Acute and Short-Term Toxicities of Conventionally Fractionated Versus Hypofractionated Whole Breast Irradiation in a Prospective, Randomized Trial

Abstract

IMPORTANCE

The most appropriate dose-fractionation for whole breast irradiation (WBI) remains uncertain.

OBJECTIVE

To assess acute and six-month toxicity and quality of life (QoL) with conventionally fractionated WBI (CF-WBI) versus hypofractionated WBI (HF-WBI).

DESIGN

Unblinded randomized trial of CF-WBI (n=149; 50 Gy/25 fractions + boost [10–14 Gy/5–7 fractions]) versus HF-WBI (n=138; 42.56 Gy/16 fractions + boost [10–12.5 Gy/4–5 fractions]).

SETTING

Community-based and academic cancer centers.

PARTICIPANTS

287 women age ≥ 40 years with stage 0–II breast cancer treated with breast-conserving surgery for whom whole breast irradiation without addition of a third field was recommended. 76% (n=217) were overweight or obese. Patients were enrolled from February 2011 through February 2014.

INTERVENTION(S) FOR CLINICAL TRIALS

CF-WBI versus HF-WBI.

MAIN OUTCOME MEASURES

Physician-reported acute and six-month toxicities using NCICTCv4.0 and patient-reported QoL using the FACT-B version 4. All analyses were intention-to-treat, with outcomes compared using chi-square, Cochran-Armitage test, and ordinal logistic regression. Patients were followed for a minimum of 6 months.

RESULTS

Treatment arms were well-matched for baseline characteristics including FACT-B total score (P=0.46) and individual QoL items such as lack of energy (P=0.86) and trouble meeting family needs (P=0.54). Maximal physician-reported acute dermatitis (P<0.001), pruritus (P<0.001), breast pain (P=0.001), hyperpigmentation (P=0.002), and fatigue (P=0.02) during radiation were lower in patients randomized to HF-WBI. Overall grade ≥2 acute toxicity was less with HF-WBI vs. CF-WBI (47% vs. 78%; P<0.001). Six months after radiation, physicians reported less fatigue in patients randomized to HF-WBI (P=0.01), and patients randomized to HF-WBI reported less lack of energy (P<0.001) and less trouble meeting family needs (P=0.01). Multivariable regression confirmed the superiority of HF-WBI in terms of patient-reported lack of energy (OR 0.39, 95% CI 0.24–0.63) and trouble meeting family needs (OR 0.34, 95% CI 0.16–0.75).

CONCLUSIONS AND RELEVANCE

HF-WBI appears to yield less acute toxicity than CF-WBI, as well as less fatigue and trouble meeting family needs six months after completing radiation. These findings should be communicated to patients as part of shared decision-making.

TRIAL REGISTRATION

NCT01266642 (https://clinicaltrials.gov/ct2/show/NCT01266642)

INTRODUCTION

To date, four randomized trials including over 7,000 women have compared conventionally fractionated whole breast irradiation (CF-WBI) to hypofractionated whole breast irradiation (HF-WBI).[1–3] With 10-year follow-up, these studies have shown equivalent rates of overall survival and local control between the two treatment regimens. Additionally, the United Kingdom START A and B trials reported less moderate or marked breast induration, telangiectasia, breast edema, and breast shrinkage in women randomized to HF-WBI.[1] Nevertheless, adoption of HF-WBI in the United States has been tepid, with only one-third of patients for whom HF-WBI is endorsed by the American Society for Radiation Oncology (ASTRO) actually receiving this treatment.[4–7]

The reasons underlying slow adoption of HF-WBI in the United States are likely multifactorial and reflect both scientific as well as pragmatic concerns.[8] Key ongoing obstacles to adoption of HF-WBI in the United States include the lingering concern that HF-WBI may actually increase toxicity due to higher dose per fraction and questions regarding the applicability of the published trials to practices that routinely use a tumor bed boost and to patients with larger body mass index (BMI) and central axis separation.[8, 9]

We sought to address these obstacles to adoption of HF-WBI by incorporating detailed toxicity and quality of life assessment into a randomized trial of HF-WBI versus CF-WBI, both followed by a tumor bed boost, and inclusive of all patients regardless of BMI or separation. Herein, we report physician-reported acute and six-month toxicities and patient-reported QoL by treatment arm.

PATIENTS AND METHODS

Methods

Enrollment

Patients were enrolled from 2011 to 2014 at The University of Texas MD Anderson Cancer Center (including both the Main Campus located in the Texas Medical Center and four surrounding MD Anderson regional centers); Orlando Health (formerly MD Anderson Orlando – Orlando, FL); and Banner MD Anderson in Gilbert, AZ. Women eligible for enrollment were age ≥ 40 years with pathologically-confirmed female carcinoma in situ (DCIS) or invasive breast cancer, stage Tis-T2, N0-N1a, M0, treated with breast conserving surgery with final negative margins (defined as no tumor on ink), with the physician-declared intent to deliver WBI without addition of a third field to cover the regional lymph nodes. Exclusion criteria included concomitant active treatment for another malignancy, history of prior breast cancer, bilateral breast cancer, prior overlapping radiation, pregnancy, or lack of fluency in English or Spanish.

Randomization

Patients were randomly allocated to treatment with either HF-WBI (42.56Gy in 16 fractions WBI) or CF-WBI (50Gy in 25 fractions WBI). The tumor bed boost if final margins were negative by ≥2mm or if there was a negative re-excision was 10Gy in 4 fractions or 12.5Gy in 5 fractions for HF-WBI and CF-WBI, respectively, and 12.5Gy in 5 fractions or 14Gy in 7 fractions if final margins were <2mm for HF-WBI and CF-WBI, respectively. The Pocock-Simon randomization method of dynamic allocation[10] was used to balance the arms of the study for post-operative physician-reported cosmetic assessment (excellent/good vs. fair/poor), bra cup size (D or higher vs. C or lower), receipt of chemotherapy (yes/no), margin status (< 2 mm vs ≥ 2 mm), and treatment location (Houston-area facilities vs. Banner MD Anderson vs. Orlando Health).

Radiation treatment

Patients were treated with megavoltage tangential portals and forward- or inverse-planned segmental fields to improve dose homogeneity. Dose was prescribed to a calculation point in the breast, within 2 cm of the chestwall-lung interface. Patient positioning in the supine or prone position was at physician discretion. Radiation oncologists were instructed to minimize the volume of tissue receiving greater than 108% of the prescription dose. Coverage of the undissected low axilla (levels I and II) was permitted if clinically indicated. The boost was delivered with either electrons or photons and could be omitted if the tumor bed volume precluded safe delivery of the boost.

Patient assessments

Patient-reported QoL was determined using the Functional Assessment of Cancer Therapy for Patients with Breast Cancer (FACT-B) version 4 in either English or Spanish.[11–13] The FACT-B was administered prior to initiation of radiation and six months after completing radiation. The developer’s guidelines were used for scoring the FACT-B, including handling of missing data.[14]

Physician assessments

The treating physician assessed toxicities using the National Cancer Institute Common Toxicity Criteria v4.0 (NCICTCv4.0). All patients underwent weekly toxicity assessments during radiation and were scheduled for assessment six months after completing radiation. Additional toxicity evaluations were at the discretion of the treating physician and/or prompted by patient need. Acute toxicities were defined as toxicities occurring during radiation or within 42 days of completion of radiation; the maximal grade of each acute toxicity is reported herein. Six-month toxicities were defined as toxicities documented at the six-month follow up visit. All toxicities were recorded by the treating physician using templates specifying common radiation-related toxicities and their definitions according to NCICTCv4.0.

Statistical methods

The primary outcome of this study is the proportion of patients with an adverse patient-reported cosmetic outcome, determined using the validated Breast Cancer Treatment Outcomes Scale (BCTOS), three years after completion of treatment. This outcome will be reported when all patients have completed a minimum of three years follow up. The trial was designed to enroll 288 evaluable patients, which yields 90% power with a 1-sided significance level of 0.10 to test the hypothesis that the probability of an adverse cosmetic outcome with HF-WBI is no more than 10% worse than the probability of an adverse cosmetic outcome with CF-WBI, assuming a prevalence of adverse cosmetic outcome of 35% with HF-WBI and 40% with CF-WBI and a drop-out rate of 5%. Prespecified secondary outcomes, which are reported herein, include differences by randomization arm in physician-reported acute and six-month toxicities and patient-reported QoL. These secondary outcomes were considered hypothesis-generating and were thus not adjusted for multiplicity.

Differences in baseline patient, tumor, and treatment characteristics by randomization arm were assessed using the chi-square test or the exact calculation of the Fisher exact test as appropriate. Race/ethnicity was determined via patient report and categorized by applying standard definitions in use by the U.S. Census Bureau. Differences by randomization arm in physician-reported acute and six month toxicities were assessed using the Cochran-Armitage test for trend or chi-square test as appropriate. Exploratory, post hoc subset analyses explored whether these toxicities differed for patients in the highest quartile of body mass index or central axis separation. Differences by randomization arm in FACT-B total score and component scores were assessed using the t-test at baseline and at the six month assessment. Difference by randomization arm between FACT-B total and component scores at six months relative to baseline was also assessed via the t-test. Given a borderline association between physical well-being and randomization arm, differences in outcome by randomization arm for each of the seven items contributing to physical well-being were assessed using the Cochran-Armitage test for trend. As statistically significant associations with randomization arm were noted for Question 1 (Q1) (“I have a lack of energy”) and Question 3 (Q3) (“Because of my physical condition, I have trouble meeting the needs of my family”), ordinal logistic regression models for Q1 and Q3 were created using proc genmod in SAS, using a multinomial distribution and cumlogit link function. We selected the following candidate variables a priori for potential inclusion in these models based on their clinical relevance: randomization arm, age, race, body mass index, estrogen receptor status (negative, positive, not tested), tumor behavior (invasive vs. in situ), chemotherapy receipt (none, neoadjuvant, or adjuvant), central axis separation, volume of breast tissue receiving 90% of prescription dose (V90), volume of breast tissue receiving 105% of prescription dose (V105), maximum point dose (D_max), tumor bed volume, and percent of dose delivered with 18 MV photons. Continuous variables were divided into quartiles as we did not have any a priori hypotheses regarding specific thresholds or cutpoints for these variables. Candidate variables were included in the final models if associated with the outcome at p<0.20 in bivariate analysis. Patients with missing outcome data were excluded from the relevant model. There were no missing covariable values. Sensitivity analyses tested whether type of FACT-B administration (electronic vs. paper) was predictive of outcome for each model.

This study was approved by the University of Texas MD Anderson Cancer Center Institutional Review Board and was independently monitored by the Institution’s Data Safety and Monitoring Board. Written informed consent was obtained from each subject. All analyses were intention-to-treat with two-sided α=0.05 and were performed using SAS v9.2 (Cary, NC).

RESULTS

Patients

A total of 432 patients were assessed for eligibility for enrollment, of whom 300 patients were registered for protocol treatment and 287 were randomized and evaluable (Figure 1). Of 149 patients randomized to CF-WBI, all (100%) received the allocated WBI and boost doses. Of 138 patients randomized to HF-WBI, 137 (99%) received a hypofractionated schedule of WBI (n=134, 42.56 Gy/16 fractions; n=2, 42.4 Gy/16 fractions; n=1, 42.52 Gy/16 fractions) and 136 (99%) received the allocated boost dose. One (1%) patient randomized to HF-WBI received conventional fractionation (46 Gy in 23 fractions followed by a 14 Gy in 7 fraction boost). Median number of elapsed days over which radiation was delivered was 36 days for CF-WBI (interquartile range [IQR] 35–36) and 22 days for HF-WBI (IQR 22–23). Half of the treatment plans (143) involved a D_max of 107% of prescription dose or higher.

Figure 1. Consort diagram.

Abbreviations: CF (conventional fractionation), HF (hypofractionation), WBI (whole breast irradiation)

In total, 25% (n=72) of patients were not non-Hispanic white, 28% (n=80) were overweight, and 48% (n=137) were obese, as defined by body mass index.[15] Median age was 60 years (IQR 54–66). Baseline patient, tumor and treatment characteristics were well matched (Table 1 and see eTable 1 in the supplement). Of those patients who received systemic therapy, type of therapy was similar between treatment arms.

Table 1.

Baseline patient, tumor, and treatment characteristics

	CF-WBI (n=149)		HF-WBI (n=138)		P*
	N	%	N	%
Patient characteristics
Age at diagnosis (years)					0.55
40–49	13	9	19	14
50–59	55	37	46	33
60–69	59	40	51	37
70 and older	22	15	22	16
Race					0.68
White Non-Hispanic	116	78	99	72
Hispanic	16	11	20	15
Black Non-Hispanic	15	10	17	12
Asian Non-Hispanic	2	1	2	1
Menopausal Status					0.23
Premenopausal	9	6	13	9
Perimenopausal	8	5	3	2
Postmenopausal	132	89	122	88
Bra Cup Size					0.53
A	13	9	7	5
B	31	21	34	25
C	50	34	46	33
D	40	27	35	25
DD	12	8	16	12
DDD	2	1	0	0
EE	1	1	0	0
BMI Quartile (kg/cm2)					0.08
<24.48	35	24	37	27
24.48 – <29.18	38	26	35	25
29.18 – <33.64	30	20	40	29
>33.64	46	31	26	19
Physician-Assessed Cosmesis					0.16
Excellent-Good	135	91	131	95
Fair-Poor	14	10	7	5
Tumor characteristics
Tumor Behavior					0.07
Invasive	110	74	114	83
DCIS	39	26	24	17
Tumor Grade					0.46
1	40	27	34	25
2	70	47	73	53
3	39	26	30	22
Unclassified†	0	0	1	1
Margin Status					0.67
negative, ≥ 2 mm	133	89	121	88
negative, < 2 mm	16	11	17	12
Quadrant					0.28
Central	16	11	27	20
Lower Inner	9	6	7	5
Lower Outer	22	15	17	12
Upper Inner	22	15	15	11
Upper Outer	80	54	72	52
Estrogen Receptor Status					0.39
Positive	130	87	118	86
Negative	18	12	16	12
Not tested	1	1	4	3
Progesterone Receptor Status					0.42
Positive	112	75	102	74
Negative	36	24	32	23
Not tested	1	1	4	3
Her2-neu Status					0.43
Positive	12	8	11	8
Negative	102	69	103	75
Not tested	35	24	24	17
Pathologic Stage among patients with invasive cancer without neoadjuvant therapy (n=196)‡
pT1mic-pT1a	16	17	12	12	0.44
pT1b	24	26	23	23
pT1c	43	46	48	47
pT2	11	12	19	19
pN0	79	84	89	87	0.02
pN1mic	14	15	6	6
pN1a	1	1	7	7
Clinical and Pathologic Stage among patients with invasive cancer with neoadjuvant therapy (n=28)‡
cT1c	2	12	2	17	0.76
cT2	14	88	10	84
cN0	13	81	11	92	0.44
cN1a	3	19	1	8
pT0	7	44	5	42	0.68
pTis	1	6	2	17
pT1a	2	13	0	0
pT1b	0	0	0	0
pT1c	4	25	3	25
pT2	2	13	2	17
pN0	16	100	12	100	.
Treatment characteristics
Chemotherapy					0.67
None	106	71	96	70
Neoadjuvant	16	11	12	9
Adjuvant	27	18	30	22
Treatment Location					0.16
Houston-area	141	95	132	96
Banner MD Anderson	4	3	0	0
Orlando Health	4	3	6	4

Abbreviations: CF (conventionally fractionated), DCIS (ductal carcinoma in situ), HF (hypofractionated), WBI (whole breast irradiation)

^*Fisher’s exact test used for race, estrogen receptor status, progesterone receptor status, and bra cup size. Chi-square test used for all other comparisons.

^†This patient’s cancer was diagnosed on core biopsy but grade could not be assigned. There was no residual disease in the lumpectomy specimen.

^‡Staging information is only presented for patients with invasive breast cancer. A total of 63 patients had DCIS. Because DCIS typically does not undergo pathologic staging of the axillary nodes, patients with DCIS are not included in the comparison of stage by randomization arm. Additionally, staging is different for patients treated with upfront surgery compared to those treated with neoadjuvant chemotherapy, which is the reason that these two groups of patients are separated in the table.

ER positive: ≥ 1% of cells stained for estrogen receptor; PR positive: ≥ 1% of cells stained for progesterone receptor; Her2-neuNeu positive: 3+ by immunohistochemistry or gene amplification by fluorescence in situ hybridization

Acute toxicity

Overall rates of any physician-assessed grade ≥ 2 and any grade ≥ 3 acute toxicity were lower with HF-WBI compared to CF-WBI (47% vs. 78%, P<.001 and 0% vs. 5%, P=0.007, respectively) (Table 2). Examining specific acute toxicities, patients treated with HF-WBI vs. CF-WBI had lower rates of physician-assessed grade fatigue (P_trend=0.02; grade≥2: 9% vs. 17%), pruritus (P_trend<0.001; grade≥1: 54% vs. 81%), breast pain (P_trend=0.001; grade≥1: 55% vs. 74%), dermatitis (P_trend<0.001; grade≥2: 36% vs. 69%), and hyperpigmentation (P_trend=0.002; grade≥2: 9% vs. 20%). In an exploratory subset analysis, there was no difference in acute grade ≥ 2 or grade ≥ 3 toxicity for patients in the highest quartile of body mass index (P=0.22 for grade ≥ 2 and P=0.55 for grade ≥ 3) or for patients in the highest quartile of central axis separation (P=0.17 for grade ≥ 2 and P=0.24 for grade ≥ 3).

Table 2.

Physician-Reported Maximal Acute Toxicities (NCI CTCAE v4.0)

	CF-WBI (n=149)		HF-WBI (n=138)		P*
	N	%	N	%
Any Grade ≥ 2 Acute Toxicity					<0.001
None	33	22	73	53
Any	116	78	65	47
Any Grade ≥ 3 Acute Toxicity					0.001
None	141	95	138	100
Any	8	5	0	0
Fatigue
0	23	15	29	21	0.02
1	101	68	97	70
2	20	13	12	9
3	5	3	0	0
Pruritus					<0.001
0	29	20	63	46
1	110	74	69	50
2	10	7	6	4
Breast Pain					0.001
0	39	26	62	45
1	97	65	69	50
2	13	9	7	5
Shoulder Arthralgia					0.46
0	124	83	120	87
1	24	16	16	12
2	0	0	2	1
3	1	1	0	0
Dermatitis					<0.001
0	1	1	8	6
1	45	30	80	58
2	101	68	50	36
3	2	1	0	0
Hyperpigmentation					0.002
0	45	30	60	44
1	74	50	66	48
2	30	20	12	9
Breast Edema					0.10
0	94	63	98	71
1	51	34	39	28
2	4	3	1	1
3	0	0	0	0
Wound Complications, Non-Infectious					0.61
0	147	99	137	99
1	2	1	1	1
Skin Ulceration					0.19
0	142	95	136	99
1	5	3	1	1
2	2	1	1	1
Seroma					0.19
0	127	85	109	79
1	21	14	28	20
2	1	1	1	1
Breast Infection					0.46
0	145	97	136	99
2	4	3	2	1
Wound Infection					0.96
0	148	99	137	99
2	1	1	1	1
Soft Tissue Necrosis of the Chest Wall/Thorax					.
0	149	100	138	100
Upper Extremity Edema					0.51
0	141	95	134	97
1	8	5	3	2
2	0	0	1	1
All others					0.20
0	133	89	128	93
1	12	8	9	7
2	4	3	1	1

Abbreviations: CF (conventionally fractionated), HF (hypofractionated), NCI CTCAE (National Cancer Institute Common Toxicity Criteria Adverse Events), WBI (whole breast irradiation)

^*Cochran-Armitage test for trend used for all P-values except chi-square used for any grade ≥ 2 toxicity and Fisher’s exact test used for any grade ≥ 3 toxicity.

Acute toxicities were recorded on a weekly basis during radiation using a structured template which specified these toxicities and their definitions. Any subsequent toxicity occurring within 42 days of treatment completion was also included in this analysis of acute toxicity.

Six-month toxicity

A total of 271 of 287 patients (94%) were evaluated for physician-assessed six-month toxicity, 142 (95%) randomized to CF-WBI and 129 (94%) randomized to HF-WBI. Patients randomized to HF-WBI experienced less physician-rated grade ≥2 fatigue compared to CF-WBI (P_trend=0.01; grade≥2: 0% vs. 6%). All other six-month toxicities were comparable between the two treatment arms (Table 3). In an exploratory subset analysis, there was no difference in six-month grade ≥ 2 or grade ≥ 3 toxicity for patients in the highest quartile of body mass index (P=0.86 for grade ≥ 2 and P=1.00 for grade ≥ 3) or for patients in the highest quartile of central axis separation (P=0.62 for grade ≥ 2 and P=1.00 for grade ≥ 3).

Table 3.

Physician-Assessed Maximal Toxicities at Six Months (NCI CTCAE v4.0)

	CF-WBI (n=142)		HF-WBI (n=129)		P*
	N	%	N	%
Combined
Any grade 2 or higher					0.81
None	96	68	89	69
Any	46	32	40	31
Any grade 3 or higher					0.18
None	140	99	129	100
Any	2	1	0	0
Constitutional
Fatigue					0.01
0	89	63	94	73
1	44	31	35	27
2	9	6	0	0
Dermatology/Skin
Hyperpigmentation					0.65
0	49	35	54	42
1	82	58	60	47
2	11	8	15	12
Skin Induration					0.43
0	121	85	104	81
1	19	13	24	19
2	2	1	1	1
Dermatitis					0.73
0	121	85	111	86
1	20	14	18	14
2	1	1	0	0
Telangiectasia					0.60
0	138	97	126	98
1	3	2	3	2
2	1	1	0	0
Skin Ulceration
0	142	100	129	100	.
Wound Complications, Non-Infectious
0	142	100	129	100	.
Infection
Breast Infection					0.83
0	141	99	128	99
2	0	0	1	1
3	1	1	0	0
Wound Infection
0	142	100	129	100	.
Lymphatics
Upper Extremity Edema					0.92
0	140	99	127	98
1	2	1	2	2
Breast Edema					0.78
0	114	80	97	75
1	21	15	30	23
2	7	5	2	2
Musculoskeletal/Soft Tissue
Fibrosis - Superficial Soft Tissue					0.89
0	111	78	100	78
1	30	21	28	22
2	1	1	1	1
Fibrosis - Deep Connective Tissue					0.26
0	121	85	104	81
1	21	15	24	19
2	0	0	1	1
Seroma					0.80
0	127	89	114	88
1	14	10	13	10
2	0	0	2	2
Soft Tissue Necrosis of the Chest Wall/Thorax
0	142	100	129	100
Pain
Breast Pain					0.89
0	99	70	92	71
1	41	29	32	25
2	2	1	5	34
Other Pain					0.49
0	132	93	123	95
1	9	6	5	4
2	1	1	1	1
Pulmonary
Cough					0.14
0	141	99	125	97
1	1	1	4	3
Dyspnea					0.14
0	142	100	127	98
1	0	0	2	2
Pneumonitis
0	142	100	129	100
Sexual/Reproductive Function
Nipple/Areolar					0.93
0	117	82	106	82
1	21	15	19	15
2	4	3	4	3
Breast Atrophy					0.72
0	93	66	82	64
1	33	23	31	24
2	16	11	16	12
Other
All others combined					0.30
0	136	96	126	98
1	5	4	3	2
2	1	1	0	0

Abbreviations: CF (conventionally fractionated), HF (hypofractionated), NCI CTCAE (National Cancer Institute Common Toxicity Criteria Adverse Events), WBI (whole breast irradiation)

^*P-value from Cochran-Armitage test for trend, with the exception of any grade 2 or higher and any grade 2 or higher, where P-value is from chi-square test.

These toxicities were recorded by the treating physician using a structured template which specified these toxicities and their definitions

Patient-reported quality of life

Prior to initiation of radiation, 286 of 287 patients (99.7%) completed the FACT-B, 148 (99%) randomized to CF-WBI and 138 (100%) randomized to HF-WBI. The randomization arms were well-matched for all components of the FACT-B, including total score (P=0.46), physical well-being (P=0.63), functional well-being (P=0.63), and breast cancer-specific concerns (P=0.86).

At the six-month follow up visit, 266 of 287 patients (93%) completed the FACT-B, 128 (93%) randomized to HF-WBI and 138 (93%) randomized to CF-WBI. At six months, there was no difference by randomization arm in FACT-B total score (P=0.20), functional well-being (P=0.10), or breast cancer-specific concerns (P=0.82). There was a trend toward improved physical well-being in patients randomized to HF-WBI vs. CF-WBI at the six month follow up visit (mean score 25.5 vs. 24.7, P=0.06), although this trend was not significant when comparing the difference at six months relative to baseline (P=0.46) (Table 4).

Table 4.

Mean Baseline and 6 Month FACT-B Scores by Randomization Arm

	CF-WBI			HF-WBI			P*
	N	Mean	(95% CI)	N	Mean	(95% CI)
Baseline
Physical Well-Being	149	24.5	(23.9–25.1)	138	24.7	(24.1–25.4)	0.63
Functional Well-Being	148	22.2	(21.4–23.0)	138	22.5	(21.6–23.4)	0.63
Emotional Well-Being	148	20.4	(20.0–20.9)	138	20.5	(19.9–21.0)	0.92
Social Well-Being	149	24.4	(23.6–25.1)	138	25.1	(24.3–25.9)	0.16
FACT-G Total Score	148	91.6	(89.7–93.4)	138	92.8	(90.9–94.8)	0.35
Breast Cancer Concerns	149	27.2	(26.4–27.9)	138	27.3	(26.4–28.2)	0.86
FACT-B Total Score	148	118.8	(116.4–121.1)	138	120.1	(117.5–122.6)	0.46
Six months
Physical Well-Being	140	24.7	(24.1–25.3)	128	25.5	(24.9–26.1)	0.06
Functional Well-Being	140	23.2	(22.5–24.0)	128	24.1	(23.4–24.9)	0.10
Emotional Well-Being	140	21.1	(20.6–21.6)	128	21.3	(20.8–21.8)	0.60
Social Well-Being	140	24.6	(23.9–25.4)	128	24.8	(24.0–25.6)	0.74
FACT-G Total Score	138	93.6	(91.8–95.5)	128	95.7	(93.9–97.6)	0.12
Breast Cancer Concerns	141	28.6	(27.8–29.4)	128	28.7	(27.9–29.5)	0.82
FACT-B Total Score	138	122.3	(119.9–124.7)	128	124.5	(122.1–126.9)	0.20
Difference between 6 month and baseline outcomes
Physical well-being	140	0.28	(−0.40–0.95)	128	0.62	(0.04–1.19)	0.46
Functional Well-Being	139	1.01	(0.26–1.76)	128	1.5	(0.69–2.32)	0.38
Emotional Well-Being	139	0.67	(0.06–1.29)	128	0.93	(0.23–1.63)	0.58
Social Well-Being	140	0.23	(−0.35–0.81)	128	−0.31	(−1.24–0.61)	0.32
FACT-G Total Score	137	2.29	(0.58–4.00)	128	2.74	(0.91–4.56)	0.73
Breast Cancer Concerns	141	1.50	(0.71–2.28)	128	1.54	(0.62–2.46)	0.94
FACT-B Total Score	137	3.85	(1.74–5.96)	128	4.27	(2.01–6.53)	0.79

Abbreviations: CF (conventionally fractionated), HF (hypofractionated), WBI (whole breast irradiation)

^*P-value from t-test.

In analyzing responses to the seven items contributing to physical well-being, there was no difference in any item prior to radiation (P≥0.22; see eTable 2 in the supplement). At the six month follow up, outcomes for Q1 (lack of energy) and Q3 (trouble meeting family needs) favored patients randomized to HF-WBI (P<0.001 and P=0.01, respectively). There was no difference by randomization arm at six months for the other items contributing to physical well-being. Ordinal logistic regression models confirmed the superiority of HF-WBI compared to CF-WBI on Q1 (lack of energy) (OR 0.39, 95% CI 0.24–0.63; P<0.001) and Q3 (trouble meeting family needs) (OR 0.34, 95% CI 0.16–0.75; P=0.007) (see eTable 3 in the supplement).

DISCUSSION

These randomized trial data demonstrate that HF-WBI followed by a tumor bed boost, in comparison to CF-WBI followed by a tumor bed boost, resulted in lower rates of physician-assessed acute toxicities during radiation and less physician-reported fatigue six months after radiation. Patient-reported outcomes reinforced this finding, with patients randomized to HF-WBI noting less lack of energy and less trouble meeting family needs six months after radiation. No measured side effects or QoL parameters were worse with HF-WBI compared to CF-WBI.

Defining the standard of care for WBI

Our study findings speak directly to the ongoing discussion seeking to define the most appropriate standard of care for dose-fractionation in WBI. In 2011, ASTRO published an evidence-based guideline on fractionation for WBI. The guideline concluded that the evidence suggests the equivalence of HF-WBI to CF-WBI for certain patient groups, notably those with pT1-2 N0 disease, age 50 years and older, not treated with chemotherapy, and where the radiation dose inhomogeneity could be limited to within ± 7% in the central axis.[16] Notably, however, the ASTRO guideline stopped short of endorsing HF-WBI as a preferred treatment strategy for such patients. Subsequently, in 2013, the ASTRO Choosing Wisely Campaign issued a stronger statement, noting “Don’t initiate whole breast radiotherapy as a part of breast conservation therapy in women age ≥50 with early stage invasive breast cancer without considering shorter treatment schedules”.

Nevertheless, evidence suggests that there has been limited adoption of HF-WBI in the United States, in contrast to other healthcare systems. A recent observational cohort study from 14 commercial health care plans in the United States reported that only 34.5% of appropriate candidates for HF-WBI received this treatment in 2013, similar to the rate seen in a study examining practice patterns in Michigan between 2011 and 2013.[4, 6] In contrast, practice patterns in the United Kingdom and Canada have demonstrated much broader uptake of HF-WBI.[17–19] Limited adoption of HF-WBI in the United States has been attributed in part to concerns regarding the applicability of the available evidence to practice patterns in the United States, where use of a tumor bed boost is much more common and where higher prevalence of obesity may result in fewer patients meeting the dose homogeneity or central axis separation criteria applied in the randomized literature.[8, 9] Within this context, results from our trial provide strong reassurance that HF-WBI with a sequential tumor bed can be safely administered with regard to acute and short-term toxicity in a patient population where three-quarters of patients were overweight or obese and half had a D-_max of 107% or higher.

Radiotherapy and fatigue

Our study findings also improve the understanding of the relevance of fatigue during and after breast radiation. Previously reported data indicate that the severity and frequency of patient-reported fatigue increase during the course of radiotherapy, peaking during the last week of treatment and impacting over three-quarters of patients.[20, 21] A recent study of 250 breast cancer patients treated with standard fractionation breast radiotherapy in Norway found that the volume of the breast receiving 40 Gy or more was a significant predictor of increased fatigue during radiotherapy, whereas the volume of the breast receiving 5 Gy was not.[22] Finally, a chart review of 161 breast cancer patients treated with CF-WBI, HF-WBI, and accelerated partial breast radiation from the Cancer Institute of New Jersey found mean fatigue was less with HF-WBI compared to CF-WBI at the first week, midway, and 4 weeks after completion of radiation therapy.[23]

Notably, this study is the first to prospectively measure and report lack of energy before initiation of radiation and six months after radiation within the context of a randomized trial. Our novel finding of a differential effect between the treatment arms on lack of energy supports that hypothesis that HF-WBI confers a substantive benefit to patients, beyond the abbreviated time to complete therapy. We hypothesize that less fatigue in the HF-WBI arm translated into less trouble meeting family needs. Strikingly, in a multivariable analysis, the negative impact of CF-WBI on both energy and ability to meet family needs was comparable or greater in magnitude to the effect of adjuvant chemotherapy on these endpoints. Further, we found that dosimetric parameters were not predictive of these patient-reported outcomes, suggesting these complications are truly driven by the selected dose-fractionation scheme and not the volume of tissue treated or relative hotspots.

The biologic mechanism underlying radiation-related fatigue is unclear. Fatigue during and acutely following CF-WBI has previously been found to be linked to higher levels of neutrophils, red blood cells, hemoglobin and D-dimer, as well as to depression and mood disturbance prior to initiation of radiation.[24][25–28] During radiation, a greater decrease in platelets, albumin, and red blood cells has been seen in those patients who develop fatigue. Receipt of WBI has also been associated with alterations in amino acid homeostasis among patients experiencing fatigue, with increased urinary excretion. [27]

Limitations

This study had limitations. First, patients were not routinely assessed within one to three weeks of concluding radiation, and thus acute toxicities may have been underascertained if they did not manifest until after completion of radiation. Second, all of the analyses reported herein were secondary and were considered hypothesis-generating. Third, it was not practical to blind patients and physicians to treatment arm within the context of this trial. Fourth, long-term toxicity data from the trial are still pending. Fifth, the dose-fractionation schema used for the standard fractionation arm of the study was 50Gy in 25 fractions; 45–50 Gy in 1.8 Gy per fraction is also a commonly used method to deliver CF-WBI, and any differences in associated acute and short-term outcome remain uncertain in their comparison with HF-WBI.

Conclusion

In this randomized trial, HF-WBI resulted in substantially less acute and short-term toxicity compared to CF-WBI. These findings should be communicated to patients as part of shared decision-making regarding election of radiotherapy regimen and are relevant to the ongoing discussion regarding the most appropriate standard of care for WBI dose-fractionation.