RADIATION THERAPY ONCOLOGY GROUP

RTOG 98-04

PHASE III TRIAL OF OBSERVATION +/- TAMOXIFEN VS. RT +/- TAMOXIFEN FOR GOOD RISK DUCT CARCINOMA IN-SITU (DCIS) OF THE FEMALE BREAST







RTOG (9804)
(Coordinating Group)
Radiation Oncology Beryl McCormick, M.D.
Memorial Sloan-Kettering Cancer Center
1275 York Avenue, Room H208
New York, NY 10021
(212) 639-6828
FAX (212) 639-8876
mccormib@mskcc.org
SWOG (CTSU/R9804)
Lori J. Pierce, M.D.
(734) 764-9922
FAX (734) 647-9654		 Medical Oncology Clifford Hudis, M.D.
(212) 639-6483
FAX (212) 717-3619
hudisc@mskcc.org
NCIC CTG (MA.26)
Eileen Rakovitch, M.D.
(416) 480-4806
FAX (416) 480-6002		 Surgery Jeanne Petrek, M.D.
(212) 639-8128
FAX (212) 794-5812
petrakj@mskcc.org
Timothy J. Whelan, M.D.
(905) 387-9495, x64703
FAX (905) 575-6308		 Pathology Nour Sneige, M.D.
(713) 794-5626
FAX (713) 794-5664
nsniege@notes.mdacc.tmc.edu
CALGB (49801)
Barbara Smith, M.D.
(617) 724-1074
FAX (617) 724-1079		 Activation Date: December 13, 1999
CTSU (R9804) Current Edition: January 15, 2002
Includes Revision 1-3




This protocol was designed and developed by the Radiation Therapy Oncology Group (RTOG) of the American College of Radiology (ACR). It is intended to be used only in conjunction with institution-specific IRB approval for study entry. No other use or reproduction is authorized by RTOG nor does RTOG assume any responsibility for unauthorized use of this protocol.









Schema
Eligibility Check
1.0 Introduction
2.0 Objectives
3.0 Patient Selection
4.0 Pretreatment Evaluations
5.0 Registration Procedures
6.0 Radiation Therapy
7.0 Drug Therapy
8.0 Surgery
9.0 Other Therapy
10.0 Pathology
11.0 Patient Assessments
12.0 Data Collection
13.0 Statistical Considerations
References
Appendix I-A Sample Consent Form - A
Appendix I-B Sample Consent Form - B
Appendix II Karnofsky Performance Status
Appendix III Staging System
Appendix IV Toxicity Criteria
Appendix V Adverse Reaction Reporting Guidelines
Appendix VI Example of Treatment Plan
Appendix VII Consensus Conference on the Classification of Ductal Carcinoma in Situ
Appendix VIII Pathologic Evaluation









RADIATION THERAPY ONCOLOGY GROUP

RTOG 98-04

PHASE III TRIAL OF OBSERVATION +/- TAMOXIFEN VS. RT +/- TAMOXIFEN FOR GOOD RISK DUCT CARCINOMA IN-SITU (DCIS) OF THE FEMALE BREAST



SCHEMA
(1/15/02)



S

T

R

A

T

I

F

Y

Age
1. < 50
2. > 50

Final Path Margins
1. Negative (re-excision)
2. 3-9 mm
3. > 10 mm

Mammographic Size of Primary
1. < 1 cm
2. > 1 cm to < 2.5 cm

Nuclei Grade
1. Low
2. Intermediate

Tamoxifen Use
1. No
2. Yes

R

A

N

D

O

M

I

Z

E		 The physician specifies tamoxifen use:



Arm 1
Observation +/- tamoxifen 20 mg per day for 5 years



Arm 2
Radiation therapy* to the whole breast +/- tamoxifen 20 mg per day for 5 years


*RT Dose: 1.8 Gy per fraction x 28 fractions, for a total dose of 50.4 Gy; OR 2.0 Gy per fraction x 25 fractions, for a total dose of 50.0 Gy; OR 2.656 Gy per fraction x 16 fractions, for a total dose of 42.5 Gy



Eligibility: (See Section 3.0 for details) (1/15/02)

- Women > 26 years of age.
- Unicentric mammographically detected DCIS.
- < 2.5 cm in greatest dimension on mammogram.
- Lesions must be classified as low or intermediate grade DCIS.
- Inked margins > 3 mm.
- Clinically node negative.
- No active connective tissue disorders.
- No prior (unless disease free > 5 years) or concurrent malignancy other than basal or squamous cell skin cancer or in situ cancer of the cervix.
- No concurrent hormone therapy (other than tamoxifen) at time of study entry.
- Women may be taking tamoxifen which may have begun up to four weeks preceding diagnosis of DCIS.
- If assigned to Arm 2, radiation must begin within 12 weeks after the final surgery.
- Not pregnant or lactating.
- Signed study-specific consent form prior to randomization.



Required Sample Size: 1790 12/3/01









RTOG Institution # ___________  
RTOG 98-04/CALGB 49801 ELIGIBILITY CHECK (12/3/01, 1/15/02)
RTOG Case # ___________  
CALGB Seq. # ___________  



_____ (Y) 1. Was the DCIS detected by mammogram?

_____ (Y) 2. Is the lesion < 2.5 cm in its greatest dimension on mammogram?

_____ (N) 3. Is the lesion palpable or multicentric?

_____ (NG1,NG2) 4. Using the Philadelphia Consensus Conference Guide (Appendix VII of protocol), how is the lesion classified?

_____ (Y) 5. Were the margins as assessed by india ink > 3 mm?

_____ (Y) 6. Are the lymph nodes clinically negative?

_____ (Y) 7. Was the post op mammogram, including magnified views of the study breast, obtained within 12 weeks of final surgery?

_____ (Y) 8. Is the post op mammogram negative for any suspicious areas?

_____ (Y) 9. Will protocol radiation therapy begin within 12 weeks of final surgery if assigned to Arm 2?

_____ (Y) 10. Will the patient be free of any hormone therapy, including anti-estrogens, HRTs, birth control pills, at the time of study entry?

_____ (Y) 11. Is the patient 26 years of age or older?

_____ (N) 12. Any prior radiation therapy or chemotherapy?

_____ (N) 13. Except for basal or squamous cell skin cancer or in situ carcinoma of the cervix, is there a prior malignancy within the last 5 years?

_____ (N) 14. Is the patient pregnant or lactating?

_____ (N) 15. Does the patient have any active connective tissue disorders?

_____ (Y/N) 16. Is the patient taking tamoxifen?

_____ (N) If yes, was the tamoxifen started more than 4 weeks prior to diagnosis of DCIS?

The following questions will be asked at Study Registration:

____________________ 1. Name of institutional person registering this case?

__________________(Y) 2. Has the Eligibility Checklist (above) been completed?

__________________(Y) 3. Is the patient eligible for this study?

____________________ 4. Date the study-specific Consent Form was signed? (must be prior to study entry)

____________________ 5. Patient’s Name

____________________ 6. Verifying Physician

____________________ 7. Patient’s ID Number

____________________ 8. Date of Birth

____________________ 9. Race

____________________ 10. Social Security Number

____________________ 11. Patient’s Country of Residence

____________________ 12. Zip Code

____________________ 13. Patient’s Insurance Status

____________________ 14. Will any component of the patient’s care be given at a military or VA facility?

____________________ 15. Treatment Start Date (if assigned to RT Arm)

____________________ 16. Age (< 50 vs. > 50)?

____________________ 17. Final Path Margins (Negative vs. 3-9 mm vs. > 10 mm).

____________________ 18. Mammographic Size of Primary (< 1 cm vs > 1 cm to < 2.5 cm).

____________________ 19. Nuclei grade (low vs. intermediate)

____________________(Y/N) 20. Is physician planning Tamoxifen for this patient?

____________________ 21. Will patient participate in Epidemiology Study? (yes vs. no)

____________________ 22. Treatment Assignment


Completed by _______________________________ Date ____________________









1.0 INTRODUCTION

1.1 With the growing acceptance of mammography as a screening tool, non-palpable duct carcinoma in situ is being diagnosed with a frequency of 20-25% in large breast practices. Retrospective studies suggest that good risk disease, i.e. small lesions, with a low-grade pathology classification, can be effectively treated with radiation or with observation.1,2,3,5 The NSABP B-17 trial designed to answer this question stratified patients by age, presence or absence of lobular carcinoma in situ, presence or absence of an axillary node dissection, and method of detection, i.e. palpable mass versus mammogram only. Size, margins and pathologic grade, recognized presently as important selection factors for possible treatment with observation only, were not factors in that trial.4 The NSABP B-24 trial, recently closed to accrual, places all patients on radiation and then randomizes them to post-radiation observation or tamoxifen, does not address the question of the efficacy of observation only in a subset of good-risk patients with duct carcinoma in situ.

1.2 Size, or extent of disease, margins, and pathology grade, are problematic selection factors because a number of pathology classification systems addressing duct carcinoma in situ have been proposed. Recently, a consensus conference was held with the purpose of defining pathologic criteria for this disease. A consensus was reached by the participating pathologists and we propose using this working system9 as a starting point to assure standardization in defining cases of pathologic "good-risk" disease. We propose distributing the consensus guidelines and an illustrative set of sample teaching cases using the format of glass slide sets for initial review and the RTOG web site for reference and reinforcement. Pathologists completing this "course" would then review a set of test questions and qualify to read slides for the purpose of determining entry criteria for this study. In an ancillary project, a limited sample of slides of patients on this study would be reviewed by a group of breast pathology experts to establish the effectiveness of this teaching technique and the reproducibility of the consensus working classification.

1.3 The mammogram is an important diagnostic test for this disease. We propose requiring that patients on this study have mammograms performed at an accredited facility.

1.4 Prospectively, in a non-randomized study of irradiated patients, age was associated with outcome. The breast treatment team at Memorial Hospital applied the criteria of 1) size less than 2.5 cm and 2) non-comedo, low-grade lesions to recommend observation in a given subset of patients. Women with larger lesions, or lesions with comedo features and high nuclear grade were irradiated. In comparing results, in a retrospective study, patient age at diagnosis impacted significantly on outcome, hence the reason for stratification in this study.6

1.5 The NSABP B24 trial recently reported a positive impact from tamoxifen in reducing the risk of both recurrent carcinoma-in-situ and invasive cancer in women treated with breast conserving surgery and radiation. A decrease in the risk of contralateral new breast cancers was also observed.7

1.6 Duct carcinoma in situ is emerging as a possible model for the prevention of progression of a cancer from the in-situ to the invasive form of the disease. Both tamoxifen and radiation will impact on biomarkers; tamoxifen is already formally under study in women at increased risk for breast cancer, and radiation is known to modulate these markers in organ systems. Family history of breast cancer, or ovarian cancer, especially with a genetic change such as BRCA 1,2, or other emerging markers, is likely to play a major role in the development and progression of this disease. This study will include a voluntary registry of patients by epidemiologic data for possible genetic or other biomarker studies at a later date. Both tissue and blood will be stored for future testing.

1.7 We propose to undertake a phase III randomized study, limited to patients with occult, "good risk" duct carcinoma in situ, comparing tamoxifen alone to the same 50 Gy whole breast radiation treatment used in both NSABP studies plus tamoxifen. To facilitate comparisons, we will adopt the same definition of a clear margin as is used in the open ECOG registry study for similar good-risk patients.

1.8 Women who fail primary treatment for this disease can go on to develop a recurrence of the in situ carcinoma, or may progress to the invasive form of the disease.4,8 Depending on the stage of the disease at the time of the recurrence, and the initial treatment, treatment of the recurrence may appropriately range from a repeat wide local excision and radiation to mastectomy and systemic chemotherapy or hormone therapy. While it is beyond the scope of this study to mandate a specific treatment plan, we propose establishing a "recurrence help hotline" through the use of e-mail and the Internet. This would give the physician of a patient on this study with a recurrence access to the expertise of the study chairmen for this protocol. We also propose tracking the therapy used in the treatment of the recurrence and establishing a tissue bank of patients who progress for later studies.

2.0 OBJECTIVES (12/3/01)

2.1 In the defined good-risk group, assess the role of whole breast radiation plus/minus tamoxifen compared to wide excision to negative margins alone plus/minus tamoxifen, in decreasing or delaying the appearance of local failure, both invasive and in situ, and preventing the need for mastectomy.

2.2 Assess distant disease free survival to affirm the hypothesis that the proportion of patients in either arm who fail with progression to invasive local disease can be successfully salvaged with further definitive local therapy and adjuvant systemic therapy as is appropriate to the individual case.

2.3 Adopt a working pathology classification system for DCIS, which can be taught to and uniformly applied by the community pathologist. This will include processing the specimen, assessing extent of disease, margin assessment, and the grading of the lesion. Pathologic relationship of any calcium present to the DCIS will also be noted.

2.4 Establish a registry for patients with an epidemiological questionnaire, for companion studies of biomarkers and genetics, to be done at a later time when research in this area has identified useful markers. Tissue and blood will be banked from each patient who agrees to participate in this aspect of the study.

2.5 Establish a tissue bank of patients who progress to local failure in the study breast.

3.0 PATIENT SELECTION

3.1 Conditions for Patient Eligibility

3.1.1 Patients must be women.

3.1.2 The DCIS must be detected by mammogram and must be unicentric.

3.1.3 Lesions < 2.5 cm. in greatest dimension on mammogram.

3.1.4 Must be classified as low (NG1) or intermediate (NG2) nuclear grade DCIS, using the Philadelphia Consensus Conference Guidelines (Appendix VII).

3.1.5 Margins as assessed by the India ink method will be 3 mm or greater.

3.1.6 A post-operative mammogram will be taken within 12 weeks after the final surgery. It will include magnification views of the study breast and must show no suspicious areas.

3.1.7 Clinically node negative.

3.1.8 Patients must be > 26 years of age to avoid the increased potential in the young patient for radiation to induce breast cancer later in life.

3.1.9 If assigned to Arm 2, radiation must begin within 12 weeks after the final surgery.

3.1.10 Patients must sign a study-specific consent form prior to randomization.

3.2 Conditions for Patient Ineligibility

3.2.1 Patients whose DCIS is palpable at the time of diagnosis, or multi-centric.

3.2.2 Lesions measuring greater than 2.5 cm in greatest dimension on mammogram.

3.2.3 High-grade lesions (NG3) as classified by the Philadelphia Consensus Conference Guidelines.

3.2.4 Final pathology margins measuring <3 mm. If the patient undergoes a further re-excision and then meets selective criteria, she may be randomized to this study.

3.2.5 Pregnant or lactating women because of the potential risk to the fetus or child from breast irradiation.

3.2.6 Active connective tissue disorders, such as lupus or scleroderma.

3.2.7 Prior history of any malignancy, except basal or squamous cell skin cancers or in situ carcinoma of the cervix, unless disease-free > 5 years.

3.2.8 Any prior irradiation or chemotherapy.

3.2.9 Patients whose post-operative mammogram shows findings for DCIS. If the patient undergoes a further re-excision and has a subsequent negative mammogram, she may be randomized to this study.

3.2.10 Other hormone therapy at the time of study entry including raloxifene, hormone-replacement therapy, or birth control pills.

3.2.11 Tamoxifen begun > 4 weeks prior to diagnosis of DCIS.

4.0 PRETREATMENT EVALUATIONS

4.1 History and physical examination, including surgical history.

4.2 Radiological evaluation including one set of mammograms performed or evaluated at an accredited facility and post-operative magnification views.

4.3 Pathology slides read by a local pathologist. (See Section 10.1.5).

4.4 Patients who agree to have blood and tissue banked must complete the Family History Assessment and Epidemiologic Questionnaire.

5.0 REGISTRATION PROCEDURES

5.1 RTOG Institutions

Patients can be registered only after pretreatment evaluation is completed and eligibility criteria are met. Patients are registered prior to any protocol therapy by calling RTOG headquarters at (215) 574-3191, Monday through Friday 8:30 am to 5:00 pm ET. The patient will be registered to a treatment arm and a case number will be assigned and confirmed by mail. The following information must be provided:

    - Institution Name & Number
    - Patient's Name & ID Number
    - Verifying Physician's Name
    - Eligibility Criteria Information
    - Stratification Information
    - Demographic Data
    - Treatment Start Date
5.2 CALGB Institutions

Registration will be accepted through the Main Member Institution only. Confirm all eligibility criteria as listed in Section 5.0. Call the CALGB Registrar (919-286-4704, Monday - Friday, 9:00 a.m. - 4:30 p.m., Eastern Time). Registrations must occur prior to initiation of therapy. Call the CALGB Registrar (919-286-4704, Monday-Friday, 9 a.m.-4:30 p.m. Eastern Time) with the following information:

    Your name
    Study #
    Institution #
    Treating Physician
    Patient’s Social Security #, or hospital ID #
    Patient’s Name, I.D.#
    Date of Signed Informed Consent
    Race, Sex, Date of Birth
    Zip code of residence
    Method of payment
    Diagnosis, Date of Diagnosis
    Eligibility Criteria met (Sec. 3.0) (yes, no)
    List of prior CALGB protocols
    Date of most recent Institutional Review Board approval (<1 year)
The CALGB Registrar will then contact the RTOG Headquarters for treatment assignment, after which the CALGB Registrar will contact the institution with the treatment assignment. RTOG Headquarters will forward a confirmation of treatment assignment to the CALGB Registrar, who will subsequently forward the confirmation of treatment assignment to the main member institution.

5.3 CTSU Investigators (8/18/00)

5.3.1 CTSU Address and Contact Information

  • For patient enrollments or to report adverse event:
    Phone – 1-888-462-3009
    Fax – 1-888-691-8039

  • To mail forms or data:
    CTSU Data Processing Manager
    CTSU Data Center
    WB 408
    1441 W. Montgomery Avenue
    Rockville, MD 20850-2062

    All other questions (including forms-specific questions) should be communicated by phone or e-mail to:
    CTSU General Information line – 1-888-823-5923 or ctsucontact@westat.com. All calls will be triaged to the appropriate CTSU representative.

  • The CTSU website is located at: www.ctsu.org

    5.3.2 Registration / Randomization, CTSU Investigators

    Prior to the recruitment of a patient for this study, investigators must be registered members of the CTSU. Each CTSU investigator or group of investigators at a clinical site must obtain IRB approval for this protocol before they can enroll patients. Patients can be registered only after pre-treatment evaluation (Section 4.0 of protocol) is completed, all pertinent documents are approved and on file and eligibility criteria are met.

    CTSU Procedures for Patient Enrollment: (12/3/01) Contact the CTSU Patient Registration Office by calling 1-888-462-3009 to alert the CTSU Patient Registrar that an enrollment is forthcoming. To enroll the patient, the investigator should complete the following forms:

  • CTSU Enrollment Coversheet
  • RTOG 98-04 Eligibility Checklist

    These forms should be faxed to the CTSU Patient Registrar at 1-888-691-8039 between the hours of 8:00 am and 4:30 pm Eastern time. The CTSU registrar will verify that the investigator is CTSU credentialed and that all regulatory requirements have been met. The registrar will also check the enrollment forms for completeness and follow-up with the site to resolve any discrepancies.

    Once investigator and patient eligibility are confirmed, the CTSU will contact the RTOG to obtain a randomization assignment and assignment of a unique patient ID. The CTSU will then contact the enrolling site and convey the patient ID number (to be used on all future forms and correspondence) and the patient’s treatment assignment. This will be confirmed by a RTOG-generated confirmation of registration e-mail to the enrolling site, followed by the mailing of a data submission calendar and case-specific labels with the patient ID number.

    5.4 NCIC CTG Investigators (12/3/01)

    5.4.1 Ethical and Regulatory Requirements

    The following documentation must be on file at the NCIC CTG central office prior to randomization:

  • Documentation of full board REB approval of the protocol and consent form

  • A copy of the REB approved consent form (on institutional letterhead)

    Please note: The REB approved consent form must include all required NCI US elements. Upon request and time permitting, consent forms may be reviewed by the NCIC CTG central office prior to REB submission.

  • REB membership (consistent with OHRP membership requirements)

  • A completed NCIC CTG Confirmation of Initial Ethical Approval Form

  • A completed NCIC CTG participant's list

  • A current curriculum vitae for all investigators (principal and additional investigators)

  • A current Cooperative Project Assurance (CPA) or Federal Wide Assurance (FWA) number

    Documented annual re-approval of the study is required as long as there are patients being followed on the study. Annual re-approval must be full board until accrual is complete and all patients have completed protocol treatments and/or protocol mandated interventions.

    Central Office Contacts:

    Ms. Cathy Sears
    Intergroup Trials Associate
    NCIC Clinical Trials Group
    82-84 Barrie Street, Queen's University
    Kingston, ON
    Canada K7L 3N6
    Phone: 613-533-6430
    Fax: 613-533-2812
    E-mail: csears@ctg.queensu.ca

    Dr. Lois Shepherd
    Hematologic Pathologist
    Physician Coordinator
    NCIC Clinical Trials Group
    82-84 Barrie Street, Queen's University
    Kingston, ON
    Canada K7L 3N6
    Phone: 613-533-6430
    Fax: 613-533-2911
    Email: lshepherd@ctg.queensu.ca

    5.4.2 Registration Procedure

    Registrations for all NCIC CTG centres will be done through the NCIC CTG Central Office. Registrations will be accepted on Monday to Friday between 8:00 AM and 6:00 PM Eastern Time. The eligibility checklist must be completed prior to registration. Registration may be done by telephone (613-533-6430) or by fax (613-533-2812). Once eligibility is confirmed by the NCIC CTG, RTOG will be contacted by the NCIC CTG between 9:30 AM and 6:00 PM Eastern Time to obtain the treatment assignment. The NCIC CTG will then relay the treatment assignment to the centre and confirm it in writing.

    6.0 RADIATION THERAPY

    6.1 Protocol Therapy (Arm 2) (12/3/01, 1/15/02)

    All patients randomized to the radiation treatment arm shall receive a total of 50.4 Gy to the entire breast in 1.8 Gy fractions x 28 fractions, OR a total of 50.0 Gy in 2 Gy fractions x 25 fractions, OR a total of 42.5 Gy in 2.656 Gy fractions x 16 fractions. Radiation treatment will be delivered in uniform daily doses through standard tangent fields Monday to Friday for 3½ to 5½ weeks. No boost will be used.

    6.2 Dose Specifications

    The dose will be prescribed to a point at the lung-chest wall interface according to the method outlined below. This prescription method ensures that the PTV (entire breast volume plus margin) receives a minimum dose equal to the prescription dose. The CTV (entire breast volume) will be defined during simulation with the patient in the supine treatment position by palpating the periphery of the breast tissue and marking it with radio-opaque markers, such as lead wire. In a patient with surgical clips placed in the tumor bed, the clips must be within the CTV. The planning target volume (PTV) is the CTV plus a margin of 1.0 to 2.0 cm, superiorly, inferiorly, medially and laterally. Tangent fields with a coplanar posterior border will be used (Figure 1, Appendix VI). The prescription point at the lung-chest wall interface is defined in the following manner: A contour of the external patient surface is obtained for a transverse plane passing through the isocenter. On the simulation film or DRR, the location of the contour plane is determined and the distance of the lung-chest wall interface from the posterior border in the contour plane is measured and demagnified (See Point A in Figure 2, Appendix VI). On the patient contour, a line is drawn through the isocenter and perpendicular to the posterior border of the tangential fields. A point is then placed along this line at the distance, A, of the lung-chest wall interface from the posterior border as measured on the simulation films or DRR’s (Figure 1, Appendix VI). Care should be taken to consider any collimator rotation of the tangential fields when defining both the contour plane on the simulation film and the posterior tangent field borders on the contour. If a CT scan through the isocenter is available, it is always possible to mark point A directly without using a measurement from a DRR.

    6.3 Technical Factors

    6.3.1 Equipment must have nominal photon energies between 4MV and 8MV.

    6.3.2 Compensators, wedges, or dynamic therapy must be used to keep the maximum PTV dose within 15% of the prescription.

    6.3.3 The beam may be shaped, with a margin, to the shape of the breast with cerrobend-type blocking or by using a multi-leaf collimator.

    6.3.4 Fields will be designed using a simulator unit or CT simulator with appropriate patient immobilization for daily accuracy. Use of an Alpha-cradle would be one example, a mammorex board is another.

    6.4 Critical Structure Dose

    The maximum distance from the posterior or deep field border to the lung/chest wall interface will be 3.0 cm anywhere in the field.

    6.5 Treatment Interruptions

    If a treatment interruption is necessary for acute radiation toxicity of the skin, aggressive treatment of the area with a product like Duoderm is encouraged to minimize the treatment break. The total time to deliver the radiation therapy should not exceed seven weeks.

    6.6 Supraclavicular Field

    The use of a third field to cover the supraclavicular area is not allowed.

    6.7 Documentation

    All treated fields require filming on simulator or CT simulator units. Portal verification must be done for all treated fields. Copies of both simulator and portal fields must be submitted to RTOG Headquarters as specified in Section 12.0.

    6.8 Side Effects

    Fatigue is the anticipated systemic reaction to radiation. Skin erythema and desquamation may also occur. Breast edema and tenderness and myositis are also acute side effects. Possible long term complications include radiation pneumonitis, rib fractures, and for left sided lesions, cardiac complications.

    7.0 DRUG THERAPY

    7.1 Tamoxifen (Nolvadex)

    7.1.1 Animal Studies

    In the rat, mouse, beagle dog, and rhesus monkey, maximal blood levels of tamoxifen are seen 1-6 hours and 24-44 hours after an oral dose. The drug is hydroxylated in the liver to a number of different compounds and excreted in the bile. After a conjugation, an extensive enterohepatic circulation exists, and the conjugated metabolites are hydrolyzed to the unhydrolyzed metabolite, reabsorbed, and reconjugated. Eventually, the drug is excreted in the feces in the metabolized form. Very little drug is excreted in the urine. Biophasic half-lives of 5-12 hours and 62-170 hours were seen in the animal experiments. The antiestrogenic properties of the metabolite are unknown; however, the monohydroxyl metabolite is thought to have activity. Tamoxifen has been shown to cause liver tumors in rats, when they receive doses 20-100 times the human dose.

    7.1.2 Human Studies

    Using a method incorporating ion pair extraction, photochemical activation, and chromatographic analysis, maximal blood levels of tamoxifen and metabolite are found to occur within 3-12 hours after a single dose of tamoxifen of 10 mg. Preliminary data indicate a half-life after a single dose in excess of 24 hours. Metabolism in humans is similar to animals but with extensive enterohepatic circulation. Half-life after prolonged 10 mg b.i.d. dosage is variable but appears to be between 4 and 14 days.

    7.1.3 Human Toxicity

    Toxicity attributable to tamoxifen is minimal and consists mainly of hot flashes (20%), transient nausea (10%), and vaginal discharge (9%). Vaginal bleeding, skin rash, and edema occur rarely. A mild leukopenia or thrombocytopenia will develop in up to 20% of the patients, usually during the second week of therapy, which resolves spontaneously within a week and does not require discontinuation of the drug. Hypercalcemia developed in approximately 1% of patients.

    Analysis of data from NSABP P-1E, an ancillary study to NSABP B-14 designed to evaluate ocular toxicity in women taking tamoxifen, and the Breast Cancer Prevention Trial suggests that women taking tamoxifen may be at a slightly increased risk for developing cataracts. In addition, women who have a cataract prior to tamoxifen may be more likely to have cataract surgery. Other eye problems, such as corneal scarring or retinal changes, have been reported in a few patients.

    An association between tamoxifen therapy and thromboembolic events has been supported by case reports, and the findings of decreased antithrombin levels inpatients receiving tamoxifen in some, but not all studies. Data from a large prospective placebo-controlled adjuvant tamoxifen trial shows that the incidence of thromboembolic events was 0.9% in tamoxifen-treated patients versus 0.2% in patients receiving placebo.

    In placebo controlled adjuvant tamoxifen trials, no hepatocellular tumors have been observed in over 3000 tamoxifen-treated patients and over 3000 patients who received placebo. In a Swedish adjuvant trial in which patients received 40 mg/day of tamoxifen, 2/931 (0.2%) cases of liver cancer were observed in contrast to 0/915 cases in patients treated with placebo.

    Tamoxifen has a estrogenic effect on the endometrium and cases of endometrial cancer in women on tamoxifen have been reported. Some of these resulted in death. The incidence of endometrial cancer is 0.3% (9/3097) in patients receiving 20 mg/day of adjuvant tamoxifen, in contrast to 0.1 (4/3091) in patients treated with placebo. The incidence of endometrial cancer was higher (1.4% versus 0.2%) in a Swedish adjuvant study which treated patients with 40 mg/day of tamoxifen.

    Other adverse reactions reported infrequently include distaste for food, depression, dizziness, and light-headedness. Unpublished data suggest a possible increase in second cancers of the gastrointestinal tract among women receiving tamoxifen, and there have been a few reports of liver cancer that have occurred in women taking tamoxifen.

    7.2 Drug Formulation and Availability

    7.2.1 Formulation (12/3/01)

    Tamoxifen is supplied in 10 mg or 20 mg tablets.

    7.2.2 Storage and Stability

    The drug substance is stable for at least five years under normal storage conditions and should be protected from light and moisture. Minimal shelf-life appears to be two years.

    7.2.3 Administration (12/3/01)

    If the physician specifies that tamoxifen will be used, patients will receive tamoxifen 20 mg per day for five years.

    7.2.4 Supplier

    The drug is commercially available for purchase. This drug will not be supplied by the NCI. Tamoxifen is available from Zeneca, Wilmington, Delaware, under the trade name Nolvadex.

    7.3 Adverse Reaction Reporting (12/3/01)

    7.3.1 The revised NCI Common Toxicity Criteria will be used to score acute radiation (< 90 days) toxicities.

    7.3.2 A copy of the CTC version 2.X can be downloaded from the CTEP Home page (http://ctep.info.nih.gov). All appropriate treatment areas should have access to a copy of the CTC version.

    This study will be monitored by the Clinical Data Update System (CDUS) version 1.1. Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due January 31, April 30, July 31 and October 31.

    7.3.3 All deaths within 30 days of completion or termination of protocol treatment regardless of cause.

    7.3.4 All fatal toxicities (grade 5) resulting from protocol treatment must be reported by telephone to the Group Chairman, to RTOG Headquarters Data Management and to the primary Study Chairman within 24 hours of discovery.

    7.3.5 All life-threatening (grade 4) toxicities resulting from protocol treatment must be reported by telephone to the Group Chairman, to RTOG Headquarters Data Management and to the primary Study Chairman within 24 hours of discovery.

    7.3.6 Appropriate data forms, and if requested a written report, must be submitted to Headquarters within 10 working days of the telephone report (FAX# 215/928-0153).

    7.3.7 A MedWatch Form must be submitted on all life threatening (grade 4) or fatal (grade 5) toxicities resulting from protocol therapy and submitted to RTOG Headquarters within 10 working days of the telephone report. An NCI AML/MDS Second Malignancy Form is required if the patient is diagnosed with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) during or subsequent to treatment on NCI/CTEP-sponsored clinical trials. The form is available at http://ctep.info.nih.gov (See Appendix V).

    7.3.8 CALGB Investigators: Adverse Drug Reactions (ADRs) for CALGB patients will be routed through the CALGB Central Office. The CALGB Central Office (773-702-9860) must be called for all toxicities that need to be reported by telephone. All written reports must be submitted within five working days to the CALGB Central Office, 208 South LaSalle Street, Suite 2000, Chicago, IL, 60604-1104, for tracking purposes. The CALGB Central Office will forward these reports to RTOG Headquarters.

    7.4 CTSU Investigators (8/18/00)

    7.4.1 Adverse Event (AE) Reporting

    This study will utilize the CTC version 2.0 for toxicity and Adverse Event (AE) reporting. A hyperlink to the CTEP home page that contains CTC information is available on the CTSU website. CTSU investigators are responsible for reporting adverse events according to the RTOG guidelines, including notification of their local IRB. All reporting should be conducted within the timeframes specified in the protocol and completed forms and reports should be faxed to the CTSU Data Center. The CTSU will review the documents to ensure that all necessary information is included and will forward them to RTOG. RTOG will then distribute the documents internally and to the appropriate regulatory agencies.

    For those AE’s requiring 24-hour phone notification, the CTSU investigator is responsible for reporting the event within 24 hours to the following persons/entities:

    · CTSU Data Center at 1-888-462-3009

    · RTOG Primary Study Chairman (see cover page of protocol)

    7.4.2 Secondary Malignancies Reporting

    All CTSU investigators are required to report secondary malignancies occurring on or following treatment on NCI-sponsored protocols. Events should be reported according to the RTOG guidelines and conducted within the timeframes specified in the protocol. Completed forms (including pertinent pathology and cytogenetics reports) should be submitted to the CTSU. Once received, the CTSU will send the forms to RTOG who will forward them to the appropriate agencies.

    7.5 NCIC CTG Investigators (12/3/01)

    Adverse Reactions must be reported according to the definitions in Sections 7.3.1 to 7.3.5 on the NCIC CTG Serious Adverse Event Form by telephone (613-533-6430) and/or fax (613-533-2812) within 24 hours of the event. Any second malignancies or myeloid dysplasia must be reported in writing on a NCIC CTG Serious Adverse Event Form within 15 working days of when the diagnosis is known to the investigator.

    Adverse Reactions will be forwarded to RTOG Headquarters by NCIC CTG as required.

    8.0 SURGERY (8/18/00)

    8.1 Patients will have completed all breast surgical procedures prior to accrual into this protocol in order to establish eligibility criteria. Surgical issues and considerations in the breast excision(s) are important and have been covered in the Standards of Breast Conservation Treatment,8 a 1992 consensus booklet published by the American Cancer Society for Professional Education. The technical surgical aspects for DCIS are similar to those for invasive cancer and concern the kind of anesthesia, needle localization technique, placement of incision, use of cautery and its effects on margin assessment, approximation of edges of the excisional cavity, clip placement to indicate site of excision, closure of the skin, and orienting the specimen in the operating room to orient it for pathologic evaluation.

    8.2 A copy of this booklet can be obtained from RTOG (Fax 215-574-0300).

    9.0 OTHER THERAPY

    Not applicable to this study.

    10.0 PATHOLOGY

    10.1 For All Patients

    10.1.1 Central pathology review is not planned for this protocol, however it is recognized that there are several significant issues related to the pathology of DCIS which have the potential to impact on the eligibility of patients for this trial.

    10.1.2 The definition of "good risk" DCIS will utilize the guidelines accepted at a classification consensus conference of DCIS (Appendix VII). Patients will be ineligible if the DCIS is of high grade, greater than 2.5 cm in greatest diameter as measured on the preoperative mammogram, or with final pathologic margin < 3 mm.

    10.1.3 High histologic grade will be defined by the presence of either of two features:

    10.1.3.1 High nuclear grade, defined as nuclear size greater than 2.5 times lymphocyte or benign ductal epithelial cell nuclei, marked pleomorphism, irregular chromatin with single or multiple nucleoli and conspicuous mitoses.

    10.1.3.2 Necrosis, defined by the presence of ghost cells with karyorrhectic debris, in one third or greater of the neoplastic ducts.

    10.1.4 Relationship to the surgical resection margin is dependent on the surgical approach.

    10.1.4.1 In cases where the surgeon submits separate samples from the wall of the biopsy cavity after removal of the excision specimen (usually representing medial, lateral, superior, inferior, and deep aspects), if no tumor is present in these biopsies, the margin will be considered adequate. The presence of tumor in any of these biopsies will be considered an inadequate margin for the purposes of this protocol.

    10.1.4.2 In cases where no separate margin biopsies are submitted, the pathologist will ink the entire surface of the specimen. This may or may not employ multiple colored inks to aid in orientation. The narrow (closest) margin of the tumor to ink will be measured on the glass slide and must be greater than or equal to 3 mm for eligibility in this protocol.

    10.1.5 In order to ensure reproducibility of histologic criteria, three tools will be employed in this study:

    10.1.5.1 A “teaching” set of photomicrographs illustrating key diagnostic features of low/intermediate and high grade lesions has been prepared and is available on the RTOG website (www.rtog.org/qa/qa.html). This has been provided as a resource for the designated pathologist from participating institutions; however, mandatory credentialing is not a requirement for study participation.

    10.1.5.2 A random sampling of 10% of cases will be reviewed by Dr. Sneige to assess the success of Sections 10.5.1 and 10.5.2 in educating pathologists in the assignment of low or intermediate histologic grade as defined in this protocol. Any discrepancies identified will not render the patient ineligible but will provide information on the approximate frequency of undergrading in this study. Material for central review must NOT be sent to RTOG (Headquarters or Tissue Bank) until requested by Dr. Sneige.

    10.2 For Patients Also Participating in the Epidemiologic Component

    10.2.1 Instructions for Plasma Collection and Handling (12/3/01)

    Blood samples should be collected before study treatment begins (Arm 2 only). One purple top (EDTA) tube (10 cc) should be drawn, and the plasma separated from the cellular component by centrifugation. The plasma should be placed in a plastic freezing tube, which must be labeled with the patient’s name, CALGB/RTOG patient numbers, CALGB/RTOG protocol numbers, date of collection, and specimen number. Samples should be stored at -20°C (a standard refrigerator freezer) until mailing.

    Samples should be sent overnight express on dry ice. Be certain sufficient dry ice is in the mailing box to keep samples frozen for at least 48 hours. A completed original CALGB Form C-384, Specimen Routing Form (for plasma) should accompany each sample. A copy of Form C-384 will also be sent to RTOG, and a copy kept for your records.

    Samples should not be sent on Fridays or on days before holidays. It is optimal to send samples in batches of 10-20 specimens for convenience and savings on shipping costs.

    BE CERTAIN TO USE AT LEAST FIVE (5) POUNDS OF DRY ICE. ALSO, SHIP OVERNIGHT EXPRESS SO THAT SPECIMENS WILL NOT ARRIVE ON A WEEKEND OR HOLIDAY. SHIP TO:

    CALGB PCO
    The Ohio State University
    B054 Graves Hall
    333 W. 10th Avenue
    Columbus, OH 43210
    (614) 688-3495
    Fax (614) 292-5618


    10.2.2 Instructions for Block Submission

    One block shall be obtained by the participating institution to be submitted to the CALGB Pathology Coordinating Office (PCO). In cases where there are mixed types of DCIS, the highest grade areas should be submitted where possible.

    The requested block must be labeled with the institutional surgical pathology number and should be sent in a properly packaged sturdy box along with copies of the original ER/PR report, institutional pathology report and consultative pathology reports (if available). A completed CALGB Tracking Form for Tissue Blocks (C-490) must also be sent with the above tissue specimens and pathology reports to the following address:

    CALGB PCO
    The Ohio State University
    B054 Graves Hall
    333 West 10th Avenue
    Columbus, OH 43210-1239
    (614) 688-3495
    Fax (614) 292-5618

    Please consider using a secure and temperature-safe method of packaging the specimens. Extreme heat precautions should be taken when packaging blocks. Use of a traceable shipping method is recommended. If the above requirements cannot be met, please include a detailed explanatory letter.

    A copy of the C-384 (RTOG BS Form) and C-490 (RTOG PS Form) forms must also be sent to RTOG. Submitting institutions should also keep a copy of these forms for their records.

    The CALGB has instituted special considerations for the small percentage (5%) of hospitals whose policy prohibits long-term storage of blocks, and the smaller percentage (4%) of hospitals whose policies prohibit release of any block. If due to institutional policy, a block cannot be sent, please call the CALGB PCO at 614-688-3495 to obtain a protocol to cut the sections at your institution. The CALGB PCO is committed to being able to return blocks within 24 hours should the submitting institution need them for medical or medicolegal reasons.

    The goal of the CALGB PCO is to provide investigators with quality histology sections for their research while maintaining the integrity of the tissue. All paraffin blocks that are to be stored at the PCO will be vacuum packed to prevent oxidation and will be stored 4°C to minimize degradations of cellular antigens. For these reasons it is preferred that the PCO bank the block until correlative studies have been initiated and the study investigator requests thin sections. Please contact the PCO if additional assurances are required by your hospital pathology department.

    10.3 CTSU Investigators (12/3/01)

    10.3.1 Plasma Submission for Patients Participating in the Epidemiological Component, CTSU Investigators

    Blood samples should be collected before study treatment begins and shipped to the address in Section 10.2.1 of the protocol. A completed original Specimen Routing Form for Plasma C-384 (RTOG-BS Form) should accompany each sample. A copy of Form C-384 should also be sent to CTSU for forwarding to RTOG, and a copy kept for your records.

    10.3.2 Pathology Submission, CTSU Investigators

    All pathology materials are to be submitted directly to the CALGB Pathology Coordinating Office (PCO) according to instructions in Section 10.2.2 of the protocol. These should be accompanied by copies of the original ER/PR report, institutional pathology report, consultative pathology reports (if available) and a completed CALGB Tracking Form for Tissue Blocks C-490 (RTOG PS Form). Please submit a copy of all of the above-mentioned reports and forms to the CTSU for forwarding to RTOG, and keep a copy for your records.

    10.4 NCIC CTG Investigators (12/3/01)

    A limited sample of slides of patients on this study will be reviewed by a group of breast pathology experts. In addition to the possible request by RTOG for pathology material for central review (as described in Section 10.1.5.3), patients registered on this study will be asked for their consent to participate in Tissue Banking. Please refer to Section 10.2.2 of the protocol for a list of required forms and materials. At randomization, NCIC CTG will request submission of pathology materials as described in Section 10.2.2. The materials are to be clearly marked with the patient’s initials and NCIC CTG and RTOG patient and study numbers. DO NOT INCLUDE PATIENT NAMES ON THE BLOCKS. The blocks should be sent with a copy of the original ER/PR report and operative and pathology notes to:

    The NCIC CTG National Tumour Bank
    Richardson Labs - Pathology 4th Floor
    Queen's University
    Stuart Street
    Kingston, Ontario, Canada
    K7L 3N6
    ATTN: Mr. Troy Feener

    Please do not submit materials to RTOG.

    Pathology material will be required at recurrence if available (if biopsy is performed as part of normal patient care). If the amount of tissue available is limited, unstained sections rather than paraffin blocks will be sufficient.

    11.0 PATIENT ASSESSMENTS

    11.1 Study Parameters

    Procedure Pre-Entry Weekly During RT In Followup
    History & Physical X   Xa
    Family History/Patient Epidemiological Questionnaire f X   Xd
    Mammography Xb   Xc
    PreEntry Specimen Radiograph Xg    
    Pathology X   Xe
    Toxicity Evaluation   X Xa


    a. Visits may alternate between the radiation oncologist and the surgeon. Patient will be seen every 3 months from study entry for 1 year; q 6 months x 2 years, then annually. Also at progression/relapse and at death.
    b. Includes pre-biopsy and post-biopsy (mag views also).
    c. Yearly
    d. At 3 and 5 years.
    e. For local failure at study breast
    f. For patients who have consented to tissue/blood storage
    g. Recommended but not mandatory (See Appendix VIII)

    11.2 Response

    11.2.1 Local failure in the study breast will be defined as biopsy-proven recurrence in the quadrant of the original lesion, and classified as DCIS or invasive cancer.

    11.2.2 Local failure in another quadrant, proven by biopsy, will be defined as a new primary lesion within the treated breast, and considered as another event within the treated breast.

    11.2.3 Biopsy-proven failure in the skin of the treated breast will be defined as another event within the treated breast.

    11.2.4 Distant failure will be defined as progression of the disease beyond the study breast and axillary lymph nodes, and should be proven by biopsy whenever possible.

    11.2.5 Overall survival.

    11.2.6 Mastectomy will be defined as removal of the study breast for any reason. Pathology of any lymph nodes removed during this procedure will be recorded, as well as any further therapy required.

    11.2.7 Contralateral breast events.

    11.2.8 Death from progression of disease.

    12.0 DATA COLLECTION

    (RTOG, 1101 Market Street, Philadelphia, PA 19107, FAX#215/928-0153)

    12.1 Summary of Data Submission - All Patients

    Item Due
    Initial Evaluation Form (I1)
    Diagnostic Pathology Report (P1)
    Pathology Form (P4)
    Surgical Operative Notes (S2)
    Surgical Pathology Report (S5)
    Specimen Radiograph Form (SP)
    Treatment Form (TF) (Arm 1)     		Within 2 weeks of study entry
    Preliminary Dosimetry Information: (Arm 2)
    RT Prescription (Protocol Treatment Form) (T2)
    Films (simulation and portal) (T3)
    Calculations (T4)    		 Within 1 week of start of RT
    Final Dosimetry Information: (Arm 2)
    Treatment Form (TF)
    Daily Treatment Record (T5)
    Isodose Distribution (T6)
    		 Within 1 week of RT end
    Initial Follow-up Form (FS) (Arm 2) At 13 weeks from study entry.
    Follow-up Form (F1) (Arm 1) At 13 weeks from study entry.
    Follow-up Form (F1) At 6, 9, 12 months; then q 6 months x 2 years, then annually. Also at progression/relapse and at death.
    Pathology Report (P1)
    Pathology Slides/Blocks (P2)     		At local failure in study breast, if applicable.
    Autopsy Report (D3) As applicable


    12.2 For Patients Who Have Agreed to Tumor and Blood Storage

    Family History (PQ) Within 2 weeks of study entry.
    Epidemiology Assessment (PF) At 3 and 5 years.
    Blood Speciment Form (BS)
    (CALGB C-384)    		 Copy, original per Section 10.2.1.
    Pathology Speciment Form (PS)
    (CALGB C-384)    		 Copy, original per Section 10.2.1.


    12.3 CALGB Institutions

    CALGB participants should submit all non-RT data forms to the CALGB Data Management Center for forwarding to RTOG Headquarters. Dosimetry materials will be submitted directly to RTOG at the address in Section 12.1. The CALGB Data Management Center address is:

    CALGB Data Management Center
    First Union Plaza, Suite 340
    2200 West Main Street
    Durham, NC 27705


    12.4 CTSU Investigators (12/3/01)

    12.4.1 Data Submission

    Data Forms: All data forms for this study are available for download from the CTSU website. CTSU investigators should use the protocol-specific RTOG forms and adhere to the RTOG schedule for data submission in Section 12.0 of the protocol. A CTSU Data Transmittal Form should accompany all forms and reports submitted to the CTSU.

    Patient registration forms should be faxed to the CTSU. See Section 10.3 for instructions on plasma collection and pathology submission and Section 12.4.2 for instructions on submitting radiation therapy documentation; CTSU should receive a copy of the Dosimetry Transmittal Form. All other forms must be mailed directly to the CTSU. The CTSU will forward all information to the RTOG.

    Mail forms or data to:

    CTSU Data Processing Manager
    CTSU Data Center
    WB 408
    1441 W. Montgomery Avenue
    Rockville, MD 20850-2062

    12.4.2 Radiation Therapy Documentation Submission Instructions, CTSU Investigators

    Dosimetry materials and data (preliminary dosimetry information and final dosimetry information) are to be submitted directly to the Dosimetry Department, RTOG, at the address in Section 12.1 of the protocol. Please note that there are two separate intervals for submission: preliminary data (T2, T3, T4) within 1 week of start of RT and final data (TF, T5, T6) within 1 week of completion of RT. See Section 12.0 of the protocol for a complete inventory of dosimetry items to be submitted. Radiotherapy Form (T1) is considered a case report form and should be sent to the CTSU Data Center for forwarding to RTOG. A copy of the Dosimetry Transmittal Form also should be sent to the CTSU for tracking purposes. Any dosimetry questions should be directed to the Dosimetry Department at RTOG headquarters (215) 574-3219.

    12.5 NCIC CTG Investigators (12/3/01)

    RTOG Case Report Forms (CRFs), with the header modified by the NCIC CTG for their use, will be used by all NCIC CTG institutions.

    A single set of case report forms (CRFs) will be sent to each centre (for photocopying and use) following local activation. CRFs should be completed and submitted directly to the NCIC CTG Central Office according to the submission schedule in section outlined in the protocol. In addition to the required forms as listed, a copy of the signed consent form must be submitted for each patient. RTOG and NCIC CTG patient numbers as well as patient initials must be recorded on each form. CRFs will be forwarded to the RTOG by the NCIC CTG. Do not send CRF’s directly to RTOG, with the exception of radiation and films and forms which should be sent directly to RTOG to the address specified in section 12.0

    The NCIC CTG address for the submission of forms is:

    National Cancer Institute of Canada Clinical Trials Group
    82-84 Barrie Street
    Queen’s University
    Kingston, Ontario
    K7L 3N6

    13.0 STATISTICAL CONSIDERATIONS

    13.1 Study Endpoints

    13.1.1 Primary Endpoint

    Local recurrence is defined as either invasive or non-invasive local recurrence.

    13.1.2 Secondary Endpoint

    - Overall survival
    - Time to distant metastasis
    - Invasive local recurrence
    - Salvage mastectomy rate

    13.2 Sample Size Determination

    13.2.1 Overview

    The study is designed to evaluate the efficacy of the additional whole breast radiation plus tamoxifen compared to wide local excision plus tamoxifen with respect to local recurrence. Silverstein and et al.12 have reported a long term experience of DCIS treated breast conservation therapy (excision alone or excision plus radiation). The 5-year local recurrence-free survival for Van Nuys classification group 1 (non-high grade DCIS without comedo-type necrosis) is about 95% (n=132). The 5-year rate for group 2 (non-high grade DCIS with comedo-type necrosis) is about 90% (n=111). For our study design, we hypothesized that the 5-year local recurrence rate for the control arm, wide excision plus tamoxifen, is 5% and 10% for low and intermediate grades DCIS, respectively. In addition, we presume that a 40% or more reduction in the 5-year local recurrence rate with radiation therapy is of clinical importance. Thus, the projected local recurrence rates in the radiation arm with tamoxifen, are 3% and 6% for the low and intermediate groups respectively.

    The results of the NSABP B-24 trial indicated a statistically significant benefit from tamoxifen for “good risk” DCIS patients. With an average follow-up of 62 months, the study showed a 34% reduction in the annual risk of all breast cancer recurrence. For this study, we assume that the hazard rate for patients in both arms will be reduced 34% during and after the tamoxifen treatment. Thus, the radiation arm maintains its 40% reduction in hazard rate compared to the observation arm, although their local recurrence rates are decreased.

    13.2.1.1 (12/3/01) The accrual to this study has been slower than anticipated with an average of 5 patients per month. This prompted discussions at the summer 2000 and winter 2001 RTOG meetings. An informal survey of the RTOG members indicated that there were several institutions where women did not go on to the study because they did not want the tamoxifen. NCIC agreed to join the study, if the tamoxifen is optional. The UK DCIS trial presented at ASCO 200013 has not yet shown a benefit in local recurrence rates with the addition of tamoxifen. Based on all of these reasons, the RTOG Breast Committee proposed to make the tamoxifen optional. This recommendation was subsequently approved by the RTOG Data Monitoring Committee at its April meeting.

    The study design was revised assuming that the nuclei grade distribution will be ½ low grade and ½ intermediate grade, and that 2/3 of the patients will receive tamoxifen and 1/3 will not. Under these assumptions, with the recurrence rates listed in Table 1 and a 40% or more reduction in the five-year local recurrence rate with radiation therapy deemed to be of clinical importance, we will be comparing five-year local recurrence rates of 6% for wide excision vs. 3.5% with the addition of whole breast irradiation.

    Table 1
    Local Recurrence Rates without Whole Breast Irradiation

      Nuclei Grade
      Low Intermediate
    Tamoxifen 3% 7%
    No Tamoxifen 5% 10%

    13.2.2 Number of Local Recurrence Events Required According to Kim and Tsiatis’ group sequential design approach14 to 3 treatment comparisons (2 interim and 1 final analyses) using two-sided logrank test statistics, a maximum of 121 local recurrence events is required to detect the hypothesized 40% reduction in hazard rate by the addition of radiation therapy with a statistical power of 80% and significance level of 0.05.

    13.2.2.1 (12/3/01) Due to the revision making the tamoxifen optional, 129 local recurrence events will now be required.

    13.2.3 Sample Size and Accrual and Follow-Up Period

    To acquire 121 local recurrence events, the sample size required in this study is determined by the accrual rate, the lengths of accrual period and follow-up period, and the projected hazard rates for both arms. The following table lists the total sample sizes for various accrual rates, considering a 1% annual loss to follow-up after year five of the study and a total of 10% of ineligible and lack-of-data cases.

    Accrual Rate (monthly)
    		 Years of Accrual Years of Follow-up Total Sample Size
    22.4 7 5 1880
    27.6 6 5 1990
    35.0 5 5 2100


    With other cooperative groups joining the study, we expect to accrue an average of 25-30 cases per month. Thus 1990 women are required to be uniformly entered within 6 years with additional 5 years of follow-up. If the average monthly accrual rate is around 35 cases, the study can close in five years (with a sample size of 2100).

    13.2.3.1 (12/3/01) The hazard rates for local recurrence will depend on the distributions of nuclei grade and tamoxifen use. The following table lists the total sample sizes for various combinations of nuclei grade and tamoxifen use distributions with six years of accrual and five years of follow-up.

    Table 2
    RTOG 9804 – DCIS Study: Sample Sizes* (Number of Failures)
    for Given Distributions of Tamoxifen Use and Nuclei Grade

      Distribution of Low (L) to Intermediate (I) Nuclei Grade
    Distribution of Tamox(T) to No Tamox(NT)          
      70 L – 30 I 60 L – 40 I 50 L – 50 I 40 L – 60 I 30 L – 70 I
    2/3 T – 1/3 NT 2089 (131) 1891 (128) 1790 (129) 1716 (133) 1583 (133)
    1/2 T – 1/2 NT 1965 (132) 1790 (129) 1716 (133) 1535 (127) 1482 (130)
    1/3 T – 2/3 NT 1836 (130) 1700 (130) 1582 (130) 1482 (130) 1433 (130)
    100% T
    Original Design    		 --- --- 1990 (121)    

    * Includes 10% ineligible/lack of data cases.

    13.2.3.2 (12/3/01) With the revisions to this study, we expect to accrue an average of 25 cases per month. Under the assumed nuclei grade and tamoxifen use distributions in Section 13.2.1, 1790 women are required to be uniformly entered within six years with an additional five years of follow-up. If the average monthly accrual rate is around 30 cases, the study can close in five years.

    13.3 Randomization

    The treatment allocation scheme described by Zelen will be used. The stratifying variables are age (<50 vs. >50), margin (3-9 mm, >10 mm, negative) and tumor mammography size (<1 cm, >1 cm).

    13.3.1 (12/3/01) Nuclei grade (low, intermediate) and tamoxifen use (yes, no) will be added as stratification variables.

    13.4 Treatment Effect on Overall Survival

    Solin et al.15 have reported the 15-year results of 268 patients treated for DCIS of the breast using breast-conserving surgery plus definitive breast irradiation. They showed 98%, 94% and 87% overall survival at 5 years, 10 years and 15 years since the start of definitive breast irradiation, respectively.

    To provide an answer to the treatment difference in overall survival for the patients in this trial, an additional five years of follow-up are necessary to obtain sufficient survival information.

    Using the overall survival rates of Solin’s series and the assumption of a 1% loss of follow-up after year 5, the proposed sample size of 1990 (10 years follow-up) would detect a 33% reduction in annual death rate due to RT with a statistical power of 80%. To protect the type I error, the survival advantage will be tested using a two-sided logrank statistics with a significance level of 0.025. Specifically, a 33% reduction translates a 10-year overall survival improvement from 91% in the excision alone arm to 94% in the excision plus RT arm.

    Note that since Solin’s series included all subtypes of DCIS and without the use of tamoxifen, the real overall survival rates for the patients in this trial may be higher than we assumed. The consequence would be that the proposed sample size may detect a larger treatment difference in overall survival than we projected.

    13.4.1 (12/3/01) With the revised sample size of 1790 patients, allowing up to a total of 10% ineligible and lack-of-data cases, and assuming 1% loss to follow-up annually after year 5, the study could detect a 35% reduction in the annual death rate with 80% statistical power. In addition, a 33% reduction could be detected with 78% power. This equates to a ten-year survival improvement from 90.87% in the excision alone arm to 93.98% in the excision plus RT arm.

    13.5 Epidemiological Considerations

    Women registered in the study may opt for the epidemiological portion of the study by agreeing to bank tumor tissue and blood. The questionnaire includes information about personal health, family history, and personal habits. Patients who agree to participate will be followed to provide any subsequent changes.

    Unlike most early epidemiology studies20 that tried to establish the association between the incidence of breast cancer (or DCIS) and many risk factors, this study tries to investigate the potential risk factors that affect the treatment outcome, i.e., what increases the risk of developing local recurrence under one treatment. The risk factors include, not exclusively, age, race, age at pregnancy, menopausal status, breast cancer family history, body mass index and habits of cigarette and alcohol use.

    We project that 30%-50% patients in the study will complete the epidemiological questionnaire. Thus, we expect to have 300-500 patients from each treatment arm to examine the risk factors proposed.

    13.5.1 (12/3/01) In this revision of the study, we expect to have 250-450 patients from each treatment arm to examine the epidemiological risk factors proposed.

    13.6 Analysis Plan

    13.6.1 Statistical Methods

    Cumulative incidence methods16 will be used to estimate the 5-year rates of local recurrence, distant metastasis, and invasive local recurrence and salvage mastectomy. Overall survival will be calculated by Kaplan-Meier method17. The treatment effect by radiation therapy with respect to all the endpoints will done using logrank test statistics18. All eligible and evaluable patients will be included in the intent-to-treat analysis.

    Cox’s proportional hazards models19 will be utilized in analyzing the risk factors proposed in epidemiological considerations.

    13.6.2 Interim Reports

    Interim reports are prepared every six months until the closure of the study. In general, the interim reports will include:

  • the patient accrual rate including the rates in each stratum;
  • protocol compliance and the quality of the submitted data;
  • the frequencies and severity of the toxicities.

    13.6.2.1 (12/3/01) The nuclei grade and tamoxifen distributions will be reported every six months:

  • Two years after tamoxifen becomes optional, the distributions of nuclei grade and tamoxifen use will be evaluated and if necessary, a recommendation will be made to the data monitoring committee to change the sample size accordingly.
  • If the difference between low and intermediate grade is more than 10% in favor of the low grade, then it will be recommended to the DMC to increase the sample size.
  • If the use of tamoxifen is closer to 1/3, then it will be recommended to the DMC to decrease the sample size.

    13.6.3 Interim Analysis for Early Stopping

    Two such interim analyses shall be performed when we observe 25% and 67% of the 121 required local recurrences. The first interim analysis is projected to take place when 70% total accrual is reached. The second interim analysis is projected to take place at the third year (2 years after the closure) during follow-up. For each of these interim analyses, toxicity, treatment delivery and efficacy statistics will be reported to the RTOG DMC. The boundary for early stopping (or the nominal significance level for the test) will be computed based on the observed number of local recurrence events according to alpha spending function approach. If the difference is highly significant, i.e., across the boundary or p value less than the nominal level, the responsible statistician will recommend to the DMC that the study be closed (if open at the time) and be written up for publication.

    13.6.3.1 (12/3/01) The two interim analyses now will be performed when we observe 25% and 75% of the 129 required local recurrences. The first interim analysis is projected to take place when 63% of total accrual is reached. The second interim analysis is projected to take place with one year of follow up (1 year after closure).

    13.6.4 The First Analysis for Reporting Treatment Effects The analysis will be done after the end of the follow-up period or 121 local recurrence events are observed (see Section 13.2.3) unless the study is stopped early according to Section 13.6.3. The report should be able to answer the questions about the primary endpoint that is whether excision plus tamoxifen and radiation improves the local control of DCIS breast cancer compared to excision and tamoxifen.

    13.6.4.1 (12/3/01) The analysis now will be done after the end of the follow-up period or when 129 local recurrence events are observed.

    13.6.5 The Second Analysis for Reporting Treatment Effects in Survival Outcome

    The survival analysis will be done when each patient in the study has been followed for at least 10 years. Besides giving updated information in local control and other disease status, it should provide a more definitive answer to the treatment effect on overall survival status of the patients.

    13.7 Inclusion of Minorities

    In conformance with the National Institute of Health Revitalization Act of 1993 with regard to inclusion of women and minority in clinical research, we have also considered the possible interaction between race and treatments. Based on RTOG breast studies (RTOG 83-06 and RTOG 97-02 [CALGB 9343]), we project that 90% of women in the study will be white, 5% will be black (not of Hispanic origin), 1.5% will be Hispanic, 3% will be Asian or Pacific Islander, and 0.5% will be American Indian or Alaskan Native. The following table lists the projected accrual for each group. If this percentage remains the same in women who have had local recurrences at the time of analysis, the statistical power for detecting the hypothesized difference is 77% and 14% for white and non-white, respectively. With a projected 13 local recurrence events in non-white population, we will be able to detect a 73% hazard reduction by radiation therapy for the subset of non-white with statistical power of 50%.

    Planned Gender and Minority Inclusion

      American Indian or Alaskan Native Asian or Pacific Islander Black, not of Hispanic Origin Hispanic White, not of Hispanic Origin Other or Unknown Total
    Female 9 60 100 30 1791 0 1990


    The projected number of local recurrence events in the non-white population is now 14. The revised Planned Gender and Minority Inclusion Table is below: (12/3/01)



    Planned Gender and Minority Inclusion

      American Indian or Alaskan Native Asian or Pacific Islander Black, not of Hispanic Origin Hispanic White, not of Hispanic Origin Other or Unknown Total
    Female 8 54 90 27 1611 0 1790









    REFERENCES (12/3/01)

    1. Lagios MD, Margolin FR, Westdahl PR, Rose MR. Mammographically detected duct carcinoma in situ. Cancer 1989; 63: 618-624, 1989.

    2. Schwartz GF. Sub-clinical ductal carcinoma in situ of the breast: Selection for treatment by local excision and surveillance alone. The Breast J 2: 41-51, 1996.

    3. Silverstein MJ, Cohlan BF, Gierson ED, et al. Duct Carcinoma in situ: 227 cases without microinvasion. Eur J Cancer 28:630-634, 1992.

    4. Fisher B, Costantino J, Redmond C, Fisher E, Margolese R, Dimitrov N, et al. Lumpectomy compared with lumpectomy and radiation therapy for the treatment of intraductal breast cancer. N Eng J Med 328: 1581-1586, 1993

    5. Solin LJ, McCormick B, Recht A, Haffty BG, et al. Mammographically detected, clinically occult ductal carcinoma in situ treated with breast conserving surgery and definitive breast irradiation. The Cancer J 2:158-165, 1996.

    6. Van Zee KJ, Liberman L, McCormick B, Tran KN, Petrek A, Borgen PI. Longterm follow-up of DCIS treated with breast conservation: Effect of age and radiation. Abstract only, Society of Surgical Oncology, 1995.

    7. Wolmark N, Dignam J, Fisher B. The Addition of Tamoxifen to Lumpectomy and Radiotherapy in the Treatment of Ductal Carcinoma In Situ (DCIS): Preliminary Results NSABP Protocol B-24. San Antonio Breast Meeting (Abs) 1998.

    8. Winchester DP, Cox JD. Standards for Breast Conservation Treatment. Ca-A Cancer Journal for Clinicians. CA42: 134-162, 1992.

    9. The Consensus Conference Committee. Consensus Conference on the Classification of Ductal Carcinoma In Situ. Cancer 1997; 80: 1798-1802.

    10. Arnesson LG, Olsen K. Linkoping experience. In: Ductal carcinoma in situ of the Breast. Silverstein MJ, Lagios MD, Poller DN, Recht A. (Editors). Williams & Wilkins, Philadelphia, PA pp. 373-377, (1997)

    11. Schwartz GF: Treatment of subclinical ductal carcinoma in situ by local excision and surveillance: A personal experience. In: Ductal Carcinoma in situ of the breast. Silverstein MJ, Lagios MD, Poller DN, Recht A. (Editors). Williams & Wilkins, Philadelphia, PA, pp. 353-360, 1997

    12. Silverstein MJ: Van Nuys experience by treatment. In: Ductal carcinoma in situ of the breast. Silverstein MJ, Lagios MD, Poller DN, Recht A. (Editors). Williams & Wilkins, Philadelphia, PA pp. 443-447, 1997.

    13. George WD, Houghton J, Cuzick J, Forbes J. Radiotherapy and tamoxifen following complete local excision (CLE) in the management of ductal carcinoma in situ (DCIS): Preliminary results from the UK DCIS Trial. Proceeding from Am Soc Clin Oncol (ASCO), San Francisco, CA, 2000.

    14. Kim K, and Tsiatis AA. Study duration for clinical trials with survival response and early stopping rule. Biometrics, 46: 81-92, 1990

    15. Solin LJ, Kurtz J, Forquet A, Amalric R, Recht, A Bornstein BA, Kuske R, Taylor M, Barrett W, Fowble B, Haffty B, Schultz DJ, McCormick B, McNeese M: Fifteen-year results of breast conserving surgery and definitive breast irradiation for the treatment of ductal carcinoma in situ of the breast. J Clin Oncol. 14:754-763, 1996a.

    16. Gray RJ: A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 16:1141-1154, 1988

    17. Kaplan EL and Meier P: Nonparameteric estimation from incomplete observations. J. Amer. Statist. Assoc. 53:457-481, 1958

    18. Mantel, N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother. Rep. 50:163-170, 1966.

    19. Cox, DR. Regression models and life-tables. Journal of the Royal Statistical Society, Series B, 34:187-202, 1972.

    20. Ernster, VL: Epidemiology and natural history of ductal carcinoma in situ. In: Ductal carcinoma in situ of the breast. Silverstein MJ, Lagios MD, Poller DN, Recht A, eds. Williams & Wilkins, Philadelphia, PA, 1997










    APPENDIX I-A

    RTOG 98-04
    CALGB 49801

    PHASE III TRIAL OF OBSERVATION +/- TAMOXIFEN VS. RT +/- TAMOXIFEN FOR GOOD RISK DUCT CARCINOMA IN-SITU (DCIS) OF THE FEMALE BREAST

    SAMPLE CONSENT FOR RESEARCH STUDY

    THERE IS A RESEARCH STUDY ABOUT YOUR CONDITION AND ITS TREATMENT. THIS CONSENT FORM WILL TELL YOU ABOUT THIS STUDY AND HOW THE TREATMENT MAY OR MAY NOT HELP YOU.

    IT IS IMPORTANT THAT YOU READ AND UNDERSTAND THIS FORM, THE STUDY AND THE TREATMENT BEFORE YOU DECIDE TO BE PART OF THIS STUDY. IF YOU HAVE ANY QUESTIONS ABOUT THIS STUDY, THE TREATMENT OR HOW IT WILL AFFECT YOU, PLEASE ASK YOUR DOCTOR.

    RESEARCH STUDY

    You have the right to know about the procedures used in this research study and the risks, benefits and alternatives to the treatment in this study. You should know and understand the treatment proposed in this study, how it will be given, how the treatment may help you, how the treatment may harm you, and the choices available to you. This form will tell you about the study, the benefits, the risks and the alternatives so you can decide whether to be a part of this research study.

    PURPOSE OF THE STUDY (12/3/01)

    You have been diagnosed with a breast cancer in the very early stage. Radiation therapy, a form of cancer treatment using high-energy x-rays, may decrease the chance of a breast cancer coming back in your breast. The anti-estrogen hormone tamoxifen also may be appropriate for your condition after a surgeon has carefully removed this small cancer. It has recently been shown that tamoxifen reduces the risk of this cancer returning. Your physician and you will decide if your treatment will include tamoxifen. In this study, observation with or without tamoxifen will be compared to breast radiation therapy with or without tamoxifen.

    Also, a small part of the tissue removed by your surgeon and one tube of blood will be stored for future research. In the future, this may be able to predict which women may get this kind of cancer. It may also predict which women with this kind of cancer will benefit from the different treatments available.

    DESCRIPTION OF PROCEDURES (1/15/02)

    This study involves at random (by chance) assignment to one of two treatment arms. It is not clear right now which of the two is better. For this reason the therapy that is to be offered to you will be based upon a method of selection called randomization. Randomization means that your physician will call a statistical office that will assign you one of the two treatments by computer. The chance of receiving one of the two treatments is approximately equal.

    If your doctor and you decide that your treatment will include tamoxifen, you will be assigned to one of the following:

    After post-operative evaluation of your breast tissue by a pathology doctor and a post-operative mammogram of your involved breast show that all signs of the cancer have been removed, you will receive tamoxifen every day for five years. You will be carefully observed by physical examinations and yearly mammograms.

    OR

    After post-operative evaluation of your breast tissue by a pathology doctor and a post-operative mammogram of your involved breast show that all signs of the cancer have been removed, you will receive 16-28 treatments of radiation to your involved breast. It will be given once a day for five days a week (except Saturday and Sunday) for 3½ to 5½ weeks. You will also take tamoxifen every day for five years. You will be carefully observed by physical examinations and yearly mammograms.

    If your doctor and you decide that your treatment will not include tamoxifen, you will be assigned to one of the following:

    After post-operative evaluation of your breast tissue by a pathology doctor and a post-operative mammogram of your involved breast show that all signs of the cancer have been removed, you will be carefully observed by physical examinations and yearly mammograms.

    OR

    After post-operative evaluation of your breast tissue by a pathology doctor and a post-operative mammogram of your involved breast show that all signs of the cancer have been removed, you will receive 16-28 treatments of radiation to your involved breast. It will be given once a day for five days a week (except Saturday and Sunday) for 3½ to 5½ weeks. You will be carefully observed by physical examinations and yearly mammograms.

    You are being asked to also donate a small amount of the tissue removed at the time of surgery, and one tube of blood, to a tissue bank. At some time in the future, when biology research doctors know best what “markers” to look for, the tests which might predict how a patient with tumors like yours respond to a treatment, will be carried out at no additional cost to you. If you agree to this, you must sign a separate consent form for this purpose. You will also be asked to complete a questionnaire about your health, family history, and whether you smoke or drink. You will complete one questionnaire when you join the study. The next one will be done three years later. One more will be required two years after that. Your answers may provide information about how possible risk factors affect your health.

    RISKS AND DISCOMFORTS

    Cancer treatments often have side effects. The treatment used in this study may cause all, some, or none of the side effects listed. In addition, there is always the risk of very uncommon or previously unknown side effects occurring.

    Tamoxifen

    Adverse reactions to tamoxifen are infrequent. They are seldom severe enough to require discontinuing treatment. The following information discusses the side effects that have been observed:

    Frequent Side Effects: hot flashes, nausea and/or vomiting, menstrual irregularities including vaginal bleeding, vaginal discharge, and dryness.

    Secondary Cancer

    1. Endometrial cancer - Tamoxifen may cause changes in the lining of the uterus. An early sign of these changes may be abnormal vaginal bleeding or pelvic pain. You should report such symptoms to your physician immediately. The level of increased risk of uterine cancer associated with tamoxifen is still uncertain. After an average of 8 years of follow-up, the annual (per year) risk observed in a large-scale trial of breast cancer patients taking 20 mg of tamoxifen daily is about 2 per 1,000 women. This means that on the average, two cases of endometrial cancer were diagnosed among every 1000 women receiving tamoxifen during each year of the study and follow-up. This level of risk is approximately three times greater than that of a similar group of women in the general population. Uterine cancer may be life-threatening illness. Some breast cancer patients who develop uterine cancer while taking tamoxifen in the above studies have later died from uterine cancer. However, most of these cancers have been diagnosed at an early stage when treatment is highly effective. The treatment is surgical removal of the uterus, fallopian tubes, and ovaries. Radiation therapy may also be necessary. In view of this risk, it is recommended that all patients receiving tamoxifen have a pelvic exam before starting treatment and at least yearly thereafter. If you have already had a total hysterectomy, there is no risk of getting uterine cancer.

    2. Other cancers - One large U.S. study showed no increase in other (non-uterine) cancers in women taking tamoxifen. However, other unpublished data suggest a possible increase in second cancers of the gastrointestinal tract among women receiving the drug. There have been a few reports of liver cancer. Although tamoxifen can cause liver cancer in rats, it is not known to be a cause of liver cancer in humans. Whether an increased risk for other (non-uterine) cancers is associated with tamoxifen is still uncertain and continues to be studied.

    Infrequent Side Effects:

    Blood Clots - Some studies have shown that tamoxifen causes an approximate 1% increase in inflammation or blood clots in the vein and pulmonary embolism (loss of blood flow to the lungs). Rarely, death has occurred from such events. Patients with an existing history of such problems should discuss tamoxifen treatment carefully with their physician.

    Liver toxicity - Abnormal liver function tests including rare cases of more severe liver abnormalities such as fatty liver, cholestasis (back up of bile), hepatitis, and hepatic necrosis (destruction of liver cells) have been observed. A few of these serious cases resulted in death but whether tamoxifen was the cause of these problems is uncertain.

    Eye changes - Women taking tamoxifen may be at a slightly increased risk for developing cataracts (a clouding of the lens inside the eye). As women age, they are more likely to develop cataracts whether or not they take tamoxifen. Cataracts may lead to a decrease in vision. Eye surgery may be required to remove the cataract and improve vision. Women who have a cataract before beginning to take tamoxifen may be more likely to have cataract surgery. Other eye problems, such as corneal scarring or retinal changes, have been reported in a few patients. You must report any changes in your vision, or other eye problems, to your physician.

    Endometrial (uterine lining) changes including polyps, hyperplasia (tissue thickening), and endometriosis (endometrial cells outside the uterus), or a decrease in platelet counts making you more prone to bleeding. Bone and tumor pain and sometimes high calcium occurred in those patients treated for metastatic disease. Patients with increased pain requires more or stronger pain relievers. Often such symptoms signaled a good response to treatment and these symptoms usually went away quickly.

    Other infrequent side effects include skin rash, swelling of your hands or feet, genital itching, depression, dizziness and light-headedness, headache, hair thinning and/or partial hair loss. Ovarian cysts have been noted in premenopausal women.

    Radiation Therapy

    Radiation therapy may cause 1) Fatigue: tiredness for no apparent reason is a temporary effect going away within a month or two after completion of radiation. 2) Skin damage: within the area of radiation, the skin may develop a sunburn-like area within 2-6 weeks after treatment. This will go away. The skin may also become slightly thick compared to skin on the untreated breast. Treated skin will also be more sensitive to sun exposure in the future. 3) Swelling: the breast will feel heavy, almost like a pre-menstrual breast, during treatment and for several months afterwards. 4) Muscle tightness: muscles in the chest wall under the treated breast can sometimes feel “sore” or tight during and after radiation treatments. 5) Although uncommon, radiation may cause a cough and difficulty breathing in that part of the lung under the treated breast. A radiologist may see a slight change in this part of your lung on chest x-ray or CT scan or similar imaging of your chest. It is very unlikely that this will cause any decrease in exercise tolerance. 6) Although uncommon, pericarditis, (irritation of the sac surrounding the heart), myocarditis (irritation of the heart muscle), or rib fractures may occur long after completion of the radiation treatments.

    Your physician will be checking you closely to see if any of these side effects are occurring. Side effects usually disappear after the treatment is stopped. In the meantime, your doctor may prescribe medication to keep these side effects under control.

    COSTS

    Routine scans will be done to evaluate your breasts. If injury occurs as a result of this research, treatment will be available. The use of medication to help control side effects could result in added costs. This institution is not financially responsible for the treatment of side effects caused by the study treatment. You will not be reimbursed for medical care other than what your insurance carrier may provide. You will not be paid for your participation in this research study.

    CONTACT PERSONS

    (This section must be completed)

    For information about your disease and research-related injury, you may contact:


    _____________________________________ ______________________
    Name Telephone Number


    For information about this study, you may contact:


    _____________________________________ ______________________
    Name Telephone Number


    For information about your rights as a research subject, you may contact:
    (OPRR suggests that this person not be the investigator or anyone else directly involved with the research)


    _____________________________________ ______________________
    Name Telephone Number


    ALTERNATIVES

    Other treatments that could be considered for your condition may include the following: (1) radiation therapy; (2) tamoxifen; (3) surgery; or (4) no treatment. These treatments could be given either alone or in combination with each other.

    Your doctor can tell you more about your condition and the possible benefits of the different available treatments. You should discuss your condition and the expected outcome with your doctor. Your doctor will be available to answer any questions. You are encouraged to ask your doctor any questions you have about this research study and the choices of treatment available to you. If you have any questions at all, please ask your doctor.

    If your disease becomes worse, if side effects become very severe, or if developments occur that indicate the research study is not in your best interest, the treatment would be stopped. Further treatment would be discussed at that time.

    BENEFITS

    Tamoxifen has been shown to decrease the risk of breast cancer coming back after surgery. For this reason, it was approved by the Food and Drug Administration for treatment of postmenopausal women with breast cancer. It is also approved for treatment of metastatic breast cancers in women and men. Studies have also shown that tamoxifen can reduce the occurrence of second breast cancers. In addition, it has been shown to lower the level of cholesterol and other fats in the blood. This may reduce the risk of heart disease. Loss of bone minerals is also slowed by tamoxifen. This may result in fewer bone fractures as women age. Also, radiation has been shown to dramatically decrease the risk of cancer returning within the breast after breast-conservative surgery.

    The information from this study may also help others by providing information about your type of cancer and its response to treatment. The information will be used scientifically. A possible personal benefit of this research study may be a decreased risk of disease recurrence and a longer survival. None of these possible benefits is certain or guaranteed.

    VOLUNTARY PARTICIPATION

    You do not have to take part in this research study. You are free to withdraw or withhold your consent from taking part in this research study at any time. If you refuse to participate, there will be no penalty or loss of benefits. You may seek care from a doctor of your choice at any time. If you do not take part in this study or if you withdraw from the study, you will continue to receive care.

    CONFIDENTIALITY (8/18/00)

    Records of your progress while on the study will be kept in a confidential form at this institution and in a computer file at the headquarters of the Radiation Therapy Oncology Group (RTOG). The confidentiality of the central computer record is carefully guarded. During their required reviews, representatives of the Food and Drug Administration (FDA), the National Cancer Institute (NCI), qualified representatives of applicable drug manufacturers, and other groups or organizations that have a role in this study may have access to medical records that contain your identity. If you are participating in this study through the Cancer Trials Support Unit (CTSU), a record of your progress will also be kept by the CTSU. However, no information by which you can be identified will be released or published.

    I have read all the above, asked questions, and received answers concerning areas I did not understand. I have had the opportunity to take this consent form home for review or discussion.

    I willingly give my consent to participate in this program. Upon signing this form I will receive a copy.



    _____________________________________ ______________________
    Patient Signature (or Legal Representative) Date




    TISSUE AND BLOOD TESTING

    I agree to the use of my blood and tumor tissue and have signed a separate consent form for that purpose.

    Yes No


    If yes, a signed and dated form must be attached to this form.








    APPENDIX I -B

    RTOG 98-04
    CALGB 49801

    PHASE III TRIAL OF OBSERVATION +/- TAMOXIFEN VS. RT +/- TAMOXIFEN FOR GOOD RISK DUCT CARCINOMA IN-SITU (DCIS) OF THE FEMALE BREAST

    CONSENT TO COLLECT AND STORE BLOOD AND TUMOR TISSUE

    The RTOG would like to keep some of your blood and tumor tissue that is not needed for your care. If you agree, the RTOG will keep the samples in a specimen bank. They may be used in future research to learn more about cancer. Researchers are trying to learn more about cancer, such as what causes cancer, how to prevent it, how to treat it better, and how to cure it. Causes of cancer may come from the environment or from genetic causes. Genetic causes are causes that people are born with and that can also affect other family members. Your cancer may come from one or both of these causes. You may be concerned that research about genetic causes may give information not only about yourself, but also about your relatives and other groups of people who are like you. If genetic testing is done on samples from the bank, the testing will be done with only coded samples so that your identity remains unknown. Because the value of the research is not known at this time, and the researcher will not know who you are, your results will not be given to you or your doctor. Even if the research that is done on your blood and/or tissue cannot be used to help you, it might help other people who have cancer or other medical problems.

    The RTOG will be responsible for making sure your samples and information are protected and kept confidential in the specimen bank. Your samples will be given a code number to protect your identity. The samples will only be given to researchers approved by the RTOG. The research study must also be approved by the Institutional Review Board (IRB) at your hospital. An IRB is a group of people who look after the rights and welfare of people taking part in research.

    The choice to let the RTOG keep your blood and tissue for doing research is up to you. No matter what you decide to do, it will not affect your care. If you decide that your blood and tissue can be kept for research but you later change your mind and tell your doctor, the specimen bank will destroy any of your samples that they still have. Otherwise, the blood and tissue may be kept until they are used up, or until the RTOG decides to destroy them.

    The people who use your samples to do research may need to know more about your health both before and after your tamoxifen and radiation treatment (if you are assigned to radiation treatment). You will be asked to complete a questionnaire about your family history three times: at study entry, then 3 years later, then 2 years after that. If researchers ask for reports about your health, the RTOG will not provide them with your name, address, or phone number unless you are willing to be contacted in the future to take part in more research. There are laws that require that research records that have your name on them be shown to people who make sure that the research is being done correctly. As mentioned before in this consent form, the RTOG, the NCI, and the FDA will be allowed to review and copy your medical records as related to this research.

    Your blood and/or tissue will be used only for research and will not be sold. Some new products might be made because of the results of the research that uses your samples. These products might be sold sometime in the future, but you will not get paid. There will be no cost to you for any specimens collected and stored in the RTOG specimen bank.

    Please review statements 1, 2, and 3 and then circle the answer that is right for you. If you have any questions, please talk to your doctor or nurse.

    1. I have been told that my samples will be coded and my identity will not be disclosed to anyone without my permission, except when required by law.

          YES                NO

    2. I agree that remaining blood and tumor tissue may be kept by the RTOG for use in future research to learn about, prevent, treat, or cure cancer.

          YES                NO

    3. I agree that my doctor (or someone he/she chooses) may contact me in the future to ask me take part in more research.

          YES                NO

    VOLUNTARY CONSENT: I certify that I have read this consent form, or that it has been read to me, and any questions I had, including explanation of all wording, have been answered to my satisfaction. I have been told that any future questions I may have about the research will be answered by Dr(s)._________________________ at _________________________. Any questions I have concerning my rights as a research subject will be answered by _________________________ .

    A copy of this consent form will be given to me.

    My signature below means that I have freely agreed to take blood and tumor storage part in this research study.

    _____________________________________ ______________________
    Patient Signature Date









    APPENDIX II


    KARNOFSKY PERFORMANCE SCALE
    100 Normal; no complaints; no evidence of disease
    90 Able to carry on normal activity; minor signs or symptoms of disease
    80 Normal activity with effort; some sign or symptoms of disease
    70 Cares for self; unable to carry on normal activity or do active work
    60 Requires occasional assistance, but is able to care for most personal needs
    50 Requires considerable assistance and frequent medical care
    40 Disabled; requires special care and assistance
    30 Severely disabled; hospitalization is indicated, although death not imminent
    20 Very sick; hospitalization necessary; active support treatment is necessary
    10 Moribund; fatal processes progressing rapidly
    0 Dead
    ZUBROD PERFORMANCE SCALE
    0 Fully active, able to carry on all predisease activities without restriction (Karnofsky 90-100).
    1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. For example, light housework, office work (Karnofsky 70-80).
    2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours (Karnofsky 50-60).
    3 Capable of only limited self-care, confined to bed or chair 50% or more of waking hours (Karnofsky 30-40).
    4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair (Karnofsky 10-20).









    APPENDIX III

    AJCC STAGING SYSTEM
    BREAST, 5th Edition

    DEFINITION OF TNM

    Primary Tumor (T)

    Definitions for classifying the primary tumor (T) are the same for clinical and for pathologic classification. The telescoping method of classification can be applied. If the measurement is made by physical examination, the examiner will use the major headings (T1, T2, or T3). If other measurements, such as mammographic or pathologic, are used, the examiner can use the telescoped subsets of T1.

    TX Primary tumor cannot be assessed
    T0 No evidence of primary tumor
    Tis Carcinoma in situ: intraductal carcinoma, lobular carcinoma in situ, or Paget's disease of the nipple with no tumor.
    T1 Tumor 2 cm or less in greatest dimension T2 Tumor more than 2 cm but not more than 5 cm in greatest dimension
    T3 Tumor more than 5 cm in greatest dimension
    T4 Tumor of any size with direct extension to (a) chest wall or (b) skin, only as described below. Note: Paget's disease associated with a tumor is classified according to the size of the tumor.

    Regional Lymph Nodes (N)

    NX Regional lymph nodes cannot be assessed (e.g., previously removed)
    N0 No regional lymph node metastasis
    N1 Metastasis to movable ipsilateral lymph node(s)
    N2 Metastasis to ipsilateral axillary lymph node(s) fixed to one another or to other structures
    N3 Metastasis to ipsilateral internal mammary lymph node(s)

    Pathologic Classification (pN)

    pNX Regional lymph nodes cannot be assessed (e.g., previously removed, or not removed for pathologic study)
    pN0 No regional lymph node metastasis
    pN1 Metastasis to movable ipsilateral axillary lymph node(s) pN2 Metastasis to ipsilateral axillary lymph nodes that are fixed to one another or to other structures
    pN3 Metastasis to ipsilateral internal mammary lymph node(s)

    Distant Metastasis (M)

    MX Presence of distant metastasis cannot be assessed
    M0 No distant metastasis
    M1 Distant metastasis (includes metastasis to ipsilateral supraclavicular lymph node[(s)])

    STAGE GROUPING

    Stage 0 Tis N0 M0
    Stage I T1* N0 M0
    Stage IIA T0
    T1*
    T2    		 N1
    N1**
    N0    		 M0
    M0
    M0
    Stage IIB T2
    T3    		 N1
    N0    		 M0
    M0
    Stage IIIA T0
    T1*
    T2
    T3
    T3    		 N2
    N2
    N2
    N1
    N2    		 M0
    M0
    M0
    M0
    M0
    Stage IIIB T4
    Any T    		 Any N
    N3    		 M0
    M0
    Stage IV Any T Any N M1

    * Note: T1 includes T1mic
    ** Note: The prognosis of patients with N1a is similar to that of patients with pN0.










    RTOG/EORTC Late Radiation Morbidity Scoring Scheme APPENDIX IV

     

    ORGAN TISSUE

    0

    GRADE 1

    GRADE 2

    GRADE 3

    GRADE 4

    5

    SKIN

    None

    Slight atrophy; Pigmentation change; Some hair loss

    Patch atrophy; Moderate telangiectasia; Total hair loss

    Marked atrophy; Gross telangiectasia

    Ulceration

    		  

    SUBCUTANEOUS

    TISSUE

    None

    Slight induration (fibrosis) and loss of subcutaneous fat

    Moderate fibrosis but asymptomatic; Slight field contracture; <10% linear reduction

    Severe induration and loss of subcutaneous tissue; Field contracture > 10% linear measurement

    Necrosis

     

    		  

    MUCOUS

    MEMBRANE

    None

    Slight atrophy and dryness

    Moderate atrophy and telangiectasia; Little mucous

    Marked atrophy with complete dryness; Severe telangiectasia

    Ulceration

    D

    E

    SALIVARY

    GLANDS

    None

    Slight dryness of mouth; Good response on stimulation

    Moderate dryness of mouth; Poor response on stimulation

    Complete dryness of mouth; No response on stimulation

    Fibrosis

    A

    T

    SPINAL

    CORD

    None

    Mild L’Hermitte’s syndrome

    Severe L’Hermitte’s syndrome

    Objective neurological findings at or below cord level treated