Lancet 2017-09-09
Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial.
Abstract
Background
Local cancer relapse risk after breast conservation surgery followed by radiotherapy has fallen sharply in many countries, and is influenced by patient age and clinicopathological factors. We hypothesise that partial-breast radiotherapy restricted to the vicinity of the original tumour in women at lower than average risk of local relapse will improve the balance of beneficial versus adverse effects compared with whole-breast radiotherapy.
Methods
IMPORT LOW is a multicentre, randomised, controlled, phase 3, non-inferiority trial done in 30 radiotherapy centres in the UK. Women aged 50 years or older who had undergone breast-conserving surgery for unifocal invasive ductal adenocarcinoma of grade 1-3, with a tumour size of 3 cm or less (pT1-2), none to three positive axillary nodes (pN0-1), and minimum microscopic margins of non-cancerous tissue of 2 mm or more, were recruited. Patients were randomly assigned (1:1:1) to receive 40 Gy whole-breast radiotherapy (control), 36 Gy whole-breast radiotherapy and 40 Gy to the partial breast (reduced-dose group), or 40 Gy to the partial breast only (partial-breast group) in 15 daily treatment fractions. Computer-generated random permuted blocks (mixed sizes of six and nine) were used to assign patients to groups, stratifying patients by radiotherapy treatment centre. Patients and clinicians were not masked to treatment allocation. Field-in-field intensity-modulated radiotherapy was delivered using standard tangential beams that were simply reduced in length for the partial-breast group. The primary endpoint was ipsilateral local relapse (80% power to exclude a 2·5% increase [non-inferiority margin] at 5 years for each experimental group; non-inferiority was shown if the upper limit of the two-sided 95% CI for the local relapse hazard ratio [HR] was less than 2·03), analysed by intention to treat. Safety analyses were done in all patients for whom data was available (ie, a modified intention-to-treat population). This study is registered in the ISRCTN registry, number ISRCTN12852634.
Findings
Between May 3, 2007, and Oct 5, 2010, 2018 women were recruited. Two women withdrew consent for use of their data in the analysis. 674 patients were analysed in the whole-breast radiotherapy (control) group, 673 in the reduced-dose group, and 669 in the partial-breast group. Median follow-up was 72·2 months (IQR 61·7-83·2), and 5-year estimates of local relapse cumulative incidence were 1·1% (95% CI 0·5-2·3) of patients in the control group, 0·2% (0·02-1·2) in the reduced-dose group, and 0·5% (0·2-1·4) in the partial-breast group. Estimated 5-year absolute differences in local relapse compared with the control group were -0·73% (-0·99 to 0·22) for the reduced-dose and -0·38% (-0·84 to 0·90) for the partial-breast groups. Non-inferiority can be claimed for both reduced-dose and partial-breast radiotherapy, and was confirmed by the test against the critical HR being more than 2·03 (p=0·003 for the reduced-dose group and p=0·016 for the partial-breast group, compared with the whole-breast radiotherapy group). Photographic, patient, and clinical assessments recorded similar adverse effects after reduced-dose or partial-breast radiotherapy, including two patient domains achieving statistically significantly lower adverse effects (change in breast appearance [p=0·007 for partial-breast] and breast harder or firmer [p=0·002 for reduced-dose and p<0·0001 for partial-breast]) compared with whole-breast radiotherapy.
Interpretation
We showed non-inferiority of partial-breast and reduced-dose radiotherapy compared with the standard whole-breast radiotherapy in terms of local relapse in a cohort of patients with early breast cancer, and equivalent or fewer late normal-tissue adverse effects were seen. This simple radiotherapy technique is implementable in radiotherapy centres worldwide.
Funding
Cancer Research UK.
Related Questions
How would you approach reirradiation in a patient with a history of whole-breast RT many years ago, now with a small intermediate-grade DCIS s/p lumpectomy with an elevated DCISionRT?
I would favor PBI with 40 in 15 or 45 in 30 (BID) with VMAT/IMRT.
Have the 10-year results from UK FAST-Forward impacted your practice with regard to patient selection?
I would consider our practice at Mayo as early adopters of ultra-hypofractionation for breast, largely driven by similar institutional trials for shorter courses and the patients we care for. As a result, we have pretty routinely offered 26 Gy/5 fraction whole breast RT since the 5-year follow-up wa...
Do you prefer to use the FAST or FAST-Forward regimen when treating stage I breast cancer with an ultra-hypofractionated approach?
We favor APBI like the Florence regimen but if technically not suitable, then FAST-Forward.
When do you add a third field for IMPORT-LOW style partial breast irradiation?
I don’t usually use the 3rd field and treat with min tangent with FIF to improve homogeneity. If planning to do conformal RT then prefer an APBI dose of 30 in 5 with VMAT technique.
Would you offer ultrahypofractionated 5 fraction breast radiation to a patient with lupus?
Favor partial breast over whole breast if feasible.APBI or IMPORT LOW volume and FAST-Forward dose of 26 in 5.
What rates of breast (not arm) lymphedema would you quote to patients post-lumpectomy and adjuvant radiation?
The UK trials report on breast edema and provide helpful numbers for counseling patients. For instance, in the UK IMPORT HIGH trial (hot off the press!), rates of breast edema in the sequential boost arm (40 Gy + 16 Gy boost) were 90% none, 7% mild, 2% moderate and <1% marked. In the lower SIB arm (...
Would you offer partial breast irradiation for women with G2 4cm DCIS with close margins of 1mm but a very large breast size?
Although size cut off is arbitrary, DCIS tumor size is one of the risk factors for IBTR. For large-volume DCIS like this case in question, what is not known is if a 1 to 1.5 cm CTV margin would capture all microscopic areas of disease or do we need to treat larger volumes. For that reason, I favor I...
Is a FAST regimen reasonable for re-treating a patient with PBI after prior whole breast radiation ten years ago?
May be reasonable but for now, we prefer 40 in 15 PBI using VMAT or multibeam IMRT.
If you are unable to meet V50% dose constraint for partial breast irradiation, do you revert to whole breast treatment?
I believe you are referencing the V50 constraint in 5 fraction PBI based on the uninvolved breast volume.In cases where this is the situation, I first see how much I am exceeding the criteria by, if it's not a lot, I will consider proceeding with 30/5. If it's significantly exceeded, one option I co...
Do you prefer IMRT to 3D for partial breast treatment?
Prefer IMRT for better conformity, dose homogeneity, and less dose to uninvolved breast. Lung dose is not a clinically meaningful difference.
In your experience, is a bra worn during radiation treatment for large-breasted patients ever beneficial?
I have used styrofoam wedges in the infra-mammary fold to reduce the effect of skin folds. I would suggest placing these wedges in a fixed position with markings to help reproduce the position.It's also important to realize that in order to reduce the risk of treatment-related morbidity, one can als...
How would you deliver whole breast radiotherapy in someone who cannot raise their ipsilateral arm above their head due to recent shoulder replacement surgery?
Sometimes this comes up. If related to axillary surgery, I will often send to physical therapy/breast therapy and delay simulation for a few weeks. However, there are some cases where there is a preexisting shoulder issue. In these cases, I try to have arm akimbo and will consider VMAT whole breast ...
How would you approach a morbidly obese patient with early stage favorable breast cancer who is premenopausal?
Yes, if favorable phenotype, would do APBI.
Are there any whole breast RT techniques or modifications to optimize cosmesis for patients who had prior breast augmentation?
There are various approaches one can take. If not suitable for APBI then one can do partial breast with tangent beam like IMPORT LOW which also decreases exposure of implant and can help reduce the probability of worsening of cosmetic outcome. The goal is to deliver as homogenous dose as possible wi...
When would you utilize hypofractionated partial breast irradiation (40 Gy/15 fxs)?
I have done this IMPORT LOW regimen for patients with implant in place, for patients with large seroma, or in patients where APBI is not suitable for cavity to breast ratio, or concern about set up reproducibility.
In a patient with a history of prior BCS+RT for early stage breast cancer who is now s/p repeat lumpectomy for a low risk in-breast recurrence, what dose/fractionation regimens are appropriate for reirradiation?
PBI using IMRT to 1.5 Gy BID to 45 Gy like phase 2 RTOG.If declines, can do once a day conventional fractionation to 45-50.4 Gy.
In a patient with favorable risk pT1N0(mic/i+) breast cancer and favorable anatomy, would you use IMPORT-LOW style PBI while incorporating the high axilla?
For N0(i+), PBI is appropriate, I would not include axilla. 40/15, 30/5. If N1mic, would not use PBI but would favor WBI, high tangents if ER+, RNI if ER-.
What early stage breast cancer patients would you give IOeRT?
I think given data from ELIOT update (11% LR with electron IORT vs. 2% WBI) and the TARGIT-A update, there is a limited role for IORT as monotherapy at this time, particularly when options like 5 fx PBI and 5 fx WBI are now possible. The ABS guidelines do not recommend either IORT technique which is...
What lung constraints do you use for early stage breast hypofractionation?
The rationale for monitoring/constraining the ipsilateral lung is to avoid symptomatic radiation pneumonitis. That being said, I don't know if I have ever seen it in a patient where we are not treating nodes.Our official scorecard for whole breast conventional fractionation (40-42.56 Gy/15-16 fx) st...
For APBI, do you prefer a brachytherapy or external beam technique?
I offer a variety of PBI techniques depending on situation and patient preference.With respect to external beam, I primarily utilize a 30 Gy/5 fraction regimen delivered with VMAT (2-3 coplanar arcs). We use breath hold regardless of laterality and CBCT to reduce motion and reduce PTV expansions. Th...