Originally published as JCO Early Release 10.1200/JCO.2009.23.9962 on September 8 2009

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Locoregional Therapy Improves Survival for Metastatic Breast Cancer Patients? Benefit Remains Questionable!

Department of Medical Oncology, National Taiwan University Hospital, Taipei, Taiwan

To the Editor:

We read with interest the article written by Le Scodan et al,¹ in which the authors demonstrated that in multivariate analysis, locoregional therapy (LRT) to primary tumor correlated with better overall survival for patients who had synchronous metastasis. Unlike previous studies,^2–5 the majority of patients in this study underwent exclusive locoregional radiation (LRR) rather than surgery as LRT. The authors concluded that LRT improved survival in metastatic breast cancers and considered LRR as an effective alternative to surgery.

Although the result appears convincing, the study was a retrospective analysis, and the most important issue in retrospective studies is selection bias, which is uncontrollable and inevitable. Before we attempt to interpret why patients benefit from LRT, we should probably first ask why some patients received LRT while others did not.

Just as the authors demonstrated in Table 1, group A (with LRT) patients were more likely to have bone-only metastasis, nonvisceral metastases, and fewer metastatic sites, and were also more likely to receive combination chemotherapy and hormone therapy.¹ All of these factors correlated to favorable survival. In particular, "bone-only metastasis" was addressed as a good prognostic factor, and approximately 70% of the 223 patients underwent LRT. However, though a small number of patients had brain metastasis, most of them did not undergo LRT (16 v 2 patients). Because brain metastasis is also a poor prognostic factor, it is highly possible that patients who received LRT were those with "better prognosis." However, neither bone-only metastasis nor brain metastasis was included in the multivariate analysis for overall survival.

To minimize the inherent selection bias in this retrospective study, and to determine if the impact of LRT on survival was statistically significant, the authors conducted multivariate analysis to adjust for other confounding factors, which were derived from univariate analysis and known prognostic factors (eg, age).¹ In this study, the variable "bone-only metastasis" was excluded from the multivariate analysis because its influence on overall survival was not significant by univariate analysis. However, in Table 2, the authors actually tested the impact of variables (such as LRT) in each "subgroup," rather than the impact of each "variable" on survival in the entire population. It was methodologically incorrect to incorporate variables obtained from univariate analysis in the subgroup for the multivariate analysis in the whole group. Some important factors may have been neglected, such as the "bone-only metastasis" in this particular study. This fundamental mistake in the aforementioned data analysis may have made the results erroneous and unreliable.

Even though the authors attempted to stratify a study population on the basis of all particular patient/tumor characteristics, the nature of the selected cohorts was still heterogeneous.¹ They may differ in performance, comorbidity, and responsiveness to treatments; in retrospective studies, this information is usually lacking. But, those factors not only affected the treatment strategy but also the outcome. In common practice, radiation is not delivered concurrently with chemotherapy in breast cancer patients. We assume that in the study by Le Scodan et al, only those patients whose systemic disease was under control had a chance of receiving LRT. Thus, the options for LRT were offered selectively to those with favorable response to systemic treatments, and it was not possible to correct this selection bias by multivariate analysis. In reality, the intergroup survival difference in Table 2 probably reflected the survival advantage secondary to favorable response to systemic therapy, rather than the administration of LRT. We believe the only way to avoid this selection bias is to conduct a prospective, randomized study. Because of the inevitable selection bias in a retrospective study and the flawed statistical analysis, the results of this study should be interpreted with caution.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Le Scodan R, Stevens D, Brain E, et al: Breast cancer with synchronous metastases: Survival impact of exclusive locoregional rediotherapy. J Clin Oncol 27:1375–1381, 2009.[Abstract/Free Full Text]

2. Khan SA, Stewart AK, Morrow M: Does aggressive local therapy improve survival in metastatic breast cancer? Surgery 132:620–627, 2002.[CrossRef][Medline]

3. Rapiti E, Verkooijen HM, Vlastos G, et al: Complete excision of primary breast tumor improves survival of patients with metastatic breast cancer at diagnosis. J Clin Oncol 24:2743–2749, 2006.[Abstract/Free Full Text]

4. Babiera GV, Rao R, Feng L, et al: Effect of primary tumor extirpation in breast cancer patients who present with stage IV disease and an intact primary tumor. Ann Surg Oncol 13:776–782, 2006.[CrossRef][Medline]

5. Gnerlich J, Jeffe DB, Deshpande A, Beers C, Zander C, Margenthaler JA: Surgical removal of the primary tumor increases overall survival in patients with metastatic breast cancer: Analysis of the 1988-2003 SEER Data. Ann Surg Oncol 14:2187–2194, 2007.[CrossRef][Medline]

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