Accelerated Radiotherapy after Breast-Conserving Surgery for Early Stage Breast Cancer
Executive Summary
Background
Radiation therapy is the standard care for patients undergoing breast-conserving surgery, as an individual-level meta-analysis based on multiple randomized, controlled trials shows that such therapy reduces recurrences and lengthens survival. The conventional radiation therapy regimen consists of about 25 treatments of 2 Gray (Gy; a measure of absorbed radiation dose), each delivered over 5 to 6 weeks. Not all patients undergo radiation therapy following breast-conserving surgery. The duration and logistics of treatment may be barriers to some women. Therefore, several accelerated radiotherapy approaches have been proposed to make the regimen less burdensome.
*Accelerated (also called “hypofractionated”) whole-breast irradiation reduces the number of fractions and the duration of treatment to about 3 weeks. This approach has been commonly used in Canada and Europe.
*Accelerated partial-breast irradiation (APBI) irradiates a limited part of the breast in and close to the tumor cavity. By reducing the area irradiated, fewer treatments are needed and the total treatment takes about 1 week. Several approaches can be used to deliver APBI, including interstitial brachytherapy, balloon brachytherapy, external beam, or intraoperative (which occurs on only 1 day) radiation.
Objective
To evaluate the outcomes, particularly local recurrence, of 2 accelerated alternatives to conventional whole-breast radiotherapy after breast-conserving surgery (BCS): 1) accelerated, hypofractionated, whole-breast irradiation therapy; and 2) accelerated, partial-breast irradiation (APBI) therapy.
Search Strategy
To update the literature, a search was performed on MEDLINE® and Embase™ in May 2012 using the following strategy: “accelerated whole breast irradiation” OR (hypofractionated AND (radiotherapy OR “radiation therapy” OR irradiation) AND breast). For accelerated partial-breast irradiation, searches were performed on MEDLINE® and Embase™ in late April 2012, using the same terms listed in the literature search cited in the consensus statement of the American Society of Radiation Oncology (ASTRO).
Selection Criteria
All comparative English-language articles in peer-reviewed journals on accelerated radiotherapy following breast-conserving surgery were included. Uncontrolled (i.e., single-arm) studies were excluded, because indirect comparisons in this setting are not reliable. Initial patient differences may account for perceived differences in treatment outcomes; they cannot be controlled for adequately to ensure the validity of the conclusions. Abstracts were excluded.
Main Results
Accelerated Whole-breast Irradiation. Four randomized, controlled trials compared accelerated whole-breast radiotherapy to 5-week whole-breast radiotherapy and 2 nonrandomized studies. Three of the 4 randomized trials are rated good quality using the modified U.S. Preventive Services Task Force criteria; the fourth trial was rated fair, and the nonrandomized studies, poor. Two of the studies are particularly useful, as they directly compared a 5-week to a 3-week regimen. They are both prospectively designed, noninferiority trials. Both trials accepted a maximum loss of efficacy of 5 percentage points in the accelerated group (one-sided α=0.025 or 0.05). Although the studies differ in the specific fractionation schedules and patient characteristics, they report no difference in local recurrence rates (i.e., recurrence of the cancer in the same breast) across treatment arms.
One study from the U.K. includes women with grade 1–3 tumors. About 75% of the women had negative lymph nodes, and about 42% had a radiation boost to the tumor bed. Randomization was stratified for hospital, type of surgery (about 15% had a mastectomy), and plans for tumor bed boost. Systemic therapy, primarily tamoxifen, was used by some patients and appears to be fairly evenly distributed across treatment groups. The treatment arms compared a total dose of 40 Gy in 15 fractions over 3 weeks to 50 Gy in 25 fractions over 5 weeks. The hazard ratios for 40 Gy accelerated whole-breast radiotherapy versus conventional whole-breast radiotherapy were not statistically significant (using the log-rank test) for local or locoregional relapse. The absolute difference in locoregional relapse rates was −0.7% (95% CI: −1.7%, 0.9%). There were statistically significant differences in the 2 treatment regimens for distant relapse and overall survival, with relapse more frequent and survival longer for the 40 Gy accelerated whole-breast irradiation. This unexpected difference between treatment arms began to appear at about 1 year. The authors speculate that it could be due to chance and might change with longer follow-up. The 6-year follow-up period on this trial is too short to reach firm conclusions; follow-up continues.
The second randomized, controlled trial from Canada compared accelerated whole-breast irradiation versus whole-breast irradiation. Of 2,429 eligible patients, 51% agreed to participate in the trial. Intention-to-treat analysis was used. The 10-year local recurrence was 6.2% for the 42.5 Gy arm accelerated whole-breast irradiation arm and 6.7% for the conventional 50 Gy whole-breast irradiation arm (absolute difference: −0.5%; 95% CI: −2.5%, 3.5%). Local recurrence rates with accelerated whole-breast radiotherapy were not worse than conventional whole-breast irradiation, when applying a noninferiority margin of 5%. In “exploratory” subgroup analyses, treatment effects were similar by age, tumor size, estrogen-receptor status, and chemotherapy use (48% had no systemic therapy). However, local recurrence at 10 years for patients with high-grade tumors was 4.7% for the conventional whole-breast irradiation arm and 15.6% for the 42.5 Gy accelerated whole-breast irradiation arm. The absolute difference equals −10.9 percentage points (95% CI: −19.1, −2.8, p=0.01).
The patients in this trial all had invasive carcinoma of the breast with negative lymph nodes and surgical margins, and they did not have a radiotherapy boost to the tumor site. Exclusion criteria for the trial were “invasive disease or ductal carcinoma in situ involving the margins of excision, tumors that were larger than 5 cm in diameter, and a breast width of more than 25 cm at the posterior border of the medial and lateral tangential beams, which could increase the heterogeneity of the radiation dose to the breast.” In the trial, lymph node status was determined by axillary dissection, but recent reports suggest that sentinel lymph node biopsy is likely to be as effective.
The overall body of evidence on accelerated whole-breast irradiation compared to conventional whole-breast irradiation suggests local recurrence rates with accelerated whole-breast radiotherapy were not worse than conventional whole-breast irradiation in patients meeting the criteria of the Canadian trial, when applying a noninferiority margin of 5%. Longer follow-up is needed for the U.K. trial.
Accelerated Partial-breast Irradiation. There are 2 randomized trials on interstitial, accelerated, partial-breast irradiation compared to conventional whole-breast irradiation, a pragmatic randomized trial on intraoperative radiotherapy compared to whole-breast external radiotherapy, and 8 nonrandomized, comparative studies. Ten of the studies focused on interstitial brachytherapy; and one, on intraoperative radiotherapy. Quality of the 2 randomized trials on interstitial brachytherapy was rated as poor. For the first, accrual was stopped before reaching the goal specified to evaluate differences in local recurrence, to allow patients to participate in another trial. The randomization process was unclear; patients deemed “technically unsuitable” for interstitial brachytherapy were given external-beam APBI, and the patient characteristics and outcomes for each type of APBI were not reported separately. Finally, the sample size of 126 was small, and the longest follow-up reported was 66 months. Similar local and regional failure rates were found in the treatment arms.
The other randomized, controlled trial on APBI was reported in 1990 and 1993, and many changes in the care of breast cancer have occurred since then. The study was rated as poor because nodal status was based on clinical exam, among other factors. Recurrence was higher for the “limited field” treatment arm (analogous to partial-breast irradiation) than for the “wide field” arm (analogous to whole-breast irradiation), but some of the “excess” recurrences in the limited field arm were axillary. This may be accounted for by the fact that the axillary area was included in the wide field radiotherapy, but not in the limited field, and the initial work-up for nodal involvement was limited. The follow-up was 65 months, and the sample size 708.
The fair quality randomized trial compared intraoperative to external-beam accelerated partial-breast irradiation. It is a noninferiority trial with 28 centers in 9 countries and a sample size of 2,232. An intention-to-treat (ITT) approach was used; 89% of the intraoperative group and 92% of the external radiotherapy group completed treatment. Patients were not blinded to treatment choice. As anticipated in advance, 14% of those in the intraoperative arm received external-beam radiotherapy as well, because of unfavorable pathologic features determined after surgery, e.g., lobular carcinoma. The predefined noninferiority margin was an absolute difference of 2.5% between groups for pathologically confirmed, ipsilateral local recurrence. After 4 years, wound seroma needing more than 3 aspirations was significantly more common in the intraoperative group than in the external radiotherapy group (2.1% vs. 0.8%, respectively; p=0.012). Conversely, Radiation Therapy Oncology Group (RTOG) toxicity grade of 3 or 4 was more common in the external radiotherapy group than in the intraoperative group (2.1% vs. 0.5%, respectively; p=0.002). The 4-year local recurrence rates in the ipsilateral breast were 1.20% (95% CI: 0.53%, 2.71%) in the intraoperative radiotherapy arm vs. 0.95% (95% CI: 0.39%, 2.31%) in the external radiotherapy arm (difference between groups=0.25%, 95% CI: -1.04%, 1.54%; log-rank test, p=0.41). Local recurrence rates after 4 years with intraoperative radiotherapy were not worse than with external irradiation, when applying a noninferiority margin of 2.5%. Fortunately for the patients, the recurrence rates are low: 6 in the intraoperative group versus 5 in the external radiotherapy group. But these small numbers make it more difficult to detect real differences between arms, if they exist.
A number of reviews and editorials discussed the preliminary results of the TARGIT-A trial. While recognizing the potential benefits of intraoperative radiotherapy (IORT), including convenience, “excellent delineation of the tumour bed under visual control, very good dose homogeneity, and high sparing of normal tissue,” a number of concerns have been expressed. They include the following:
*If IORT is performed during the surgery to excise the tumor, the definitive pathology is not available when the radiotherapy is performed. Therefore, a subset of patients must undergo whole-breast external beam radiotherapy as well following surgery. The article reports that 14% of patients in the IORT arm also received whole-breast external-beam radiotherapy. When only those who received IORT during initial surgery are considered, 21% received whole-breast external-beam radiotherapy. There are limited data suggesting that breast symptoms and pain following treatment may be greater for patients receiving both IORT and whole-breast external radiotherapy compared with IORT alone and that patients’ satisfaction is greater for whole-breast external radiotherapy or IORT alone compared to the combined treatment.
*Is the radiation dose and type actually equivalent to the standard radiation therapy regimen? Of particular concern is the rapid drop in dose with distance from the applicator and whether any residual disease will eradiated. Some argue that the TARGIT-A trial alleviates this concern, while others do not.
*The length of follow-up is insufficient to determine long-term toxicity and efficacy, particularly since only 19% of the participants in the TARGIT-A trial completed 4 years of follow-up. The median follow-up is not reported but appears to be around 2 years.
While the INTRABEAM® device used in this trial is subject to U.S. Food and Drug Administration (FDA) regulation, it does not fall under the regulatory purview of the U.S. Nuclear Regulatory Commission. In some states, the participation of radiation oncologists in delivering radiation is not required.
The other 8 nonrandomized, comparative studies were all rated as poor, due to potential baseline differences in treatment groups, lack of multivariable analyses to account for them, inclusion of patients who did not meet eligibility criteria, variations in treatment within arms, and generally small sample sizes and insufficient follow-up.
Overall, the body of evidence on interstitial and intraoperative APBI compared to conventional whole-breast irradiation is insufficient, and there are no comparative studies for external-beam or balloon APBI.
Author’s Conclusions and Comments
Accelerated Whole-breast Irradiation. The evidence suggests that accelerated whole-breast irradiation provides a reasonable, shorter alternative to conventional whole-breast irradiation among women who had breast-conserving surgery and are at low risk of recurrence. In a Canadian trial, the 10-year local recurrence was 6.2% for the 42.5 Gy accelerated whole-breast irradiation arm and 6.7% for the conventional whole-breast irradiation arm (absolute difference: −0.5%, 95% CI: −2.5%, 3.5%). Accelerated whole-breast irradiation cuts the radiotherapy treatment time by about 40% without any apparent negative consequences after 10 years of follow-up. The results should be interpreted in the context of a noninferiority design with a margin of 5%.
Patient selection is key, and at this point, only patients similar to those in the Canadian trial should be considered for this therapy. Outcomes could vary in women with other disease characteristics. The patients in this trial all had invasive carcinoma of the breast with negative lymph nodes and surgical margins. Exclusion criteria for the trial included “invasive disease or ductal carcinoma in situ involving the margins of excision, tumors that were larger than 5 cm in diameter, and a breast width of more than 25 cm at the posterior border of the medial and lateral tangential beams, which could increase the heterogeneity of the radiation dose to the breast.” In the trial, lymph node status was determined by axillary dissection, but recent reports suggest that sentinel lymph node biopsy is likely to be as effective. Forty-one percent of the women took tamoxifen, despite the fact that 71% had estrogen-receptor positive tumors.
While the current evidence on this radiotherapy regimen is convincing, it is not as compelling as that for conventional whole-breast irradiation. Additional randomized, controlled trials or longer follow-up of the existing trials could uncover additional concerns. Some potential adverse events, such as cardiac ischemia, may take longer to become evident. This regimen has been widely used outside the U.S. without substantial reports of major adverse events. Potential patients should be carefully selected and should make a decision with their physicians based on full information, while the results of longer follow-up for the START B trial are awaited.
Accelerated Partial-breast Irradiation. The data on APBI compared to whole-breast irradiation are insufficient to draw any conclusions about the relative effectiveness of these modalities. Furthermore, it is becoming increasingly clear that each type of APBI should be judged on its own merits, and studies comparing different APBI techniques to each other as well as to whole-breast irradiation are needed. Fortunately, a number of large randomized, controlled trials are underway. Given the current level of evidence, it is important for patients to be well-informed about the uncertainty regarding the outcomes of this approach. This information should include failure rates for the specific devices (e.g., explantation for MammoSite™, incomplete expansion of the catheters for some of the hybrid devices), as well as the uncertainty regarding their comparative effectiveness. Accelerated whole-breast irradiation may present an intermediate alternative for women who meet the criteria for the Canadian trial, and the critical importance of completing radiotherapy for the majority of patients undergoing breast-conserving surgery deserves emphasis.
In a 2009 review of the APBI trials currently underway, Mannino and Yarnold (note Yarnold is a lead author on the START A and B trials) raise several concerns regarding variations across the trials. The extent of the initial breast-conserving surgery can vary substantially across studies, as well as the definition of the targeted tumor cavity. A larger margin is usually drawn around the tumor cavity for 3D conformal radiotherapy, for example, because of the need to allow for variations in set-up and respiration motion. Studies of APBI usually distinguish between “same site relapse,” i.e., close to the irradiated area and elsewhere relapse, yet it is unclear whether what constitutes the same site varies across studies. The percentage of relapses occurring “elsewhere” in the ipsilateral breast in studies of whole-breast radiotherapy following breast-conserving surgery range from 18% to 42% (these studies may include some patients at higher risk of recurrence). Proponents of APBI have sometimes asserted that “elsewhere” tumors are rare, that they are mostly new primary tumors (rather than a recurrence), or that earlier studies have shown that radiotherapy is not effective on these tumors in any case. Mannino and Yarnold challenge each of these points in turn, although they also conclude that the results of the trials currently underway will provide level 1 evidence for or against APBI.
Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel made the following judgments about whether accelerated radiotherapy meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria to decrease recurrence and reduce treatment sequelae after breast-conserving surgery for early stage breast cancer.
1. The technology must have final approval from the appropriate governmental regulatory bodies.
The various radiotherapy modalities presented in this Assessment have been approved or cleared for marketing by the U.S. Food and Drug Administration (FDA). The brachytherapy and intraoperative devices, however, contain a black box warning required by the FDA indicating that “The safety and effectiveness of the … [device] as a replacement for whole-breast irradiation in the treatment of breast cancer has not been established.”
2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.
Accelerated Whole-breast Irradiation. Two randomized, controlled trials rated as good quality with over 3,000 participants compared accelerated and conventional whole-breast irradiation. Local recurrence rates with accelerated whole-breast radiotherapy were not worse than conventional whole breast irradiation, when applying a noninferiority margin of 5%. Follow-up for one study was 6 years, which is insufficient; results of longer follow-up are being collected. The follow- up period for the other study, however, was 12 years, with 10-year recurrence rates reported. This time period is sufficient to gauge the relative outcomes of these two treatment approaches. However, these results only apply to women similar to those in the Canadian trial, who had invasive carcinoma of the breast with negative lymph nodes and surgical margins. Exclusion criteria for the trial included “invasive disease or ductal carcinoma in situ involving the margins of excision, tumors that were larger than 5 cm in diameter, and a breast width of more than 25 cm at the posterior border of the medial and lateral tangential beams, which could increase the heterogeneity of the radiation dose to the breast.” In the trial, lymph node status was determined by axillary dissection, but recent reports suggest that sentinel lymph node biopsy is likely to be as effective.
Accelerated Partial-breast Irradiation. Two poor quality randomized trials; one fair quality randomized trial; and 8 poor quality nonrandomized, comparative studies on APBI compared to conventional whole-breast radiotherapy were found. Ten of the studies focused on interstitial brachytherapy; and one, on intraoperative radiotherapy. They are insufficient to permit conclusions concerning the effect of interstitial or intraoperative brachytherapy on health outcomes. No comparative studies were found on external-beam or balloon APBI, and thus the evidence on these modalities is insufficient as well.
3. The technology must improve the net health outcome.
Accelerated Whole-breast Irradiation. Indirect evidence is available on the impact of accelerated whole-breast irradiation on the net health outcome. A number of trials and individual-level meta-analyses have demonstrated that the use of radiation therapy after breast-conserving therapy reduces recurrence and improves survival. In the Canadian trial, local recurrence rates with accelerated whole-breast radiotherapy were not worse than conventional whole-breast irradiation, when applying a noninferiority margin of 5%. Therefore, the available evidence suggests that accelerated whole-breast irradiation also improves the net health outcome compared to no radiotherapy for women who meet the criteria for Canadian clinical trial (i.e., invasive carcinoma of the breast with negative lymph nodes and surgical margins).
Accelerated Partial-breast Irradiation. Since available evidence is insufficient to permit conclusions regarding the equivalence of APBI and conventional whole-breast irradiation and since APBI has not and cannot ethically be compared to using no radiation therapy after breast-conserving surgery, it cannot be determined whether accelerated radiotherapy improves the net health outcome.
4. The technology must be as beneficial as any established alternatives.
Accelerated Whole-breast Irradiation. Evidence is available that accelerated whole-breast irradiation is not worse than the longer whole-breast regimen, when applying a noninferiority margin of 5%. With treatment duration of 3 weeks rather than 5 weeks, it is more convenient and less taxing for patients and may improve adherence with the standard of care that women undergo radiation therapy following breast-conserving surgery.
Accelerated Partial-breast Irradiation. Since available evidence is insufficient to permit conclusions, it cannot be determined whether accelerated partial-breast irradiation is as beneficial as whole-breast, standard radiotherapy after breast-conserving surgery for early stage breast cancer. Longer follow-up—ideally in randomized controlled trials, several of which are underway for APBI—is needed to ascertain whether accelerated radiotherapy is as beneficial as the current standard of care.
5. The improvement must be attainable outside the investigational settings.
Accelerated Whole-breast Irradiation. The 2 major studies on accelerated whole-breast irradiation were large, multicenter trials conducted at 10 sites in Canada and 23 sites in the U.K. These results should be attainable outside investigational settings.
Accelerated Partial-breast Irradiation. Whether accelerated partial-breast radiotherapy improves health outcomes after breast-conserving surgery for early stage breast cancer has not been demonstrated in the investigational setting.
Based on the above, accelerated whole-breast radiotherapy after breast-conserving surgery for early stage breast cancer meets the TEC criteria for women who meet the entry criteria for the Canadian trial (i.e., invasive carcinoma of the breast with negative lymph nodes and technically clear surgical margins; exclusion criteria for the trial included “invasive disease or ductal carcinoma in situ involving the margins of excision, tumors that were larger than 5 cm in diameter, and a breast width of more than 25 cm at the posterior border of the medial and lateral tangential beams, which could increase the heterogeneity of the radiation dose to the breast”). Accelerated partial-breast radiotherapy after breast-conserving surgery for early stage breast cancer does not meet the TEC criteria.
Full Study
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adjuvant; APBI; axilla; Axxent; BCT; boost; brachytherapy; breast cancer; breast carcinoma; breast-conserving therapy; catheter; ClearPath; conformal radiation; conservation; distant recurrence; Early Breast Cancer Trialists’ Collaborative Group; early stage; EB; hypofractionated; implantation; interstitial; intraoperative; IORT; ipsilateral; iridium; local recurrence; lumpectomy; lymph node, intracavitary; MammoSite; multicatheter; multi-catheter; partial breast irradiation; partial mastectomy; quadrantectomy; radiation; radiotherapy; SAVI; SenoRad; WBRT; Xoft;
