Tumor Bed Boost After Whole-Breast Radiotherapy Leads to Improved Local Control
Tumor Bed Boost After Whole-Breast Radiotherapy Leads to Improved Local Control
Abstract & Commentary
Synopsis: Although there have been many published reports supporting postoperative radiation therapy to optimize local control following breast conservation surgery, a consensus regarding the optimal total dose and fractionation has not been reached. The EORTC undertook a randomized trial in women with lumpectomies for stages I or II carcinoma to determine whether a boost to the tumor cavity following whole-breast radiotherapy improved local control and survival in comparison to whole-breast treatment alone. A statistically significant benefit was identified favoring the boost arm.
Source: Bartelink H, et al. N Engl J Med. 2001;345: 1378-1387.
The european organization for research and Treatment of Cancer (EORTC) set out to determine whether a boost dose of radiation to the excision site of T1 or T2 breast cancers offered a local control and/or survival benefit to women who were candidates for breast conservation surgery. Their starting point was 50 Gy to the whole breast, based on the earlier published results from the NSABP B06 trial. They designed a randomized trial powered with a 90% probability of detecting a 5% improvement in 10-year survival. After a median follow-up of 5 years, the data monitoring committee decided to publish its first preliminary analysis of the results based on differences in local control favoring the boost arm.
Between 1989 and 1996, 5569 women in 31 centers in 9 participating European countries had lumpectomies resulting in gross total resections of tumors which were T1-2 on palpation or mammogram. There were 5318 women whose final microscopic margins were negative, 24% of whom needed a re-excision to achieve the clean margins. Ninety-nine percent of patients had an axillary dissection performed. Postoperatively, those patients with microscopically negative margins, disease limited to one quadrant, < 70 years old, with an ECOG status < 2 were enrolled in a randomized trial evaluating the effect of a 16 Gy boost on tumor control in the breast, and on survival. Patients received 50 Gy whole-breast RT in both arms, followed by the boost in the investigational arm. All tumor specimens were reviewed in a central lab. Patients were stratified by age, menopausal status, intraductal component, tumor size, nodal status, and treating center.
Median age was 55 years (r, 23-84). Sixty-two percent of patients were postmenopausal. Twenty-one percent had nonpalpable lesions. Fifty-two percent were T1 and 48% were T2. Ninety percent were node-negative. The median number of lymph nodes dissected was 12 (r, 0-49). The intention at the time of lumpectomy was to take a 1 cm margin of normal tissue around the tumor. In general, tamoxifen was given to postmenopausal node-positive patients, and adjuvant chemotherapy was administered to premenopausal node-positive patients. According to the protocol, patients were to commence radiotherapy within 9 weeks of surgery if no chemotherapy was planned, and within 6 months of surgery if chemotherapy was given.
There were 2657 women randomized to the standard treatment arm and 2661 women randomized to the boost arm. The 2 groups were demographically similar. Median time to initiation of RT was 39 days for patients not receiving chemotherapy (r, 3-156), and 52 days for patients given chemotherapy (r, 14-468). The whole-breast RT was either via linear accelerator or cobalt unit, and the boost was accomplished with electrons, tangential photon fields, or interstitial iridium-192 brachytherapy. The boost target was 1.5 cm around the tumor resection bed unless an extensive intraductal component was noted, in which case the boost margin was 3 cm. The median RT dose in the standard arm was 50 Gy (r, 2-73), and 66 Gy in the boost arm (r, 23-79). Treatment was prescribed to the isocenter of the fields.
Most patients were treated per protocol. Only 2% of patients in the standard arm received a boost, and 1% in the boost arm did not get a boost. For patients who were boosted, 63% received electrons, 27% photons, 8% interstitial, and 1% unknown. A total of 272 women were treated to the locoregional lymph nodes, either because their axilla was not dissected, or they had metastases to the highest lymph nodes dissected. There were 1089 patients who received RT to the internal mammary lymph nodes, although Bartelink and colleagues did not specify the number by treatment arm.
There were 479 deaths at a median follow-up of 5.1 years. Deaths from breast cancer were identical at 7% in either treatment arm. There were 291 local recurrences, including 182 (7.3%) in the standard arm, and 109 (4.3%) in the boost arm (P < .001). Five-year overall and distant metastasis-free survival was 91% and 87% in both groups. Among the local recurrences, 47% occurred in the tumor bed, and 9% in the lumpectomy scar. The hazard ratio for local recurrences was 0.59 with the boost. Local recurrences were lower in the boost arm in every age category. The largest clinical benefit was seen in patients < 40 years, where local recurrences occurred in 19.5% of patients in the standard arm, vs. 10.2% in the boost arm (P = .001). The smallest benefit was seen in the 51-60-year-old group, where there were 20% fewer local recurrences in the boost arm (P = NS). Breast cosmesis was good or excellent in 86% of patients in the standard arm, and 71% in the boost arm.
Bartelink et al concluded that the addition of a boost dose of radiation nearly halved the odds of a local recurrence, but that the absolute benefit varied with individual risk factors. A multivariate analysis determined that age < 50 years was the only factor which could be linked to the extent of the benefit afforded by the boost. They recommended that boosts be given to women < 50 years. The explanation offered in terms of why younger women benefited more from a boost than older patients did was that local control with 50 Gy alone is excellent in older patients. Finally, Bartelink et al felt that at least 10 years of follow-up was needed before any difference in overall survival emerges.
Comment by Edward J. Kaplan, MD
The preliminary results from this EORTC randomized trial add to our knowledge about postoperative care of the breast. By looking at the figure showing actuarial local control in the ipsilateral breast published in the article, one can see that the curves for the 2 treatment arms continue to diverge. There are 741 patients who have been followed for 8 years. Thus, it is likely that the results will remain robust as the data mature. This is in agreement with early published results from a French randomized study of 1024 women which showed that a 10 Gy boost following 50 Gy to the whole breast led to a significant reduction in local recurrences (P = .04).1
There are several interesting issues related to the way this study was conducted. First, the study excluded purely intraductal lesions, and women > 70 years were ineligible to participate per the protocol criteria, although some actually made it into the trial. Given the effect of age on the results, had there been more elderly women included, the significance of the trial results may not have held up for the entire study population. In fact, several recent retrospective studies looking at local control outcomes following breast conservation surgery also concluded that younger women, usually defined as < 35-40 years, have significantly higher local recurrence rates than their older counterparts.2-5 Despite the fact that the boost group did better than the standard treatment group for every age level in the EORTC trial, so far there is no statistically significant difference for women > 50 years.
The techniques permitted for boosting in the Bartelink paper are also worthy of discussion since they were heterogeneous. Although Bartelink et al do not give any detail about how the location of the resection bed was determined, it was probably by clinical inspection. This sounds straightforward, but sometimes is not, especially when a surgeon has "burrowed" to the tumor and the scar is not directly over the resection cavity. Boost technique was not a significant factor in terms of local failures, according to the multivariate analysis done by Bartelink et al. Although little has been published on this topic, Frazier’s recent retrospective study assessing the same 3 methods of boosting did not find any differences in local recurrence rates by method.6
It remains to be seen whether the local control differences will translate into a survival benefit with longer follow-up. One caveat should be borne in mind. There were 1089 patients who received treatment to their internal mammary lymph nodes, but we are not told the breakdown by treatment arm. This may be an important confounding factor since we know that IMN irradiation has been responsible for an increase in cardiac deaths in previous trials.
My overall impression of the trial results is that they lend support to the current standard of care in this country, and may help to further refine our approach. Prescribing 50 Gy to the isocenter at 2 Gy per fraction per the EORTC is essentially equivalent to my habit of prescribing 46.8 Gy to the breast volume within the 95% isodose envelop at 1.8 Gy per fraction. Similarly, a 16 Gy boost prescribed to a point is the equivalent of a 14.4 Gy boost prescribed to the 85% isodose line. Based on the EORTC results and the other data mentioned, an area that bears further study is dose escalation in younger patients. In terms of the older age population, it is too soon to tell whether a boost can be omitted.
References
1. Romestaing P, et al. J Clin Oncol. 1997;15:963-968.
2. Guenther JM, et al. Arch Surg. 1996;131:632-636.
3. Kim JH, et al. J Am Coll Surg. 1998;187:94-95.
4. Jobsen JJ, et al. Eur J Cancer. 2001;37:1820-1827.
5. Kurtz JM. Strahlenther Onkol. 2001;177:33-36.
6. Frazier RC, et al. Am J Clin Oncol. 2001;24:26-32.
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