d i a t i o n sources employed i n these c l i n i c a l t r i a l s w i l l be x-ray generaLors which produce x-ray beams w i t h a p h o t o n energy of 4 KeV or more, p referab ly with t reatment d i s t ances of 100 cm or more.

4 . 3 4 External R a d i a t i o n Fields

Radiation f i e l d dimensions w i l l follow the gu ide l ines ou t l ined i n the Radiation Therapy Procedures Eanual. w i l l be t h r o u g h the L4/5 i n t e r space. La tera l margins w i l l be 1 cm or more beyond the l a t e r a l margins of the bony p e l v i s and the i n f e r i o r border w i l l be a t the i n f e r i o r border o f t h e o b t u r a t o r foramen o r below the lowest extension o f d i sease w i t h a n adequate margin, whichever i s t h e lowest .

The s u p e r i o r border

For the l a t e r a l f i e l d the a n t e r i o r f i e l d should be a horizontal l i n e drawn a t t he a n t e r i o r border of the symphysis pub i s , a n d t h e p o s t e r i o r border should be a horizontal l i n e drawn t h r o u g h the i v f o r i o r a n t e r i o r m a r a i n o f 52 . The supe r io r i n f e r i o r borders o f t he l a t e r a l f i e l d s w i l l be a t the same loca t ion 2s the a n t e r i o r a n d p o s t e r i o r f i e l d s .

A fou r f i e l d technique w i l l be used f o r a l l p a t i e n t s . Normal t i s s u e s not requi r ing t reatment should be sh ie lded where poss ib l e . d i a g r a m .

The recommended blocking i s shown i n the f i e l d

Recommended Elockincj Arrangement Field

ANTERIOR POSTERIOR LATEKAL

4.35 Required K a t e r i a i i 2d>zi j> ic : :

GOG Forms G a n d I should be completed a n d submitted a t the completion of therapy. the s imulat ion and por ta l v e r i f i c a t i o n f i lms as well a s copies of t he implant l o c a l i z a t i o n f i lms . t reatment summary, dosimetry and ca l cu la t ions should a l s o be submit ted.

They should be accompanied by copies of

A copy of t h e t rea tment r eco rd ,

4.36 Radiation Therapy Qual i ty Control a n d Documentation

The Radiologic Physics Center , under the sponsorship of the American Associat ion of P h y s i c i s t s i n Medicine, w i l l supe rv i se the dosimetry con t ro l f o r t h i s c l i n i c a l t r i a l . To p a r t i c i p a t e in the t r i a l the i n s t i t u t i o n s must demonstrate the a b i l i t y t o achieve a n accuracy o f 53% i n measuring the ou tpu t of t h e i r sources and 55% i n d e l i v e r i n g t h e prescr ibed dose.

4 . 4 Chemotherapy

4 . 4 1 C i s p l a t i n (P la t ino le ’ - FISC +119875)

4 . 4 1 1 Formulation: C i s p l a t i n i s ava i l ab le 2s a dry powder suppl ied in 10 rng and 50 mg v ih ls a n d i n aqueous s o l u t i o n in 50 mg and 100 mg v i a l s with 100 mg mannitol and 90 mg sodium c h l o r i d e .

4 . 4 1 2 P repa ra t ion : The 10 mg a n d 50 mg v i a l s should be r e c o n s t i t u t e d w i t h 10 rnl or 50 ml s t e r i l e water f o r i n j e c t i o n , USP r e s p e c t i v e l y . Each m l of t h e r e s u l t i n g s o l u t i o n w i l l conta in 1 mg o f P l a t i n o l . Recons t i t u t ion as recommended r e s u l t s i n a c l e a r c o l o r l e s s s o l u t i o n .

NOTE: Alurriinum r e a c t s with P lz t ino l causing p r e c i p i t a t i o n formation and lo s s o f potency. Therefore , needles o r intravenous s e i s coniz in ing aluminum p a r t s t h a t may come in c o n t a c t w i z h the d r u g must not be used f o r t he p repa ra t ion o r admin i s t r a t ion o f P ; a t i n o l .

?,?vi sed 5 /11/92

.. -a- GOG #123

4.413 Storaae : Unopened v i a l s of dry powder a r e s t a b l e f o r t he m e indica ted on the package when s t o r e d a t room temperature. The aqueous so lu t ion should be s t o r e d a t room temperature a n d protected from l i g h t . r e c o n s t i t u t e d so lu t ion i s s t a b l e f o r 20 hours a t room temperature .

The

- NOTE: Once r e c o n s t i t u t e d , the s o l u t i o n should be kept a t room temperature. I f t he r e c o n s t i t u t e d s o l u t i o n i s r e f r i g e r a t e d , a p r e c i p i t a t e w i l l form.

4 . 4 1 4 Adverse e f f e c t s : Leukopenia, thrombocytopenia, anemia nausea, vomiting, nephro toxic i ty , o t o t o x i c i t y , per iphera l neuropathy, e l e c t r o l y t e imbalance, hypocalcemia, hypomagnesemia, aminoglycoside o t o t o x i c i t y , ocu la r t o x i c i t y , and a l l e r g i c r eac t ions . Infre uent : Cardiac abnorma l i t i e s , anorexia , e levated S&and a lopec ia .

- NOTE: Aminoglycoside a n t i b i o t i c s given b e f o r e , w i t h , o r a f t e r c i s p l a t i n may p o t e n t i a t e rena l t o x i c i t y and should be avoided whenever poss ib l e .

Severe renal t o x i c i t y can be l a r g e l y avoided by induct ion of a d i u r e s i s be fo re , during and a f t e r t r ea tmen t .

Mild renal dysfunct ion i s a common complicat ion (10%) of chronic therapy a n d may r equ i r e d i s c o n t i n u a t i o n of therapy i f B U N > 30 mg/dl or c r e a t i n i n e > 2.0 mg/dl develop.

Mild o r severe e l e c t r o l y t e abnormal i t ies may occur (5%) a s acu te or chronic complicat ions, e s p e c i a l l y hypokalemia o r h omaqnesemia. Monitoring of e l e c t r o l y t e s and 9-r- e e c t r o y t e replacement wi l l u sua l ly c o r r e c t t h e s e abnorma l i t i e s . Rarely, severe hypomaanesemia and hypocalcemia may r equ i r e replacement therapy and d i scon t inua t ion of t rea tment w i t h c i s p l a t i n .

A l l e r g i c r eac t ions a r e r a r e . r e s p i r a t o r y symptoms , a1 l e r g i c r e a c t i o n s r e q u i r e

I f accompanied by

d i s c o n t i n u a t i o n of t rea tment . Patch o r skin t e s t s a r e recommended f o r p a t i e n t s w i t h suspected a l l e r g y t o c i s p l a t i n . r e a c t i o n s should be a v a i l a b l e in t h e t rea tment a r e a .

A n emergency s e t f o r t h e t rea tment o f a l l e r g i c

Local nec ros i s a n d thrombophlebi t is can be avoided by ca re fu l admi ni s t r a t i on -

Neurotoxic i ty may be r e l a t e d t o cumulat ive dose and severe t o x i c i t y can be l a r g e l y avoided by ca re fu l monitoring f o r evidence o f pares thes i2s a n d t imely d i s c o n t i n u a t i o n o f t r ea tmen t . Ataxia has been desc r ibed .

-9- GOG #123

Ototoxicity may occur.

NOTE : __.

Eighth (VIII) nerve toxicity resulting in hearing loss and (less commonly) vestibular symptoms, i s a well-documented complication of cisplatin treatment and is usually related t o total cumulative dose. It is advised that patients placed on cisplatin, whether as a single agent therapy or combination, be questioned concerning hearing loss. Patients with a history of hearing loss should be considered for pre-treatment audiometry with follow-up audiometry as clinically indicated. It is recommended that patients be queried concerning hearing loss before each course of cisplatin.

4.415 Supplier: Bristol

4.416 Administration: 500 ml of 4 normal or f normal saline should be infused intravfiously one hour before.cisplatin. Increased oral intake should be encouraged starting' the day before. Additional fluid may be given as needed for symptomatic support. Cisplatin will be dissolved in sterile water, 1 mg/ml. The dosage to be given will be 40 mg/m2 up to 70 mg cisplatin maximum, to be given once per week during external radiation on a day when radiation will be delivered, and once during intracavitary cesium application(s). A maximum of six doses of cisplatin will be given. mg/min. Immediately after completion of the cisplatin infusion, an additional 500 ml of 4 normal or 3 normal saline should be infused over 1 hour, This is the minimum fluid administration recommendation and more fluid may be given at the discretion of the treating physician.

The solution should be infused at a rate of 1

4.5 Pathology

4.51 Required piithology materials and representative stained slides showing documentation of invasive cancer should be submitted along with a copy of the pathology report from a participating institution.

-10- GOG $123

~ 5.0 TREATMENT PLAN A N D E N T R Y / R A N D O M I Z A T I O N P R O C E D U R E

An o r i g i n a l , signed Form HHS-596, i n d i c a t i n g p r i o r approval by t h e i n s t i t u t i o n ' s Human Rights or C l i n i c a l T r i a l s Cormnittee f o r p a r t i c i p a t i o n i n t h i s s tudy m u s t be forwarded t o the GOG Administrative Off i ce before p a t i e n t e n t r i e s onto the s tudy w i l l be accepted. t he informed consent being used ( i f i t d i f f e r s from t h e suggested f o r m appended t o the p ro toco l ) o r a l e t t e r from the P r inc ipa l I n v e s t i g a t o r s t a t i n g t h a t t h e suggested form i s being used, must accompany the HHS-596 Form.

I n a d d i t i o n , a copy o f

5.1 Telephone Entry

When a s u i t a b l e candida te has been obtained f o r protocol e n t r y , the following s t e p s s h o u l d be taken:

5.11

5 .12 Make c e r t a i n a l l e l i g i b i l i t y requirements according t o Sec t ion

A Consent Form m u s t be signed by the p a t i e n t o r guardian. , -

3.0 have been met.

5.13 Fast Fact Sheet da ta should be ga thered . W i t h t h i s d a t a i n h a n d , the GOG O f f i c e should be c a l l e d v ia t h e "WATS" l i n e : i-800-523-2917, Munday througtl Fr iday , 3 am t o 5 pm EST/EDT.

5 .14 EntrylRandomization w i l l t ake p lace on the te lephone a f t e r cons ide ra t ion o f Fas t Fact Sheet da t a .

5 .15 T h e i n s t i t u t i o n w i l l e n t e r t he p a t i e n t ' s name, GOG number, a n d assigned regimen i n t h e appropr i a t e place i n t h e i r L o g Book t o v e r i f y t h e p a t i e n t ' s e n t r y .

5.2 Treatment Plan a n d Entry/Randomization Procedure

5 . 2 1 Regimen I - Radiat ion Therapy Plus A d j u v a n t Hysterectomy ( s e e Sec t ions 4 .2 and 4 . 3 )

After randomizat ion, p a t i e n t s w i l l undergo combined ex te rna l and i n t r a c a v i t a r y r a d i a t i o n therapy followed by e x t r a f a s c i a : hysterectomy. Total doses of 7500 cGy t o po in t A a n d 5500 cGy t o p G i n t i? wi l l be achieved u s i n g combined ex te rna l a n d one o r two i n t r a c a v i t a r y a p p l i c a t i o n s fol lowing which t h e e x t r a f z s c i a l hysterectomy w i l l be c a r r i e d out no l a t e r t h a n s i x weeks fol lowing the i d s t day of t rea tment ( s e e Appendix V f o r d e s c r i p t i o n a n d s u r g i c a l p rocedure) .

5 . 2 2 Regimen I! - Radiat ion Therapy Plus Weekly C i s p l a t i n Infus ion Plus E x t r z f a s c i a l Hysterectomy ( s e e Sec t ions 4.3 a n d 4 . 4 )

Afte r randomization p a t i e n t s wi l l undergo r a d i a t i o n therapy t o rece ive a t o ~ a l dose o f 7500 cGy t o po in t A and 5500 cGy t o po in t

6 U S l h c a cbmtiination o f externa l a n d I n t r a c a i ;;dry radiat ' lor . therapy: t h e i n t r a c 6 v i t a r y app l i ca t ions the p a t i e n t v!ill r ece ive 2 n Infus ion o f c i s p l a t i n 40 n i g / m 2 n o t t o exceed 70 m g mximum i n dny Single i n f u s i o n , u p t o a maxi inurn o f 6 doses of c i s p l a t i n .

Each week'during external r a d i a t i o n therapy and d u r i n g

5 .23 Treatment o f P a t i e n t s with Pos i t ive Pa ra -ao r t i c Lymph Nodes

P a t i e n t s found t o have pos i t i ve para-aor t ic lymph nodes a t pre- t reatment f i n e needle a s p i r a t i o n o r e x t r a p e r i toneal Surg ica l node sampling a re not e l i g i b l e f o r t h i s protocol and must not be en tered o n t h i s s tudy .

P a t i e n t s found t o have pos i t i ve pa ra -ao r t i c lymph nodes a t t he time o f pos t - r ad ia t ion e x t r a f a s c i a l hysterectomy may be t r e a t e d a t t he d i s c r e t i o n o f the inves t iga to r . add i t iona l treatirient must be provided oil Q tornis.

Documentaticn of

6 . 0 J R EATME NT MOD I F I C A T I Of4 S

6 . 1

6 . 2

6 . 3

5 .4

C l in i ca l S tag ing

There N i l 1 be no c l i n i c a l s t ag ing modif icat ions. '

Surg ica l Procedures

P re- t rea trnen t ex t r ape r i toriea 1 s t a g i n g 1 ymp h a deriec tomy i s opt i ona 1 i n t h i s s tudy . I f performed i t i s t o be performed according to the GOG Surgica l Procedure fclariual Guide1 ines a s provided i n Appendix I\ ' . The e x t r a f a s c i a l hysterectomy t h a t i s t o be done a f t e r r a d i a t i o n therapy s h o u l d be performed a s descr ibed in Appendix V .

Radi o the rapy Procedures

t r e a t m e n t may be i n t e r r u p t e d f o r u p t o one week f o r Grade 3 o r 4 a a s t r o i r i t e s t i n a l or hematologic t o x i c i t y . -

Chemotherapy Procedures

Cisplatin infusion61 therapy should be modified a s o u t l i n e d below

6.4 1 C i sp 1 a t i n Modi f i ca t i ons

6.411 Rausea a n d Vomiting

kni iernet ics o f the i n v e s t i g a t o r ' s choice should be used p r o p h y l a c t i c a l l y .

6 . 4 1 2 Lena1 kcverse Effec:j I

? f c r e a t i n i n e r i s e s t o g r e a t e r t h a n 2.0 rng:, ob ta in c r e a t i n e c learance ( C c r ) . I f Ccr i s 50 rnl/rnin o r g r e a t e r , cont inue therapy. I f t he Ccr i s l e s s than 50, hold c i s p l a t i n t reatment a n d check Ccr weekly. When t h e Ccr i s 50 or more o r the serum c r e a t i n i n e i s l e s s t h z n o r equal t o 2 . 0 m g x , resume therapy w i t h a decrease o f 50% in c i s p l a t i n dose. c r e a t i n i n e g r e a t e r than 2.0 mg% f o r more than 4 weeks requi res n o t i f i c a t i o n o f the Study Chairman a n d Group C h a i r m a n a n d removal o f p a t i e n t from s tudy .

Pe r s i s t ence of Ccr l e s s than 50 or serum

S e l e c t i v e renal t ubu la r de fec t s a r e sometimes observed. Fypocal cenii a w i t h hypomagnesemi a a n d hypokal emi a a r e common a n d p o t e n t i a l l y severe . calcium a n d potassium a r e usua l ly e f f e c t i v e . . Severe tubu la r d e f e c t s , al though r a r e , may r e q u i r e chronic replacement therapy. mechani sins of hypocalcemia ( f o r example, G I o r melabol i c should be considered.

6 . 4 1 3 Hematologic Adverse Ef fec t s

Replacement of magnesium,

Diagnost ic t e s t s f o r a l t e r n a t i v e

C i s p l a t i n s h o u l d be withheld f o r WBC l e s s than 3,00O/mcl The blood count should be repeated and c i sp l a t i n weekly dose resumed when the WBC reaches 3,00O/mcl. Radiat ion t r ea tmen t s , inc luding i n t r a c a v i t a r y implant , should cont inue unless KBC drops below 1,00O/mcl, a t which po in t r a d i a t i o n t rea tments should be suspended u n t i l WBC i s again above 1,00O/mcl.

-13- GOG 6123

7.0 STUDY PARAMETERS AIU'D SERIAL OBSERVATIONS

7 . 1 Observations a n d Tests

The following observat ions a n d t e s t s a r e t o be performed and documented on the appropr ia te form:

P r io r t o D u r i n g Radiation Therapy Week1 Y - Tests 8 Observations Treatment

Physical Examination X X 3

Tumor Measurements in 0.5 cms, with Cal ipers and Centimeter Rule X

Cervical Biopsy C l i n i c a l Staging

X X

Diagnost ic T e s t s : Chest X-Ray X CT Scan with Contrast ' X IVP' 1 cystoscopy 1

C B C D i f f e r e n t i a1 P l a t e l e t s Crea t in ine SGOT A 1 kal ine Phosphatase B i l i r u b i n Audiometry

Lymph Node Assessment by h e of t he Following Tes ts : X

- Surgical Staging** - Lymphangiogram w / w i t h o u t

Fine Needle Aspiratio:' - CT Scan with Contrzst

2

3 3

3 X X x

* Requirement s a t i s f i e d i f t e s t was done pre-entry a n d included p a r a - a o r t i c a n d h i g h common i l i a c nodes ( see Sec t ion 3 .12 ) .

** See s e c t i o n 4.21 4- Mus: be repor ted on Form D .

Optional 1 2 Or a t t he time o f i n t r a c z v i t a r y i r r a d i a t i o n . 3 Follow-up q 3 months x 2 years then q 6 months x 3 years

Y

7 . 2

.c

- 1 4 - GOG #123

Adverse Ef fec t s Reporting Procedures

The adverse r eac t ion must be reported t o b o t h N C I and GOG. fol lowing guide l ines must be followed:

The

- NCI - The requirement f o r t imely repor t ing of adverse events f o r commercial agents s h o u l d be reported t o the I n v e s t i g a t i o n a l Drug Branch, Cancer Therapy Evaluation Program, within 10 working days.

7.21 Any ADR which i s both s e r i o u s ( l i f e t h rea t en ing , f a t a l ) a n d .

unexpected.

7 . 2 2 Any increased incidence o f a known ADR which has been repor ted i n the package i n s e r t or t h e l i t e r a t u r e .

7 .23 Any death on study i f c l e a r l y r e l a t e d t o t he commercial a g e n t ( $ ) .

7.24 Report t h e ADR on Form FDA 1639. The form should be mailed t o :

Inves t iga t iona l Drug Branch

Bethesda, MD 20824 a n d

J Copies LO GOG Adminis t ra t ive O f f i c e

P . O . BOX-30012

- GOG - Prompt r epor t ing of a l l adverse events i s mandatory.

7.25 Adverse Drug Reactions

7.251 U n k n o w n Grade 2, 3, or 4 *

7.252 Known Grade 4 (except myel osuppression)

7.26 Complete GOG t o x i c i t y form.

7.27 Telephone GOG Adminis t ra t ive Off ice 1-800-225-3053.

-15- GOG + I 2 3

8.0 EVALUATION CRITERIA

8.1 Object ive Response

The major parameters o f response wi l l be complete c l i n i c a l c l e a r a n c e , p e r s i s t e n c e , time o f recur rence , length o f s u r v i v a l , and s i t e s o f recurrence.

8.11 Complete C l in i ca l Clearance

Complete c l i n i c a l c learance w i l l be recorded as observed and the dura t ion of time from the onse t o f therapy t o achievement of complete c l i n i c a l c learance o f tumor recorded.

8.12 Pe r s i s t ence

Response wi l l be assessed i n some cases by p e r s i s t e n c e , which i s def ined as da t e from e n t r y through t h r e e months a f t e r therapy without disappearance o f d i s e a s e .

8.13 Time t o Recurrence

Response wi l l be assessed by time t o recurrence which i s def ined as da t e from e n t r y t o protocol t o da t e of reappearance of d i s e a s e .

8.14 S u r v i v a l

Surgical w i l l be def ined as observed length of l i f e from e n t r y t o protocol t o d e a t h , o r f o r l i v i n g p a t i e n t s , the da t e of l a s t con tac t r ega rd le s s o f whether o r n o t th i s con tac t i s on 2 subsequent p r o t o c o l .

8.15 S i t e s o f Recurrence

Response w i l l be assessed by s i t e ( s ) o f recur rence e s p e c i a l l y l o c a l l y i n p e l v i c r eg ions , or d i s t a n t , in r e l a t i o n t o t h e o r i g i n a l d i sease p a t t e r n a n d t he therapy .

9.0 DURATION OF STUDY

9 . 1 I t i s est imated t h a t t he accrual phzse o f t h i s s tudy wi l l be f i v e y e a r s .

9 . 2 The p a t i e n t should be fol lowed, submi t t ing a Form Q q u a r t e r l y f o r t w o years and every s i x months f o r t h ree add i t iona l y e a r s .

-16- GOG #123

10.0 STUDY M O N I T O R I N G A N D REPORTING PROCEDURES

10.1 An o r i g i n a l , signed Form HHS-596, i nd ica t ing p r i o r approval by the i n s t i t u t i o n ' s Human Rights o r Cl in ica l T r i a l s Committee f o r p a r t i c i p a t i o n i n t h i s s tudy must be forwarded t o the GO6 Adminis t ra t ive Off ice before p a t i e n t e n t r i e s on to t h e s tudy wi l l be accepted. ( i f i t d i f f e r s from t h e suggested form appended t o the p ro toco l ) o r a l e t t e r from t h e Pr inc ipa l Inves t iga to r s t a t i n g t h a t t he suggested form i s being used, m u s t accompany t h e HHS-596 Form.

I n a d d i t i o n , a copy of t he informed consent being used

10 .2 A p a t i e n t consent form must be signed by the p a t i e n t o r guardian p r i o r t o s tudy e n t r y .

appropr i a t e GOG forms. A l l adverse reac t ions must be immediately repor ted t o the Adminis t ra t ive Off ice by phone: A l l adverse r eac t ions phoned in wi l l be immediately d i r e c t e d t o t h e Study C h a i r m a n f o r f u r t h e r a c t i o n . A t pe r iod ic i n t e r v a l s t h e GOG t o x i c i t y and t rea tment forms, along with t h e Study Chairman's a c t i o n s , a r e forwarded by t h e Adminis t ra t ive Of f i ce t o t h e GOG Data a n d Sa fe ty Monitoring Board, t o the Group Chairman, Study Chairman and medical onco log i s t ass igned t o t h a t p ro tocol .

All r epor t ing forms a r e p r in t ed i n mul t i -par t s e t s . Af te r completion of forms, remove the i n s t i t u t i o n a l copy and l o g in on a Transmit ta l form. Mail a l l forms a n d Transmi t ta l t o t h e GOG S t a t i s t i c a l Of f i ce . T ransmi t t a l s must a l s o accompany a l l shipments of s l i d e s a n d films.

10.3 A l l adverse r eac t ions (See Appendix I ) must be recorded on the

1-800-225-3053.

10.4 The following forms must be completed f o r a l l p a t i e n t s t h a t a r e en tered onto t h i s protocol and must be rece ived in t h e GOG S t a t i s t i c a l Off ice no l a t e r t h a n :

FOUR WEEKS AFTER ENTRY

- Form A ( P a t i e n t R e g i s t r a t i o n ) - Form D (Pre- t rea tment Summary Shee t ) - Form E (Anatomical Diagram o f Cl in ica l Tumor Locat ion)

SIX WEEKS A F T E R ENTRY

For Cervical Biopsy:

- Form C (Surg ica l Report ing Form) - Form F (Pathology Form) - Pathorogy Report Four copies o f the i n s t i t u t i o n ' s d i c t a t e d

p a t h o ] ogy r e p o r t . - S l i d e s Representa t ive s t a i n e d s l i d e s of t h e c e r v i c a l biopsy.

For FNA (F ine Needle A s p i r a t i o n )

- Form F (Pathology form) fo r negative FNA f o u r copies o f t he i n s t i t u t i o n ' s d i c t a t e d cytology r e p o r t .

-17-

For ex t r ape r i toneal node sampl i ng :

. GOG $123

Form C (Surgical Reporting Form) m i v e Report Three copies o f the i n s t i t u t i o n ' s d i c t a t e d ope ra t ive r epor t with a s epa ra t e in t roductory paragraph desc r ib ing c l i n i c a l as well as s u r a i c a l f i nd inas . Form F (Pathology Form)4 Pathology Report oatholoav reDort.

4

Four copies o f the i n s t i t u t i o n ' s d i c t a t e d

Discharge Summary - Three copies from the s t a g i n g su rge ry

- NOTE:

TWO WEEKS AFTER IhlITIATION OF TREATMENT

FORM F , PATHOLOGY REPORTS AND SLIDES - MUST BE SUBMITTED TOGETHER WITH ONE TRANSMITTAL.

- Form D-1 (Medical Treatment Reporting Form) - m u s t be completed and m-ed immediately a f t e r the i n i t i a l t rea tment and must be received no l a t e r t h a n two weeks a f t e r each t rea tment course . A course wi l l be considered every week.

E L E V E N WEEKS AFTER R A N D O M I Z A T I O N

- Form G (Radiat ion Therapy Form) - (Diagram of I r r a d i a t e d F ie lds ) - Two copies of t he d a i l y t rea tment records - Two copies o f the dosimetry c a l c u l a t i o n - Two copies of t he isodose d i s t r i b u t i o n curves , except f o r

p a t i e n t s t r e a t e d v i a AP-PA p o r t a l s a lone - One copy of t h e po r t a l f i lm f o r each ex te rna l f i e l d

( i . e . , A P , P A , l e f t l a t e r a l , r i g h t l a t e r a l , e t c . )

- NOTE: RADIATION THERAPY FORMS, REPORTS AND FILMS - MUST B E SUBMITTED TOGETHER KITH O N E TRANSMITTAL.

TEN WEEKS AFTER COMPLETION OF R A D I A T I O N THERAPY (FOR E X T R A F A S C I A L HYSTERECTOMY)

- Form C (Surg ica l Reporting Form) f o r t he e x t r a f a s c i a l hysterectomy

- Operat ive Report - Three copies o f t h e i n s t i t u t i o n ' s d i c t a t e d ope ra t ive r e p o r t from the e x t r a f a s c i a l hysterectomy

- Form F (Pathology Report) - Pathoiogy Report - Four copies o f t he i n s t i t u t i o n ' s d i c t a t e d

pathology r e p o r t from t h e e x t r a f a s c i a l hysterectomy. - S l i d e s - A s l i d e from each p o s i t i v e s i t e ( i nc lud ing any p e r s i s t e n t

cancer i n t h e c e r v i x ) - Discharae Surnmry Three copies of the d ischarge summary which

c l e a r l y summarizes t h e c l i n i c a l , su rg ica l and pa thologic f i n d i n g s , a s well as documents pos topera t ive recovery wi th s p e c i f i c documentation of presence o r absence o f wound c o n p l i c z t i o n s , o ther morbidi ty and m o r t a l i t y information ( s e e Appendix I , Adverse Ef fec t s C r i t e r i a ) .

'.- 18- GOG X123

TWO WEEKS AFTER VISIT

(Follow-up Form) must be completed and mailed wi th in two

- a change in therapy - progression i s documented - t he p a t i e n t ' s death - completion o f protocol therapy; then q u a r t e r l y f o r t h e f i r s t t w o

yea r s , semi-annually f o r an addi t iona l t h r e e y e a r s , a n d t h e r e a f t e r annual ly o r a t time o f recurrence u n t i l dea th .

- N O T E : Any add i t iona l t rea tment given a f t e r completion of protocol therapy must be documented on Q Forms.

.-19- 1 GOG #123

11.0 STKTJSTICAL CONSIDERATIONS

11.1 This study ass igns p a t i e n t therapy by randomization balancing assigned t reatment regimens within i n s t i t u t i o n . Entry a n d t r ea tmen t assignment wi l l be accomplished via te lephone a f t e r e l i g i b i l i t y i s v e r i f i e d using the f a s t f a c t s h e e t .

11.2 The pr inc ipa l parameters t o be c o l l e c t e d , analyzed and repor ted t o determine the e f f i c a c y of weekly c i s p l a t i n during r ad io the rapy :

11.21 Outcome va r i ab le s : recur rence- f ree ( R F ) i n t e r v a l , su rv iva l and local cont ro l r a t e

1 1 . 2 2 Tumor c h a r a c t e r i s t i c s

11.23 Host c h a r a c t e r i s t i c s

1 1 . 2 4 Adverse Ef fec t s ( f requency a n d s e v e r i t y )

11.25 Therapy adminis tered

11.3 The annual accrual i s 45 p a t i e n t s .

1 1 . 4 The hypothesis o f i n t e r e s t i s : "Does weekly c i s p l a t i n with r a d i a t i o n therapy improve the RF i n t e r v a l ( s u r v i v a l ) when compared w i t h r ad ia t ion a lone i n t h i s p a t i e n t population (1-s ided a l t e r n a t i v e hypothes is )? The R F hazard r a t e for the control aroup i s 0.009359/month ( i . e . t h e pe rcen t R F a t 1 , 2 , & 3 y e a r s a r e 89%, 80%, a n d 71%, respec t ive ly) [ l : . 0.005777/month ( i . e . , t h e pe rcen t RF a t 1 , 2 , & 3 y e a r s a r e 93%, 87X, and 81%, r e s p e c t i v e l y ) [ l ] by the use o f weekly c i s p l a t i n would be c l i n i c a l l y important improvement. This d i f f e r e n c e w i l l r e q u i r e the accruzl of 270 p a t i e n t s (and 36 months o f follow-up o r e q u i v a l e n t l y , 65 recurrences i n the con t ro l a rm)[2] . This wi l l produce a s t a t i s t i c a l power ( p r o b a b i l i t y of a t r u e - p o s i t i v e s tudy) o f 0.80 when keeDing the p r o b a b i l i t y of a type ? e r r o r a t .05. This sample s i z e w i l l y i e l d the same e r r o r p r o b a b i l i t i e s i f weekly c i s p l a t i n with r ad ia t ion therapy decreases the hazard r a t e f o r su rv iva l by 41% (based on h a z a r d r a t e f o r con t ro l group: 0.007709/mo. ) .

A 38% decrease i n t he R F hazard r a t e t o

11.5 The est imated accrual phase of t h i s s tudy i s 6 yea r s a n d t h r e e y e a r s of follow-up w i l l be requi red before f i n a l a n a l y s i s .

11 .6 There wi l l be t h r e e i n t e r i m ana lyses conducted when 135, 180 and 225 p z t i e n t s have been e n t e r e d . The goa l wi l l be t o i d e n t i f y a l a r g e improvement i n t h e R F r a t e zmong the weekly c i s p l a t i n group. The snter im iogr-rank t e s t s , a d j u s t i n g f o r i m p o r t a n t p rognos t ic f a c t o r s , w i l l be performed a t approximately 3 r d , 4 t h a n d 5 th yea r i n t o the accrual per iod . The c r i t i c a l values o f the ch i -square t e s t s t a t i s t i c a r e 5 . 3 5 , 4 . 6 0 , 4.35 and 2.71 ( a t f i n a l a n E l y s i s ) , r e s p e c t i v e l y . These c r i t i c a l values correspond t o t h e fol lowing p r o b a b i l i t i e s

- 20- GOG. 8123

c r i t i c a l values of t he chi-square t e s t s t a t i s t i c a r e 4 . 1 6 , 4 .16 a n d 2.71 ( a t f i n a l a n a l y s i s ) , r e spec t ive ly . correspond t o the following p r o b a b i l i t i e s (one-sided f avor ing the experimental therapy) : 0.021, 0.021 and 0.05. i nc rease the type 1 e r r o r from 0.050 t o 0.075[3).

These c r i t i c a l va lues

This s topping r u l e w i l l

1 Assuming the exponent ia l f a i l u r e time model.

2 P l a n n i n g the d u r a t i o n o f a comparative c l i n i c a l t r i a l w i t h l o s s t o follow-up a n d a period o f continued observation. Rubenstein, L F , Gzi.1 MH, Santner TJ, Journal of Chronic Diseases 34:469, 1981.

3 Determined t h r o u g h s imula t ion o f 5,000 t r i a l s .

. -21-

12.0 GIBLIOGRAPHY

1.

2.

3.

4 .

5 .

6.

7 .

8.

9 .

Fle t che r G H : "Cancer of t h e Uter ine Cervix" Am 3 Roentgenol. Ther. Nuc. Ned. 111:225-242, 1971.

R a d .

F l e t che r GH "Squamous c e l l carcinoma of t h e u t e r i n e ce rv ix" i n F l e t che r GH Textbook o f Radiotherapy. 3rd Ed. Lea & Feb ige r , Ph i l ade lph ia , 1980, p . 7 2 4 .

Perez C A , Breaux S , Madoc-Jones H , e t a l : "Radia t ion therapy alone i n the t rea tment of Carcinoma o f t h e u t e r i n e c e r v i x ; I , a n a l y s i s of tumor recur rence . Cancer 51:1393, 1983.

Nelson AJ, F l e t che r G H , Wharton T: Ind ica t ions for ad juvant conserva t ive hysterectomy in s e l e c t e d cases of carcinoma o f t he u t e r i n e c e r v i x , - AJR 123:91, 1975.

Keys H. Personal Communication, 1991.

Whitney CW. Personal Communication, 1991.

P iver MS, Shashikant L B , Malfetano JH. "Cisdiamminedichloroplatinum I 1 based c c m i n a t i o n chemotherapy f o r con t ro l o f ex tens ive p a r a - a o r t i c l y m p h node metastases i n cervicaT cance r " , Gynecol Oncol 26:71-76, 1987.

Pot i sh R A , Twiggs L8, Adcock L L , Savage A E , Prem W, L e v i t t SH. "Ef fec t o f c i s p l a t i n on to l e rance t o r a d i a t i o n therapy i n advanced c e r v i c a l cance r " , Am 3 Clin Oncol ( C C T ) 9:387-391, 1987.

Malfetano JH, Keys H . "Aggressive mult i rnodal i ty therapy f o r c e r v i c a l cancer w i t h involved p a r a - a o r t i c l y m p h nodes", Gynecol Oncol i n p r e s s .

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A P P E N D I X I 1 1

PRf-INVASIVf CARCINOMA

S T A G t 0: Carcinoma in situ, inrraepithelisl crrcinoma.

(Carer o f Stage 0 should no: bt includcd tn any therapeutic s t a t i s tics )

: N V A S l V E CkRCIHOHA

STAGE 1 :

S T A G E 11:

Carcinoma strictly confined Lo the cervix (extension t o the corpus should be disregarded).

S T A G E 1A: Preclinical carcinomas of the cervix. that is. those diagnosed only by microscopy.

S T A G E I X ! : Piintmrl microscopically evident strombl invasion

STAG[ l A 2 : Lesions detected microscopically that can be measured. The upper limit o f the measurement should not show a depth of invasion of more than 5 rrm taken from the base of the epithelium. either surface or glandular. from which it originates. and a sPc@nd dimension, the horizontal spreae. must not exceed 7 mn. Larger 1es)ons should be s t a g e d a s 18.

STAGE 18: Lesions o f greater dimensions than Staoe 1 A Z whcthrr seen clinically or not. invo)vemen; shculd not 21KCr rhe staging bul should be specificflly recorded so as t o determine whether 11 should affect treatment decisions in the fu :ure .

Preformed space

The Carcinoma extends beyond the cervix b u t has not extended on t o the pelvic wall. The c a r c i n m a tnvolvts the vsoina. but not the lover third.

STAGE I J A : No obvious parame;rial involvement.

STAGE I I E : Obvious parame:rial involvement.

The ccrtinomr h z s errended or, f c :he Delvi: v r l l . On r e c ; h l eraninc:ion. there I S no cancer-fret space between t h o :urnor and :he Deivic w r l ? . ; h e tumor involves the l ower I h I r C o r th? v d p i n r . A ; > c?ses with hydro-nepnrosis o r non- f u n c t ionlnq k idne?.

M o t e s on S t a c i n o

S t r g c 1 A c a r c l n m d s h o u l d i n c l u d e min jmdl m r c r o s c o p i c a l l y e v i d n t s r-1 i n v a s i o n a s Ucll as r u I 1 c a n c e r o u s t u m o r s o f n e c i u r a b l c s l z e . 5 t a g e I A s h o u l d bc s u b d i v i d e d I n t o those l e s i o n s w l t h m i n u t e f o c l o r l n v r s i o n v i s i b l e o n l y m l c r o s c o p l c a l l y a s S t a g e I A I and t h e m c r o r c o p i c a l l y n u a s u r a b \ t m i c r o c a m i n o m a s a s S t a g e I b 2 i n o r d e r t o g a i n f u r t h e r t n o r l e d g e o f t h e c l l n l c a l b e h a v i o r o f t h e s e l e s i o n s . 'The t e r n 1E o c c u l t s h o u l d b e t n i t t t d .

Tt*c dlagnosis o f b o t h S t a g e I A l a n d 1 A t s h o u l d . b c b a s e d on microscopic c x a r i n r t l o n of r e m v e d t i s s u e . p r e f e r a b l y a c o n e . w h i c h m u s t i n c l u d e t h e e n t i m l c r l o n . As n o t e d a b o v e . the lorer l i m i t of S t a g e I A Z should be t h a t I t c a n be m e a s u r e d n a c r o s c o p l c d ~ ~ y ( e v e n i f d o t s n e e d t o b e p l a c e d o n t h e s l l d e b e f o r e Y a s u r C m C n t ) a n d thc u p p e r l i m i t o f I A t i s g i v e n by measu remcn : o f t h e trg l a r g e s t d i m e n s i o n s i n a n y g i v e n s e c t i o n . The d e p t h o f i n v a s i o n s h o u l d n o t be more t h a n 5 mn t a k e n from t h e b a s c o f t h e e p r t h e l i u m , c i t h c r s u r f a c e O r g l r n d u l r r . f rm v h i c h i t o r i g i n a t e s . 'The s e c o n d dimension. t h e h o r t z o n r a l s p r e a d . r u s t n o t e x c e e d 7 nn. V a s c u l a r s p a c e r n u o l v u w n t , e i t h e r v e n o u s o r 1 p P h A t l C . s h o u l d n o t a l t e r t h e s t a g i n g b u t s h o u l d be s p r c l f i c a l l y r e c o r d e d a s i t may r f f c c t t r e a t m e n t d e c i s i o n s i n t h e f u t u r e .

L e s i o n s o f greater s i z e S h o u l d b e r L a g e d a s IL.

A s d r u l e . i t i s impossible to e s t i m t e c i i n i c d l l y h e t h c r a C a n c e r O f t h c c e r v i x h a s e x t e n d e d t o t n e C o r p u J . [ a t e n s i o n t o Khe c o r p u s : h o u l d t h e r e f o r : b e d i s r e g a r d e d .

A p a t i e n : w l t h a s r o w t h f i x e d t o t h e p e l v i c w a l l by a ghor: a n 4 i n d u r c t e d . b u t no: n o d u l a r . p a r a m e t r i u c . S h o u l d be a1lo:reC i o S'.dae 1 1 6 . '!I i s impossible a t c l i n i c a l e x a m i n a t i o n t o d e c i d e whe:her a s m o o t h a n C i n d u r d t e d p a r a m e t r i u m i s t m l y c a n c e r o u s o r o n l y i n f l a m t o r y . l h e r e f o r p , t h e c a s e shoulC be p l a c e d i n SLage 1 1 1 e v e n I f a c c o r d i n g t o t h e o t h e r fInCings t h e c a s e s h o u l d be aI1o:ttd t o S t a g e I or S u g e 1 1 .

The p r e s e n c e o f t h e b o l l w s edema a s s u c h s h o u l C no: p e n n i r a c a s e t o be a ~ ~ o t l e d t o S t a g e IY. R l d g e s a n d f u r r o w s i n t o thr: b l a d d e r w a l l s h o u l l be f n t e r p r c t t d a s r i p s o f S U ~ ~ U C O U S i n v o l v m n t of t h e b l a d d e r i f t h e y r e m a i n f i x e d to t h e g r o r t h a t p a l p a t t o n ( i . e . , exam1nr : ion f r m :he v a g i n a o r t h e r e c t u m d u r l n l ; c y s t o s c o p y ) . A c y t o l o g i c a l f i n d i n 5 of m l \ g n a n t c c l l s i n washings f r m t h e u r l n a r y bladder r e q u t r c s f u r : h e r e x a m i n a t i o n a n d a b i o p s y f r o m t h e * a l l O f t h e b l i i d d e r .

Puroose

I n d i c a t i o n

Contra ind ica t ions

A P ~ E N D I X I V

PELVIC AND PARA-AOililC W E W L I N G

1 ) His to logic eva lua t ion f o r nodal rnet i is tas is

2 ) Reduction o f nodal tumor b u l k .

3 ) Surgica l -pa thologic s t ag ing of gynecologic malignancy.

4 ) P r o v i d e gu ide l ines f o r subsequent t h e r a p y .

GOG “ 1 2 3

1 ) Invasive gynecologic malignancy.

1 ) Cytologic o r h i s t o l o g i c evidence of pulmonic or s u p r a c l a v i c u l a r ex tens ion o f d i s e a s e .

2 ) Poor surg ica l r isk.

Coptent of Procedure A ) Pe lv ic Node Sampling

I ) i d e n t i f y t h e b i f u r c a t i o n of t h e comrnon i l i a c , ex i e rnz l i l i a c , hypogzs t r i c a r t e r i e s and ve ins and t he ure te r .

Any en larged o r susp ic ious nodes w i l l be exc i sed o r b iops ied if u n r e s e c t a b l e .

2)

2 ) Nodal t i s s u e f r o n t h e d i s t z l o n e - h a l f of e z c h coinmon i l i a c z r t e r y should De removed,

4) The nodal t i s s u e from t h e z n t e r i o r 2 n d meclizl a s p e c t of t n e proximzl 1 / 2 o f t h e ex te rnz l i l i a c a r t e r y a n d ve in will be e x c i s e d .

5) The d i s t z l 1 / 2 of t h e o b t u t z t o r f z t p a d . . a n t e r i o r r o t h e o b t u r e t o r nerve i s exc i sed . .

6 ) L igz t ion o f t n e proxiiiizl 2 n d d i s t z l attachments o f t h e nod21 tissue 2 n d r e t r o p e r i t o n e a l s u c r i o n d r z i nage i s recommended.

2 ) A o r t i c Node Sampling - 1 ) ine biiurcztion o f i n e z o r t z , t n e i n f e r i o r vena cave , t h e ova r i zn v e s s e l s , :he i n f e r i o r mesen te r i c :;:pry, t h e u rcze r s 2 n d duodenum should SE i d e n c i f i e c .

2 ) Any en9iarG@d o r s u s a i c i o u s nodes w - i ’ t l be excised o r biopsied if u n r e s e c t a b l e .

Pe lv ic 2nd Parn-hr:;c Node S a m p l i n g (Cor,: ‘ 1 . )

3 ) The nodal t i s s u e over the d i s t a l vena cava from rhe leve l of the i n f e r i o r mesenter ic a r t e r y t o the mid r i g h t common i l i a c a r t e r y i s removed.

4 ) The nodal t i s s u e between the a o r t a and t h e l e f t u r e t e r from the i n f e r i o r m e s e n t r i c a r t e r y t c the l e f t mid c o m n i l i a c a r t e r y i s removed.

5 ) Liga t ion o f t he proximal and d i s t a l nodal t i s s u e i s recommended.

6 ) Dissec t ion cephalad to the i n f e r i o r mesen te r i c a r t e r y i s r e s t r i c t e d t o t hose c a s e s wi;h palpably susp ic ious nodes above t h a t l e v e l .

Comnents: A p u s i t i v p pe lv i c or p a r a - a o r t i c node i n d i c a t e s no f u r t h e r sampling from t h a t a r e a need be pe r fo r txd . P a l o a b l y m s i t i v e nodes must bo sampied f o r h i s t o l o g y .

A D V E R S E EFFECTS THAT ! M Y BE ASSOCiATED W I T H AH UNEVENTFUL P g O C E D U R E

SYSTEM

Hemiitopoietic Geni t o u r j nary G z s t r o i n t e s t i n a l Hepeti c Pulmnary Czrd i ovzscu lz r Per iphera l Neurologic Centrzl Neurol o g i c Cutaneous Lymphzii c s Fever A I 1 e r g i c

GRADE ( u p t o and i n c l u d i n s )

c 0 0 0 0 i I 0 2 2

I

0 1

A P P E N D I X V

Hematopoietic 2 Geni t o u r i nery I Ga st ro i n t e s t i n a 1 1 Hepatic 1 Pul rnonzry . 1 Cardi ovas c u l ar 1 Per iphera l Neurologic 1 Centrzl Neurol ogi c 0 Cutaneous 2 Lyrnphztics i Fever 2

7

c A l l e r g i c 0

Purpose

Ind ica t ions

Lon t ra ind ica t ions

EXTRA-FASCIAL HYSTERECTOKY

Surgical removal of the u te rus

I ) Invasive cerv ica l carcinoma c l i n i c z l l y confined t o the cerv ix following r a d i a t i o n the rapy

2 ) Endometrial c2rcinoma

3 ) Micrcinvasive cerv ica l carc inona -

1 ) More advanced s t ages o f d i s e a s e ( s u r g i c a l a n d c l i n i c a l )

2 ) Poor r i s k zurg icz l p a t i e n t

Content of Procedure hemoval o f t h e corpus and cerv’x wi thout cont iguous parametr ia l t i s s u e . The u t e r i n e a r t e r y should be t r ansec ted a t t he u t e r i n e wall medial t o t h e u r e t e r . The pubocervical f z s c i a should not be e n t e r e d , and t h e e n t i r e corpus and ce rv ix shou ld be removed. The u r e t e r should nc t be unroofed, 2nd no vaginal c u f f is r equ i r ed .

A D V E R S E EFFECTS THAT M A Y B E ASSOCIATED KITH AN UNEVENTFUL P R O C E D U R E

SYSTEH G R A D E ( u p t o a n d i n c l u d i n g )

PurDos e :

1 n d i cz ~i on:

1 ) Cytoloaic evaluat ion o f pa lpable masses c - lymph nodes.

2 ) Cytologic evaluat ion o f lymph nodes o r ;;,asses i d e n t i f i a b l e by d iagnos t ic technioues such 2s

CT Scan, U1 trasound and Lymphangiography.

3 ) Cytoloaic eva lua t ion of " a t r i s k " t i s s u o fol lowing i r r a d i a t i o n (e .c j . , pa rame t r i a l t i s s u e ) .

c ) Accurate pathologic21 s t a g i n g of S y n e c o l o g j c malignancy.

Evaluat ion c f gynecolosic mal 'griancy, e ' t h e r primary o r recurren:.

1 ) Lymph nodes i n any s i t e de t ec t ed by e i t h e r pa lpa t ion o r radiographic d i a g n o s t i c t e c h n i q u e s .

2 ) Kzsses c f 2 n y si:? de tec ted by e i t h e r p z l p a t i o n o r rad iographic d i a a n o s t i c t echn iques .

3 ) T i s sue k n o w n t o have contained n e l i a n a n t c e l l s p r i o r t o therapy ( i r r a d i a t i o n or chemotherapy) .

Contr2 i n d i cz t i o n : Poss ib ly mzl ignant ovar.;an c y s t where puncture mi ~ h t r e s u l t i n intra-abdominal d i sseminat jon o f cance r c e l l s .

C o n r e n t o f Procedure: 1 ) Necesszry ma ie r i z l s

2 . 22 cauoc needles o f var ious 1enGths b . 20 cc syr inges c . s y r i n c e p i s t o l handle d . Franzen needie holder e . f r o s t e d o l 2 s s s l i d e s f . 05: z iconol g . 19 cc b l o o l c o l l e c t i o n tubes w i t h

3 cc sa:ine and 1 cc of 1:lOOO heDarin.

2 ) For pz lpable m a s s e s or lymph nodes, 10cz.l a n e s t h e s i z i s u t i l i z e d unless t h e procedure i s performed i n t h e ope rz t ing TOGE under Gther a n e s t h e s i a . T h e m 8 S O r l_mDh node i s pzlpzted and a needle cf z p p r o c r i z t e i e n c t t ; i s inser ted and v igorous ly a s i j i r a t e d wh i l e r n o v i n s ;he t i p o f t he needie s l i g h t l y ( 2 - + i n c h ) j z t h e G S S . A i ~ e r r e l e z s e of t h e s u c t i o n , t h e needle j s w<:hdrawn. f o r m a s s e s o r lyn;?i; nodes i o e n f i f i e d by d i a g n o s t i c s t u d i e s , :he n e e d l e i s ' n s e r t e d m d e r C T , u? t r z sound , or f l u o r o s c o p i c g u i d z n c e zr ,d aspirz:-+ i n t n e s a m e f z s n i o n .

# APPE!<DIX i’! rercuraneous r i n e Neeoie f i sp i r a r ion (Cont ‘ d . )

3 ) The mixture o f c e l l s a n d t i s s u e f l u i d i n t h e needie i s f o r c e f u l l y e j ec t ed onto a g l a s s s l i d e and by placing another s l i d e f ace down on t h e f i r s : , t w o t h i n smears a r e made by s e p a r a t i n g t h e s l i d e s r ap id ly with a s l i d i n g motion t o p rov ide duplicate prepa ra t ions .

4 ) Both s l i d e preparat ions a r e immersed innnediztely i n 9 5 % a lcoho l . The needle i s then inmersed i n t he sa l ine /hepa r in so lu t ion a n d , by a1 t e r n a t e l y a s p i r a - t i n g a n d expel l ing t h e f l u i d , suspens ion o r any remaining c e l l s i s achieved.

5 ) Tne alcohol immersed s l i d e nay be s t a i n e d by t h e Papanicolaou technique a f t e r a l coho l f i x a t i o n .

6 ) The c e l l suspension i s t a k e n imned ia t e ly t o t h e cytology labora tory and processed by som; c e l l concentration technique such a s membrane f i l t r a z i o n .

ADVERSE EFFECTS THAT MAY BE ASSOCIATED WITH AN UNEVENTFUL P R O C E D U R E - Svs tern Grade I

Henatopoi e t i c Geni tour inary Gzs t ro in t es t inal Hepa t i c P u l rronary C a r d i o v a s c u l z r Per i pherzl t.ieurol o c i c Central Neurol og i c

Cu tan eo us Lyrnpha t i cs

Fever A1 7 e r c i c

0

0 0

0

0

0 e 0 1 0 1

0

- * COG P i ? :

APPENDIX V I 1

FAST FACT SHEET

Name of I n s t i t u t i o n Name of a f f i l i a t e , i f app l i cab le Name o f P a t i e n t : l a s t , f i r s t , middle i n i t i a l Hospi ta l cha r t number Date o f b i r t h Previous GOG number(s), ( i f any)

1. 2. 3 . 4 . 5.

6 . 7 .

9. 10. 11.

a .

1 2 . 13. 14. 15.

16 . 17 . i 8 . 19.

Was the informed consent s igned? Does the p a t i e n t have p r i m a r y , p rev ious ly unt rea ted ce rv ica l cancer? What i s the s t age o f t h i s d i sease? What i s the c e l l type? Does the p a t i e n t have a l a r g e bulky l e s i o n , e i t h e r 2 4 cm or ba r re l shaped l e s i o n ? Which one? Has the p a t i e n t had a CT scan o r lymphangiograrn? What were the r e s u l t s ? Was a f i n e needle a s p i r a t i o n (FNA) done? What were the r e s u l t s ? Were t h e p e l v i c and/or p a r a - a o r t i c lymph nodes s u r g i c a l l y nega t ive? LAB RESULTS:

Date o f r e s u l t s WBC P1 a t e l e t s Crea t i n i ne

Neaative or P o s i t i v e ?

Is the b i l i r u b i n l e s s t h a n o r equal t o 2 x normal? Is the SGOT less t h a n or equzl t o 2 x normal?

Has the p a t i e n t h a d a c h e s t x-ray a n d a l k a l i n e phosphatase? Has the p a t i e n t h a d any previous pe lv i c r a d i a t i o n o r systemic chemotherapy? What i s the GO6 performance s t a t u s ? Does the p a t i e n t have previous o r concomitant malignancy o t h e r t h a n skin (exc luding melanoma)? Has the p a t i e n t had a previous p a r t i a l or t o t a l hysterectomy? Is the p a t i e n t considered "medical ly inope rab le"? What d a t e wzs diaanosSs made? Date t reetment t o s t a r t ?

. A

VOLUNTEER AGREEMENT AFFIDAVIT i For use of this form, see AR 7 0 - 2 5 or AR 40-38, the proponent aged& is OTSG

~~

PRIVACY ACT OF 1974 10 USC 3013, 44 usc 3101 and 10 USC 1071-1087. AUTHORITY: / '

PRINCIPLE PURPOSE: TO document voluntary participation in the Cliniical

Investigation and Research Program, SSN and home address will be used for identification and locating purposes.' Information derived from the study will be used to document the study, implementation of medical programs, adjudication of claims; and for the mandatory reporting of medical conditions as required by law. Information may be furnished to Federal, State and local agencies.

DISCLOSUR\ The furnishing of your SSN and home address is mandatory and cessary to provide identification and to contact you if future rmation indicates that your health may be adversely affected.

Fai re to provide the information my preclude your voluntary partr ipation in this investigational study.

\

\PART A ( 1 ) - VOLUNTEER AFFIDAVIT Volunteer Subiects iAApproved Department of the Armv Research Studies

Volunteers under ovisions of AR.40-38 and AR 70-25 are authorized all ich is the proximate result of

I, SSN : (last name, first name), (9 digits).

birthday, do hereby (age)

(patient lastname, firstnarne), to participate in the GOG 123, Title: "A Randomized Comparison of Radiat Hysterectomy Versus Radiation

my in Patients with Bulky

\ The Center Judqe Advocate Telephone ( 2 0 6 ) 968,-3113 at Madiqan Armv Medical Center, Tacoma, WA 98431.-5418

(Name, Address and Phone Number of Hospital (Include Area Code))

I understand that I may at any time during the course of\this study revoke my consent and withdrawal have the person I represent withdrawn from the study without further penalty or loss of benefits; however, I/the person I represent may be required (military volunteer) or requested (civilian volunteer) to undergo certain examination if, in the opinion of the attending physician, such examination are necessary for myjthe person I represent's health and well-being. My/the person I represent's refusal to participate will involve no penalty or l o s s of benefits to which I am/the person I represent is otherwise entitled.

j P A R T B - (To be completed bv investiaator:) (tvpe in) INSTRUCTIONS FOR ELEMENTS OF INFORMED CONSENT (Provide a detailed explanation in accordance with Appendix C AR 40-38 or AR 70-25)

R E V E R S E O F DA FORM 5 3 0 3 - R , MAY 69

GENERAL INFORMATION: You have been asked to participate in a clinical investigation research study. Your participation is voluntary. Refusal to participate will involve no penalty or loss of benefits to which you are otherwise entitled. You may discontinue participation at any time without penalty or loss of benefits to which you are entitled. However, if you decide to discontinue participation, you must inform Dr. Potter who will discuss alternative treatment. There is no additional cost to you for participation in this study.

I N I T I A L S O F V O L U N T E E R

This study is being carried out in over 90 hospitals throughout the United States under the sponsorship of the Gynecologic Oncology Group (GOG), an organization dedicated to clinical research in the field of gynecologic cancer. The GOG is funded by the Federal Government through the National Cancer Institute (NCI). In general, the research carried out by these medical centers compares the effectiveness of different methods of treating cancer of the female genital organs. In this manner, the best treatments --- whether old or new --- can be established. The optimal treatment of large cervical cancer is confined to the cervical tissue (Stage IB-Bulky) has not yet been defined. Neither radiation nor surgery is superior to the other. Attempts have been made to combine radiation followed by surgery with inconclusive results obtained. In a study performed recently by the GOG, "Patients treated with radiation and surgery appeared to have less recurrences in the treatment area (the pelvis) than those patients who received radiation only. At this point in time it is not clear whether this will ultimately affect the cure rate since many recurrences can develop outside of the treatment area. The addition of chemotherapy to radiation therapy in more advanced stages of cervical cancer appears to improve overall cure as well as decreasing recurrences within the treatment area. It is not known whether this same result would occur in Bulky Stage IB cervical cancers. The purpose of this study is to answer the question of whether adding chemotherapy for this stage disease will result in more cures.

Approximately 1 patient per year will be entered into this study at Madigan Army Medical Center. Nation wide this study will require 225 patients. It is anticipated that this will require approximately 5 years to enter this many patients and an additional 3 years of follow up after completion of this study before a final interpretation of the information may take place.

A I M AND METHOD O F S T U D Y : All patients entered into this study will have already undergone tests to determine the Stage of the cancer and absence of lymph node spread beyond the pelvic structures. If you chose to participate in this study you will be randomized to receive either radiation with a hysterectomy or radiation and chemotherapy with a hysterectomy. This randomization process is performed at the GOG headquarters and is much like flipping a coin.

\ I

_(PART B - [To be com2leted by i n v e s t i s a t o r : ) ( t w e in) (Continuedl

- REVERSE O F DA FORM 5 3 0 3 - R , MAY 8 9

The radiation treatment and hysterectomy is the same for all patients. Radiation will be given daily Monday-Friday over 4-5 weeks. This is much like receiving a X-ray. After completion of the radiation therapy a local radiation device will be inserted into the cervix either once or twice. This will require an anesthetic and hospitalization. 3-6 weeks after the completion of radiation therapy you will undergo an operation to remove the uterus, both tubes and ovaries. If you are randomized to the group that receives chemotherapy while you are receiving radiation treatment you will also receive a chemotherapy agent known as Cisplatin. This will be given through the vein while in the hospital, once a week, while you are receiving the external radiation and also once with the radiation insertion. If you are treated with two radiation insertions the second will not include chemotherapy. A hysterectomy will be done just like in the first group. After the completion of treatment you will be seen every three months for two years, then every 6 months for an additional 3 years. After that you will be seen yearly.

INITIALS OF VOLUNTEER

BENEFITS: The possible benefit to you might be longer control of your disease and relief from your symptoms. This drug/treatment is not guaranteed to work nor is it considered a cure.

RISKS AND DISCOMFORTS: Cisplatin: common side effects from this drug include nausea, vomiting, and loss of certain trace metals and salts from the blood. These trace metals and salts may be replaced through medication taken by mouth. The nausea and vomiting can usually be controlled with medication. Less common side effects include kidney damage that in rare cases may be permanent. This kidney damage can be lessened by the use of intravenous fluids and maintaining good hydration with fluids by mouth after therapy. Should nausea and vomiting prevent adequate fluid intake, you must notify your doctor so that you may be admitted to the hospital and given intravenous fluids, if necessary. A decrease in hearing can occur and rarely may lead to deafness. Usually this hearing l o s s is not noticeable in the range of normal speech. Numbness and tingling in the hands and feet can occur and may lead to difficulty walking, performing fine motion such as buttoning clothes, and very rarely severe numbness and muscle weakness that can confine you to a wheelchair. Occasionally allergic reactions may occur.

Radiation: Patients who receive radiation treatment for cancer of the cervix can expect to have a change in bowel movements. Generally, this occurs after 2-3 weeks of treatment with more frequent bowel movements being common. This may result in frequent watery stools (diarrhea). This can be controlled with diet and medication, however, sometimes requires an interruption in the radiation treatment and sometimes hospitalization. Occasionally, patients have nausea and vomiting with this therapy. This a l s o can be controlled with medication. On the long term basis, approximately 1 in 20 patients will have injury to other organs such as the intestines or urinary system. This can occasionally

L

c"./J"'" /LA{ . \

(PART B - (To.be completed bv i n v e s t i q a t o r : ) ( t ~ p e i n 1 ( C o n t i n u e d )

require additional surgery to control these complications. This injury can be in the form of a blockage of an organ, a communication between two organs that is abnormal (this is called a fistula), or bleeding from the bladder or bowel. Radiation treatment can also effect the body's ability to produce blood cells. This includes the red blood cells which are necessary for oxygen carrying, the white blood cells which are necessary to fight infection, and platelets which are necessary to aid in clotting. Cisplatin usually does not affect the blood cells to any significant degree when used by itself , however, when used with other medications or radiation may contribute to this effect on the blood cells.

Hysterectomy: Surgery to remove the uterus, tubes, and ovaries (hysterectomy) may result in complications of bleeding, infection, and injury to other structures. The risk of injury to other structures is increased in patients who have received previous radiation treatment. Even so, the likelihood of having significant injury to other organs is less than 5%. This injury to other organs may develop either at the time of surgery or as a late complication of surgery. These include blockage and abnormal communications as described in the radiation therapy side effects. If any injury to the surrounding structures occurs, additional surgery may be necessary to correct this problem. The hysterectomy will require an anesthetic and hospitalization for approximately 1 week after surgery. As with any surgery and anesthesia there is a small chance of dying from complications of surgery. The likelihood of this happening is approximately 1 in 1000 patients. A separate consent form will be used at the time of the hysterectomy, as well as, at the time of placement of the devices into the cervix for the local radiation.

As with any new treatment method, there is always the possibility that some previously unknown side effect may occur.

SAFEGUARDS: Every reasonable effort will be made to minimize the side effects or reactions to therapy. If symptoms should occur, they will be treated appropriately. If side effects are severe, your physician may discontinue your participation in this study, and alternative treatment will be offered to you. During treatment this will include weekly blood tests to evaluate your blood count and blood chemistries.

If you choose to discontinue participation in this study the alternative could include radiation, surgery or both.

By consenting to participate in this study, you are responsible for carrying out instructions and that you must relate to your doctors, nurses, or other study personnel any information that might be pertinent to the study, such as any side effects of a treatment or procedure. Any reluctance you might have to continue in the study

REVERSE OF DA FORM 5 3 0 3 - R , MAY 8 9 INITIALS OF VOLUNTEER

" JPART B - ( T O be COmDleted by investiaator:) (type in) (Continued)

SIGNATURE OF WITNESS

must also be reported. Any new information that develops regarding the study and any treatment which might affect your willingness to participate will be made available to you.

~

DATE

CONFIDENTIALITY: The confidentiality of your medical records will be maintained in accordance with the Privacy Act. The Food and Drug Administration, the Department of Defense and the/ GOG may

treatment, but confidentiality will be maintained.

investigational procedures, essential medical treatmht (including hospitalization) is available. The extent of/medical care provided, should it become necessary, is limited ang will be within the scope authorized for DOD health care beneficiakies. Necessary medical care does not include domiciliary care. f injury occurs, information regardi g your legal rights as subject can be obtained from the Of ice of the Center Judge Ad ocate, MAMC, (206)

inspect the records in order to evaluate the overall

COMPENSATION: In the event of physical injury

4 J 968-3113.

You are free to ask questions now or at ime during the study

You will be provided with a copy of this form to take with

by contacting Dr. Potter at (206) 968-1730.

you.

I do - inclusion of this form in my outpatient medical treatment record.

do not - /(check one & initial) consent to the

SIGNATURE OF LEGAL GUARDIAN IDATE I (If v d u n e r is a amor)

SIGNATURE OF VOLUNTEER

PERMANENT ADDRESS OF VOLUNTEER TYPED NAME OF WITNESS

/

VGLUNTEER AGREEMENT AFFIDAVIT For use of this fo;m, see AR 70-25 or AR 40-38, the proponent

PRIVACY ACT O F 1974 / AUTHORITY: 10 USC 3013, 44 USC 3101 and 10 USC 1071-1087. / P R I N C I P L E PURPOSE:

/ /

To document voluntary participation in the Clin'cal Investigation and Research Program, SSN and me address will be

from the study will be used to document the study, implementation of medical programs, adjudication of claims; 'and for the mandatory reporting of medical conditions as required,/by law. Information may be furnished to Federal, State and local jgencies.

used for identification and locating purposes. hd: Information derived DI SCLOSUR\e The furnishing of your SSN and hoc& address is mandatory and

cessary to provide identification ahd to contact you if future in ormation indicates that your healgh may be adversely affected.

to provide the information' my preclude your voluntary parti ipation in this investigatio+l study.

\PART A ( 1 ) - VOLUNTEER'AFFIDAVIT Volunteer Subjects iAApproved Department ofithe Army Research Studies

\ '/ Volunteers under of AFU40-38 and AR 70-25 are authorized all

njury or disease which is the proximate result of necessary medical care their participation in

I, SSN: (9 digits). (last name, first name),

birthday, do hereby (age)

(patient last name, first name),

Stage IB Carcinoma of the Cervix."

,/

I have been given an portunity to ask questionb oncerning this investigational study. Any such qu stions were answered to my f 11 and complete satisfaction. Should any further uestions arise concerning my ri hts/the rights of the person

\ "\

i I represent on st .$ y related injury, I may contact

Telephone (206) 96'8-3113 The Center Judqe Advocate at Madiqan A r m y Medical Center, Tacoma, WA 9843L-5418

(Name, Address and Phone Number of Hospital (I'clude Area Code))

I understand that I may at any time during the course of,,this study revoke my consent and withdrawal have the person I represent withij.rawn from the study without further penalty or loss of benefits; however, I/thelperson I represent may be required (military volunteer) or requested (civilian va'lunteer) to undergo certain examination if, in the opinion of the attending\ physician, such examination are necessary for my/the person I represent's health and well-being. My/the person I represent's refusal to participate will involve no penalty or loss of benefits to which I am/the person I represent is otherwise entitled.

/PART B - (To be completed by investisator:) (tVDe in) INSTRUCTIONS FOR ELEMENTS OF INFORMED CONSENT (Provide a detailed explanation in accordance with Appendix C AR 40-38 or AR 7 0 - 2 5 )

GENERAL INFORMATION: You have been asked to participate in a clinical investigation research study. Your participation is voluntary. Refusal to participate will involve no penalty or loss of benefits to which you are otherwise entitled. You may discontinue participation at any time without penalty or loss of benefits to which you are entitled. However, if you decide to discontinue participation, you must inform Dr. Potter who will discuss alternative treatment. There is no additional cost to you for participation in this study.

This study is being carried out in over 90 hospitals throughout the United States under the sponsorship of the Gynecologic Oncology Group (GOG), an organization dedicated to clinical research in the field of gynecologic cancer. The GOG is funded by the Federal Government through the National Cancer Institute (NCI). In general, the research carried out by these medical centers compares the effectiveness of different methods of treating cancer of the female genital organs. In this manner, the best treatments --- whether old or new --- can be established. The optimal treatment of large cervical cancer is confined to the cervical tissue (Stage IB-Bulky) has not yet been defined. Neither radiation nor surgery is superior to the other. Attempts have been made to combine radiation followed by surgery with inconclusive results obtained. In a study performed recently by the GOG, IIPatients treated with radiation and surgery appeared to have less recurrences in the treatment area (the pelvis) than those patients who received radiation only. At this point in time it is not clear whether this will ultimately affect the cure rate since many recurrences can develop outside of the treatment area. The addition of chemotherapy to radiation therapy in more advanced stages of cervical cancer appears to improve overall cure as well as decreasing recurrences within the treatment area. It is not known whether this same result would occur in Bulky Stage IB cervical cancers. The purpose of this study is to answer the question of whether adding chemotherapy for this stage disease will result in more cures.

Approximately 1 patient per year will be entered into this study at Madigan Army Medical Center. Nation wide this study will require 225 patients. It is anticipated that this will require approximately 5 years to enter this many patients and an additional 3 years of follow up after completion of this study before a final interpretation of the information may take place.

AIM AND METHOD OF STUDY: All patients entered into this study will have already undergone tests to determine the Stage of the cancer and absence of lymph node spread beyond the pelvic structures. If you chose to participate in this study you will be randomized to receive either radiation with a hysterectomy or radiation and chemotherapy with a hysterectomy. This randomization process is performed at the GOG headquarters and is much like flipping a coin.

~~ ~~

REVERSE OF DA FORM 5303-R, MAY 8 9 INITIALS OF VOLUNTEER

JPART B - (To be completed by inves t iaa tor : ) ( type i n ) (Continued)

The radiation treatment and hysterectomy is the same for all patients. Radiation will be given daily Monday-Friday over 4-5 weeks. This is much like receiving a X-ray. After completion of the radiation therapy a local radiation device will be inserted into the cervix either once or twi.ce. This will require an anesthetic and hospitalization. 3-6 weeks after the completion of radiation therapy you will undergo an operation to remove the uterus, both tubes and ovaries. If you are randomized to the group that receives chemotherapy while you are receiving radiation treatment you will also receive a chemotherapy agent known as Cisplatin. This will be given through the vein while in the hospital, once a week, while you are receiving the external radiation and also once with the radiation insertion. If you are treated with two radiation insertions the second will not include chemotherapy. A hysterectomy will be done just like in the first group. After the completion of treatment you will be seen every three months for two years, then every 6 months for an additional 3 years. After that you will be seen yearly.

- REVERSE O F DA FORM 5303-R, MAY 89

BENEFITS: The possible benefit to you might be longer control of your disease and relief from your symptoms. This drug/treatment is not guaranteed to work nor is it considered a cure.

INITIALS OF VOLUNTEER

RISKS AND DISCOMFORTS: Cisplatin: common side effects from this drug include nausea, vomiting, and loss of certain trace metals and salts from the blood. These trace metals and salts may be replaced through medication taken by mouth. The nausea and vomiting can usually be controlled with medication. Less common side effects include kidney damage that in rare cases may be permanent. This kidney damage can be lessened by the use of intravenous fluids and maintaining good hydration with fluids by mouth after therapy. Should nausea and vomiting prevent adequate fluid intake, you must notify your doctor so that you may be admitted to the hospital and given intravenous fluids, if necessary. A decrease in hearing can occur and rarely may lead to deafness. Usually this hearing loss is not noticeable in the range of normal speech. Numbness and tingling in the hands and feet can occur and may lead to difficulty walking, performing fine motion such as buttoning clothes, and very rarely severe numbness and muscle weakness that can confine you to a wheelchair. Occasionally allergic reactions may occur.

Radiation: Patients who receive radiation treatment for cancer of the cervix can expect to have a change in bowel movements. Generally, this occurs after 2-3 weeks of treatment with more frequent bowel movements being common. This may result in frequent watery stools (diarrhea). This can be controlled with diet and medication, however, sometimes requires an interruption in the radiation treatment and sometimes hospitalization. Occasionally, patients have nausea and vomiting with this therapy. This also can be controlled with medication. On the long term basis, approximately 1 in 20 patients will have injury to other organs such as the intestines or urinary system. This can occasionally

(PART B - (TO be completed bv inves t iqator : ) ( t v D e i n ) (Continued)

REVERSE O F DA FORM 5303-R, MAY 89

require additional surgery to control these complications. This injury can be in the form of a blockage of an organ, a communication between two organs that is abnormal (this is called a fistula), or bleeding from the bladder or bowel. Radiation treatment can also effect the body's ability to produce blood cells. This includes the red blood cells which are necessary for oxygen carrying, the white blood cells which are necessary to fight infection, and platelets which are necessary to aid in clotting. Cisplatin usually does not affect the blood cells to any significant degree when used by itself, however, when used with other medications or radiation may contribute to this effect on the blood cells.

INITIALS O F VOLUNTEER

Hysterectomy: Surgery to remove the uterus, tubes, and ovaries (hysterectomy) may result in complications of bleeding, infection, and injury to other structures. The risk of injury to other structures is increased in patients who have received previous radiation treatment. Even so, the likelihood of having significant injury to other organs is less than 5%. This injury to other organs may develop either at the time of surgery or as a late complication of surgery. These include blockage and abnormal communications as described in the radiation therapy side effects. If any injury to the surrounding structures occurs, additional surgery may be necessary to correct this problem. The hysterectomy will require an anesthetic and hospitalization for approximately 1 week after surgery. As with any surgery and anesthesia there is a small chance of dying from complications of surgery. The likelihood of this happening is approximately 1 in 1000 patients. A separate consent form will be used at the time of the hysterectomy, as well as, at the time of placement of the devices into the cervix for the local radiation.



If you choose to discontinue participation in this study the alternative could include radiation, surgery or both.

By consenting to participate in this study, you are responsible for carrying out instructions and that you must relate to your doctors, nurses, or other study personnel any information that might be pertinent to the study, such as any side effects of a treatment or procedure. Any reluctance you might have to continue in the study

W

(PART B - (To be completed by investiaator:) (type in) (Continued)

must also be reported. Any new information that develops regarding the study and any treatment which might affect your willingnegs to participate will be made available to you. /

/

SIGNATURE OF WITNESS

CONFIDENTIALITY: be maintained in accordance with the Pri Drug Administration, the Department of inspect the records in order to evaluate t treatment, but confidentiality will be maintained.

COMPENSATION: In the event of physical investigational procedures, essential me hospitalization) is available. provided, should it become necessary the scope authorized for DOD health medical care does not include domic information regardi g your legal rights as subject can be obtained from the Of ice of the Cen

The confidentiality of your medical recoS k s will

968-3113. 4 You are free to ask questions now by contacting Dr. Potter at (206)

You will be provided with a copy o

DATE

Fill out completely / ~~~

I do inclusion of this form in my outpatient medical treatment record.

do not -/(check one & initial) consent to the

SIGNATURE OF VOLUNTEER I DATE SIGNATURE OF LEGAL GUARDIAN (If volunteer is a minor)

PERMANENT ADDRESS OF VOLUNTEER TYPED NAME OF WITNESS

PAGE 5 OF DA FORM 5303-R, MAY 89

' VOLUNTEER AGREEMENT AFFIDAVIT For u'se of this form, see AR 70-25 or AR 40-38; the proponent agency IS OTSG

PRNACY ACT OF 1974

Autho r i t y : 10 USC 3013, 44 USC 3101 and 10 USC 1071-1087

P r i n c i p l e Purpose: To docunent vo lun ta ry p a r t i c i p a t i o n i n the C l i n i c a l I n v e s t i g a t i o n and Research Program. SSN and home address w i l l be used f o r i d e n t i f i c a t i o n and l o c a t i n g purposes.

Rout ine Uses:

Disclosure:

The SSN and home d r e s s w i l l be used f o r i d e n t i f i c a t i o n and l o c a t i n g purposes. I n fo rma t ion de r i ved from the s tudy w i l l be used t o d o c w n t the study; inp lementat ion o f medical programs, teaching, a d j u d i c a t i o n o f c la ims, and f o r t h e mandatory r e p o r t i n g of medical c o n d i t i o n as required by law. l n f o m t i o n may be furn ished t o Federal, S ta te and l o c a l agencies.

The f u r n i s h i n g o f your SSN and hame address i s mandatory and necessary t o p rov ide i d e n t i f i c a t i o n and t o contact you i f f u t u r e i n fo rma t ion i n d i c a t e s t h a t your h e a l t h may be adversely a f fec ted . F a i l u r e t o p rov ide the i n f o r m a t i o n may prec lude your vo lun ta ry p a r t i c i p a t i o n i n t h i s i n v e s t i g a t i o n a l study.

PART A - VOLUNTEER AFFlDAVlT

Vo lv r tee r Subjects i n Approved Oepartment o f t he Arrny Research Studies Volunteers under the provisions of AR 40-38 and AR 7 0 - 2 5 are authorized all

necessary medical care €or injury or disease which is the proximate result of their participation in such studies.

I, SSN having full capacity to consent and having attained my birthday, do hereby volunteer to participate in the research protocol GOG 123: A Randomized Comparison of Radiation Therapy and Adjuvant Hysterectomy Versus Radiation Therapy and Weekly Cisplatin and Adjuvant Hysterectomy an Patients with Bulky Stage IB Carcinoma of the Cervix under the direction of LTC Mark E. Potter, M.D., U . S . Army Medical Corps, conducted at Madigan Army Medical Center.

The implications of my voluntary participation; the nature, duration and purpose of the research 6tudy; the methods and means by which it is to be conducted; and the inconveniences and hazards that may reasonably be expected have been explained to me by

I have been given an opportunity to ask questions concerning this investigational study. Any such questions were answered to my full and complete satisfaction. Should any further questions arise concerning my rights on study-related injury I may contact the Center Judge Advocate at Madigan Army Medical Center, (206) 968-3113.

my consent and withdraw from the study without further penalty or loss of benefits; however, I may be required (military volunteer) or requested (civilian volunteer) to undergo certain examinations if, in the opinion of the attending physician, such examinations are necessary €or my health and well-being. My refusal to participate will involve no penalty or loss of benefits to which I am otherwise entitled.

I understand that I may at any time during the course of this study revoke

PART B - EXPLANATION OF WHAT IS TO BE DONE GENERAL INFORMATION: You have been asked to participate in a clinical research study. Your participation is voluntary. Refusal to participate will involve no penalty or l o s s of benefits to which you are entitled. However, if you decide to discontinue participation, you must inform Dr. Potter who will discuss alternative treatment. There is no additional cost to you for participation in this study.

This study is being carried out in over 90 hospitals throughout the United States under the sponsorship of the Gynecologic Oncology Group (GOG), an organization dedicated to clinical research in the field of gynecologic cancer. The GOG is funded by the Federal Government through the National Cancer Institute

DA Form 5303-R Revised 28 Sep 93 Initials of volunteer Page 1 of 5 Title GOG 123

. - VOLUNTEER AGREEMENT A F F I D A V I T ' e

( N C I ) . In general, the research carried out by these medical centers compares the effectiveness of different methods of treating cancer of the female genital organs. In this manner, the best treatments - whether old or new - can be established. The optimal treatment of large cervical cancer confined to the cervical tissue (Stage IB-Bulky) has not yet been defined. Neither radiation nor surgery is superior to the other. Attempts have been made to combine radiation and surgery with inconclusive results obtained. In a study performed recently by the GOG, patients treated with radiation and surgery appeared to have less recurrences in the treatment area (the pelvis) than those patients who received radiation only. is not clear whether this will ultimately affect the cure rate since many recurrences can develop outside of the treatment area. The addition of chemotherapy to radiation therapy in more advanced stages of cervical cancer appears to improve overall cure as well as decreasing recurrences within the treatment area. It is not known whether this same result would occur in Bulky Stage IB cervical cancers. The purpose of this study is to answer the question of whether adding chemotherapy to radiation plus surgery for this stage disease will result in more cures.

At this point in time it

Approximately 1 patient per year will be entered into this study at Madigan Army Medical Center. Nationwide this study will require 225 patients. It is anticipated that it will require approximately 5 years to enter this many patients and an additional 3 years of follow up after completion of this study before a final interpretation of the information may take place.

You may not take part in this study if you are pregnant and you must take precautions while on the medications and radiation therapy not to become pregnant. A blood sample (1 tablespoon) will be taken to run a pregnancy test before you start treatment to make sure that you are not pregnant.

AIM AND METHOD OF STUDY: All patients entered into this study will have already undergone tests to determine the stage of the cancer and absence of lymph node spread beyond the pelvic structures. If you choose to participate in this study you will be randomized to receive either radiation with a hysterectomy (Group I) or radiation and chemotherapy with a hysterectomy (Group XI). This randomization process is performed at the GOG '

headquarters and is much like flipping a coin. The radiation treatment and hysterectomy are the same for both groups. Radiation will be given daily Monday - Friday over 4 - 5 weeks. This is much like receiving a x-ray. After completion of this radiation therapy, a radiation device will be inserted into the cervix to deliver the radiation more directly to the cancer. This procedure will be done once or twice depending on the amount of radiation to delivered. This will require an anesthetic and hospitalization. 3 - 6 weeks after the completion of radiation therapy you will undergo an operation to remove the uterus, both tubes and ovaries. If you are randomized to Group I, you will receive a chemotherapy agent known as Cisplatin. This will be given through the vein while in the hospital, once a week, while

DA Form 5303-R Revised 28 Sep 9 3 Initials of volunteer Page 2 of 5 T i t l e GOG 123

8 VOLUNTEER AGREEMENT AFFIDAVIT

you are receiving the external radiation and also once with the radiation insertion. If you are treated with two radiation insertions, the second will not include chemotherapy. After the completion of treatment you will be seen every 3 months for 2 years, then every 6 months for an additional 3 years. After that you will be seen yearly.

BENEFITS: The possible benefit to you would be longer control of your disease and relief from your symptoms. is not guaranteed to work nor is it considered a cure.

This drug/treatment

R I S K S AND DISCOMFORTS: Cisplatin: common side effects from this drug include nausea, vomiting, and loss of certain trace metals and salts from the blood. These trace metals and salts may be replaced through medication taken by mouth. The nausea and vomiting can usually be controlled with medication. Less common side effects include kidney damage that in rare cases may be permanent. This kidney damage can be lessened by the use of intravenous fluids and maintaining good fluid intake by mouth after therapy. Should nausea and vomiting prevent adequate fluid intake, you must notify your doctor so that you may be admitted to the hospital and given intravenous fluids, if necessary. A decrease in hearing can occur and rarely may lead to deafness. Usually this hearing loss is not noticeable in the range of normal speech. Numbness and tingling in the hands and feet can occur and may lead to difficulty walking, performing fine motion such as buttoning clothes, and very rarely severe numbness and muscle weakness that can confine you to a wheelchair. Occasionally, allergic reactions may occur.

Radiation: Patients who receive radiation treatment for cancer of the cervix can expect to have a change in bowel movements. Generally, this occurs after 2 - 3 weeks of treatment with more frequent bowel movements being common. This may result in frequent watery stools (diarrhea). This can be controlled with diet and medication; however, it sometimes requires an interruption in the radiation treatment and sometimes hospitalization. Occasionally, patients have nausea and vomiting with this therapy. This also can be controlled with medication. On the long term basis, approximately 1 in 20 patients will have injury to other organs such as the intestines or urinary system. This can occasionally require additional surgery to control these complications. This injury can be in the form of a blockage of an organ, a communication between two organs that is abnormal (this is called a fistula), or bleeding from the bladder or bowel. Radiation treatment can also affect the body's ability to produce blood: the red blood cells which are necessary for oxygen carrying, the white blood cells which are necessary to fight infection, and platelets which are necessary to aid in clotting. Cisplatin usually does n o t affect the blood cells to any significant degree when used by itself; however, when used with other medications or radiation it may contribute to this effect on the blood cells.

Hysterectomy: Surgery to remove the uterus, tubes, and ovaries (hysterectomy) may result in complications of bleeding,

DA Form 5303-R Revised 28 Sep 93 Initials of volunteer Page 3 of 5 Title GOG 123

VOLUNTEER AGREEMENT AFFIDAVIT',

infection, and injury to other structures. The r i s k of injury to other structures is increased in patients who have received previous radiation treatment. Even so, the likelihood of having significant injury to other organs is less than 5 % . This injury to other organs may develop either at the time of surgery or as a late complication of surgery. These include blockage and abnormal passages as described in the radiation therapy side effects. additional surgery may be necessary to correct this problem. hysterectomy will require an anesthetic and hospitalization for approximately 1 week after surgery. As with any surgery and anesthesia, there is a small chance of dying from complications of surgery. The likelihood of this happening is approximately 1 in 1000 patients. A separate consent form will be used at the time of the hysterectomy, as well as at the time of placement of the devices into the cervix for the local radiation.

If any injury to the surrounding structures occurs, The



If you choose to discontinue participation in this study the alternative treatment could include radiation, surgery or both.

By consenting to participate in this study, you are responsible for carrying out instructions and you must relate to your doctors, nurses, or other study personnel any information that might be pertinent to the study, such as any side effects of a treatment or procedure. Any reluctance you might have to continue in the study must also be reported.

ALTERNATIVE TREATMENTS: Alternative treatments to this protocol may include additional chemotherapy or other experimental programs. You may also elect to have no further therapy and to receive supportive care only. These alternatives have been discussed with you by your doctor prior to enrollment in the study.

CONFIDENTIALITY: Records from this study will be available for review by members of the Institutional Review Board at Madigan and by representatives of the Food and Drug Administration. Otherwise, only the physicians conducting this study will have access to the records from this study. Information gained from this study may be used as part of a scientific publication, but you will in no way be personally identified.

OTHER INFORMATION: Significant findings that occur during this study that might affect your decision to participate in the study will be discussed with you. The results of the research will be

DA Form 5303-R Revised 28 Sep 93 Initials of volunteer Page 4 of 5 T i t l e GOG 123

YOLUNTEER AGREEMENT AFFIDAVIT

made available to you if you so desire and may be obtained from your physician. Complete results may not be known for several years.

Your participation in this study may be terminated without your consent if conditions occur which might make your continued participation dangerous or detrimental to your health; or if military contingency requires it; or if you become ineligible for military care as authorized by Army regulation.

SIGNATURE OF VOLUNTEER

PERMANENT ADDRESS OF VOLUNTEER

If you should require medical care for injuries or disease which result from participation in this study, the medical care to which you will be entitled is the same as that to which you are already entitled as a DoD health care beneficiary. This does not include domiciliary or nursing home care.

DATE

TYPED NAME OF WITNESS

You are encouraged to ask any questions, at any time, that will help you to understand how this study will be performed and how it will affect you. You may contact Dr. Potter at (206) 968-1735.

You will be given a copy of this consent document for your records.

IF THERE IS ANY PORTION OF THIS EXPLANATION THAT YOU DO NOT UNDERSTAND, ASK THE INVESTIGATOR BEFORE SIGNING THIS FORM.

-~~~ ~ ~~

I do 0 do not 0 (check one & initial) consent to the inclusion of this form in my outpatient medical treatment record.

I DA Form 5303-R GOG 123 Revised 28 Sep 93 Page 5 of 5

.- /- -

I

DEPARTMENT OF THE ARMY HEADQUARTERS, MADIGAN ARMY MEDICAL CENTER

TACOMA, WASHINGTON 98431-5000 \

R E P L I TO ATTENTION OF

HSHJ-CI 2 April 1993

SUBJECT: Minutes of the Human Use Committee, 5 March 1993

1. The meeting convened at 1300 hours, 5 Mar 93

2. a. Members present:

COL Alfred S. Buck, MC COL Dan C. Moore, MC MAJ James H. Timmons, MC CPT Curtis S . Hansen, MS Christopher D. Hober, DAC Diane Stajduhar, R.N. Peggy R. Churchman, L.V.T. Nancy Whitten, DAC

Chairman Chief, Dept Clin Investigation Representative, Dept Radiology Representative, Pharmacy Service Chief, Public Affairs Office Representative, Dept Nursing Non-institutional member Recorder, non-voting member

b. Members absent:

JAG Officer Representative, Dept Ministry & Pastoral Care Representative, Social Work Service

c. Non-members present:

Susan Webb, R.N. Nursing Research Service

3 . The minutes of the previous meeting (5 Feb 9 3 ) were approved as written.

4 . The following protocols have been completed (see Encl 1):

5. Revisions to the following protocols as required by the Human Use Committee at previous meetings were submitted and approved (see Encl 1):

6 . Continuing Review - the following protocol was reviewed and approved for continuation for one year:

A Comparative Study of the Safety and Efficacy of Clarithromycin and Eryped (Erythromycin Ethylsuccinate) Suspensions in the Treatment of Children with Community-Acquired Pneumonia by COL Marvin Krober, MC

7. Revisions to the following protocols were reviewed and approved:

a. Components of Prenata Care and Low Birthweight by LTC Jerome Kopelman, MC (see Encl 2)

HSHJ-CI 2 April 1993 SUBJECT: Minut& of'the Human Use Committee, 5 March 1993 J RISK - . STATUS: Other than minimal

MEDICAL MONITOR: COL Robert E. Jones, MC

DECISION: APPROVE 7 ; DISAPPROVE: 0

STIPULATIONS: In consent form, change the pronouns to second person and correct formatting errors and typos

h. SWOG 9215: Oualitv of Life on Breast Cancer Adjuvant Trial JSWOG 8931) by MAJ Timothv P. Rearden, MC

Dr. Moore stated that this is a quality of life questionnaire that will be used with SWOG 8931. He added that the Alternatives to participation paragraph should be completed using the usual SWOG paragraph.

RISK STATUS: Other than minimal

MEDICAL MONITOR: COL Robert E. Jones, MC

DECISION: APPROVE 7; DISAPPROVE: 0

STIPULATIONS: In the consent form change all the pronouns to second personland correct typos and formatting errors, and complete the alternative paragraph.

i. The followins GOG protocols were alsproved with the stipulations that an Alternative to Participation paragraph and a pregnancy exclusion paragraph be added where necessary, that the consent forms be rewritten in second person where necessary, and that spelling and formatting errors be corrected to the satisfaction of Ms Whitten. Patients on 26NN, 102N, 114, and 117 will be surgically sterile. Protocols 120, 121, 123, and 125 need a pregnancy exclusion clause.

11) GOG 26NN: A Phase I1 Trial of Piroxantrone in Patients with Advanced and Recurrent Ovarian Elsithelial Carcinoma bv LTC Mark E. Potter, MC

1 2 1 GOG 102N: Intraperitoneal Administration of Recombinant Alpha- 2 Interferon Alternatina with Cisplatin in Patients with Residual Ovarian Carcinoma bv LTC Mark E. Potter, MC -

( 3 1 GOG 114: A Phase I11 Randomized Study of Intravenous CisDlatin and CycloDhosphamide versus Intravenous Cisplatin and Taxol versus Hiqh Dose Intravenous CarboDlatin Followed by Intravenous Taxol and Intraperitoneal Cisplatin in Patients with Optimal Staqe I11 Epithelial Ovarian Carcinoma bv LTC Mark Potter, MC

1 4 1 GOG 117: Adjuvant 1fosfami.de and Mesna with Cisplatin in Patients with ComDletely Resected Staqe I or I1 Mixed Mesodermal Tumors of the Uterus by LTC Mark E. Potter, MC

7

http://1fosfami.de

. (5) GOG 120: A Randomized Comparison of Hvdroxvurea Versus Hydroxvurea, 5-FU Infusion and Bolus Cisplatin Versus Weekly CisDlatin as Adjunct to Radiation Therapy in Patients With Staqes IIB, 111, IVA Carcinoma of the Cervix and Neqative Periaortic Nodes by LTC Mark E. Potter, MC

(6) GOG 121: A Phase Two Trial of Hiqh Dose Meaestrol Acetate JMeqace) in Advanced or Recurrent Endometrial Carcinoma by LTC Mark E. Potter, MC

(7) GOG 123: A.Randomized Comparison of Radiation Therapy and Adjuvant Hysterectomy versus Radiation Therapy and Weekly CisPlatin and Adjuvant Hysterectomy in Patients with Bulky Staae IB Carcinoma of the Cervix by LTC Mark E. Potter. MC

( 8 ) GOG 125: Extended Field Radiation Theram with Concomitant 5- FU Infusion and Cisplatin Chemotherapy in Patients with Cervical Carcinoma Metastatic to Para-Aortic LVmDh Nodes by LTC Mark Potter, MC

10. The meeting adjgOru+ at 1440 hours.

NANCY J. qTT3EN, DAC Recorder

/&.?kc%- DAN C. MOORE, M.D. COL, MC Chief, Department of Clinical Investigation

n

ALFRED~S . BUCK , M. D . COL, MC Chairman

APPROVE/-

LESLIE M. B&ER, M.D. Brigadier General, MC Commanding

8

TITLE: Protocol GOG #123, ARichard J. Farrell, COL, MC Chief, Pharmacy Service Patricia J. Basta,...

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Transcript of TITLE: Protocol GOG #123, ARichard J. Farrell, COL, MC Chief, Pharmacy Service Patricia J. Basta,...