Clinical trial NCT01452672: Resource-sparing Post-mastectomy Radiotherapy in Breast Cancer
Official title: Resource-sparing Radiotherapy for Breast Cancer
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Breast Cancer
Keywords: Breast cancer
Radiotherapy
Post-mastectomy
Molecular characterization
Lead sponsor: International Atomic Energy Agency
Sponsor class: OTHER_GOV
Collaborators: name: International Network for Cancer Treatment and Research
First posted: 2011-10-17
Enrollment: 600
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 81
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study compares two different field set-ups in patients with breast cancer following a breast resection (mastectomy). These two set-ups are as follows: arm a - radiotherapy to the chest-wall only, and arm b - radiotherapy to the chest-wall and the supraclavicular fossa.

Patients in both treatment arms will receive radiotherapy with a shortened fractionation schedule.

Study hypothesis: irradiation of the chest-wall only is not inferior to irradiation of the chest-wall and supraclavicular fossa in terms of loco-regional control, survival and treatment toxicity.

Detailed description: Post-mastectomy radiotherapy (PMRT) substantially reduces the risk of loco- regional failure as shown in several studies and meta-analyses. Two large trials for pre-menopausal node-positive breast cancer patients treated with mastectomy and chemotherapy showed that PMRT not only reduced loco- regional failure rates but also improved disease-free and overall survival rates.

Although the benefit of PMRT is clear, the optimal volume of tissues to be covered by the radiotherapy fields is controversial. Since the chest wall is the most likely location of recurrence, there is uniform consensus that the chest wall should be irradiated. However, areas of controversy exist regarding irradiation of the regional lymph nodes (axillary, supraclavicular and internal mammary lymph nodes), optimal radiation dose, and dose-fractionation.

If equivalent results could be achieved by omitting irradiation of the supraclavicular region in patients receiving adjuvant systemic therapy, this will simplify and expedite treatment in this patient population. Furthermore, the use of a shortened fractionation schedule of 40 Gy in 15 fractions (2.67 Gy per fraction) over 3 weeks which has been used in the UK and Canada for post-mastectomy patients for several decades will shorten the duration of treatment by reducing the number of patient visits for radiotherapy and increase the number of patients who can be treated. Treatment will be more convenient for patients and a reduction in the number of treatments could result in savings for strained health care systems.

This is a randomized comparison of two different radiotherapy field set-ups for post-mastectomy treatment of locally advanced breast cancer. Patients who have undergone modified radical mastectomy including axillary lymph node dissection will be randomized to receive one of two radiotherapy treatment arms, A and B following the completion of adjuvant chemotherapy. The radiotherapy for treatment Arm A consists of irradiation of the chest wall only while Treatment Arm B includes irradiation of the chest wall and the ipsilateral supraclavicular field. Patients on both treatment arms will receive radiation with a shortened fractionation schedule. Patients will be evaluated for local control, regional control, survival and treatment toxicity.

Eligibility criteria: Inclusion Criteria:

1. Patients must be older than 18 and less than 81 years of age
2. WHO (ECOG) Performance Status of 0-2
3. Histologically confirmed diagnosis of infiltrating ductal carcinoma of the breast, lobular carcinoma or mixed (ductal and lobular) type.

   Note: Tumor diagnosis will be performed at the participating center according to the center's routine procedures.
4. Patients must have had a modified radical mastectomy (MRM) in which 6 or more axillary nodes were removed.
5. All patients should receive adjuvant chemotherapy following MRM. The initiation of radiation therapy must allow for the full recovery of blood counts (WBC \> 3.0 x 109/L, Granulocytes \> 1.5 x109/L and platelets \> 75 x 109/L).

   Note: MRM should have been performed at maximum 3 months prior to the start of adjuvant chemotherapy.

   Special Note: Patients who have not received adjuvant chemotherapy will be required to receive adjuvant chemotherapy as per Appendix 3 prior to study entry and initiation of radiotherapy must allow for the full recovery of blood counts (WBC \> 3.0 x 109/L, Granulocytes \> 1.5 x109/L and platelets \> 75 x 109/L MRM should have been performed within 3 months prior to the start of adjuvant chemotherapy.
6. Patients must have received adjuvant chemotherapy according to one of the two regimens found in Appendix 3.
7. Negative surgical margins by histopathology at the time of MRM. Note: Negative surgical margins means that there are no cancer cells at the inked margin of resection or otherwise at the margins of the mastectomy specimen.
8. The following indicators in the histological samples must be known :

   1. Tumor size
   2. Tumor site (quadrant, central, axillary tail)
   3. Presence of extensive intraductal component (EIC)
   4. Estrogen and Progesterone Receptor Status and the method of staining and detection.
   5. HER2 Status (optional), if given, the method must be provided.
9. Patients with the following TNM stages, all being M0: pT1 N1, pT2 N1, pT3 N0, pT0 N2, pT1 N2, pT2 N2, T3 N1, pT3 N2 (see Appendix 4 for TNM Stage)
10. Histological grades 1 - 3 (as per WHO criteria)
11. Patients must consent to return for scheduled treatments and follow up.
12. Written informed consent document signed

Exclusion Criteria:

1. Pathological pN3 (metastasis in 10 or more lymph nodes, clinically apparent internal mammary metastasis, metastasis in the supraclavicular lymph nodes)
2. Stages IIIB, IIIC and IV (any T4, any N3 or M1)
3. Recurrence of breast cancer following MRM and/or adjuvant chemotherapy.
4. Concomitant primary cancer in the contralateral breast.
5. History of other malignancy except carcinoma in situ of the cervix or non-melanoma skin cancer
6. Pregnant or breast-feeding
7. Previous chemotherapy other than adjuvant chemotherapy for treatment of the present breast cancer
8. Other severe concomitant disease that could impact upon the ability to deliver treatment or increase the risk of toxicity (such as uncompensated congestive heart failure, unstable coronary heart disease, uncompensated chronic obstructive pulmonary disease, collagen vascular diseases including systemic lupus erythematosus, systemic sclerosis, dermatomyositis, and ataxia telangiectasia).
9. Contraindications to radiation therapy (such as previous irradiation of the breast or chest wall)
10. Severe psychiatric disorder that may interfere with the process of informed consent and/or treatment or follow-up compliance.

Primary outcomes:
measure: Local control.
timeFrame: 4 years
measure: Regional control.
timeFrame: 4 years
measure: Overall survival.
timeFrame: 4 years
measure: Disease-free survival.
timeFrame: 4 years
measure: Acute adverse events.
timeFrame: 4 years
measure: Late adverse events.
timeFrame: 4 years
Secondary outcomes:
measure: Patients' demographics.
timeFrame: 4 years
measure: Reproductive history.
timeFrame: 1 year
measure: Family history.
timeFrame: 1 year
measure: Characterization of molecular profile of breast cancer patients.
timeFrame: 4 years
Other outcomes:
Locations:
city: Havana
country: Cuba
facility: Instituto Naciolal de Oncologia y Radiobiologia (INOR)
city: Cairo
country: Egypt
facility: Cairo National Cancer Institute
state: Fom El-Khalig
city: Alexandria
country: Egypt
facility: Alexandria Ayadi Almostakbal Oncology Cenre.
city: Accra
country: Ghana
facility: Korle Bu Teaching Hospital
city: Rabat
country: Morocco
facility: Institut National d'Oncologie
city: Ibadan
country: Nigeria
facility: University of Ibadan College Hospital
city: Peshawar
country: Pakistan
facility: Institut of Radiotherapy and Nuclear Medicine (IRNUM)
city: Lima
country: Peru
facility: Instituto Nacional de Enfermedades Neoplasicas
city: Istanbul
country: Turkey
facility: Cerraphasa Medical Faculty
Study officials:
affiliation: International Atomic Energy Agency
name: Eduardo Rosenblatt, MD
role: STUDY_CHAIR
References:
citation: Nielsen HM, Overgaard M, Grau C, Jensen AR, Overgaard J. Loco-regional recurrence after mastectomy in high-risk breast cancer--risk and prognosis. An analysis of patients from the DBCG 82 b&c randomization trials. Radiother Oncol. 2006 May;79(2):147-55. doi: 10.1016/j.radonc.2006.04.006. Epub 2006 Apr 27.
citation: Adenipekun A, Campbell OB, Oyesegun AR, Elumelu TN. Radiotherapy in the management of early breast cancer in Ibadan: outcome of chest wall irradiation alone in clinically nodes free axilla. Afr J Med Med Sci. 2002 Dec;31(4):345-7.
citation: Truong PT, Olivotto IA, Whelan TJ, Levine M; Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. Clinical practice guidelines for the care and treatment of breast cancer: 16. Locoregional post-mastectomy radiotherapy. CMAJ. 2004 Apr 13;170(8):1263-73. doi: 10.1503/cmaj.1031000.
citation: Owen JR, Ashton A, Bliss JM, Homewood J, Harper C, Hanson J, Haviland J, Bentzen SM, Yarnold JR. Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: long-term results of a randomised trial. Lancet Oncol. 2006 Jun;7(6):467-71. doi: 10.1016/S1470-2045(06)70699-4.
citation: Whelan T, MacKenzie R, Julian J, Levine M, Shelley W, Grimard L, Lada B, Lukka H, Perera F, Fyles A, Laukkanen E, Gulavita S, Benk V, Szechtman B. Randomized trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer. J Natl Cancer Inst. 2002 Aug 7;94(15):1143-50. doi: 10.1093/jnci/94.15.1143.