This prospective phase II study was conducted in the Department of Radiation Oncology, Regional Cancer Centre, XXXX, XXXX. Primary objective was to assess grade 2 acute skin toxicity with hypofractionated WBI with SIB completed in 10 fractions. Secondary objectives of the study were to determine dose distribution, target coverage, dose homogeneity dose conformity of the target volume, late toxicity and cosmetic outcomes.
Patient selection
Patients who had undergone BCS were included in this study. Institutional Ethics Committee approval was taken. Informed consent was taken from all the patients. The trial was registered with clinicaltrials.gov no. XXXX. Inclusion criteria were: primary cancer of breast of any histology, age >18-70 years, post BCS with clear margins, healed scar, Karnofsky performance status (KPS) >70, regional nodal radiation when indicated(depending on risk factors) and no distant metastasis. Neoadjuvant or adjuvant chemotherapy was allowed. Adjuvant endocrine therapy was given to patients with hormone receptor positive tumors. Exclusion criteria were: mastectomy, history of prior primary malignancy, prior irradiation to breast or chest, pregnancy and collagen vascular disease.
Radiotherapy planning
All patients were made to lie supine on a carbon fiber breast board or wing board or a T bar with ipsilateral arm abducted to 900 and face turned to the opposite side. Radiopaque markers were placed for defining the superior, inferior, medial and lateral borders and the surgical scar. Three skin markings were placed along with the fiducials below the breast folds for the purpose of reproducibility and the location of tumor bed with respect to fiducials.
All patients underwent a normal free-breathing scan with virtual computerized tomogram (CT) breast simulation. Axial cuts were taken from the mandible to the upper abdomen with a slice thickness of 3 mm. The 4D-CT images with recording of the respiratory signals were acquired, taking organ motion into account. The delineation of the tumor cavity and contouring of the OARs was done by using RTOG guidelines. Contouring for the target volumes were done on maximum intensity projection (MIP) of the 4D-CT. The OARs contoured were heart, bilateral lungs, contralateral breast, esophagus, spinal cord, left anterior descending artery and thyroid.
The affected breast was contoured as the clinical target volume (CTV) excluding 5mm from the skin. An additional 5mm (0.5cm) margin for setup error and motion was then added to CTV to form the planning target volume (PTV), shredding(removing) it from lungs and body by 5mm to spare the skin. The nodal areas, when indicated according to the risk factors, were also contoured following RTOG contouring guidelines.
Boost RT planning
In each patient, tumor bed was delineated using clinical, radiological (mammography/CT/ultrasound of breast), surgical (intra operative notes, external and internal surgical scar location) findings, seroma cavity and surgical clips location. ITV was generated by contouring tumor bed in all phases of respiratory cycles on 4D-CT. All delineation was done on MIP images. A margin of 5mm was added to the cavity to form PTV BOOST SIB. A dose of 34 Gy/10#/2wk to the PTV TOTAL and 40 Gy/10#/2wk to the PTV SIB BOOST was delivered with IGRT using the RapidArc® technique. Partial arcs were used for RT planning. Dose distribution and target coverage criteria for PTV TOTAL and PTV SIB BOOST were: 98% of volume should receive >95% of dose and 2% volume should receive < 107% of dose. Conformity and homogeneity indices were also calculated for each plan[12-14].
Dose constraints given were; ipsilateral mean lung dose (MLD) ≤10Gy, V16Gy < 20% and contralateral lung V5 <5%. Mean heart dose (MHD) <7Gy, V18 <5% for left side and <1% for the right side. LAD Dmax and Dmean <15Gy and <8Gy, respectively from left breast. Contralateral breast Dmean <3Gy. Thyroid V25 and V30 should be <50% and <25%, respectively. Dmax and Dmean for oesophagus 20Gy and <5Gy, respectively. Dmax for the spinal cord and brachial plexus should be <30Gy and <40Gy, respectively.
Cone beam CT was done on the first three consecutive days and then orthogonal images were taken daily for set-up verification. All patient were treated in free breathing.
Assessments
Toxicities: Baseline assessment was done for all the patients. The physicians examined patients for any toxicity every week during treatment, at the treatment completion and during the follow-up visits. First follow up was at 1 month of completion of. Patients were followed every 3 months in the 1st year, every 4 months in the 2nd year, every 6 months thereafter. Toxicities were scored according to Radiation Therapy Oncology Group (RTOG) and Late Effects on Normal Tissues (LENT)/Subjective, Objective, Management and Analytic (SOMA) grading scale. Acute toxicities are reported at 1 and 3 month of completion of radiotherapy. Late effects are reported at 6 months and 4 years follow up.
Cosmesis: Cosmetic effects were assessed in the treated breast and compared with the opposite breast and also with the baseline photographic evaluation. Both objective and subjective parameters were used. The Harvard/NSABP/RTOG scale proposed by Harris et al. was used to evaluate the cosmetic parameters[15]. Variability in both objective and subjective assessment was evaluated. Changes in terms of colour, shape, size, any swelling, symmetry, texture and position of nipple were noted in the treated breast. The assessment was done at baseline (before the start of radiation treatment), at the time of completion of treatment, at 1 month, 3 months, 6 months, 1 year and 3 years after completion of treatment. The long-term cosmetic effects were reported at 4 years. For subjective evaluation, a standard scale for assessment of cosmetic effect due to RT after BCS was used. For objective qualification, digital photography of the patient was used, before and after the treatment. Digital photo, in a front view of the patient including the sternal notch and both the breast with a light background with adequate light were taken. Two views with hands by side and hands raised above the head were taken for all the patients. A picture of the scar was also taken by the same person to avoid variability of clicked photos.
For cosmesis, both subjective (hyperpigmentation, change in shape, change in size, nipple changes, heaviness, pain) and objective (skin reaction, overall grade, edema, induration, subcutaneous fibrosis, tenderness, scar changes and any other skin changes/ulceration) response was considered. All the parameters were noticed for any change with time and graded upon accordingly.
Clinical Outcomes: Disease-free survival (DFS) and overall survival(OS) were summarized by Kaplan-Meier curves. Local recurrence was defined as recurrence in the in the involved breast, axilla, supraclavicular fossa and internal mammary nodes. Distant metastases were defined as disease occurring in the other sites. Local recurrence and distant metastases were used to calculate DFS. Time was calculated from the date of completion of RT. OS was defined from the date of diagnosis till the last follow-up or death due to breast cancer.
Statistical analysis
The purpose of the trial was to reject the experimental treatment from further study if it is too toxic, and to accept it for further study if the toxicity is acceptable. The primary endpoint was grade 2 acute skin toxicity, and other toxicities were considered secondary endpoints. The study was designed as a phase II trial with the following assumptions:
- Grade 2 skin toxicity ≥ 36% was considered unacceptable, and grade 2 skin toxicity ≤ 11% was considered acceptable. Hence the hypotheses of interest were H0: r ³ 36% against HA: r £ 11%, where r is the proportion of patients with grade 2 skin toxicity
- The type I error rate (a, probability of accepting an overly toxic treatment, a false positive outcome) was set to 5%
- The type II error rate (b, probability of rejecting an acceptably toxic treatment, a false negative outcome) was set to 10% - i.e., the power is equal to 90%
Under these assumptions, using a one-sided Fisher’s exact test, the design consists of treating 27 evaluable patients, and
- if at most 5 patients have grade 2 skin toxicity, the treatment was considered acceptable (5/27=19%)
if at least 6 patients have grade 2 skin toxicity, the treatment was considered too toxic (6/27=22%)