Deemphasize Dogma: Consider the Local Control–Overall Survival Link

Authors Winkfield and Harris kindly submit to the reader an article that reemphasizes the link between local control (LC) and overall survival (OS). Today, in the era of multidisciplinary patient care, it may seem surprising that this connection needs restating. However, one need only consider the plethora of systemic therapy papers that only report disease-free survival (DFS) and overall survival to realize that LC, and by extension local therapy, is less valued.

Breast Cancer Progression: ­Evolving Theories

This has not always been the case. As reported by Winkfield and Harris the predominant theory of breast cancer progression during most of the last century is exemplified by the Halsted radical mastectomy. According to the Halsted theory, breast cancer spreads contiguously from the primary site through local, then regional nodes, before reaching distant sites. This tenaciously held surgeon-centric theory was eventually replaced by the chemotherapist-centric Fisher theory. The Fisher theory describes breast cancer as being largely a systemic disease at the time of diagnosis. A subsequent theory, the Hellman hypothesis, describes breast cancer as a spectrum of disease ranging from one that remains primarily local to one that metastasizes early in its development.

Transition from one predominant theory to the next was not smooth. Samuel Hellman, in his unforgettable 1993 publication, drew an analogy between the persistence of belief in the Halsted and then the Fisher hypotheses to religious dogma and the Spanish Inquisition.[1] In doing so Hellman stresses that these medical dogmas, as in the Inquisition, stifle progress or scientific discovery. By presenting data that support the relationship between improved local control and improved survival, Winkfield and Harris are countering the dogmatic belief that considered these endpoints essentially independent and consequently may have prevented scientific progress.

The 4:1 Hypothesis

The authors use the results of the 2005 Early Breast Cancer Trialists’ Collaborative Group (Oxford) meta-analysis as evidence of the link between LC and OS.[2] One of the conclusions from this meta-analysis is that for every four local recurrences prevented there would be one life saved. Winkfield and Harris expand on this 4:1 hypothesis by suggesting that in certain breast cancer subtypes the ratio may be smaller (eg, 2:1). The main evidence for their hypothesis is from the reanalyses of the Danish postmastectomy radiation therapy (PMRT) trials.[3] In these re-analyses, the reduction in local failure associated with radiation is compared to the reduction in mortality in good-, intermediate-, and poor-risk recurrence groups, as well as luminal A, luminal B, HER2, or basal tumor subtypes. While provocative, the hypothesis awaits verification from similar analyses of other prospective studies. Hopefully these will be forthcoming.

Radiation-Induced Cardiotoxicity

As alluded to by the authors, this 4:1 correlation can be influenced by radiation-induced cardiotoxicity. In 1987 Cuzick et al showed on meta-analysis that PMRT was associated with a decrease in survival that was secondary to an increase in cardiac events.[4] Although this survival detriment was no longer significant in a subsequent meta-analysis by Cuzick et al, and the modern PMRT trials have not reported a significant increase in cardiac events, there are data that suggest one should still be concerned.[5,6] Prosnitz et al and Marks et al reported a decrease in cardiac perfusion as determined by single photon emission computed tomography (SPECT) in women receiving left-sided irradiation for breast cancer.[7,8] Yu et al later found a significant association between the decrease in cardiac perfusion experienced by these women and complaints of angina.[9]

Winkfield and Harris correctly state that one should minimize cardiac radiation exposure to maximize long-term survival. One relatively new technique that holds promise is active breathing control (ABC).[10,11] During deep inspiration breath-hold the heart is furthest from the chest wall. Delivering radiation at these times would minimize the dose delivered to the heart. To investigate the efficacy of ABC, a randomized phase III trial evaluating cardiac perfusion changes, as determined by SPECT, in women receiving left breast or chest wall radiation with or without ABC nears completion at Johns Hopkins. This study should help to objectively determine if ABC, a relatively simple technique, can prevent cardiac toxicity.

Conclusion

This review by Winkfield and Harris concisely presents information that links improved LC to improved OS. Time will tell if this association will be widely accepted. A measure of success would be the routine reporting of not only DFS and OS but also local and locoregional failure in all future breast cancer clinical trials. By doing this, we deemphasize dogma, gather scientific data, and advance our understanding of breast cancer.

Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Hellman S: Dogma and inquisition in medicine. Breast cancer as a case study. Cancer 71:2430-2433, 1993
2. Clarke M, Collins R, Darby S, et al: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 366:2087-2106, 2005.
3. Kyndi M, Overgaard M, Nielsen HM, et al: High local recurrence risk is not associated with large survival reduction after postmastectomy radiotherapy in high-risk breast cancer: A subgroup analysis of DBCG 82 b&c. Radiother Oncol 90:74-79, 2009.
4. Cuzick J, Stewart H, Peto R, et al: Overview of randomized trials comparing radical mastectomy without radiotherapy against simple mastectomy with radiotherapy in breast cancer. Cancer Treat Rep 71:7-14, 1987
5. Cuzick J, Stewart H, Rutqvist L, et al: Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol 12:447-453, 1994
6. Ragaz J, Olivotto IA, Spinelli JJ, et al: Locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemotherapy: 20-year results of the British Columbia randomized trial. J Natl Cancer Inst 97:116-126, 2005
7. Marks LB, Yu X, Prosnitz RG, et al: The incidence and functional consequences of RT-associated cardiac perfusion defects. Int J Radiat Oncol Biol Phys 63:214-223, 2005
8. Prosnitz RG, Hubbs JL, Evans ES, et al: Prospective assessment of radiotherapy-associated cardiac toxicity in breast cancer patients: Analysis of data 3 to 6 years after treatment. Cancer 110:1840-1850, 2007
9. Yu X, Prosnitz RR, Zhou S, et al: Symptomatic cardiac events following radiation therapy for left-sided breast cancer: Possible association with radiation therapy-induced changes in regional perfusion. Clin Breast Cancer 4:193-197, 2003
10. Berson AM, Emery R, Rodriguez L, et al: Clinical experience using respiratory gated radiation therapy: Comparison of free-breathing and breath-hold techniques. Int J Radiat Oncol Biol Phys 60:419-426, 2004
11. Jagsi R, Moran JM, Kessler ML, et al: Respiratory motion of the heart and positional reproducibility under active breathing control. Int J Radiat Oncol Biol Phys 68:253-258, 2007.