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ORIGINAL ARTICLE
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Comparison of two radiation boost schedules in postlumpectomy patients with breast cancer


1 Department of Radiation Oncology, Regional Cancer Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Radiation Oncology, MMIMSR, MMU, Mullana, Ambala, Haryana, India
3 Department of General Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Submission02-Aug-2019
Date of Decision09-Oct-2019
Date of Acceptance19-Dec-2019
Date of Web Publication13-Oct-2020

Correspondence Address:
Budhi Singh Yadav,
Department of Radiation Oncology, Regional Cancer Centre, Postgraduate Institute of Medical Education and Research, Sector-12, Chandigarh
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_549_19

 > Abstract 


Background: We have been practicing hypofractionation, 40 Gy in 16 fractions over 3 weeks for whole breast irradiation (WBI) for the past five decades with or without boost at our center. In this study, we compared two boost schedules of 10 Gy/5#/1 week with 16 Gy/8#/1.5 weeks in postlumpectomy patients with breast cancer after WBI.
Materials and Methods: From June 2012 to June 2016, the study included 87 breast cancer patients postbreast conservation surgery. The institutional ethics committee approved the study, which was registered with ClinicalTrials.gov (ClinicalTrials.gov identifier no. CT02142907). All patients were treated with WBI of 40 Gy/16#/3 weeks. WBI was followed by tumor bed boost of 10 Gy/5#/1 week in 44 patients and 16 Gy/8#/1.5 weeks in 43 patients, either with electron beam therapy or 3D CRT with photons. The primary endpoint of the study was the comparison of local control between two schedules. Secondary endpoints were acute and late radiation toxicities, cosmetic score analysis, disease-free survival (DFS), and overall survival (OS). The assessment of acute and late skin toxicity was made as per RTOG scores and LENT-SOMA scale. The cosmetic assessment was made with Harvard/NSABP/RTOG Breast Cosmesis Grading Scale.
Results: Median follow-up was 55 months (range 18–78 months). Local recurrence was seen in 1 (2.3%) patient in the 16 Gy boost only. Acute Grade 2 skin toxicity was 33% in 16 Gy boost arm compared to 23% in 10 Gy boost arm. Late skin toxicities were also high in patients with 16 Gy boost. Grade ≥2 induration was seen in 4.5% and 14% of patients with 10 Gy and 16 Gy boost, respectively. None of the patients with 10 Gy boost had Grade 2 edema as compared to 5% with 16 Gy. Pigmentation was observed in 9% and 23% patients with 10 Gy and 16 Gy boost, respectively. Grade 1 fibrosis was 2% versus 12% in patients with 10 Gy and 16 Gy boost, respectively. The cosmetic score was good/excellent in 91% and 84% of patients with 10 Gy and 16 Gy boost, respectively. Distant metastasis occurred in 2 (4%) and 3 (7%) patients in 10 Gy and 16 Gy boost, respectively. DFS and OS at 5 years were comparable between the two boost schedules.
Conclusion: Local control was comparable with 10 Gy and 16 Gy boost. Acute and late skin toxicities were higher with 16 Gy boost dose. The cosmetic score was better with 10 Gy boost. DFS and OS was comparable with the two boost schedules. Hence, a boost of 10 Gy/5# after WBI may be adequate in patients with breast cancer.

Keywords: Breast cancer, lumpectomy, radiation boost



How to cite this URL:
Yadav BS, Sharma SC, Singh G, Dahiya D. Comparison of two radiation boost schedules in postlumpectomy patients with breast cancer. J Can Res Ther [Epub ahead of print] [cited 2020 Oct 31]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=298076




 > Introduction Top


Breast cancer is the most common cancer diagnosed in women, with the highest rates in the US and Australia followed by the UK.[1] Breast-conserving surgery (BCS) followed by radiation therapy to the intact breast is an established standard of care for the majority of women with early-stage invasive breast cancer. The recommended whole-breast irradiation (WBI) schedule is 45–50 Gy and is followed by a boost of 10–16 Gy to the tumor bed. The results of breast conservation therapy are comparable with mastectomy; however, it gives a better quality of life to breast cancer patients.[2] Many women now prefer BCS compared to mastectomy. This has led to increased demand for radiotherapy. Giving fewer daily radiation fractions have been proven to be beneficial in terms of local control, survival and cosmetic outcome.[3],[4],[5] To give fewer daily fractions, the dose per fraction is increased. It reduces the demand for radiation resources and is also beneficial to the patient and family. Reducing the number of boost fractions is a further step to achieve this goal.

We have been practicing hypofractionation 40 Gy in 16 fractions over 3 weeks WBI for the past five decades with or without the boost of 10–16 Gy. The optimum boost dose posthypofractionation has not been settled in breast cancer. There has been recent surge in hypofractionation in breast cancer post-START trials.[3],[4] The optimum boost dose posthypofractionation has not been settled in breast cancer. In this study, we compared boost schedule of 10 Gy/5#/1 week with 16 Gy/8#/1.5 weeks in postlumpectomy patients of breast cancer after WBI. The aim of this study was to compare local control and toxicities with two boost schedules.


 > Materials and Methods Top


Between June 2012 to June 2016, the study randomized 87 breast cancer patients post-BCS by computer generated randomization. The institutional ethics committee approved the study, which was registered with ClinicalTrials.gov (ClinicalTrials.gov identifier no. NCT02142907. Patients were staged according to the American Joint Committee on Cancer 7th edition, International Union against cancer of breast carcinoma. Histologically proven postlumpectomy cases of carcinoma breast suitable for whole-breast radiotherapy were enrolled in this study. BCS in the form of lumpectomy with axillary clearance was carried out in the department of surgery under general anesthesia. Patients were evaluated in the Department of Radiotherapy PGIMER, Chandigarh by doing a thorough clinical examination followed by routine investigations which included hemogram, liver function tests, kidney function tests, and chest X-ray. Patients were treated by standard rectangular tangential field radiotherapy to whole breast. Computerized tomography (CT)-based treatment planning was done for the boost phase.

Inclusion criteria were women between the age of 18 and 70 years, unicentric primary breast cancer with invasive ductal histology, BCS, negative surgical margins, and stage T1-3, N0-3a, M0. Exclusion criteria were tumor histology with invasive or in situ lobular carcinoma or pure ductal carcinoma in situ, skin involvement, prior neoadjuvant chemotherapy, pregnant and lactating, bilateral breast cancer, history of prior primary malignancy and/or irradiation to the chest, and active collagen vascular disease.

Informed written consent was obtained from all patients. A planning CT scan was done for each patient. The patients were positioned on a breast board with sternum parallel to the table, and the ipsilateral arm abducted above the head. Before the CT scan, skin marks were placed to enable the patient repositioning during treatment. Radioopaque markers were placed to locate the whole breast and the scar on CT images.

Patients were scanned from the level of the larynx to upper abdomen with a scan slice thickness of 5 mm. The CT scan included the complete bilateral lungs, both breasts and the heart. Then, CT images were transferred to the treatment planning system.

The lumpectomy cavity was contoured on each CT slice. The clinical target volume (CTV) consisted of lumpectomy cavity uniformly expanded in three dimensions by 1 cm; however, the volume was constrained to lie 5 mm within the external contour and up against the pectoralis major muscles. The planning target volume was generated by the isotropic expansion of CTV. The ipsilateral breast was contoured within the radio-opaque markers excluding the anterior chest wall muscles. The organs at risk (OAR) contoured were heart, bilateral lungs, and opposite breast. The cranial extent of the heart included the infundibulum of the right ventricle, the right atrium, and right auricle but excluded the pulmonary trunk, ascending aorta, and superior vena cava. The lowest external contour of the heart was the caudal border of the mediastinum. The pericardium was excluded from the heart volume. Both lungs were contoured. The contralateral breast was contoured as the breast parenchyma was visible on CT images.

After contouring the target volumes and OAR, standard whole-breast rectangular field plans were generated. Dose prescribed was 40 Gy/16#/3 weeks. This was followed by a boost of 10 Gy/5#/1 week or 16 Gy/8#/1.5 weeks by three-dimensional conformal radiotherapy (3D-CRT) with photons or electrons. Plans were evaluated both quantitatively (analyzing dose-volume histograms) and qualitatively (by visually inspecting isodose curves). Plans were inspected for conformity and doses delivered to target and OAR.

The first follow-up was after 1 month of treatment, subsequently every 2 months till 6 months, three monthly till 1 year, four monthly till 2 years and 6 monthly till 5 years. Patients were examined clinically for acute and late effects, cosmetic outcome and loco-regional recurrence or metastasis during the follow-up. Required investigations were done if indicated.

Radiobiological rationale

From clinical data, we know that the radiobiological parameter α/β for breast cancer is low. For acute skin effects, a α/β beta of 10 and for late skin effects an α/β of 3, the biologically effective dose (BED) of WBI 40 Gy/16#/3 weeks for acute and late skin effects is 50 Gy and 73.3 Gy3; and with boost of 10 Gy/5#/5 days, it is 62 Gy and 89.9 Gy3; and for 16 Gy/8#/1.5 week, it will be 69.2 Gy and 99.9 Gy3; respectively.

Statistical analysis

The primary endpoint of the study was comparison of local recurrence between the two boost arms. Local recurrence was defined as recurrence in the treated breast. Secondary endpoints were acute and late radiation toxicities, cosmetic score analysis, disease-free survival (DFS), and overall survival (OS). The assessment of acute and late skin toxicity was done as per the RTOG scores and LENT SOMA scale. The cosmetic assessment was done with Harvard/NSABP/RTOG Breast Cosmesis Grading Scale. DFS and OS were estimated using the Kaplan–Meier curves and compared using log-rank tests. Skin, subcutaneous toxicity, and cosmetic assessment were made before treatment and then on regular follow-up during the study. Chi-square test was used to compare radiation toxicity parameters. Descriptive statistics including mean and standard deviation were obtained for all variables. For cosmesis, we report the percentage of patients with one of four levels of cosmesis, and the results were also dichotomized as the proportion of patients with an excellent or good result versus the proportion with fair or poor results. The length of follow-up was calculated as the time from recruitment until time of the first event or last follow-up assessment, whichever occurred first. Values of P < 0.05 were taken as statistically significant. All tests were performed using Statistical Package for the Social Sciences v. 16.0 (IBM, India).


 > Results Top


Patients and disease characteristics were balanced, as shown in [Table 1]. The mean age of the patients was 43 years (range 22–67 years). Median follow-up was 55 months (range 18–78 months). Local recurrence was seen in 1 (2.3%) patient in the 16 Gy arm [Table 2]. So far there has been no local recurrence in the 10 Gy arm. Distant metastasis occurred in 2 (4%) and 3 (7%) patients in 'd 16 Gy boost, respectively. One (2%) patient in 10 Gy arm and 2 (7%) patients in the 16 Gy arm had died of breast cancer. Acute Grade 2 skin toxicity was more in patients with 16 Gy boost, 33% as compared to 23% in 10 Gy boost arm. Late skin toxicities were also higher in patients with 16 Gy boost [Table 3]. Grade ≥2 induration was seen in 4.5% and 14% patients with 10 Gy and 16 Gy boost, respectively. None of the patients with 10 Gy boost had Grade 2 edema as compared to 5% with 16 Gy. Pigmentation was observed in 9% and 23% patients with 10 Gy and 16 Gy boost, respectively. Grade 1 fibrosis was 2% versus 12% in patients with 10 Gy and 16 Gy boost, respectively [Table 3].
Table 1: Patient and tumor characteristics

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Table 2: Recurrence rate

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Table 3: Radiation toxicities and cosmesis

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Cosmetic score was good/excellent in 91% and 84% of patients with 10 Gy and 16 Gy boost, respectively. It was fair/poor in 9% and 16% with 10 Gy and 16 Gy boost, respectively [Table 3]. No telangiectasia, pulmonary toxicity, radiation-induced heart disease, brachial plexopathy, or rib fracture was seen with any of the boost schedules till the last follow-up.

DFS and OS were comparable in two boost schedules. DFS at 5 years was 89% (95% confidence interval [CI], 72%–100%) with 10 Gy as compared to 86% (95% CI, 74%–98%) with 16 Gy boost schedule (P = 0.33). OS at 5 years was 92% (95% CI, 80%–100%) and 88% (95% CI, 74%–100%) with 10 Gy and 16 Gy boost, respectively (P = 0.16).


 > Discussion Top


The results of the present study showed that local control was comparable with two boost schedules after WBI of 40 Gy/16#/3wks in patients with breast cancer. RTOG acute Grade 2 skin toxicity was more with 16 Gy boost, 33% as compared to 23% with 10 Gy boost. However, cosmetic score was better with 10 Gy boost schedule.

Local recurrence

The addition of tumor bed boost after WBI has been reported to reduce the local recurrence rate in the range of 20%–50%.[6],[7],[8] Local recurrence was seen in 1 (2.3%) patient in the 16 Gy arm [Table 2]. There was no local recurrence in the 10 Gy arm. In the study by Poortmans et al., at 10 years, the cumulative incidence of local recurrence was 17.5% (95% CI: 10.4%–24.6%) versus 10.8% (95% CI: 5.2%–16.4%) for the low and high boost dose groups, respectively (hazard ratio [HR] = 0.83, 95% CI: 0.43–1.57, P > 0.1).[7] In START B trial also the boost dose was 10 Gy/5#/1 week in 41.4% and 43.8% of patients in the control and study arms, respectively.[4] They reported that local relapse at 5 years was 2.2% which is comparable to 2.3% in the present study.

The other trial which used similar dose fraction was the Canadian trial that compared 42.5 Gy/16#//3 weeks with 50 Gy/25#/5 weeks and reported 5 years local relapse rate of 2.8% in the hypofractionated schedule and 3.2% after conventional 5 weeks schedule.[5] This is also comparable to our study. However, boost was not delivered in the Canadian study, but they included early-stage patients only.[5]

Romestaing et al. in a randomized clinical trial of 1024 patients with early breast cancer from Lyon, France, concluded that delivery of a boost of 10 Gy to the tumor bed after 50 Gy to the whole breast following limited surgery significantly reduced the risk of early local recurrence from 4.5% to 3.6% with no serious deterioration in the cosmetic results. These are also comparable to our study.[9] Similarly, in a study from Budapest local recurrence was reduced from 15.5% to 6.7% with boost irradiation.[10]

Acute toxicity

Boost radiotherapy may increase acute skin toxicity. RTOG acute Grade 2 skin toxicity in the present study was 23% and 33% with 10 Gy and 16 Gy boost, respectively. We did not come across any study in the English literature where two such radiotherapy boost schedules have been compared posthypofractionated WBI or had reported acute toxicity data. In a study by Poortmans et al., they compared 10 Gy versus 26 Gyboost after WBI with traditional fractionation has not reported acute toxicities.[7] In a systematic review by Hamilton et al., RTOG acute Grade 2 skin toxicity with boost ranged from 1% to 73% in cohort studies and 6%–43% in case series. Acute toxicity was lower with IMRT and VMAT as compared to 3D-CRT.[6] In the UK Fast study, Grade 2 skin toxicity was 12.4% in the hypofractionation group as compared to 46.3% in the conventional group. In a similar study by Taher et al., they reported Grade 2 toxicity of 40% with hypofractionation and 60% with the traditional fractionation.[11] Shaitelman et al. reported Grade 2 or higher acute toxicity rate of 47% after hypofractionated WBI followed by boost.[12] Acute Grade 2 skin toxicities in the present study fall within the range reported by other studies.

Acute Grade 3 toxicity reported by Hamilton et al. ranged from 1% to 7% with various WBI and boost techniques.[6] Grade 3 toxicity in the present study was 4.5% and 5% with 10 Gy and 16 Gy boost, respectively [Table 3]. These toxicities are well within this reported range. All patients in the present study were treated by 3D-CRT.

Cosmesis

Boost may also lead to increased late toxicity with adverse effect on the cosmesis and quality of life in patients with breast cancer. The cosmetic outcome was better with 10 Gy boost as compared to 16 Gy, 91% and 84%, respectively. This cosmetic outcome in the present study is also comparable to that reported by START B trial.[4] In a review by Hamilton et al. excellent/good cosmetic outcomes with boost after WBI, ranged from 65% to 100% across different studies with follow-up ranging from 1.5 to 60 months.[6] Kovac et al. also reported excellent/good cosmesis in 88.3% of patients at 4 years with 3D-CRT photon boost.[13]

Late toxicity

Late Grade 2 breast induration in the present study was 4.5% with 10 Gy and 14% with 16 Gy boost. In the review by Hamilton et al. Grade 2 breast induration-fibrosis ranged from 1% to 9% and telangiectasia ranged from 0% to 6%.[6] In a study by Poortmans et al., severe fibrosis was seen in 3% versus 13% patients with low and high boost dose, respectively.[7] In START A and B study, 61% and 44% of patients, respectively, were given boost after WBI.[3],[4] Breast shrinkage was reported in 21%–23% patients in START trials hypofractionation arms at 5 years. The results of our study are also consistent with the RMH/GOC pilot and START A trials.[3],[14]

None of the patients with10 Gy boost had Grade 2 edema as compared to 5% with 16 Gy boost. Grade 2 edema rate was 8.8% and 4.8% in START A and START B trials, respectively. In the present study, Grade 1 fibrosis was seen in 2% and 12% of patients with 10 Gy and 16 Gy boost, respectively. None of our patients had Grade 2 fibrosis. In the Canadian study by Whelan et al. Grade 2 late skin toxicity and fibrosis were 8.9% and 8.1%; 11.9% and 10.4% with hypofractionation and traditional fractionation, respectively.[5] In a similar study from Hungary by Kovacs et al., they observed Grade 1 and 2 fibrosis in 12.9% patients with photons boost at 4 years follow-up.[13] Higher boost dose is likely to increase breast fibrosis. In “Boost versus No Boost” study, moderate-to-severe fibrosis increased from 13% to 28% with boost dose of 16 Gy.[8] In the present study also it was seen that a higher boost dose of 16 Gy leads to higher moderate (Grade 2) fibrosis 12% as compared to only 2% with 10 Gy. It is pertinent to mention here that fibrosis rates are higher with traditional fractionation with boost (28%) than with hypofractionation with boost (12%). Fibrosis rate of hypofractionation followed by boost (12%) is comparable to traditional fractionation without boost (13%).

The gain in local control with a higher boost dose should be weighed against the adverse cosmetic outcome and it should be explained to the patient. It is not only boost dose which affect the cosmetic outcome but other factors such as tumor location, volume of excision, and surgical complications such as hematoma and infection. Romestaing et al. in their study reported Grade 1 and 2 telangiectasia of 12.4%.[9] None of our patients developed telangiectasia so far; this might be due to shorter follow-up or hypo-fractionationated radiotherapy that may be associated with less telangiectasia. In START trials, telangiectasia rate has been reported to be 4% (START A) and 3% (START B) at 10 years.

Survival

There was no difference in DFS [Figure 1] and OS [Figure 2] at 5 years with two boost schedules in the present study. In a randomized study by Bartelink et al., they concluded that a boost dose of 16 Gy led to improved local control in all age groups. The cumulative incidence of local recurrence was 10.2% versus 6.2% for the no boost and the boost group, respectively (P <.0001), but there was no difference in survival. The benefit was higher in young and patients with high-grade tumors.[8] However, a long-term follow-up of the same study reported that the boost reduced the 20-year local recurrence rate from 31% (95% CI, 22%–39%) to 15% (95% CI, 8%–21%) (HR, 0.37; 95% CI, 0.22–0.62; P < 0.001) in high-risk patients (≤50 years with DCIS present).[15] However, these patients were treated with conventional dose of 50 Gy, while we have used hypofractionation for WBI in our patients. Similarly, there was no statistically significant difference in survival between the high boost dose of 26 Gy and the low boost dose of 10 Gy in the study by Poortmans et al. in patients with early breast cancer.[7]
Figure 1: Disease free survival

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Figure 2: Overall survival

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Median follow-up of 55 months may be short to comment on the late effects on other organs such as the lungs and heart with this schedule, but there were no such adverse effects were seen. The other limitation of the study is that the WBI was with hypofractionation but the boost schedules were with conventional fractionation. Hence, in future, there will be a proposal to deliver the boost also with hypofractionation with biological equivalent doses of 10 Gy and 16 Gy. Since dose fractionation in the present study was similar to the START B Trial so it is unlikely to add to the adverse outcome and we expect to achieve similar DFS and OS on long-term follow-up. The further small number of patients under power the study to look for local recurrence, but it is being carried out to include more patients and that will be reported in future.


 > Conclusion Top


In this study of comparison of two radiation boost schedules of 10 Gy and 16 Gy to the primary tumor area after WBI of 40 Gy/16#/3 weeks, local control rate was comparable, and a boost dose of 10 Gy may be associated with lesser acute and late toxicities, good cosmetic outcome and similar survival in patients with breast cancer after BCS. Patients will be followed to assess long-term effects and more patients will also be recruited to strengthen the data. Hence, we recommend a boost of 10 Gy/5# after WBI in patients with breast cancer.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.  Back to cited text no. 1
    
2.
Christiansen P, Carstensen SL, Ejlertsen B, Kroman N, Offersen B, Bodilsen A, et al. Breast conserving surgery versus mastectomy: Overall and relative survival – A population based study by the Danish Breast Cancer Cooperative Group (DBCG). Acta Oncol 2018;57:19-25.  Back to cited text no. 2
    
3.
START Trialists' Group, Bentzen SM, Agrawal RK, Aird EG, Barrett JM, Barrett-Lee PJ, et al. The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: A randomised trial. Lancet Oncol 2008;9:331-41.  Back to cited text no. 3
    
4.
START Trialists' Group, Bentzen SM, Agrawal RK, Aird EG, Barrett JM, Barrett-Lee PJ, et al. The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: A randomised trial. Lancet 2008;371:1098-107.  Back to cited text no. 4
    
5.
Whelan T, MacKenzie R, Julian J, Levine M, Shelley W, Grimard L, et al. Randomized trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer. J Natl Cancer Inst 2002;94:1143-50.  Back to cited text no. 5
    
6.
Hamilton DG, Bale R, Jones C, Fitzgerald E, Khor R, Knight K, et al. Impact of tumour bed boost integration on acute and late toxicity in patients with breast cancer: A systematic review. Breast 2016;27:126-35.  Back to cited text no. 6
    
7.
Poortmans PM, Collette L, Horiot JC, Van den Bogaert WF, Fourquet A, Kuten A, et al. Impact of the boost dose of 10 Gy versus 26 Gy in patients with early stage breast cancer after a microscopically incomplete lumpectomy: 10-year results of the randomised EORTC boost trial. Radiother Oncol 2009;90:80-5.  Back to cited text no. 7
    
8.
Bartelink H, Horiot JC, Poortmans PM, Struikmans H, Van den Bogaert W, Fourquet A, et al. Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost versus no boost EORTC 22881-10882 trial. J Clin Oncol 2007;25:3259-65.  Back to cited text no. 8
    
9.
Romestaing P, Lehingue Y, Carrie C, Coquard R, Montbarbon X, Ardiet JM, et al. Role of a 10-Gy boost in the conservative treatment of early breast cancer: Results of a randomized clinical trial in Lyon, France. J Clin Oncol 1997;15:963-8.  Back to cited text no. 9
    
10.
Polgár C, Fodor J, Orosz Z, Major T, Mangel L, Takácsi-Nagy Z, et al. The effect of tumour bed boost on local control after breast conserving surgery. First results of the randomized boost trial of the National Institute of Oncology. Magy Onkol 2001;45:385-91.  Back to cited text no. 10
    
11.
Taher AN, El-Baradie MM, Essa H, Zaki O, Ezzat S. Hypofractionation versus conventional fractionation radiotherapy after conservative treatment of breast cancer: Early skin reactions and cosmetic results. J Egypt Natl Canc Inst 2004;16:178-87.  Back to cited text no. 11
    
12.
Shaitelman SF, Schlembach PJ, Arzu I, Ballo M, Bloom ES, Buchholz D, et al. Acute and Short-term toxic effects of conventionally fractionated vs hypofractionated whole-breast irradiation: A randomized clinical trial. JAMA Oncol 2015;1:931-41.  Back to cited text no. 12
    
13.
Kovacs A, Lakosi F, Liposits G, Toller G, Hadjiev J, Vandulek C, et al. 3-D conformal photon boost in the treatment of early stage breast cancer: Four year follow up results. Pathol Oncol Res 2011;17:17-23.  Back to cited text no. 13
    
14.
Owen JR, Ashton A, Bliss JM, Homewood J, Harper C, Hanson J, et al. 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;7:467-71.  Back to cited text no. 14
    
15.
Vrieling C, van Werkhoven E, Maingon P, Poortmans P, Weltens C, Fourquet A, et al. Prognostic factors for local control in breast cancer after long-term follow-up in the EORTC boost vs no boost trial: A randomized clinical trial. JAMA Oncol 2017;3:42-8.  Back to cited text no. 15
    


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