Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized Trial of Hypofractionated Radiotherapy Post-Lumpectomy in Women With Node Negative Breast Cancer
Brief Summary: To determine if hypofractionated radiotherapy to the whole breast (4,250 cGy/16 fractions over 22 days) is equally effective to standard fractionated radiotherapy (5,000 cGy/25 fractions over 35 days) in women with node negative breast cancer who have undergone lumpectomy.

The primary outcome is local breast recurrence and secondary outcomes include morbidity and cost effectiveness.


Options:
A: Inclusion Criteria:

1. The female patient has a histological diagnosis of invasive carcinoma of the breast, and no evidence of metastatic disease.
2. Has had a lumpectomy (including segmental resection and partial mastectomy), that is, surgical excision of the tumour with a rim of normal tissue.
3. Patient has not had an axillary dissection, OR for patients who have had an axillary dissection, all nodes are negative for metastatic disease.

Exclusion Criteria:

1. Tumour greater than 5 cm in greatest diameter on pathological examination.
2. The presence of invasive or intraductal (noninvasive) breast cancer involving the surgical margins.
3. Clinical evidence prior to surgery of infiltration of the skin of the involved breast such as edema, ulceration, or fixation of the tumour to underlying muscle, or inflammatory breast cancer.
4. Bilateral malignancy of the breast (synchronous or metachronous).
5. More than one primary invasive tumour in the same breast.
6. Previous surgery for breast cancer.
7. Pathological status of axilla is unknown.
8. Status for adjuvant systemic therapy not determined.
9. For patients not treated with adjuvant chemotherapy: unable to commence radiation therapy within 16 weeks of last surgical procedure on the breast.
10. For patients treated with adjuvant chemotherapy: unable to commence radiation therapy within 8 weeks of the last dose of chemotherapy.
11. Serious nonmalignant disease (eg. cardiovascular, renal, etc.) which would preclude surgical or radiation treatment.
12. Currently pregnant or lactating.
13. Breast deemed too large to permit satisfactory radiation (ie. separation \> 25 cm).
14. Previous concomitant malignancies of any type except squamous, or basal cell carcinomas of the skin, or carcinoma \\fIin situ\\fR of the cervix which have been effectively treated.
15. Geographic inaccessibility for follow-up.
16. Psychiatric or addictive disorders which preclude obtaining informed consent or adherence to the protocol.
B: Inclusion Criteria:

* Pathologically confirmed ductal carcinoma in situ of the breast or early invasive breast cancer defined as pathologic stage Tis, T1, or T2, N0, N1mic, or N1a (pathologic staging of the axilla is required for all patients with invasive disease but is not required for patients with ductal carcinoma in situ \[DCIS\] only); (upfront pathologic stage cannot be assigned to patients treated with neoadjuvant chemotherapy; for such patients, the criteria for pathologic stage shall be applied to the initial clinical stage)
* Treatment with breast conserving surgery
* Final surgical margins must be negative, defined as no evidence for ductal carcinoma in situ or invasive breast cancer touching the inked surgical margin; if the invasive or in situ breast cancer approaches within less than 1 mm of the final surgical margin, then a re-excision is strongly encouraged; lobular carcinoma in situ at the final surgical margin will be disregarded
* Age 40 years or older. This age cutoff is justified because breast cancers in women under the age of 40 are known to have a significantly higher risk of IBTR presumably due to underlying biologic differences.
* Female sex.
* Attending radiation oncologist declares intention to treat the whole breast only and that a third radiation field to treat regional lymph nodes is not planned (radiation of the undissected level I/II axilla with high tangents is allowed)
* If the patient has a history of a prior non-breast cancer, all treatment for this cancer must have been completed prior to study registration and the patient must have no evidence of disease for this prior non-breast cancer
* Patients must be enrolled on the trial within 12 weeks of the later of two dates: the final breast conserving surgical procedure or administration of the last cycle of concurrent cytotoxic chemotherapy

Exclusion Criteria:

* Pathologic or clinical evidence for a stage T3 or T4 breast cancer
* Pathologic evidence for involvement of 4 or more axillary lymph nodes, or imaging evidence of involvement of infraclavicular, supraclavicular, or internal mammary lymph nodes
* Clinical or pathologic evidence for distant metastases
* Any prior diagnosis of invasive or ductal carcinoma in situ breast cancer in either breast
* Current diagnosis of bilateral breast cancer
* History of therapeutic irradiation to the breast, lower neck, mediastinum or other area in which there could potentially be overlap with the affected breast
* Patients not fluent in English or Spanish (The BCTOS will be available in these two languages)
* Patient is pregnant
C: Inclusion Criteria:

* Informed consent
* Histologically proven breast carcinoma
* Stage I or II (T1-3N0 or T1-2N1 M0, AJCC/TNM 6th edition)
* Surgery with clear margins
* Pre-operative medical imaging (at least CT, MRI, and/or PET-scan)

Exclusion Criteria:

* Prior breast or thoracic radiotherapy
* Pregnancy or lactation
* Fertile patients without effective contraception
* Psychiatric or addictive disorders
D: Inclusion criteria

* The patient must have a life expectancy of at least 10 years, excluding her diagnosis of breast cancer. (Comorbid conditions should be taken into consideration, but not the diagnosis of breast cancer.)
* The interval between the last surgery for breast cancer treatment (lumpectomy, mastectomy, axillary dissection, or re-excision of lumpectomy margins) and randomization must be less than or equal to 84 days.
* All of the following staging criteria must be met:

  * Primary tumor must be T1-3 by clinical and pathologic evaluation.
  * Ipsilateral nodes must be cN0-1 by clinical evaluation.
  * Ipsilateral nodes must be pN1, pN2a, or pN3a by pathologic evaluation.
  * M0
* Patients must have undergone either a total mastectomy and an axillary dissection or a lumpectomy and an axillary dissection. Sentinel node biopsy is permitted, but must be followed by an axillary dissection.
* The tumor must be invasive adenocarcinoma on histologic examination.
* The tumor must be determined to be HER2-positive prior to randomization. Assays performed using fluorescent in situ hybridization (FISH) require gene amplification to be eligible. Assays using immunohistochemistry (IHC) must be performed at an NSABP-approved reference laboratory and require a strongly positive staining score.
* Patients must have an analysis of both estrogen and progesterone receptors performed on the primary tumor prior to randomization. "Marginal," "borderline," etc., results (i.e., those not definitely negative) will also be considered positive regardless of the methodology used.
* At the time of randomization, the patient must have had the following: history and physical exam, EKG, and PA and lateral chest x-ray within the past 3 months; and a bilateral mammogram (or unilateral if patient has had a mastectomy) and a pelvic exam (for women who have a uterus and who will be taking tamoxifen) within the past year.
* Within 3 months prior to entry, the patient must have a baseline left ventricular ejection fraction (LVEF) measured by MUGA scan equal to or greater than the lower limit of normal for the radiology facility. (If LVEF is \> 75%, the investigator should consider having the LVEF determination reviewed prior to randomization. Following randomization, the LVEF determination may be reviewed up until the time of the post-AC MUGA. Please note that if a more accurate value is obtained from the review of the baseline MUGA, the corrected value must be submitted to the NSABP Biostatistical Center before the post-AC MUGA is performed.)
* At the time of randomization:

  * The postoperative absolute neutrophil count (ANC) must be ≥ 1500/mm3 (or \<1500/mm3 if, in the opinion of the investigator, this represents an ethnic or racial variation of normal).
  * Postoperative platelet count must be ≥ 100,000/mm3. Significant underlying hematologic disorders must be excluded when the platelet count is above the upper limit of normal for the lab.
* There must be postoperative evidence of adequate hepatic function, i.e., total bilirubin must be ≤ ULN for the lab unless the patient has a chronic grade 1 bilirubin elevation (\>ULN to ≤1.5 x ULN) due to Gilbert's disease or similar syndrome; and alkaline phosphatase must be \<2.5 times the ULN for the lab; and the serum glutamic-oxaloacetic transaminase (SGOT \[AST\]) must be \<1.5 times the ULN for the lab.
* There must be postoperative evidence of adequate renal function (serum creatinine within or less than the institution's normal range).
* Patients must have no clinical or radiologic evidence of metastatic disease. Suspicious findings must be confirmed as benign by radiologic evaluation or biopsy. A patient with skeletal pain is eligible for inclusion in the study if bone scan and/or roentgenological examination fails to disclose metastatic disease.
* Patients with a history of non-breast malignancies are eligible if they have been disease-free for 5 or more years prior to randomization and are deemed by their physician to be at low risk for recurrence. Patients with the following cancers are eligible if diagnosed and treated within the past 5 years: carcinoma in situ of the cervix, melanoma in situ, and basal cell and squamous cell carcinoma of the skin.
* Prior to randomization, the investigator must designate whether the patients who had a lumpectomy will receive local or locoregional radiation therapy. For patients who had a mastectomy, the investigator must designate whether or not the patient will receive radiation therapy. (Pre-randomization discussion and/or consultation with a radiation oncologist is encouraged.) Note: Irradiation of any internal mammary nodes is prohibited in this trial.
* Special conditions for eligibility of lumpectomy patients: irradiation and surgery
* Patients treated by lumpectomy and axillary node dissection to be followed by breast radiation therapy must meet all the eligibility criteria in addition to the following: Generally, lumpectomy should be reserved for tumors \<5 cm. However, at the investigator's discretion, patients treated with lumpectomy for tumors ≥ 5 cm are eligible. The margins of the resected specimen must be histologically free of invasive tumor and DCIS as determined by the local pathologist. In patients in whom pathologic examination demonstrates tumor present at the line of resection, additional operative procedures may be performed to obtain clear margins. This is permissible even if axillary dissection has been performed. Patients in whom tumor is still present at the resected margin after re-excision(s) must undergo total mastectomy to be eligible. Whole breast irradiation is required. Irradiation of regional lymph nodes is optional, but partial breast irradiation and irradiation of any internal mammary nodes are prohibited in this trial. Intent to irradiate the axilla or other regional node groups must be declared by the investigator prior to randomization for stratification purposes.
* Special conditions for eligibility of mastectomy patients: irradiation. The decision to use locoregional irradiation in patients who have undergone total mastectomy and axillary node dissection must be declared by the investigator prior to randomization for stratification purposes. Failure to adhere to the radiation therapy plan will be a protocol violation.

Exclusion criteria

* Bilateral malignancy or a mass or mammographic abnormality in the opposite breast suspicious for malignancy unless there is biopsy proof that the mass is not malignant.
* Primary tumor staged as T4 for any reason.
* Nodes staged as clinical N2 or N3 for any reason and nodes staged as pathologic pN2b, pN3b, or pN3c.
* Prior history of breast cancer, including DCIS (patients with a history of lobular carcinoma in situ \[LCIS\] are eligible).
* Treatment including radiation therapy, chemotherapy, biotherapy, and/or hormonal therapy administered for the currently diagnosed breast cancer prior to randomization. The only exception is hormonal therapy, which may have been given for up to a total of 28 days anytime after diagnosis and before randomization. In such a case, hormonal therapy must stop at or before randomization and be re-started if indicated following chemotherapy.
* Prior anthracycline or taxane therapy for any malignancy.
* Any sex hormonal therapy, e.g., birth control pills, ovarian hormonal replacement therapy, etc. (These patients are eligible only if this therapy is discontinued prior to randomization.)
* Therapy with any hormonal agents such as raloxifene (Evista®), tamoxifen, or other selective estrogen receptor modulators (SERMs), either for osteoporosis or prevention. (Patients are eligible only if these medications are discontinued prior to randomization. These medications are not permitted while on the study except for the use of tamoxifen as described in the protocol)
* Nonmalignant systemic disease (cardiovascular, renal, hepatic, etc.) that would preclude a patient from being subjected to any of the treatment options or would prevent prolonged follow-up.
* Cardiac disease that would preclude the use of Adriamycin, Taxol or Herceptin. This includes:
* Active cardiac disease:

  * angina pectoris that requires the use of antianginal medication;
  * cardiac arrhythmia requiring medication;
  * severe conduction abnormality;
  * clinically significant valvular disease;
  * cardiomegaly on chest x-ray;
  * ventricular hypertrophy on EKG; or
  * patients with poorly controlled hypertension, i.e., diastolic greater than 100 mm/Hg. (Patients with hypertension who are well controlled on medication are eligible for entry.)
* History of cardiac disease:

  * myocardial infarction documented as a clinical diagnosis or by EKG or any other tests;
  * documented congestive heart failure; or
  * documented cardiomyopathy.
* Psychiatric or addictive disorders that would preclude obtaining informed consent.
* Pregnancy or lactation at the time of proposed randomization. This protocol excludes pregnant or lactating women based on the fetal toxicity of both tamoxifen and Taxol which are listed as Pregnancy Category D agents. Pregnant women who received tamoxifen have experienced fetal deaths, birth defects, spontaneous abortions, and vaginal bleeding. Women of reproductive potential must agree to use an effective barrier method of contraception. Hormonal birth control methods are not permitted.
* Sensory/motor neuropathy ≥ grade 2, as defined by the NCI's Common Toxicity Criteria version 2.0.
* Contraindications to corticosteroid use which, in the opinion of the investigator, would preclude participation in this study.
* Concurrent treatment with other investigational agents.
* Sensitivity to benzyl alcohol.
* Special conditions for ineligibility of lumpectomy patients: irradiation and surgery. For patients treated by lumpectomy with axillary dissection, breast irradiation is required. Please see guidelines for radiation therapy in Appendix A. In addition, the following patients will also be ineligible:

  * Patients with diffuse tumors (as demonstrated on mammography) that would not be considered surgically amenable to lumpectomy.
  * Patients treated with lumpectomy in whom there is another clinically dominant mass or mammographically suspicious abnormality within the ipsilateral breast remnant. Such a mass must be biopsied and demonstrated to be histologically benign prior to randomization or, if malignant, must be surgically removed with clear margins.
  * Patients in whom the margins of the resected specimen are involved with invasive tumor or ductal carcinoma in situ (DCIS). Additional surgical resections to obtain free margins are allowed. Patients in whom tumor is still present after the additional resection(s) must undergo mastectomy to be eligible.

Answer: A