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Latest developments in local treatment: radiotherapy for early breast cancer
Annals of Oncology 16 (Supplement 2): ii170 – ii173, 2005 doi:10.1093/annonc/mdi701
Latest developments in local treatment: radiotherapy for early breast cancer J. Yarnold Section of Radiotherapy, Institute of Cancer Research & Royal Marsden Hospital, Downs Road, Sutton, UK
Introduction
Partial breast irradiation
Accelerated hypofractionation
A promising strategy that aims to optimise local tumour control and late adverse effects in low recurrence risk women
The response to radiotherapy fraction size is non-linear, and is well described by a linear quadratic model in which radiation
Recent advances in the local treatment for early breast cancer include the systematic overview of radiotherapy effects, evaluation of partial breast radiotherapy and trials testing simpler radiotherapy regimens based on fewer, larger fractions delivered using intensity-modulated radiotherapy.
Local-regional control is an important determinant of mortality
q 2005 European Society for Medical Oncology
Downloaded from http://annonc.oxfordjournals.org/ at University of Otago Science Library on July 21, 2015
The most recent systematic overview undertaken by the Early Breast Cancer Collaborative Group indicates that after surgery for early breast cancer, radiotherapy reduces absolute breast cancer mortality by an average of 5% at 10 years [1]. The effects are comparable after mastectomy or breast conservation surgery, with or without adjuvant systemic therapies and in the presence or absence of metastatic axillary nodes. As for systemic therapies, the absolute benefits depend on prognosis, corresponding to one to five additional node-negative women alive and five to 10 additional node-positive women alive at 10 years for every 100 women treated. The overview confirms that prevention of 20 isolated local-regional recurrences in 100 women allocated to radiotherapy prevents five breast cancer deaths. Thus, the prevention of four local recurrences by radiotherapy (or surgery) prevents one breast cancer death, including patients with positive axillary nodes. Since radiotherapy is a local treatment, and breast cancer mortality is caused mainly by distant metastases, this constitutes powerful evidence that distant metastases are prevented in a significant proportion of patients by optimising surgery and radiotherapy. The overview also shows that the benefits of radiotherapy can be completely offset by an increase in cardiac and cerebrovascular deaths. It is reassuring that a recent metanalysis of postmastectomy radiotherapy trials using modern radiotherapy techniques confirm an overall survival gain without suggestion of an excess non-breast cancer mortality [2]. Similarly, metanalysis of trials of breast conserving surgery and radiotherapy report an absolute survival benefit of 8.6% after radiotherapy [3].
involves irradiating only part of the breast after complete microscopic excision of the primary tumour. Breast cancer multifocality has been studied by serial whole-organ sectioning of mastectomies, showing that the density of tumour foci decreases with distance from the reference tumour [4]. In a _ 2 cm microstudy of 264 specimens with primary tumours < scopic diameter, 28% had non-invasive foci and 14% had invasive tumour foci at a distance >2 cm from the edge of the reference tumour. If these primary tumours had been removed with a margin of 3–4 cm, only 7–9% of patients would have had residual invasive cancer in the remaining breast tissue. Patterns of local relapse reported in trials of breast conservation with or without radiotherapy are consistent with these pathological findings. For example, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-06 trial reported 86% of local recurrences within or close to the index quadrant [5]. Similarly, the Milan trial reported 79% of local recurrences at or close to the original tumour site [6]. The pathological and clinical data are supported by limited genetic data consistent with the hypothesis that ipsilateral breast relapse occurring outside the index quadrant, and often much later than recurrences close to the original tumour, are more likely to be new primary tumours rather than recurrences [7]. The pathological and clinical patterns of local recurrence have led to several randomised trials investigating the effects of partial breast irradiation delivered by brachytherapy, intraoperative or external beam techniques [8 –11]. Randomised trials in Europe and North America are testing a range of approaches including ELIOT (electron intra-operative therapy), a mobile linear accelerator with a robotic arm undergoing evaluation in Milan; intra-beam using 50 kV photons and undergoing evaluation in the TARGIT trial; interstitial brachytherapy, MammoSite brachytherapy and three-dimensional conformal external beam radiotherapy for partial breast irradiation in an NSABP/Radiation Therapy Oncology Group trial; and intensity-modulated radiotherapy delivering partial breast radiotherapy in the proposed UK IMPORT LOW trial. Until these studies mature and appropriate patient subgroups are identified, there is no justification for including these techniques as part of standard management.
ii171
Figure 1. Schema illustrating the non-linear relationship between fraction size and tissue response after radiotherapy. As fraction size increases above 2 Gy, the non-linear contribution becomes relatively more important.
proportional to D2) is important, and where total dose must be reduced substantially to compensate for increased effect of larger fraction sizes. Higher values of a/b (>6 Gy) are typical of tissues relatively insensitive to fraction size. These include squamous carcinomas and early-responding healthy tissues, including epidermis and gastro-intestinal epithelium. In these tissues, the linear component (response proportional to D) dominates, and total dose needs to be reduced less to compensate for increased fraction size. A relatively low a/b value in the range 4 –5 Gy was first estimated for the response of locally advanced and recurrent chest wall breast cancer in the mid-1980s, based on clinical observations reported much earlier [16, 17]. More recently, a direct estimate of 4.1 Gy (95% confidence interval 1–9.7) has been estimated for the a/b value of breast cancer based on local breast cancer control recorded in a randomised trial involving 1410 UK patients testing alternative regimens involving 13 fractions over 5 weeks (Table 1) [18]. In addition, a recent comparison of 50 Gy in 25 fractions of 2 Gy and 42.5 Gy in 16 fractions of 2.67 Gy in a trial involving 1345 Canadian patients has reported no significant differences in local tumour recurrence between arms (Table 1) [19]. If the test and control schedules in the Ontario trial are truly iso-effective with respect to tumour control, it suggests an a/b value of 3 Gy (this could be an underestimate if tumour proliferation rates, and the 2 weeks difference in overall treatment time, are relevant). Similar fractionation sensitivity, including an a/b value as low as 1.5 Gy, has recently been suggested for prostate cancer [20]. If the relatively high fractionation sensitivity of breast cancer is confirmed in the current START trial involving 4451 UK women, the implications are that larger fraction sizes have no disadvantages, and perhaps significant
Table 1. Schema of Ontario trial (n = 1345) testing a 16-fraction schedule of whole breast radiotherapy over 3 weeks + 1 day against 50 Gy in 25 fractions over 5 weeks [19] Trial arm
Total dose (Gy)
Number of fractions
Fraction size (Gy)
Treatment time (weeks)
Control
50
25
2.0
5
Test arm
42.5
16
2.65
3 (+1 day)
Table 2. Schema of current START trial (n = 4551) testing alternative schedules of whole-breast radiotherapy against 50 Gy in 25 fractions [28] Trial arm
Total dose (Gy)
Number of fractions
Fraction size (Gy)
Treatment time (weeks)
Control
50
25
2.0
5
Test arm 1
39.0
13
3.0
5
Test arm 2
41.6
13
3.2
5
Control
50
25
2.0
5
Test arm
40
13
2.67
3
Trial A
Figure 2. Schema illustrating actual (for late complications and squamous carcinomas) and postulated (for breast cancer) differences in responses to radiotherapy fraction size. As fraction size increases above 2 Gy, the nonlinear contribution becomes relatively more important for breast than squamous carcinomas.
Trial B
Downloaded from http://annonc.oxfordjournals.org/ at University of Otago Science Library on July 21, 2015
response / aD+bD2, where a and b are constants and D is the dose per fraction (Figure 1) [12]. The relationship is approximately linear at low fraction sizes (radiation response / D), but is upwardly bending at higher doses (response / D2). The classical assumption is that human tumours are relatively insensitive to radiotherapy fraction size compared with late-reacting normal tissues (Figure 2). This means that as fraction size increases above 2 Gy, tumour responses increase relatively more slowly than late normal tissue responses. This assumption is consistent with the responses of animal tumours and human squamous carcinomas at several primary sites [13–15]. The implication for radio_ 2 Gy minimise the level of late therapy is that fraction sizes < normal tissue injury for a given level of antitumour effect when, as usual, late normal tissue responses are dose-limiting. The hypothesis under discussion is that breast cancer may be more sensitive to fraction size than previously assumed on the basis of responses of squamous carcinomas. If true, the implications would be that fraction sizes >2 Gy would not necessarily be disadvantageous, and may have clear advantages in radiotherapy for primary breast cancer. The a/b value [units are Gray (Gy)] in the linear quadratic model is an empirical descriptor of sensitivity to fraction size. Values of a/b in the range 1–6 Gy are typical of tissues sensitive to fraction size, where the quadratic component (response
ii172 Table 3. Schema of current FAST trial (n = 900) testing a once-weekly five-fraction schedule of whole-breast radiotherapy against 50 Gy in 25 fractions delivered using three-dimensional dose compensation Trial arm
Total dose (Gy)
Number of fractions
Fraction size (Gy)
Treatment time (weeks)
Control
50
25
2.0
5
Test arm 1
30
5
6.0
5
Test arm 2
28.5
5
5.7
5
Figure 3. Schema of proposed IMPORT trial evaluating modulation of fraction size across the breast (‘concomitant boost’) compared with standard dose escalation techniques (‘sequential boost’).
Downloaded from http://annonc.oxfordjournals.org/ at University of Otago Science Library on July 21, 2015
advantages, for women with primary breast cancer (Table 2). Since it is unlikely that 13-, 15- or 16-fraction schedules would represent the limit of what might be achieved, further studies are justified to test the limits of hypofractionation (use of fraction sizes >2 Gy) in breast cancer. Testing hypofractionation is an expanding research area. For example, once-weekly fractions of 6 Gy are predicted to be equivalent to five once-daily fractions of 2 Gy, assuming a/b values of 3 Gy [12]. This estimate is based on late human skin reactions (telangiectasia), which vary with fraction size and total dose in a way predicted accurately by the linearquadratic model [21, 22]. However, there is very limited experience of large fraction sizes in the context of curative breast cancer radiotherapy. Six fractions of 6.5 Gy over 6 weeks to the whole breast or chest wall using tangential megavoltage fields were evaluated in a series of 84 patients followed up for 36–94 months at Guildford, UK [23]. Acute skin reactions were reportedly mild, and only one out of 36 patients treated to whole breast developed a severe delayed skin reaction. In a recent French study, 152 women were treated with five fractions of 6.5 Gy over 5 weeks, with three local relapses at a median follow up of >5 years, but there were no comments on normal tissue responses [24]. Randomised clinical trials are needed to formally test the safety of this approach prior to evaluating efficacy (tumour control) in a large trial. This forms the background to the current UK FAST trial (n = 900) testing 50 Gy in 25 fractions of wholebreast radiotherapy against two dose levels of a five-fraction schedule delivered over 5 weeks (5.7 or 6 Gy per fraction) using full dose compensation (Table 3). The primary end point is late normal tissue response in the breast. If 3-year data are encouraging, a large phase III trial is planned in order to evaluate local tumour control, quality of life and health economic consequences. Hypofractionation lends itself to acceleration, taking advantage of the relative sparing of early skin reactions as fraction size increases and the absence of a significant time dependency for late adverse effects. Tumour repopulation has recently been tested as a determinant of treatment outcome in the context of adjuvant systemic therapy. In a randomised comparison of conventional 3-weekly schedules of doxorubicin and cyclophosphamide with the same chemotherapy doses given at 2-weekly intervals (using growth factors to accelerate marrow recovery), the hazard ratios for disease-free and overall survival associated with 2-weekly chemotherapy were 0.74 (P = 0.01) and 0.69 (P = 0.01), respectively, in 2005 patients
[25]. Recent reports of accelerated radiotherapy fractionation in head and neck cancer indicate that very modest shortening of treatment has a detectable impact on local control. In a trial of 1476 patients randomised to five (control arm) or six (test arm) fractions per week of conventional radiotherapy, local tumour control in the test arm was 76% patients compared with 64% in the control group [26]. In this study, shortening treatment by only 7 days was associated with a 12% absolute reduction in local recurrence at the primary site, a reduction in the odds of recurrence of 16%. The possible implications for primary breast cancer are that modest reductions in treatment time may translate into worthwhile gains in tumour control without enhanced late normal tissue injuries. If the predicted late adverse effects of once-weekly 5.7–6 Gy fraction sizes are confirmed in the proposed FAST trial, it will encourage future evaluation of accelerated hypofractionation. At this stage, studies are underway evaluating the early and late normal tissue responses of 30 Gy in five fractions of 6 Gy delivered over 15 days, and the evaluation of a 5-day regimen is being considered. Finally, the implications of advanced radiotherapy techniques for delivering the biological advantages of hypofractionation are worth considering. Rather than increase dose intensity by increasing the number of 2 Gy fractions, it creates opportunities for escalating dose intensity by modulating fraction size across the breast. Even if the fractionation sensitivity of breast cancer is not quite as great as the normal tissues of the breast, the shorter overall treatment times needed to deliver concomitant boost using intensity modulated radiotherapy could be advantageous if tumour proliferation is a significant determinant of local control [27]. The implications of doseescalated, intensity-modulated radiotherapy are to be tested in the proposed UK IMPORT HIGH trial. The hypothesis is that higher doses per fraction to high-risk areas and lower fraction sizes to low-risk areas of the breast will offer a clinically superior and cost-effective approach of matching dose intensity to tumour recurrence risk compared with standard sequential boost techniques (Figure 3).
ii173 In conclusion, future prospects for exploiting the biology of hypofractionation in breast cancer using advanced radiotherapy technologies look bright, including a possibility of testing five-fraction, 5-day schedules of dose-escalated, intensitymodulated radiotherapy by the end of the decade.
References
Downloaded from http://annonc.oxfordjournals.org/ at University of Otago Science Library on July 21, 2015
1. EBCTCG. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists Collaborative Group. Lancet 2000; 355: 1757–1770. 2. Whelan TJ, Julian J, Wright J et al. Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis. J Clin Oncol 2000; 18: 1220–1229. 3. Vinh-Hung V, Verschraegen C. Breast-conserving surgery with or without radiotherapy: pooled-analysis for risks of ipsilateral breast tumor recurrence and mortality. J Natl Cancer Inst 2004; 96: 115 –121. 4. Holland R, Veling SH, Mravunac M, Hendriks JH. Histologic multifocality of Tis, T1-2 breast carcinomas. Implications for clinical trials of breast-conserving surgery. Cancer 1985; 56: 979–990. 5. Fisher B, Anderson S, Redmond CK et al. Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1995; 333: 1456–1461. 6. Veronesi U, Marubini E, Mariani L et al. Radiotherapy after breastconserving surgery in small breast carcinoma: long-term results of a randomized trial. Ann Oncol 2001; 12: 997– 1003. 7. Smith TE, Lee D, Turner BC et al. True recurrence vs. new primary ipsilateral breast tumor relapse: an analysis of clinical and pathologic differences and their implications in natural history, prognoses, and therapeutic management. Int J Radiat Oncol Biol Phys 2000; 48: 1281–1289. 8. Vicini FA, Chen PY, Fraile M et al. Low-dose-rate brachytherapy as the sole radiation modality in the management of patients with earlystage breast cancer treated with breast-conserving therapy: preliminary results of a pilot trial. Int J Radiat Oncol Biol Phys 1997; 38: 301 –310. 9. Perera F, Yu E, Engel J et al. Patterns of breast recurrence in a pilot study of brachytherapy confined to the lumpectomy site for early breast cancer with six years’ minimum follow-up. Int J Radiat Oncol Biol Phys 2003; 57: 1239–1246. 10. Vaidya JS et al. Intra-operative breast radiation: the targeted intraoperative radiotherapy (Targit) trial. Breast Cancer Res Treat 2003; 82: S2. 11. Veronesi U, Orecchia R, Luini A et al. A preliminary report of intraoperative radiotherapy (IORT) in limited-stage breast cancers that are conservatively treated. Eur J Cancer 2001; 37: 2178–2183. 12. Jones B, Dale RG, Deehan C et al. The role of biologically effective dose (BED) in clinical oncology. Clin Oncol (R Coll Radiol) 2001; 13: 71–81.
13. Yarnold JR et al. Fraction Sensitivity of Change in Breast Appearance after Radiotherapy for Early Breast Cancer: Long-term Results of a Randomised Trial. Czech Republic: Praha 2002; S25. 14. Thames HD, Hendry JH, Moore JV et al. The high steepness of dose–response curves for late-responding normal tissues. Radiother Oncol 1989; 15: 49–53. 15. Thames HD, Bentzen SM, Turesson I et al. Time–dose factors in radiotherapy: a review of the human data. Radiother Oncol 1990; 19: 219–235. 16. Douglas BG. Superfractionation: its rationale and anticipated benefits. Int J Radiat Oncol Biol Phys 1982; 8: 1143– 1153. 17. Cohen L. Radiotherapy in breast cancer I. The dose-time relationship theoretical considerations. Br J Radiol 1952; 25: 636–642. 18. Owen JR et al. Fractionation sensitivity of breast cancer: results of a randomised trial. Eur J Oncol Suppl 2003; S9. 19. Whelan T, MacKenzie R, Julian J et al. Randomized trial of breast irradiation schedules after lumpectomy for women with lymph nodenegative breast cancer. J Natl Cancer Inst 2002; 94: 1143–1150. 20. Brenner DJ, Hall EJ. Fractionation and protraction for radiotherapy of prostate carcinoma. Int J Radiat Oncol Biol Phys 1999; 43: 1095–1101. 21. Turesson I, Thames HD. Repair capacity and kinetics of human skin during fractionated radiotherapy: erythema, desquamation, and telangiectasia after 3 and 5 years’ follow-up. Radiother Oncol 1989; 15: 169–188. 22. Turesson I. The progression rate of late radiation effects in normal tissue and its impact on dose-response relationships. Radiother Oncol 1989; 15: 217–226. 23. Rostom AY, Pradhan DG, White WF. Once weekly irradiation in breast cancer. Int J Radiat Oncol Biol Phys 1987; 13: 551 –555. 24. de Lafontan B et al. Loco-regional relapses and survival after breastconserving surgery and hypofractionated radiation therapy in elderly women with invasive breast cancer. Breast Cancer Res Treat 2003; 82 (Suppl 1): S38. 25. Citron ML, Berry DA, Cirrincione C et al. Randomized trial of dosedense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003; 21: 1431–1439. 26. Overgaard J, Hansen HS, Specht L et al. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial. Lancet 2003; 362: 933–940. 27. Rew DA, Wilson GD. Cell production rates in human tissues and tumours and their significance. Part 1: an introduction to the techniques of measurement and their limitations. Eur J Surg Oncol 2000; 26: 227–238. 28. Winfield E, Deighton A, Venables K et al. Survey of UK breast radiotherapy techniques: background prior to the introduction of the quality assurance programme for the START (standardisation of radiotherapy) trial in breast cancer. Clin Oncol (R Coll Radiol) 2002; 14: 267–271.
Latest developments in local treatment: radiotherapy for early breast cancer J. Yarnold Section of Radiotherapy, Institute of Cancer Research & Royal Marsden Hospital, Downs Road, Sutton, UK
Introduction
Partial breast irradiation
Accelerated hypofractionation
A promising strategy that aims to optimise local tumour control and late adverse effects in low recurrence risk women
The response to radiotherapy fraction size is non-linear, and is well described by a linear quadratic model in which radiation
Recent advances in the local treatment for early breast cancer include the systematic overview of radiotherapy effects, evaluation of partial breast radiotherapy and trials testing simpler radiotherapy regimens based on fewer, larger fractions delivered using intensity-modulated radiotherapy.
Local-regional control is an important determinant of mortality
q 2005 European Society for Medical Oncology
Downloaded from http://annonc.oxfordjournals.org/ at University of Otago Science Library on July 21, 2015
The most recent systematic overview undertaken by the Early Breast Cancer Collaborative Group indicates that after surgery for early breast cancer, radiotherapy reduces absolute breast cancer mortality by an average of 5% at 10 years [1]. The effects are comparable after mastectomy or breast conservation surgery, with or without adjuvant systemic therapies and in the presence or absence of metastatic axillary nodes. As for systemic therapies, the absolute benefits depend on prognosis, corresponding to one to five additional node-negative women alive and five to 10 additional node-positive women alive at 10 years for every 100 women treated. The overview confirms that prevention of 20 isolated local-regional recurrences in 100 women allocated to radiotherapy prevents five breast cancer deaths. Thus, the prevention of four local recurrences by radiotherapy (or surgery) prevents one breast cancer death, including patients with positive axillary nodes. Since radiotherapy is a local treatment, and breast cancer mortality is caused mainly by distant metastases, this constitutes powerful evidence that distant metastases are prevented in a significant proportion of patients by optimising surgery and radiotherapy. The overview also shows that the benefits of radiotherapy can be completely offset by an increase in cardiac and cerebrovascular deaths. It is reassuring that a recent metanalysis of postmastectomy radiotherapy trials using modern radiotherapy techniques confirm an overall survival gain without suggestion of an excess non-breast cancer mortality [2]. Similarly, metanalysis of trials of breast conserving surgery and radiotherapy report an absolute survival benefit of 8.6% after radiotherapy [3].
involves irradiating only part of the breast after complete microscopic excision of the primary tumour. Breast cancer multifocality has been studied by serial whole-organ sectioning of mastectomies, showing that the density of tumour foci decreases with distance from the reference tumour [4]. In a _ 2 cm microstudy of 264 specimens with primary tumours < scopic diameter, 28% had non-invasive foci and 14% had invasive tumour foci at a distance >2 cm from the edge of the reference tumour. If these primary tumours had been removed with a margin of 3–4 cm, only 7–9% of patients would have had residual invasive cancer in the remaining breast tissue. Patterns of local relapse reported in trials of breast conservation with or without radiotherapy are consistent with these pathological findings. For example, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-06 trial reported 86% of local recurrences within or close to the index quadrant [5]. Similarly, the Milan trial reported 79% of local recurrences at or close to the original tumour site [6]. The pathological and clinical data are supported by limited genetic data consistent with the hypothesis that ipsilateral breast relapse occurring outside the index quadrant, and often much later than recurrences close to the original tumour, are more likely to be new primary tumours rather than recurrences [7]. The pathological and clinical patterns of local recurrence have led to several randomised trials investigating the effects of partial breast irradiation delivered by brachytherapy, intraoperative or external beam techniques [8 –11]. Randomised trials in Europe and North America are testing a range of approaches including ELIOT (electron intra-operative therapy), a mobile linear accelerator with a robotic arm undergoing evaluation in Milan; intra-beam using 50 kV photons and undergoing evaluation in the TARGIT trial; interstitial brachytherapy, MammoSite brachytherapy and three-dimensional conformal external beam radiotherapy for partial breast irradiation in an NSABP/Radiation Therapy Oncology Group trial; and intensity-modulated radiotherapy delivering partial breast radiotherapy in the proposed UK IMPORT LOW trial. Until these studies mature and appropriate patient subgroups are identified, there is no justification for including these techniques as part of standard management.
ii171
Figure 1. Schema illustrating the non-linear relationship between fraction size and tissue response after radiotherapy. As fraction size increases above 2 Gy, the non-linear contribution becomes relatively more important.
proportional to D2) is important, and where total dose must be reduced substantially to compensate for increased effect of larger fraction sizes. Higher values of a/b (>6 Gy) are typical of tissues relatively insensitive to fraction size. These include squamous carcinomas and early-responding healthy tissues, including epidermis and gastro-intestinal epithelium. In these tissues, the linear component (response proportional to D) dominates, and total dose needs to be reduced less to compensate for increased fraction size. A relatively low a/b value in the range 4 –5 Gy was first estimated for the response of locally advanced and recurrent chest wall breast cancer in the mid-1980s, based on clinical observations reported much earlier [16, 17]. More recently, a direct estimate of 4.1 Gy (95% confidence interval 1–9.7) has been estimated for the a/b value of breast cancer based on local breast cancer control recorded in a randomised trial involving 1410 UK patients testing alternative regimens involving 13 fractions over 5 weeks (Table 1) [18]. In addition, a recent comparison of 50 Gy in 25 fractions of 2 Gy and 42.5 Gy in 16 fractions of 2.67 Gy in a trial involving 1345 Canadian patients has reported no significant differences in local tumour recurrence between arms (Table 1) [19]. If the test and control schedules in the Ontario trial are truly iso-effective with respect to tumour control, it suggests an a/b value of 3 Gy (this could be an underestimate if tumour proliferation rates, and the 2 weeks difference in overall treatment time, are relevant). Similar fractionation sensitivity, including an a/b value as low as 1.5 Gy, has recently been suggested for prostate cancer [20]. If the relatively high fractionation sensitivity of breast cancer is confirmed in the current START trial involving 4451 UK women, the implications are that larger fraction sizes have no disadvantages, and perhaps significant
Table 1. Schema of Ontario trial (n = 1345) testing a 16-fraction schedule of whole breast radiotherapy over 3 weeks + 1 day against 50 Gy in 25 fractions over 5 weeks [19] Trial arm
Total dose (Gy)
Number of fractions
Fraction size (Gy)
Treatment time (weeks)
Control
50
25
2.0
5
Test arm
42.5
16
2.65
3 (+1 day)
Table 2. Schema of current START trial (n = 4551) testing alternative schedules of whole-breast radiotherapy against 50 Gy in 25 fractions [28] Trial arm
Total dose (Gy)
Number of fractions
Fraction size (Gy)
Treatment time (weeks)
Control
50
25
2.0
5
Test arm 1
39.0
13
3.0
5
Test arm 2
41.6
13
3.2
5
Control
50
25
2.0
5
Test arm
40
13
2.67
3
Trial A
Figure 2. Schema illustrating actual (for late complications and squamous carcinomas) and postulated (for breast cancer) differences in responses to radiotherapy fraction size. As fraction size increases above 2 Gy, the nonlinear contribution becomes relatively more important for breast than squamous carcinomas.
Trial B
Downloaded from http://annonc.oxfordjournals.org/ at University of Otago Science Library on July 21, 2015
response / aD+bD2, where a and b are constants and D is the dose per fraction (Figure 1) [12]. The relationship is approximately linear at low fraction sizes (radiation response / D), but is upwardly bending at higher doses (response / D2). The classical assumption is that human tumours are relatively insensitive to radiotherapy fraction size compared with late-reacting normal tissues (Figure 2). This means that as fraction size increases above 2 Gy, tumour responses increase relatively more slowly than late normal tissue responses. This assumption is consistent with the responses of animal tumours and human squamous carcinomas at several primary sites [13–15]. The implication for radio_ 2 Gy minimise the level of late therapy is that fraction sizes < normal tissue injury for a given level of antitumour effect when, as usual, late normal tissue responses are dose-limiting. The hypothesis under discussion is that breast cancer may be more sensitive to fraction size than previously assumed on the basis of responses of squamous carcinomas. If true, the implications would be that fraction sizes >2 Gy would not necessarily be disadvantageous, and may have clear advantages in radiotherapy for primary breast cancer. The a/b value [units are Gray (Gy)] in the linear quadratic model is an empirical descriptor of sensitivity to fraction size. Values of a/b in the range 1–6 Gy are typical of tissues sensitive to fraction size, where the quadratic component (response
ii172 Table 3. Schema of current FAST trial (n = 900) testing a once-weekly five-fraction schedule of whole-breast radiotherapy against 50 Gy in 25 fractions delivered using three-dimensional dose compensation Trial arm
Total dose (Gy)
Number of fractions
Fraction size (Gy)
Treatment time (weeks)
Control
50
25
2.0
5
Test arm 1
30
5
6.0
5
Test arm 2
28.5
5
5.7
5
Figure 3. Schema of proposed IMPORT trial evaluating modulation of fraction size across the breast (‘concomitant boost’) compared with standard dose escalation techniques (‘sequential boost’).
Downloaded from http://annonc.oxfordjournals.org/ at University of Otago Science Library on July 21, 2015
advantages, for women with primary breast cancer (Table 2). Since it is unlikely that 13-, 15- or 16-fraction schedules would represent the limit of what might be achieved, further studies are justified to test the limits of hypofractionation (use of fraction sizes >2 Gy) in breast cancer. Testing hypofractionation is an expanding research area. For example, once-weekly fractions of 6 Gy are predicted to be equivalent to five once-daily fractions of 2 Gy, assuming a/b values of 3 Gy [12]. This estimate is based on late human skin reactions (telangiectasia), which vary with fraction size and total dose in a way predicted accurately by the linearquadratic model [21, 22]. However, there is very limited experience of large fraction sizes in the context of curative breast cancer radiotherapy. Six fractions of 6.5 Gy over 6 weeks to the whole breast or chest wall using tangential megavoltage fields were evaluated in a series of 84 patients followed up for 36–94 months at Guildford, UK [23]. Acute skin reactions were reportedly mild, and only one out of 36 patients treated to whole breast developed a severe delayed skin reaction. In a recent French study, 152 women were treated with five fractions of 6.5 Gy over 5 weeks, with three local relapses at a median follow up of >5 years, but there were no comments on normal tissue responses [24]. Randomised clinical trials are needed to formally test the safety of this approach prior to evaluating efficacy (tumour control) in a large trial. This forms the background to the current UK FAST trial (n = 900) testing 50 Gy in 25 fractions of wholebreast radiotherapy against two dose levels of a five-fraction schedule delivered over 5 weeks (5.7 or 6 Gy per fraction) using full dose compensation (Table 3). The primary end point is late normal tissue response in the breast. If 3-year data are encouraging, a large phase III trial is planned in order to evaluate local tumour control, quality of life and health economic consequences. Hypofractionation lends itself to acceleration, taking advantage of the relative sparing of early skin reactions as fraction size increases and the absence of a significant time dependency for late adverse effects. Tumour repopulation has recently been tested as a determinant of treatment outcome in the context of adjuvant systemic therapy. In a randomised comparison of conventional 3-weekly schedules of doxorubicin and cyclophosphamide with the same chemotherapy doses given at 2-weekly intervals (using growth factors to accelerate marrow recovery), the hazard ratios for disease-free and overall survival associated with 2-weekly chemotherapy were 0.74 (P = 0.01) and 0.69 (P = 0.01), respectively, in 2005 patients
[25]. Recent reports of accelerated radiotherapy fractionation in head and neck cancer indicate that very modest shortening of treatment has a detectable impact on local control. In a trial of 1476 patients randomised to five (control arm) or six (test arm) fractions per week of conventional radiotherapy, local tumour control in the test arm was 76% patients compared with 64% in the control group [26]. In this study, shortening treatment by only 7 days was associated with a 12% absolute reduction in local recurrence at the primary site, a reduction in the odds of recurrence of 16%. The possible implications for primary breast cancer are that modest reductions in treatment time may translate into worthwhile gains in tumour control without enhanced late normal tissue injuries. If the predicted late adverse effects of once-weekly 5.7–6 Gy fraction sizes are confirmed in the proposed FAST trial, it will encourage future evaluation of accelerated hypofractionation. At this stage, studies are underway evaluating the early and late normal tissue responses of 30 Gy in five fractions of 6 Gy delivered over 15 days, and the evaluation of a 5-day regimen is being considered. Finally, the implications of advanced radiotherapy techniques for delivering the biological advantages of hypofractionation are worth considering. Rather than increase dose intensity by increasing the number of 2 Gy fractions, it creates opportunities for escalating dose intensity by modulating fraction size across the breast. Even if the fractionation sensitivity of breast cancer is not quite as great as the normal tissues of the breast, the shorter overall treatment times needed to deliver concomitant boost using intensity modulated radiotherapy could be advantageous if tumour proliferation is a significant determinant of local control [27]. The implications of doseescalated, intensity-modulated radiotherapy are to be tested in the proposed UK IMPORT HIGH trial. The hypothesis is that higher doses per fraction to high-risk areas and lower fraction sizes to low-risk areas of the breast will offer a clinically superior and cost-effective approach of matching dose intensity to tumour recurrence risk compared with standard sequential boost techniques (Figure 3).
ii173 In conclusion, future prospects for exploiting the biology of hypofractionation in breast cancer using advanced radiotherapy technologies look bright, including a possibility of testing five-fraction, 5-day schedules of dose-escalated, intensitymodulated radiotherapy by the end of the decade.
References
Downloaded from http://annonc.oxfordjournals.org/ at University of Otago Science Library on July 21, 2015
1. EBCTCG. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists Collaborative Group. Lancet 2000; 355: 1757–1770. 2. Whelan TJ, Julian J, Wright J et al. Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis. J Clin Oncol 2000; 18: 1220–1229. 3. Vinh-Hung V, Verschraegen C. Breast-conserving surgery with or without radiotherapy: pooled-analysis for risks of ipsilateral breast tumor recurrence and mortality. J Natl Cancer Inst 2004; 96: 115 –121. 4. Holland R, Veling SH, Mravunac M, Hendriks JH. Histologic multifocality of Tis, T1-2 breast carcinomas. Implications for clinical trials of breast-conserving surgery. Cancer 1985; 56: 979–990. 5. Fisher B, Anderson S, Redmond CK et al. Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1995; 333: 1456–1461. 6. Veronesi U, Marubini E, Mariani L et al. Radiotherapy after breastconserving surgery in small breast carcinoma: long-term results of a randomized trial. Ann Oncol 2001; 12: 997– 1003. 7. Smith TE, Lee D, Turner BC et al. True recurrence vs. new primary ipsilateral breast tumor relapse: an analysis of clinical and pathologic differences and their implications in natural history, prognoses, and therapeutic management. Int J Radiat Oncol Biol Phys 2000; 48: 1281–1289. 8. Vicini FA, Chen PY, Fraile M et al. Low-dose-rate brachytherapy as the sole radiation modality in the management of patients with earlystage breast cancer treated with breast-conserving therapy: preliminary results of a pilot trial. Int J Radiat Oncol Biol Phys 1997; 38: 301 –310. 9. Perera F, Yu E, Engel J et al. Patterns of breast recurrence in a pilot study of brachytherapy confined to the lumpectomy site for early breast cancer with six years’ minimum follow-up. Int J Radiat Oncol Biol Phys 2003; 57: 1239–1246. 10. Vaidya JS et al. Intra-operative breast radiation: the targeted intraoperative radiotherapy (Targit) trial. Breast Cancer Res Treat 2003; 82: S2. 11. Veronesi U, Orecchia R, Luini A et al. A preliminary report of intraoperative radiotherapy (IORT) in limited-stage breast cancers that are conservatively treated. Eur J Cancer 2001; 37: 2178–2183. 12. Jones B, Dale RG, Deehan C et al. The role of biologically effective dose (BED) in clinical oncology. Clin Oncol (R Coll Radiol) 2001; 13: 71–81.
13. Yarnold JR et al. Fraction Sensitivity of Change in Breast Appearance after Radiotherapy for Early Breast Cancer: Long-term Results of a Randomised Trial. Czech Republic: Praha 2002; S25. 14. Thames HD, Hendry JH, Moore JV et al. The high steepness of dose–response curves for late-responding normal tissues. Radiother Oncol 1989; 15: 49–53. 15. Thames HD, Bentzen SM, Turesson I et al. Time–dose factors in radiotherapy: a review of the human data. Radiother Oncol 1990; 19: 219–235. 16. Douglas BG. Superfractionation: its rationale and anticipated benefits. Int J Radiat Oncol Biol Phys 1982; 8: 1143– 1153. 17. Cohen L. Radiotherapy in breast cancer I. The dose-time relationship theoretical considerations. Br J Radiol 1952; 25: 636–642. 18. Owen JR et al. Fractionation sensitivity of breast cancer: results of a randomised trial. Eur J Oncol Suppl 2003; S9. 19. Whelan T, MacKenzie R, Julian J et al. Randomized trial of breast irradiation schedules after lumpectomy for women with lymph nodenegative breast cancer. J Natl Cancer Inst 2002; 94: 1143–1150. 20. Brenner DJ, Hall EJ. Fractionation and protraction for radiotherapy of prostate carcinoma. Int J Radiat Oncol Biol Phys 1999; 43: 1095–1101. 21. Turesson I, Thames HD. Repair capacity and kinetics of human skin during fractionated radiotherapy: erythema, desquamation, and telangiectasia after 3 and 5 years’ follow-up. Radiother Oncol 1989; 15: 169–188. 22. Turesson I. The progression rate of late radiation effects in normal tissue and its impact on dose-response relationships. Radiother Oncol 1989; 15: 217–226. 23. Rostom AY, Pradhan DG, White WF. Once weekly irradiation in breast cancer. Int J Radiat Oncol Biol Phys 1987; 13: 551 –555. 24. de Lafontan B et al. Loco-regional relapses and survival after breastconserving surgery and hypofractionated radiation therapy in elderly women with invasive breast cancer. Breast Cancer Res Treat 2003; 82 (Suppl 1): S38. 25. Citron ML, Berry DA, Cirrincione C et al. Randomized trial of dosedense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003; 21: 1431–1439. 26. Overgaard J, Hansen HS, Specht L et al. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial. Lancet 2003; 362: 933–940. 27. Rew DA, Wilson GD. Cell production rates in human tissues and tumours and their significance. Part 1: an introduction to the techniques of measurement and their limitations. Eur J Surg Oncol 2000; 26: 227–238. 28. Winfield E, Deighton A, Venables K et al. Survey of UK breast radiotherapy techniques: background prior to the introduction of the quality assurance programme for the START (standardisation of radiotherapy) trial in breast cancer. Clin Oncol (R Coll Radiol) 2002; 14: 267–271.