Originally published as JCO Early Release 10.1200/JCO.2007.15.2488 on February 19 2008

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pignol, J.-P. Articles by Paszat, L. Search for Related Content PubMed PubMed Citation Articles by Pignol, J.-P. Articles by Paszat, L. Related Articles Related Editorial Related Correspondence Social Bookmarking                            What's this?

A Multicenter Randomized Trial of Breast Intensity-Modulated Radiation Therapy to Reduce Acute Radiation Dermatitis

Jean-Philippe Pignol, Ivo Olivotto, Eileen Rakovitch, Sandra Gardner, Katharina Sixel, Wayne Beckham, Thi Trinh Thuc Vu, Pauline Truong, Ida Ackerman, Lawrence Paszat

From the Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario; Department of Radiation Oncology, Vancouver Island Cancer Centre, Victoria, British Columbia; Department of Medical Physics, Durham Regional Cancer Centre, Oshawa, Ontario; and Department of Radiation Oncology, Hôpital Notre-Dame, Montreal, Quebec, Canada

Corresponding author: Jean-Philippe Pignol, MD, PhD, Sunnybrook Health Sciences Centre T2-144, 2075, Bayview Ave, Toronto, Ontario, M4N 3M5 Canada; e-mail: Jean-Philippe.Pignol{at}sunnybrook.ca

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Purpose Dermatitis is a frequent adverse effect of adjuvant breast radiotherapy. It is more likely in full-breasted women and when the radiation is distributed nonhomogeneously in the breast. Breast intensity-modulated radiation therapy (IMRT) is a technique that ensures a more homogeneous dose distribution.

Patients and Methods A multicenter, double-blind, randomized clinical trial was performed to test if breast IMRT would reduce the rate of acute skin reaction (notably moist desquamation), decrease pain, and improve quality of life compared with standard radiotherapy using wedges. Patients were assessed each week during and up to 6 weeks after radiotherapy.

Results A total of 358 patients were randomly assigned between July 2003 and March 2005 in two Canadian centers, and 331 were included in the analysis. Breast IMRT significantly improved the dose distribution compared with standard radiation. This translated into a lower proportion of patients experiencing moist desquamation during or up to 6 weeks after their radiation treatment; 31.2% with IMRT compared with 47.8% with standard treatment (P = .002). A multivariate analysis found the use of breast IMRT (P = .003) and smaller breast size (P < .001) were significantly associated with a decreased risk of moist desquamation. The use of IMRT did not correlate with pain and quality of life, but the presence of moist desquamation did significantly correlate with pain (P = .002) and a reduced quality of life (P = .003).

Conclusion Breast IMRT significantly reduced the occurrence of moist desquamation compared with a standard wedged technique. Moist desquamation was correlated with increased pain and reduction in the quality of life.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Because of the widespread use of mammography, breast cancer is commonly diagnosed at an early stage.^1,2 The standard treatment for early-stage disease is breast-conserving surgery followed by adjuvant radiation therapy (RT) to the whole breast. This approach leads to low recurrence rates with a good cosmesis and provides an effective alternative to mastectomy.^3-10 However, about one third of women will develop significant acute skin toxicity after whole breast irradiation.¹¹ These reactions are painful and typically occur in the inframammary fold, and have also been associated with a reduction in health-related quality of life.^11,12 Previous studies have attempted to identify factors associated with an increased risk of acute radiation-induced toxicity after conventional whole breast irradiation. These include large breast size and the delivery of excessive radiation dose (> 10% of prescribed dose) to areas within the breast.¹² The areas receiving excessive dose are known as radiation hot spots, and are due to the limitations of conventional RT techniques to account for the complex three-dimensional (3D) shape of the breast, resulting in the inability to deliver a homogeneous dose throughout the breast.¹³ Breast intensity-modulated radiation therapy (IMRT) is a novel technique that can deliver a more homogeneous dose of radiation throughout the breast and efficiently removes the radiation hot spots.^13-17 This raises the possibility that breast irradiation using IMRT may lead to a significant reduction in severe radiation-induced skin toxicity.¹³ IMRT is more complex than conventional techniques and it is unknown to what extent, if any, breast IMRT can provide a clinical benefit to patients with early-stage breast cancer.

We report the results of a multicenter, phase III, double-blinded clinical trial in which patients were randomly assigned to receive either breast IMRT or a standard RT treatment after complete excision of an early-stage breast cancer.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Study Design
Patients with early-stage breast cancer referred for adjuvant RT to the Sunnybrook Health Sciences Centre (SHSC; Toronto, Ontario, Canada) or the British Columbia Cancer Agency–Vancouver Island Centre (VIC; Victoria, British Columbia, Canada) were enrolled onto a phase III, double-blinded, multicenter, randomized, controlled trial. Patients received adjuvant RT using either a standard wedge missing-tissue compensation technique or breast IMRT. The primary end points were the rates of acute dermatitis and moist desquamation. The sample size was calculated to identify an absolute 15% improvement from a previously reported 36% rate of moderate to severe acute skin toxicity.¹¹ A planned sample size of 308 patients (154 for each arm) was needed for an 80% power to test this hypothesis ( = .05, two sided).¹⁸ A total sample size of 340 was planned to allow for a 10% dropout or lost to follow-up rate. The study protocol was approved by the institutional research ethics board of each participating center, and was registered at the National Institutes of Health (www.clinicaltrials.gov No. NCT00187343).

Eligibility
Eligibility criteria included women with early-stage breast cancer referred for adjuvant RT to the breast alone. Patients were treated by breast-conserving surgery with a confirmed histologic diagnosis of invasive carcinoma or ductal carcinoma in situ, with three or fewer involved lymph nodes. Patients were excluded if they had four or more positive nodes, an Eastern Cooperative Oncology Group performance status 1, bilateral breast cancer, a postoperative wound infection, previous radiation to the same breast, a connective tissue disorder, or were pregnant. All patients provided written informed consent.

Random Assignment
Eligible patients were randomly assigned to receive 50 Gy in 25 fractions (2 Gy per fraction) to the whole breast using either standard RT with wedge compensation or breast IMRT. An additional boost dose of 16 Gy was used at the discretion of the radiation oncologist in accordance with the results of the European Organisation for Research and Treatment of Cancer (EORTC) randomized clinical trial.⁹ Given that the breast size and the total dose were factors associated with increased skin toxicity,^11,12 the random assignment was stratified for the use of a boost and breast size, and blocked 1:1 to ensure that the two arms were equally balanced.¹⁹ Breast size was defined as small (bra sizes 32A or 32B, 34A or 34B, and 36A), medium (bra sizes 32C, 34C, 36B or 36C, and 38A, 38B, or 38C), or large (larger bra sizes).¹¹ The randomization was performed centrally at SHSC after the patient had completed computed tomography (CT) simulation.

Interventions
All patients underwent CT simulation for RT planning. The involved breast was treated using a pair of parallel-opposed megavoltage beams to cover the whole glandular breast tissue. The two treatment arms differed by the missing tissue compensation method (two dimensional [2D] v 3D) used to account for variations in breast shape. The standard arm used a tungsten wedge inserted in the beam path and the experimental arm used breast IMRT. For the standard arm, the selection of the optimal wedge angle was done iteratively, minimizing hot spots in the whole breast volume. The experimental arm technique was called breast IMRT for consistency with previous reports,^13-17 and to follow the definition of compensating filter IMRT by Purdy.²⁰ Details of the dosimetry steps were reported elsewhere.²¹ Briefly, a multileaf collimator was used to generate several field-in-fields to compensate for missing tissue. Based on treatment planning availability at each site, an inverse algorithm was used to select the breast IMRT segment weights at SHSC, and a forward-planning method was used at VIC. It resulted in a smaller number of segments added to the open beam at SHSC (mean, 4.0 ± 1.1 standard deviation) compared to VIC (mean, 5.7 ± 0.6 standard deviation). In previously published work, we demonstrated that the two techniques were equivalent to minimize the dose distribution heterogeneity.²¹ For both arms, differential dose-volume histograms were calculated to evaluate various dosimetry end points for each patient. No contouring of normal tissue was done, and to eliminate the buildup area automatically, the clinical target volume was defined as the volume receiving at least 95% of the prescribed dose.

The beam energy (6 MV or mixed energies) was selected depending on the breast separation (> or < 25 cm) and/or the presence of an excessive dose hot spot on the dose distribution. If a boost was required, the planning involved a clinical mark-up and the use of a direct electron beam. The electron beam energy was selected using CT images to ensure that the surgical cavity was covered appropriately. The planning technique and dose prescription was similar at both sites, and it involved the dose calculation using heterogeneity correction and the plan normalization to a prescription point set at mid-separation, two thirds of the distance between the skin and the base of the tangential fields, such that the clinical target volume was covered by the 50 Gy isodose line. Dosimetry quality assurance included a central medical record review for each of the VIC patients and two thirds of the SHSC patients. Standard skin care during the radiation treatment was similar between sites.

Study End Points
Clinical outcomes included the intensity of acute skin reaction or pain using the National Cancer Institute Common Toxicity Criteria (NCI CTC) version 2.0 scale²² and the occurrence of moist desquamation.^11,12,23 The type and maximal intensity of each symptom and its location in the breast were recorded weekly during the 5 to 7 weeks of RT and at weeks 1, 2, 4, and 6 after treatment by trained clinical research assistants. Quality-of-life data were coded using the EORTC Quality of Life Questionnaire C-30 general module and the BR-23 module self-assessment questionnaires at baseline, the last week of treatment, and 1 month later.^24,25 To ensure unbiased symptom measurement, both patients and the clinical research assistants were blinded to the treatment arm. Moreover, the skin assessment was done in a separate clinic, and to ensure consistency and accuracy in the skin symptom coding, each clinical research assistant was trained for 3 weeks by the local principal investigator. Each patient's baseline information included height and weight, breast size measured by bra size, age, skin type coded using the Fitzpatrick classification,²⁶ smoking habits, and the existence of diabetes or high blood pressure.

Statistical Analysis
The comparisons of patient characteristics and dosimetry outcomes between the two treatment arms were done using ² tests for categoric variables and using the Wilcoxon rank sum test for continuous variables.²⁷ The proportions of maximum observed toxicity were compared across the two treatment arms using the ² test.²⁷ A comparison was considered significant at the 5% level of significance for two-sided tests. Univariate and multivariate logistic regression models including technical, dosimetry, and clinical parameters were developed to evaluate the factors associated with moist desquamation.²⁸ The multivariate model was adjusted for boost delivery and breast size (the stratification variables), but the continuous dosimetry variable breast volume receiving at least 95% of the dose was used instead of bra size. The EORTC Quality of Life Questionnaire C-30 and BR-23 data were processed to calculate the global health status/quality of life and breast symptoms scale values at each assessment. The outcomes used for analysis were change in scale values from baseline to end of treatment. Changes in scale from baseline were compared with treatment and pain grade using the Wilcoxon rank sum test. Pain grade was compared to treatment and grade of moist desquamation at the end of treatment using the ² test.²⁷ All statistical analysis was performed using the SAS software (SAS Institute Inc, Cary, NC).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Patient and Treatment Characteristics
Between July 2003 and March 2005, 358 patients were enrolled onto the study and 331 patients met eligibility for analysis. Twenty-seven patients (7.5%) were excluded from the analysis, mainly because of treatment protocol violation or withdrawal of the consent. Of the 331 patients, 170 received breast IMRT and 161 received a standard wedge technique (Fig 1).

View larger version (34K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Patient flow chart. IMRT, intensity-modulated radiation therapy; RT, radiation therapy.

View larger version (36K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. The sagittal dose gradient, defined as the gradient between the dose prescription point and the dose calculated in the breast crease 1 cm from the skin surface at mid-separation, is improved for breast intensity-modulated radiation therapy (IMRT) compared with the standard wedge technique. RT, radiation therapy.

View this table: [in this window] [in a new window]   Table 2. 2 Analysis Between the True Arms

View larger version (18K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Differential and cumulative frequencies of various toxicities (grade 3 to 4, moist desquamation and pain) from treatment start to the last clinical assessment for (A, C) breast intensity-modulated radiation therapy and (B, D) standard radiation therapy.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Numerous trials aiming to prevent acute radiation adverse effects to skin using creams or hygiene have been reported, but none of these trials demonstrated an effective prevention of skin reactions.^30-33 To our knowledge, our study is the first multicenter randomized trial demonstrating a successful reduction in acute radiation skin toxicity using an improved radiation technique, breast IMRT.

In 2002, Vicini et al¹³ reported the first clinical use of breast IMRT in a prospective series and suggested a reduced occurrence of acute skin adverse effects. In 2006, Freedman et al³⁴ reported the results of a matched-pair analysis of 131 patients treated using either breast IMRT (73 patients) or standard RT (58 historical patients). There was a significant reduction in the rate of moist desquamation using breast IMRT compared with the standard technique using wedge compensation. In that study, the two groups were not comparable regarding the total radiation dose, the use of mixed beam energy, and chemotherapy delivery. In the absence of a randomization, it is unknown if these factors might have increased the rate of acute skin reactions.^12,35,36

Our multicenter, randomized trial confirmed the dramatic improvement in the dose distribution homogeneity using breast IMRT, and demonstrated that it translated into a significant 17% absolute reduction in the frequency of moist desquamation. There was a trend toward improved acute grade 3 to 4 skin reactions (9.5% lower for breast IMRT), but this difference was not statistically significant. The lack of statistical significance may result from the nonspecificity and frequency of some symptoms included in the scale. For example, edema was often present at the time of the first skin assessment, before the radiation treatment, and might be due to the effects of breast and axillary surgery. In addition, the majority of the patients experienced erythema at some point of their treatment for both techniques (Fig 2), such that this parameter has no discriminative value. Conversely, moist desquamation is a parameter that is more specifically induced by radiation. It is easily recognized and measured by clinical research assistant, and it is the most clinically significant acute toxicity induced by radiation. Nearly 48% of patients had moist desquamation at some point of their treatment in the standard treatment arm using wedges. Compared with other series reporting rates of moist desquamation captured the last week or the week after the end of RT and ranging from 20% to 38%,^30,31,34 our rates look high. However, we are reporting cumulative and not differential rates of moist desquamation (Fig 2). To ensure this, the maximal skin toxicity was recorded; patients were asked to return to the treatment center 1, 2, 4, and 6 weeks after the end of the RT. In the standard treatment arm of our series, only 20.9% of our patients experienced moist desquamation the last week of treatment, and this value is consistent with those reported by other authors. In our study, there was no significant difference in the pain scores or quality of life scores between the two arms at the end of the radiation treatment. However, when moist desquamation was present at the time the quality-of-life questionnaire for pain assessment was completed, there was also an increased level of pain and a worsening of the quality of life score. This finding further justifies attempts to reduce the occurrence of moist desquamation.

There are possibly additional benefits of breast IMRT. There is accumulating clinical evidence showing that telangiectasia is a late sequelae of acute skin reactions,³⁷ and that dose inhomogeneity causes an increased risk of fibrosis and inferior cosmetic outcome.³⁸ Recently, Donovan et al³⁹ reported the results of a single-institution randomized trial of breast IMRT versus standard 2D compensation for large breasted women. This study found a significant change in the breast appearance after 5 years. In addition, Haffty et al suggested that increasing dose distribution homogeneity would benefit patients receiving chemotherapy in regard to the possible additional detrimental effect on the cosmetic outcome.^40-42 Similarly, the low acceptance of shorter courses of breast RT outside Canada and United Kingdom is related to concern regarding delayed complications and reduced cosmetic outcome.^10,41 The increased homogeneity produced by breast IMRT could improve the acceptance of a shorter course, which will impact on the cost of the technique. Finally, using of a lower number of monitor units and avoiding a beam modifier reduces the scatter dose, hence possibly reducing the risk of secondary cancer.⁴²

The present results support the shift from 2D to 3D dose compensation. CT simulation, 3D dose distribution treatment planning systems, and treatment unit with multileaf collimation are now becoming standard equipment in radiation oncology, such that breast IMRT should be offered to patients receiving adjuvant breast RT instead of the standard wedge technique.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Conception and design: Jean-Philippe Pignol, Ivo Olivotto, Eileen Rakovitch, Katharina Sixel, Wayne Beckham, Lawrence Paszat

Provision of study materials or patients: Jean-Philippe Pignol, Ivo Olivotto, Eileen Rakovitch, Katharina E. Sixel, Wayne Beckham, Pauline Truong, Ida Ackerman, Lawrence Paszat

Collection and assembly of data: Jean-Philippe Pignol, Ivo Olivotto, Eileen Rakovitch, Sandra Gardner, Katharina Sixel, Wayne Beckham, Thi Trinh Thuc Vu, Pauline Truong, Ida Ackerman

Data analysis and interpretation: Jean-Philippe Pignol, Ivo Olivotto, Eileen Rakovitch, Sandra Gardner, Katharina Sixel, Wayne Beckham, Thi Trinh Thuc Vu, Ida Ackerman, Lawrence Paszat

Manuscript writing: Jean-Philippe Pignol, Eileen Rakovitch, Sandra Gardner, Lawrence Paszat

Final approval of manuscript: Jean-Philippe Pignol, Ivo Olivotto, Eileen Rakovitch, Lawrence Paszat

	ACKNOWLEDGMENTS

 
The trial was made possible through the dedicated work of Gerrit deBoers, David Lee, Alexandre Mamedov, Alice Chung, Wafaa Attalla, Aurora de Borja, Linda Chan, Junella Lee, Amy Spink, Kathy Rouhi, Marlene Cardoso, Chris Bell, Brenda Schultz, Helene Gaffney, Bill Bendorffe, Marion Goldie, Dorothy Sayers, Stephanie Oldfield, Julia Gillespie, Tracy Mitchell, Anna Wojcicka, Ewa Szumacher, Edward Chow, Veronique Benk, May Tsao, Mary Doherty, Elaine Wai, Vaj Basrur, and Sam Kader.

	NOTES

 
published online ahead of print at www.jco.org on February 19, 2008.

Supported by Grant No. CIHR MCT-63156 from the Canadian Institute for Health Research.

Presented at the 48th American Society for Therapeutic Radiology and Oncology meeting, November 5, 2006, Philadelphia, PA; at the Radiological Society of North America, April 29, 2006, Chicago, IL; and at the Annual Meeting of the Canadian Association of Radiation Oncologists, October 9, 2007, Toronto, Ontario, Canada.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
1. Elkin EB, Hudis C, Begg CB, et al: The effect of changes in tumor size on breast carcinoma survival in the U.S.: 1975-1999. Cancer 104:1149-1157, 2005[CrossRef][Medline]

2. Anderson WF, Jatoi I, Devesa SS: Assessing the impact of screening mammography: Breast cancer incidence and mortality rates in Connecticut (1943-2002). Breast Cancer Res Treat 99:333-340, 2006[CrossRef][Medline]

3. Goldhirsch A, Glick JH, Gelber R, et al: Meeting highlights: International expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol 16:1569-1583, 2005[Abstract/Free Full Text]

4. Clarke M, Collins R, Darby S, et al: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 366:2087-2106, 2005[Medline]

5. Clark RM, Whelan T, Levine M, et al: Randomized clinical trial of breast irradiation following lumpectomy and axillary dissection for node-negative breast cancer: An update. J Natl Cancer Inst 88:1659-1664, 1996[Abstract/Free Full Text]

6. Liljegren G, Holmberg L, Bergh J, et al: 10-Year results after sector resection with or without postoperative radiotherapy for stage I breast cancer: A randomized trial. J Clin Oncol 17:2326-2333, 1999[Abstract/Free Full Text]

7. Forrest AP, Stewart HJ, Everington D, et al: Randomised controlled trial of conservation therapy for breast cancer: 6-year analysis of the Scottish trial. Lancet 348:708-713, 1996[CrossRef][Medline]

8. Fisher B, Anderson S, Bryant J, et al: Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347:1233-1241, 2002[Abstract/Free Full Text]

9. Bartelink H, Horiot JC, Poortmans P, et al: Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 345:1378-1387, 2001[Abstract/Free Full Text]

10. Whelan T, MacKenzie R, Julian J, et al: Randomized trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer. J Natl Cancer Inst 94:1143-1150, 2002[Abstract/Free Full Text]

11. Fisher J, Scott C, Stevens R, et al: Randomized phase III study comparing best supportive care to Biafine as a prophylactic agent for radiation-induced skin toxicity for women undergoing breast irradiation: Radiation Therapy Oncology Group (RTOG) 97-13. Int J Radiat Oncol Biol Phys 48:1307-1310, 2000[Medline]

12. Fernando IN, Ford HT, Powles TJ, et al: Factors affecting acute skin toxicity in patients having breast irradiation after conservative surgery: A prospective study of treatment practice at the Royal Marsden Hospital. Clin Oncol 8:226-233, 1996[CrossRef]

13. Vicini FA, Sharpe M, Kestin L, et al: Optimizing breast cancer treatment efficacy with intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 54:1336-1344, 2002[CrossRef][Medline]

14. Lo YC, Yasuda G, Fitzgerald TJ, et al: Intensity modulation for breast treatment using static multi-leaf collimators. Int J Radiat Oncol Biol Phys 46:187-194, 2000[CrossRef][Medline]

15. Kestin LL, Sharpe MB, Frazier RC, et al: Intensity modulation to improve dose uniformity with tangential breast radiotherapy: Initial clinical experience. Int J Radiat Oncol Biol Phys 48:1559-1568, 2000[CrossRef][Medline]

16. Chui CS, Hong L, Hunt M: A simplified intensity modulated radiation therapy technique for the breast. Med Phys 29:522-529, 2002[CrossRef][Medline]

17. van Asselen B, Schwarz M, van Vliet-Vroegindeweij C, et al: Intensity-modulated radiotherapy of breast cancer using direct aperture optimization. Radiother Oncol 79:162-169, 2006[CrossRef][Medline]

18. Fleiss JL: Statistical Methods for Rates and Proportions (ed 2). New York, NY, John Wiley & Sons, 1981

19. Piantadosi S: Clinical Trials: A Methodologic Perspective. New York, NY, John Wiley & Sons, 1997

20. Purdy JA: The development of intensity modulated radiation therapy, in Sternick ES (ed): The Theory and Practice of Intensity Modulated Radiation Therapy. Madison, WI, Advanced Medical Publishing, 1997, pp 1-15

21. Mihai A, Rakovitch E, Sixel K, et al: Inverse vs. forward breast IMRT planning. Med Dosim 30:149-154, 2005[CrossRef][Medline]

22. Trotti A, Byhardt R, Stetz J, et al: Common toxicity criteria: Version 2.0—An improved reference for grading the acute effects of cancer treatment: Impact on radiotherapy. Int J Radiat Oncol Biol Phys 47:13-47, 2000[CrossRef][Medline]

23. Archambeau JO, Pezner R, Wasserman T: Pathophysiology of irradiated skin and breast. Int J Radiat Oncol Biol Phys 31:1171-1185, 1995[CrossRef][Medline]

24. Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organization for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365-376, 1993[Abstract/Free Full Text]

25. Sprangers MA, Groenvold M, Arraras JI, et al: The European Organization for Research and Treatment of Cancer breast cancer-specific quality-of-life questionnaire module: First results from a three-country field study. J Clin Oncol 14:2756-2768, 1996[Abstract/Free Full Text]

26. Astner S, Anderson RR: Skin phototypes 2003. J Invest Dermatol 122:30-31, 2004

27. Snedecor GW, Cochran WG: Statistical Methods (ed 7). The Iowa State University Press, Ames, IA, 1980

28. Hosmer DW, Lemeshow S: Applied Logistic Regression. New York, NY, John Wiley & Sons, 1989

29. Das IJ, Cheng CW, Fein DA, et al: Patterns of dose variability in radiation prescription of breast cancer. Radiother Oncol 44:83-89, 1997[CrossRef][Medline]

30. Roy I, Fortin A, Larochelle M: The impact of skin washing with water and soap during breast irradiation: A randomized study. Radiother Oncol 58:333-339, 2001[CrossRef][Medline]

31. Boström A, Lindman H, Swartling C, et al: Potent corticosteroid cream (mometasone furoate) significantly reduces acute radiation dermatitis: Results from a double-blind, randomized study. Int J Radiat Oncol Biol Phys 59:257-265, 2001

32. Williams MS, Burk M, Loprinzi CL, et al: Phase III double-blind evaluation of an aloe vera gel as a prophylactic agent for radiation-induced skin toxicity. Int J Radiat Oncol Biol Phys 36:345-349, 1996[Medline]

33. Szumacher E, Wighton A, Franssen E, et al: Phase II study assessing the effectiveness of Biafine cream as a prophylactic agent for radiation-induced acute skin toxicity to the breast in women undergoing radiotherapy with concomitant CMF chemotherapy. Int J Radiat Oncol Biol Phys 51:81-86, 2001[Medline]

34. Freedman GM, Anderson PR, Li J, et al: Intensity modulated radiation therapy (IMRT) decreases acute skin toxicity for women receiving radiation for breast cancer. Am J Clin Oncol 29:66-70, 2006[CrossRef][Medline]

35. Fernando IN, Powles TJ, Ashley S, et al: An acute toxicity study on the effects of synchronous chemotherapy and radiotherapy in early stage breast cancer after conservative surgery. Clin Oncol 8:234-238, 1996[CrossRef]

36. Back M, Guerrieri M, Wratten C, et al: Impact of radiation therapy on acute toxicity in breast conservation therapy for early breast cancer. Clin Oncol 16:12-16, 2004[CrossRef]

37. Lilla C, Ambrosone CB, Kropp S, et al: Predictive factors for late normal tissue complications following radiotherapy for breast cancer. Breast Cancer Res Treat 106:143-150, 2007[CrossRef][Medline]

38. Coles CE, Moody AM, Wilson CB, et al: Reduction of radiotherapy-induced late complications in early breast cancer: The role of intensity-modulated radiation therapy and partial breast irradiation—Part I, normal tissue complications. Clin Oncol 17:16-24, 2005[CrossRef]

39. Donovan E, Bleakley N, Denholm E, et al: Randomised trial of standard 2D radiotherapy (RT) versus intensity modulated radiotherapy (IMRT) in patients prescribed breast radiotherapy. Radiother Oncol 82:254-264, 2007[CrossRef][Medline]

40. Haffty BG, Kim JH, Yang Q, et al: Concurrent chemo-radiation in the conservative management of breast cancer. Int J Radiat Oncol Biol Phys 66:1306-1312, 2006[Medline]

41. Sartor CI, Tepper JE: Is less more? Lessons in radiation schedules in breast cancer. J Natl Cancer Inst 94:1114-1115, 2002[Free Full Text]

42. Woo TCS, Pignol JP, Rakovitch E, et al: A prospective study of scattered radiation during breast radiotherapy. Int J Radiat Oncol Biol Phys 65:52-58, 2006[CrossRef][Medline]

Submitted November 7, 2007; accepted January 8, 2008.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Editorial

• Should Intensity-Modulated Radiation Therapy Be the Standard of Care in the Conservatively Managed Breast Cancer Patient?
  Bruce G. Haffty, Thomas A. Buchholz, and Beryl McCormick
  JCO 2008 26: 2072-2074 [Full Text]

Related Correspondence

• Skin-Sparing Intensity-Modulated Radiotherapy of the Breast
  Dirk Vordermark
  JCO 2008 26: 3292 [Full Text]
• Skin-Sparing Intensity-Modulated Radiotherapy of the Breast
  Edwin Bölke, Christiane Matuschek, Stephan Gripp, Wilfried Budach, Peter Arne Gerber, and Matthias Peiper
  JCO 2008 26: 5305-5306 [Full Text]

This article has been cited by other articles:

				T. A. Buchholz Radiation Therapy for Early-Stage Breast Cancer after Breast-Conserving Surgery N. Engl. J. Med., January 1, 2009; 360(1): 63 - 70. [Full Text] [PDF]

				J.-P. Pignol, I. Olivotto, and E. Rakovitch In Reply: J. Clin. Oncol., November 10, 2008; 26(32): 5306 - 5306. [Full Text] [PDF]

				E. Bolke, C. Matuschek, S. Gripp, W. Budach, P. A. Gerber, and M. Peiper Skin-Sparing Intensity-Modulated Radiotherapy of the Breast J. Clin. Oncol., November 10, 2008; 26(32): 5305 - 5306. [Full Text] [PDF]

				D. Vordermark Skin-Sparing Intensity-Modulated Radiotherapy of the Breast J. Clin. Oncol., July 1, 2008; 26(19): 3292 - 3292. [Full Text] [PDF]

				J.-P. Pignol, E. Rakovitch, and I. Olivotto In Reply J. Clin. Oncol., July 1, 2008; 26(19): 3292 - 3293. [Full Text] [PDF]

				B. G. Haffty, T. A. Buchholz, and B. McCormick Should Intensity-Modulated Radiation Therapy Be the Standard of Care in the Conservatively Managed Breast Cancer Patient? J. Clin. Oncol., May 1, 2008; 26(13): 2072 - 2074. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pignol, J.-P. Articles by Paszat, L. Search for Related Content PubMed PubMed Citation Articles by Pignol, J.-P. Articles by Paszat, L. Related Articles Related Editorial Related Correspondence Social Bookmarking                            What's this?