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, which 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), which 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).
Objective
To evaluate the outcomes, particularly local recurrence, of 2 accelerated alternatives to conventional whole-breast radiotherapy after breast-conserving surgery: 1) accelerated, hypofractionated, whole-breast irradiation therapy; 2) accelerated, partial-breast irradiation (APBI) therapy.
Search Strategy
For accelerated whole-breast irradiation, papers from the 2007 TEC Assessment were supplemented by those identified in the recent California Technology Assessment Forum report on this technology, as well as reference lists and review articles. For accelerated partial-breast irradiation, a MEDLINE® search was performed in September 2009, using the same terms listed in the literature search cited in the consensus statement of the American Society of Radiation Oncology (ASTRO). Abbreviated searches to update the literature were performed in February 2010.
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, unless copies of the slide presentation used at a national professional meeting could be obtained or the abstracts provided follow-up data for a previously published comparative article that described the study in detail.
Main Results
Accelerated Whole-Breast Irradiation. Four randomized, controlled trials compared accelerated whole-breast radiotherapy to 5-week whole-breast radiotherapy, as well as a fifth, older, nonrandomized study. Three of the 4 trials are rated good quality using the modified U.S. Preventive Services Task Force criteria; the fourth trial was rated fair, and the nonrandomized study, 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 local or locoregional recurrence in the accelerated group at 5 or 10 years (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 appeared 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 after 5 years 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 (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, test for interaction, 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 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.
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, controlled trials on interstitial or external-beam, accelerated, partial-breast irradiation (APBI) compared to conventional whole-breast irradiation, as well as 7 nonrandomized, comparative studies. All of these studies evaluated interstitial or external brachytherapy; no published comparative studies were found that assessed balloon brachytherapy or intraoperative APBI. Quality of both trials 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 relatively small, and 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 the initial groups were potentially unbalanced and 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 other 7 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 APBI compared to conventional whole-breast irradiation is weak, and it is extremely weak (i.e., no comparative studies) for balloon brachytherapy, intraoperative APBI, and external-beam APBI.
Authors' 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%. In "exploratory" subgroup analyses, treatment effects were similar by age, tumor size, estrogen-receptor status, and chemotherapy use. 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; test for interaction: p=0.01).
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, and they did not have a radiotherapy boost to the tumor site. 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 received tamoxifen, despite the fact that 71% had disease that was shown to be estrogen-receptor positive.
Patients selecting this accelerated whole-breast radiotherapy should be told that while the current evidence on this radiotherapy regimen is solid, it is not as strong 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 given 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 aware of 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. The intermediate alternative provided by accelerated whole-breast irradiation should also be presented to women who meet the criteria for the Canadian trial, as well as the critical importance of completing radiotherapy for the majority of patients undergoing breast-conserving surgery.
In a 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-CRT, 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.
Summary of Application of the Technology Evaluation Criteria
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 devices, however, contain a black box warning required by the FDA indicating that "The safety and effectiveness of the … [brachytherapy 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, and they did not have a radiotherapy boost to the tumor site. 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, controlled trials and 7 poor quality nonrandomized, comparative studies on interstitial APBI compared to conventional whole-breast radiotherapy were found. They are insufficient to permit conclusions concerning the effect of interstitial brachytherapy on health outcomes. No comparative studies were found on balloon brachytherapy, external-beam APBI, or intraoperative APBI, and thus the evidence on these modalities are 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 meet the criteria for Canadian clinical trial (i.e., invasive carcinoma of the breast with negative lymph nodes and surgical margins, and no radiotherapy boost to the tumor site).
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 up to approximately 10 years after treatment.
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 surgical margins, and no radiotherapy boost to the tumor site; 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
Accelerated Radiotherapy After Breast-Conserving Surgery for Early Stage Breast Cancer
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accelerated; adjuvant; APBI; ASTRO; axilla; Axxent; BCT; boost; brachytherapy; breast cancer; breast carcinoma; breast-conserving therapy; catheter; ClearPath; conformal radiation; conservation; cosmesis; distant recurrence; dose fractionation; Early Breast Cancer Trialists??? Collaborative Group; early stage; EB; fraction; fractionation; hypofractionated; hypofractionation; implantation; interstitial; intraoperative; IORT; ipsilateral; iridium; irradiation; local recurrence; lumpectomy; lymph node, intracavitary; MammoSite; multicatheter; multi-catheter; partial breast irradiation; partial mastectomy; quadrantectomy; radiation; radiotherapy; SAVI; SenoRad; START A; START B; WBRT; whole breast; whole-breast; wide-field; Xoft;
