Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer

PRIMARY OBJECTIVES:

I. To evaluate whether the reconstruction complication rate at 24 months post radiation is non-inferior with hypofractionation.

SECONDARY OBJECTIVES:

I. To evaluate the incidence of acute and late radiation complications, based on Common Terminology Criteria for Adverse Events (CTCAE) 4.0 toxicity.

II. To evaluate the local and local regional recurrence rate. III. To compare reconstruction complication rates based on reconstruction method (autologous +/- implant versus \[vs\] implant only) and timing of reconstruction received (immediate vs. intent for delayed).

TERTIARY OBJECTIVES:

I. To evaluate reconstructed breast photographic cosmetic scores with hypofractionated radiation compared to standard fractionation 24 months after radiation.

II. To evaluate reconstructed breast photographic cosmetic scores 24 months after radiation based on the method and timing of reconstruction received.

III. To estimate the incidence of arm lymphedema by treatment arm. IV. To compare physical well-being, psychosocial well-being, sexual well-being, satisfaction with breast/nipples/abdomen, and satisfaction with overall outcome between the treatment arms at 24 months after radiation.

V. To estimate patient satisfaction with trial participation by treatment arm as measured by the Was It Worth It Questionnaire at 24 months after radiation.

VI. To compare the direct and indirect patient costs for radiation therapy by treatment arm.

VII. To compare patient reported total health care service utilization 12 months after the completion of radiation.

VIII. To compare the economic impact of treatment. IX. To analyze polymorphisms in MDM2 and in genes including TP53, ATM, TGFB1, IL4, IL6, and IL10 and determine correlations with a higher likelihood of adverse radiation reactions (radiation sensitivity) and with toxicities.

X. To analyze polymorphisms in MDM2 and in genes including TP53, ATM, TGFB1, IL4, IL6, and IL10 to determine correlations with secondary endpoints such as local-regional control.

OUTLINE: Patients are randomized to 1 of 2 groups.

GROUP I: Patients undergo radiation therapy daily on Monday-Friday for 5-6 weeks.

GROUP II: Patients undergo hypofractionated radiation therapy daily on Monday-Friday for 3-4 weeks.

After completion of study, patients are followed up for 5 years.

• Radiation Therapy (Radiation): Undergo RT
• Questionnaire Administration (Other): Ancillary studies
• Quality-of-Life Assessment (Other): Ancillary studies
• Laboratory Biomarker Analysis (Other): Correlative studies
• Hypofractionated Radiation Therapy (Radiation): Undergo hypofractionated RT

Primary outcomes

• Proportion of Breast Reconstruction Complications [24 months]: The primary endpoint of this trial is the rate of ipsilateral breast reconstruction complications defined (in the protocol in 10.0. Measurement of effect) as; Capsular contracture (Baker Grade III or IV only), Complete failure of the implant/skin flap, Unplanned admission for reconstruction related issue(s) including but not limited to infection, wound healing complication or pain, Unplanned return to the operating room for recon related issue including but not limited to infection, prosthesis exposure, failed reconstruction, implant removal, wound healing complications or contracture management. Note: Routine revisions such as dog-ear corrections, fat grafting, and contralateral breast revision will be recorded, but not counted towards the primary endpoint; ii) Complications related to the contralateral breast will be collected but will not count towards the assessment of the primary endpoint, ipsilateral breast complications will be counted towards the primary endpoint.

Secondary outcomes

• Incidence of Acute and Late Radiation Complications Based on Common Terminology Criteria for Adverse Events 4.0 Toxicity [5 years]: The proportion of patients with acute or late radiation complications, will be estimated separately by treatment arm and will be compared across the two arms using two-sample test of proportions (Z test) with a two-sided alternative.
• Local and Local Regional Recurrence [3 years]: The cumulative incidence of local and local regional recurrence will be estimated separately by treatment arm using the cumulative incidence function treating death as the competing risk and will be compared using Gray's test.
• Local and Local Regional Recurrence-free Survival [3 years]: Local and local regional recurrence free survival rate at three years will be summarized for each arm using the Kaplan-Meier estimators, and will be compared using a log rank test. Any recurrence or death will be considered an event.
• Reconstruction Complication Rates Based on Reconstruction Method (Autologous +/- Implant Versus [vs.] Implant Only) and Timing of Reconstruction Received (Immediate vs. Intent for Delayed) [Up to 5 years]: Between-arm differences in reconstruction complication rates will be assessed separately within each of the six subgroups based on type and timing of reconstruction. Between-arm differences in complication rates will also be assessed within the two broader subgroups of patients who receive implant only and those who receive autologous based reconstruction. Within each subgroup, the comparison will be done using a two-sample Z test of proportions with a two-sided alternative.
• Reconstructed Breast Photographic Cosmetic Scores [At 24 months]: Two year photographic cosmetic scores will be summarized by treatment arm and will be compared across the treatment arms using a Wilcoxon rank-sum test with a two-sided alternative. The proportions of patients with poor global cosmetic score (defined as a cosmetic score of 3: poor or large difference) at 24 months after radiation will be summarized separately by treatment arm and will be compared using a two-sample test of proportions with a two-sided alternative.
• Reconstructed Breast Photographic Cosmetic Scores Based on the Method and Timing of Reconstruction Received [At 24 months]: Two year photographic cosmetic scores and the proportions of patients with poor global cosmetic score will be assessed separately by timing and method of reconstruction subgroups using similar method described above.
• Incidence of Arm Lymphedema as Measured by Percent Change in Ipsilateral Arm Volume Post-radiation From Its Pre-radiation Volume [Up to 5 years]: The proportions of patients with arm lymphedema (defined as a change of 10% or greater in ipsilateral arm volume from the pre-radiation therapy \[RT\] volume) at 2 year post radiation will be summarized and will be compared across the two treatment arms using a two-sample test of proportions (Z test) with a two-sided alternative. Change in ipsilateral arm volume at each of the following time-points: 6, 12, 24 and 60 months post-radiation (relative to pre-RT) will be compared using a two sample t-test with a two-sided alternative. The changes in arm volume at these time points will also be analyzed as a repeated measure using a linear mixed model with patient as the random effect.
• Physical Well-being, Psychosocial Well-being, Sexual Well-being, Satisfaction With Breast/Nipples/Abdomen, and Satisfaction With Overall Outcome [At to 24 months]: Change in Lymphedema and Breast Cancer Questionnaire and Breast Lymphedema scores at 24 months post-radiation (relative to pre-RT) and patient satisfaction scores as measured by the Breast Questionnaire overall outcome scale will be summarized and will be compared across the treatment arms using a two-sample t-test with a two-sided alternative. Linear mixed models will also be used to assess these scores longitudinally.
• Patient Satisfaction With Trial Participation by Treatment Arm as Measured by the Was It Worth It Questionnaire [At 24 months]: Was It Worth It questionnaire responses to each of the five questions at 24 months will be summarized and the will be compared across treatment arms using a chi-square tests with a two-sided alternative.
• Economic Analyses [Up to 5 years]: Direct costs of medical care to each patient will be estimated using utilization information from the health care expense survey and the health care utilization survey, along with publicly available Medicare reimbursement rates. In particular, based on the reported number of outpatient visits to the radiation oncologist, medical oncologist, surgeon who performed mastectomy, plastic surgeon or physical therapist, and the number of visits to the emergency room, the number of hospital admissions, and the number of surgical procedures to breast reconstruction, Medicare reimbursement rates can be used to estimate what the direct cost to each patient would be if that patient were covered by Medicare. Generalized linear models will then be used to model these costs as a function of treatment, time on study, and all available baseline patient characteristics to assess the extent to which estimated direct cost is impacted by the type of radiation dosing.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Histologically confirmed invasive carcinoma of the breast of any of the following histologies (ductal, lobular, mammary, medullary, or tubular); patients with metaplastic breast cancer are not eligible
* Patients will be staged according to the TNM staging system

  * For patients not receiving neoadjuvant chemotherapy, pathologic staging must be T0N1-2a, T1N1-2a, T2N1-2a, T3N0-2a, and all M0 status
  * For patients receiving neoadjuvant chemotherapy, clinical pre-chemo staging and post mastectomy pathological staging is required for all patients; patients who have received neoadjuvant chemotherapy and are pathologically cT0-2 and N0 are only eligible if biopsy-proven clinically N1 or N2 disease is documented prior to the start of neoadjuvant chemotherapy; cT3N0 patients or ypT3N0 patients who receive neoadjuvant chemotherapy may be eligible based on clinical or pathological T stage, and do not require pathologically positive lymph nodes
  * Note: Higher of the clinical or pathological T and N stage are used for final staging, if receiving neoadjuvant chemotherapy; all patients with clinical, radiographic or pathological T4, N3 or involved internal mammary disease (N1b, N1c, and N2b) are not eligible. N1mic patients are eligible.
* No prior therapeutic radiation therapy to the chest, neck or axilla; prior radioactive oral iodine is permitted
* No prior history of ipsilateral breast cancer (invasive disease or ductal breast carcinoma in situ \[DCIS\]); lobular carcinoma in situ (LCIS) and benign breast disease is allowed
* No history of prior or concurrent contralateral invasive breast cancer; benign breast disease, LCIS or DCIS of contralateral breast is allowed
* No active collagen vascular diseases, such as: systemic lupus erythematous, scleroderma, or dermatomyositis
* Negative inked histologic margins from mastectomy pathology (no invasive cells at margin). Patients with DCIS at margin are eligible.
* No significant post mastectomy complications in the ipsilateral breast requiring an unplanned re-operation or admission for intravenous (IV) antibiotics; re-operation for margins evaluation, nodal completion and routine reconstruction is acceptable
* Radiation oncologist intends to treat all target volumes and respect all normal tissues in accordance with the dosimetric constraints described (simulation before registration recommended)
* Radiation oncologist is planning to treat regional lymph nodes including internal mammary nodes and meet acceptable protocol dosimetric requirements
* Radiation oncologist is NOT planning to utilize a chest wall/scar boost
* Patient must have undergone immediate reconstruction at the time of mastectomy or be planning to undergo reconstruction within 18 months after radiation
* Treating physician and patient must plan to start radiation treatment within the timeframes specified in protocol.
* If a tissue expander is utilized it needs to be a fluid filled expander, NO air expander (unless completely deflated) during radiation therapy
* For patients with diabetes, hemoglobin A1C test must have been performed =< 90 days prior to registration
* No co-existing medical conditions with life expectancy < 5 years
* No other malignancy within 5 years of registration with the exception of basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the cervix
* Negative pregnancy test (serum or urine HCG) in women of child-bearing potential ≤ 7 days prior to registration. Patients who have received a bilateral tubal ligation still require a negative pregnancy test for eligibility. A female of childbearing potential is a sexually mature female who has not undergone a hysterectomy or bilateral oophorectomy and has not been naturally postmenopausal for at least 12 consecutive months
* Women of child-bearing potential must agree to utilize a form of birth control or agree to undergo sexual abstinence during radiation therapy
* Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance status 0-1
* Patients must be able to read and comprehend English, in order to be able to complete study questionnaires; however, patients participating through Canadian Cancer Trials Group (CCTG) institutions who can read and comprehend French are eligible

Participant flow

Outcome results

• Proportion of Breast Reconstruction Complications (Primary), Number, proportion of participants: Group I (Radiation Therapy) 0.102; Group II (Hypofractionated Radiation Therapy) 0.123
• Incidence of Acute and Late Radiation Complications Based on Common Terminology Criteria for Adverse Events 4.0 Toxicity (Secondary), Number, proportion of participants: Group I (Radiation Therapy) 0.077; Group II (Hypofractionated Radiation Therapy) .050
• Local and Local Regional Recurrence (Secondary), Number, percentage of patients with event: Group I (Radiation Therapy) 2.2 (0.2 to 2.3); Group II (Hypofractionated Radiation Therapy) 0.7 (0.2 to 2.2)
• Local and Local Regional Recurrence-free Survival (Secondary), Number, percentage of patients without event: Group I (Radiation Therapy) 96.2 (94.3 to 98.2); Group II (Hypofractionated Radiation Therapy) 97.0 (95.4 to 98.7)
• Reconstruction Complication Rates Based on Reconstruction Method (Autologous +/- Implant Versus [vs.] Implant Only) and Timing of Reconstruction Received (Immediate vs. Intent for Delayed) (Secondary)
• Reconstructed Breast Photographic Cosmetic Scores (Secondary)
• Reconstructed Breast Photographic Cosmetic Scores Based on the Method and Timing of Reconstruction Received (Secondary)
• Incidence of Arm Lymphedema as Measured by Percent Change in Ipsilateral Arm Volume Post-radiation From Its Pre-radiation Volume (Secondary)
• Physical Well-being, Psychosocial Well-being, Sexual Well-being, Satisfaction With Breast/Nipples/Abdomen, and Satisfaction With Overall Outcome (Secondary)
• Patient Satisfaction With Trial Participation by Treatment Arm as Measured by the Was It Worth It Questionnaire (Secondary)
• Economic Analyses (Secondary)

Adverse events

Time frame: Adverse events were followed for 73 months and mortality was followed for 80 months.

Serious adverse events by term

7 more terms not shown.

Other adverse events by term

160 more terms not shown.

759 more sites not listed.

• Study Protocol and Statistical Analysis Plan (PDF, 2021-10-22)

• Matthew Poppe, MD, Study chair, Huntsman Cancer Hospital, University of Utah